Psiconeuroendocrinology PDF
Psiconeuroendocrinology PDF
Psiconeuroendocrinology PDF
ENDOCRINOLOGY
The Scientific Basis of Clinical Practice
This page intentionally left blank
PSYCHONEURO-
ENDOCRINOLOGY
The Scientific Basis of Clinical Practice
Edited by
Washington, DC
London, England
Note: The authors have worked to ensure that all information in this
book is accurate at the time of publication and consistent with general
psychiatric and medical standards, and that information concerning drug
dosages, schedules, and routes of administration is accurate at the time of
publication and consistent with standards set by the U. S. Food and Drug
Administration and the general medical community. As medical research
and practice continue to advance, however, therapeutic standards may
change. Moreover, specific situations may require a specific therapeutic
response not included in this book. For these reasons and because human
and mechanical errors sometimes occur, we recommend that readers fol-
low the advice of physicians directly involved in their care or the care of
a member of their family.
Books published by American Psychiatric Publishing, Inc., represent the
views and opinions of the individual authors and do not necessarily rep-
resent the policies and opinions of APPI or the American Psychiatric As-
sociation.
Copyright © 2003 American Psychiatric Publishing, Inc.
ALL RIGHTS RESERVED
Manufactured in the United States of America on acid-free paper
07 06 05 04 6 5 4 3 2
First Edition
Typeset in Adobe’s Berling Roman and Galahad Regular
American Psychiatric Publishing, Inc.
1000 Wilson Boulevard
Arlington, VA 22209-3901
www.appi.org
Library of Congress Cataloging-in-Publication Data
Psychoneuroendocrinology : the scientific basis of clinical practice /
edited by Owen M. Wolkowitz, Anthony J. Rothschild.
p. cm.
Includes bibliographical references and index.
ISBN 0-88048-857-3 (alk. paper)
1. Psychoneuroendocrinology. 2. Mental illness—Endocrine aspects.
I. Wolkowitz, Owen M., 1952– II. Rothschild, Anthony J.
QP356.45 .P795 2003
616.89—dc21
2002028228
British Library Cataloguing in Publication Data
A CIP record is available from the British Library.
To Janet, Gavin, and Mikaela
and to the memory of my parents
O.M.W.
A.J.R.
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi
Part I
Introduction
Chapter 1
Introduction and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Owen M. Wolkowitz, M.D., and Anthony J. Rothschild, M.D.
Chapter 2
Historical Roots of Psychoneuroendocrinology . . . . . . . . . . . . . . . . . . 9
Steven E. Lindley, M.D., Ph.D., and Alan F. Schatzberg, M.D.
Part II
Peptide Hormones
Chapter 3
Neuropeptides and Hypothalamic
Releasing Factors in Psychiatric Illness . . . . . . . . . . . . . . . . . . . . . . . 29
Dominique L. Musselman, M.D., M.S., and
Charles B. Nemeroff, M.D., Ph.D.
Chapter 4
Chronobiology and Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Robert L. Sack, M.D., Alfred J. Lewy, M.D., Ph.D.,
Magda Rittenbaum, M.D., and Rod J. Hughes, Ph.D.
Chapter 5
Prolactin, Growth Hormone, Insulin, Glucagon, and Parathyroid
Hormone: Psychobiological and Clinical Implications . . . . . . . . . . . 107
Mady Hornig, M.D., and Jay D. Amsterdam, M.D.
Part III
Adrenocortical Hormones
Chapter 6
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness . . 139
Anthony J. Rothschild, M.D.
Chapter 7
Psychiatric Manifestations of Hyperadrenocorticism and
Hypoadrenocorticism (Cushing’s and Addison’s Diseases). . . . . . . 165
Monica N. Starkman, M.D., M.S.
Chapter 8
Psychiatric Effects of Glucocorticoid Hormone Medications . . . . . . 189
Victor I. Reus, M.D., and Owen M. Wolkowitz, M.D.
Chapter 9
Dehydroepiandrosterone in Psychoneuroendocrinology . . . . . . . . . 205
Owen M. Wolkowitz, M.D., and Victor I. Reus, M.D.
Part IV
Gonadal Hormones
Chapter 10
Menstrual Cycle–Related and Perimenopause-
Related Affective Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
David R. Rubinow, M.D., and Peter J. Schmidt, M.D.
Chapter 11
Endogenous Gonadal Hormones in
Postpartum Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Lisa S. Weinstock, M.D., and Lee S. Cohen, M.D.
Chapter 12
Clinical Psychotropic Effects of Gonadal
Hormone Medications in Women . . . . . . . . . . . . . . . . . . . . . . . . . . 303
Uriel Halbreich, M.D., Steven J. Wamback, B.S., and
Linda S. Kahn, Ph.D.
Chapter 13
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids . . . 331
Harrison G. Pope Jr., M.D., and David L. Katz, M.D., J.D.
Part V
Thyroid Hormones
Chapter 14
Thyroid Function in Psychiatric Disorders . . . . . . . . . . . . . . . . . . . 361
David O’Connor, M.D., Harry Gwirtsman, M.D., and
Peter T. Loosen, M.D., Ph.D.
Chapter 15
Psychiatric and Behavioral Manifestations of
Hyperthyroidism and Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . 419
Michael Bauer, M.D., Ph.D., Martin P. Szuba, M.D., and
Peter C. Whybrow, M.D.
Chapter 16
Thyroid Hormone Treatment of Psychiatric Disorders . . . . . . . . . . 445
Stephen Sokolov, M.D., F.R.C.P.C., and Russell Joffe, M.D.
Part VI
Laboratory Testing
Chapter 17
Laboratory Evaluation of Neuroendocrine Systems . . . . . . . . . . . . . 469
David Michelson, M.D., and Philip W. Gold, M.D.
Chapter 18
Endocrine Imaging in Depression . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Kishore M. Gadde, M.D., and K. Ranga R. Krishnan, M.D.
Part VII
Stress
Chapter 19
Stress and Neuroendocrine Function: Individual
Differences and Mechanisms Leading to Disease. . . . . . . . . . . . . . . 513
Bruce S. McEwen, Ph.D.
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
Contributors
xi
xii PSYCHONEUROENDOCRINOLOGY
†
Deceased.
Contributors xv
3
4 PSYCHONEUROENDOCRINOLOGY
ness. DHEA and its metabolite, DHEA sulfate, are the most plentiful
adrenal corticosteroids in humans, yet their functions remain uncertain.
Moderating between claims of a youth-enhancing super-hormone and
therapeutic nihilism, the authors put the current DHEA hype into scien-
tific perspective and point to possible novel treatments involving this in-
teresting hormone.
Drs. Rubinow and Schmidt review the prevalent psychiatric disorders
associated with the menstrual cycle and the perimenopausal years in
women. In addition to reviewing the normal physiology of these occur-
rences and posing questions regarding hormonal causality of these be-
havioral disturbances, they highlight current approaches to diagnosis and
treatment.
Drs. Weinstock and Cohen review postpartum behavioral changes,
distinguishing between postpartum “blues,” depression, and psychosis. In
addition to reviewing what is known about the endocrine and nonendo-
crine causes of these disorders, they suggest prophylactic and therapeutic
approaches for patients who are experiencing or are at risk for contract-
ing these conditions.
Dr. Halbreich, Mr. Wamback, and Dr. Kahn review the mood and
cognitive effects of exogenously administered female gonadal hormones
(e.g., oral contraceptives and estrogen replacement therapy), paying par-
ticular attention to the specific behavioral effects of estrogen alone versus
estrogen-progestin combinations. The chapter includes abundant clinical
recommendations, often derived from the authors’ clinical experience, in
areas where controlled data are not yet available.
Drs. Pope and Katz extensively review the literature on use of ana-
bolic and androgenic steroids, including studies from their own labora-
tory. Although they acknowledge that much remains to be discovered
regarding vulnerability to anabolic steroid–induced behavioral changes,
the authors provide general conclusions, treatment recommendations,
and forensic guidelines.
Drs. O’Connor, Gwirtsman, and Loosen provide a thorough review of
thyroid function in psychiatric disorders. Included are delineations of dif-
ferent levels of thyroid dysfunction (e.g., peripheral thyroid hormone lev-
els, thyroid-stimulating hormone levels, and antithyroid antibodies) in
disorders as diverse as mood disorders, alcoholism, anxiety disorders, pre-
menstrual dysphoric disorder, eating disorders, and schizophrenia. Im-
portant, but often overlooked, effects of somatic treatments on thyroid
function are also reviewed.
Drs. Bauer, Szuba, and Whybrow delineate psychiatric syndromes
seen in patients with hyperthyroidism or hypothyroidism. Examination
of the psychiatric sequelae of such endocrinologic diseases illuminates
Introduction and Overview 7
In his 1956 book, The Stress of Life, Hans Selye (the father of stress
physiology) wrote
8 PSYCHONEUROENDOCRINOLOGY
We are on our guard against external intoxicants, but hormones are parts
of our bodies; it takes more wisdom to recognize and overcome the foe
who fights from within....
What can we do about this? Hormones are probably not the only reg-
ulators of our emotional level. Besides, we do not yet know enough about
their workings to justify any attempt at regulating our emotional key by
taking hormones.
Now, more than 45 years after Selye wrote these words and with the
cumulative benefit of the observations reviewed in this volume, we are in
a much stronger position to “regulate our emotional key” by recognizing
and correcting hormonal imbalances that may result in behavioral distur-
bances.
Chapter 2
Historical Roots of
Psychoneuroendocrinology
Work for this chapter was supported by NIMH Grant MH50604, a NARSAD
Young Investigator Award, and a DANA Research Fellowship.
9
10 PSYCHONEUROENDOCRINOLOGY
vide clues for avoiding future mistakes in this very exciting and expanding
field. This review is not meant to be exhaustive, and it relies mostly on the
insight and material provided by other authors (Bleuler 1982; Hughes
1977; McCann 1992a; Money 1983; Peart 1979; Sawyer 1988; Tattersall
1994; Tourney 1969; Tower 1981; Welbourn 1992; Wilson 1984), but its
goal is to try to set the historical stage for the chapters that follow.
Ancient Concepts
noted that glands, as well other tissues, influence each other by releasing
products into the bloodstream (Peart 1979, p. 274), and Albert von
Haller in 1766 hypothesized that glands without ducts, such as the thy-
roid, pour special substances into the circulation (Welbourn 1992,
p. 138). By 1844, a recognizable modern concept of endocrine glands
was described by the physiologist Johannes Mueller, who wrote, “Glands
without ducts exercise their plastic influences on the fluids within them
and those which circulate through them and return to the general circu-
latory system” (see Bleuler 1982, p. 2).
Clues to the chemical nature of endocrine products were first ob-
tained from the most externally accessible gland, the testes (Money
1983). The physiological and behavioral effects of the testes had been ob-
served with the first castrations of domesticated animals and in eunuchs.
Aristotle (384–322 B.C.) wrote about the effects of castration in both an-
imals and humans, and Galen concluded, “Is it then astonishing that a
certain power is communicated from the testicles to the whole body?...
This faculty is the cause in man of masculinity” (quoted in Peart 1979,
p. 272). However, these early investigators and philosophers attributed
the loss of testicular functioning to semen, not hormones. Evidence to the
contrary was provided by the experiments of John Hunter, an English
anatomist and surgeon, in the mid-eighteenth century. In experiments
with cockerels, he noted that testicular replacement produces secondary
sex characteristics in castrated animals. However, because he was mainly
interested in organ transplantation, he published only a few brief reports
on his observations (reviewed in Money 1983; Welbourn 1992).
Not until 1849 did Arnold Adolph Berthold describe evidence for
what are now known as hormones. Berthold observed that transplanta-
tion of testes reversed the effects of castration on sexual and aggressive
behaviors and physical characteristics in chickens, confirming Hunter’s
findings. But Berthold attributed this effect to internal secretions from
the gland. Furthermore, he commented that the effects of testicular se-
cretions must influence “the whole organism of which, it must be admit-
ted, the nervous system forms a very substantial part,” foreshowing our
understanding of the effect of androgens on the central nervous system
(CNS) (Sawyer 1988). Because his experiments involved problems with
immune rejection associated with organ transplantation, they were diffi-
cult to replicate and were largely ignored until the early twentieth cen-
tury (Peart 1979; Welbourn 1992).
In 1855 Claude Bernard, professor of physiology at the Collége de
France, Paris, coined the term internal secretion to describe the secretion
of newly synthesized glucose from the liver. In the same year, Thomas
Addison correctly ascribed a role to the adrenal glands in his descriptions
Historical Roots of Psychoneuroendocrinology 13
The initial reaction of the scientific community and the public in general
was skepticism and ridicule. For example, an editorial in Wiener Mediz-
inische Wochenschrift stated, “Professor Brown-Séquard’s audience ap-
pears to have received an impression of the intellectual capacity of the
aged scientist very different from the one which he, in his elevated frame
of mind, evidently expected to produce. This lecture must be regarded as
further proof of the necessity of retiring professors who have attained
their threescore years and ten” (Beach 1981, p. 332). Despite this initial
reaction, by the end of 1889, 12,000 physicians had tested his extract and
had reported remarkable cures for a wide variety of illnesses. Besides se-
nile disability, efficacy for this treatment was reported for glycosuria,
neurasthenia, tabes dorsalis (314 cures out of 415 trials), pulmonary tu-
berculosis, heart disease, leprosy, malaria, Addison’s disease, and cancer
(Tattersall 1994). Dr. Brown-Séquard reportedly believed that the ex-
tract increased the “nervous force” in the body, allowing one to better
fight disease. A number of pharmaceutical companies, including Bur-
roughs, Wellcome, began to manufacture various organ extracts, a craze
that continued into the 1920s (Tattersall 1994).
The bad reputation that these organ extract therapies—generally
called organotherapy—received in the general medical community re-
sulted in a loss of respectability for endocrinology. It was said that “any
young physician who dared embark on a career in the field of internal se-
cretions was looked [at] askance, [was] considered naive and gullible[,]
or [was] suspected of straying into the realm of quackery and heading for
the endocrine gold fields” (Tattersall 1994, p. 730). Even the reported ef-
ficacy of thyroid replacement for myxedema was viewed with skepticism
because of the similarities to organotherapy (Peart 1979). Furthermore,
because of the remarkable psychological effects reported, many endocri-
nologists doubted whether scientific methods could be applied to inves-
tigating the psychological effects of hormones (from Beach 1981).
Bleuler (1982, p. 6), “most early descriptive studies of the behavioral con-
sequences of endocrine disorders based their findings on single observa-
tions and therefore often over-generalized their findings, sometimes with
unfortunate results.” For example, Benjamin Rush is quoted as stating
that the larger size of the thyroid gland in women “was necessary to guard
against the female system from the influence of the more numerous
causes of irritation and vexation of the mind to which they are exposed
than the male sex” (Kathol 1992, p. 400). Sometimes these simplistic
generalizations led to invasive therapies. In 1872, Robert Battery, a Geor-
gia surgeon, advocated ovariectomy for dysmenorrhea. Over time the
clinical indications for ovariectomy were broadened to include psychiat-
ric conditions such as neurosis (Welbourn 1992). A theory that schizo-
phrenia resulted from a defect in adrenal hormone production led to
adrenalectomies in a number of schizophrenic patients (Bleuler 1982).
Despite these clinical misadventures, the availability of efficacious
treatments for endocrine disorders produced many real dramatic psychi-
atric cures, as illustrated in the following 1892 description by Drs. Shaw
and Stansfield of the treatment a female patient with myxedema (see
Kathol 1992, p. 403):
Following the birth of her second child she had an attack of lactational
melancholia and inflicted a wound on her throat....Symptoms of myxe-
dema were first noticed when she was pregnant with her third child. The
principal mental symptoms were mental confusion and inability to con-
centrate or employ herself. She had considerable insight into her mental
state and became languid and disinterested in her occupation and her
children....The mental condition became worse and she was certified and
sent to the Banstead Asylum in April 1891....To the ordinary symptoms
of myxedema were added occasional stupor, aphonia, rigidity, and eroto-
mania. She would periodically get into other patients’ beds and when be-
ing bathed, unless the nurses were careful, would seize and almost
strangle them in excess of her sexual desire. All sorts of remedies were
tried to no avail: hot baths, massage, injections of pilocarpine (until, in-
deed, profuse salivations resulted), tonics and electricity....Finally it was
decided to treat the patient with glycerine extract of the thyroid of the
sheep. The committee purchased the sheep, killed them, and dissected
out the thyroid. A 20% glycerine extract was made by pounding and mac-
erating the gland for forty-eight hours and then straining it through sev-
eral layers of very fine muslin. The patient was given an injection every
second day. The reaction was remarkable. In ten weeks’ time, Mrs. H was
out on trial and at the expiration of her trial she was discharged and re-
covered.
In the great field of neurology and psychiatry, to which work beyond com-
pution and praise has been devoted, discouragement has remained the dom-
inant note precisely where efforts on behalf of sufferers should have proved
more telling. Nowhere has therapeutics remained less efficient....And
yet, no single line of medical thought offers greater opportunity for de-
velopment through the intermediary of the ductless glands. (Sajous 1917,
p. 1)
Development of Neuroendocrinology
Another set of developments was taking place during the first half of the
twentieth century that would further link hormones with brain function:
the discoveries of endocrine secretions from the pituitary and of CNS
control of these secretions. These developments have been outlined in
detail by a number of investigators in the field (Brooks 1988; Hughes
1977; McCann 1975, 1992a, 1992b; Sawyer 1988). Although its anat-
omy had been investigated, the function of the pituitary remained a mys-
tery until the description of two cases of acromegaly by Pierre Marie in
1886. In 1927 Philip Smith demonstrated that the pituitary gland pro-
duced hormones that stimulated the adrenal cortex, thyroid, and gonads
and also stimulated growth. By the early 1930s, the remaining pituitary
hormones had been discovered (reviewed in McCann 1992b).
The role of the hypothalamus in control of the pituitary was also first
suggested from clinical observations of patients with endocrine disorders
as early as the beginning of the twentieth century. In 1901, Alfred Fröh-
lich in Vienna diagnosed the adiposogenital syndrome in a 14-year-old
obese boy with arrested sexual development that Fröhlich attributed to
damage in the hypothalamus (Sawyer 1988). In 1921, Percival Bailey and
Frédéric Bremer confirmed and extended early findings that lesions of
discrete areas of the hypothalamus in dogs induced the adiposogenital
Historical Roots of Psychoneuroendocrinology 19
The seminal studies of Cannon and Selye sparked a great deal of inter-
est in psychiatry, because since antiquity many psychiatric disorders—
depressive disorders in particular—had been linked to “stress” (Board and
Persky 1957). Early studies were limited methodologically and relied on
indirect measures of adrenal function, such as changes in lymphocyte and
eosinophil levels, alterations in levels of inorganic phosphates, and varia-
tions in urinary concentrations of potassium, sodium, and uric acid. In
retrospect, it is not surprising that many of these early studies generated
conflicting results. In the 1950s, as more direct measures of urinary and
plasma cortisol levels became available, a number of researchers demon-
strated that stressful life situations, states of arousal, and various states of
emotional distress in humans were linked with these indices of increased
adrenal activity (Bliss et al. 1955, 1956; Bryson and Mertin 1954; Cleghorn
and Graham 1950; Friedman et al. 1963; Price et al. 1957; Renold et al.
1951; Rubin and Mandell 1966).
In these early HPA axis studies, clinical depression was a focus of in-
quiry because it was viewed as a common, time-limited state of profound
emotional distress and therefore should have an influence on adrenal
Historical Roots of Psychoneuroendocrinology 21
activity (Board and Persky 1957; Bryson and Mertin 1954; Rizzo et al.
1954). In 1956, using a direct measure of adrenal activity, plasma concen-
tration of 17-hydroxycorticosteroid, a group of researchers from Michael
Reese Hospital demonstrated increased levels of this substance in pa-
tients with severe depression (Board and Persky 1957; Board et al. 1956).
This finding has been widely replicated since that time, using various di-
rect measures of adrenal activity (Carpenter and Bunney 1971; Gibbons
1964; Gibbons and McHugh 1966; Gibbons et al. 1960; Kocsis et al.
1984; McClure 1966; Rothschild et al. 1993; Sachar 1967; Sachar et al.
1973; Stokes et al. 1984). In the study of depression, through the appli-
cation of increasingly sophisticated measurements of HPA activity—such
as the dexamethasone suppression test (DST), described by Carroll and
co-workers in 1981—increasingly consistent observations have been re-
ported. The DST has since become one of the most widely studied mea-
surements in biological psychiatry (reviewed by Arana et al. 1985). As a
result of the isolation of corticotropin-releasing hormone (Vale et al.
1981), investigators have been able to examine more directly the state of
CNS control of adrenal activity in depressed subjects (reviewed by Gold
and Chrousos 1985; Nemeroff 1993). With the appreciation of HPA
hyperactivity in depression, interest has been focused on how this hyper-
secretion affects CNS functioning (reviewed by Rothschild et al. 1989;
Wolkowitz 1994; Wolkowitz et al. 1985, 1987, 1989, 1993a, 1993b);
this finding may contribute to the pathophysiology of the symptoms of
depression, particularly in patients with psychotic depression (reviewed
in Schatzberg and Rothschild 1988; Schatzberg et al. 1985). It has also
has led to attempts to manipulate the HPA axis for therapeutic benefit in
depressed patients (O’Dwyer et al. 1995; Rothschild and Schatzberg
1992; Ur et al. 1992; Wolkowitz et al. 1992), which could possibly fulfill
the hopes of the early researchers in psychoneuroendocrinology.
References
Arana GW, Baldessarini RJ, Ornsteen M: The dexamethasone suppression test for di-
agnosis and prognosis in psychiatry. Arch Gen Psychiatry 42:1193–1204, 1985
Beach FA: Historical origins of modern research on hormones and behavior. Horm
Behav 15:325–376, 1981
Bleuler M: The development of psychoneuroendocrinology, in Handbook of Psy-
chiatry and Endocrinology. Edited by Beumont PJV, Burrows GD. New
York, Elsevier Biomedical Press, 1982, pp 1–13
Bliss EL, Migeon CJ, Hardin Branch CH, et al: Adrenocortical function in schizo-
phrenia. Am J Psychiatry 112:358–365, 1955
Bliss EL, Migeon J, Hardin Branch CH, et al: Reaction of the adrenal cortex to
emotional stress. Psychosom Med 18:56–76, 1956
Board F, Wadeson R, Persky H: Depressive affect and endocrine functions. Ar-
chives of Neurology and Psychiatry 78:612–620, 1957
Board F, Persky H, Hamburg DA: Psychological stress and endocrine function:
blood levels of adrenocortical and thyroid hormones in acutely disturbed pa-
tients. Psychosom Med 18:324–333, 1956
Brooks CM: The history of thought concerning the hypothalamus and its func-
tions. Brain Res Bull 20:657–667, 1988
Bryson RW, Mertin DF: 17-Ketosteroid excretion in a case of manic-depression
psychosis. Lancet 365–367, 1954
Cannon WB: Bodily Changes in Pain, Hunger, Fear and Rage: An Account of
Recent Researches Into the Function of Emotional Excitement. New York,
Appleton, 1915
Cannon WB: Stresses and strains of homeostasis. American Journal of the Medi-
cal Sciences 189:1–14, 1935
Carpenter WT Jr, Bunney WE Jr: Adrenal cortical activity in depressive illness.
Am J Psychiatry 128:31–40, 1971
Carroll BJ, Feinberg M, Greden JR, et al: A specific laboratory test for the diag-
nosis of melancholia. Arch Gen Psychiatry 38:15–22, 1981
Cleghorn RA, Graham BF: Studies of adrenal cortical activity in psychoneurotic
subjects. Am J Psychiatry 106:668–672, 1950
Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology,
6th Edition. New York, Oxford University Press, 1991
Fleming D: Walter B. Cannon and homeostasis. Soc Res (New York) 51:609–640,
1984
Historical Roots of Psychoneuroendocrinology 23
Price DB, Thaler M, Mason JW: Preoperative emotional states and adrenal corti-
cal activity. Archives of Neurology and Psychiatry 77:656–656, 1957
Renold AE, Quigley TB, Kennard HE, et al: Reaction of the adrenal cortex to
physical and emotional stress in college oarsman. N Engl J Med 244:744–
757, 1951
Rizzo ND, Fox HM, Laidlaw JC, et al: Concurrent observations of behavioral
changes and of adrenocortical variations in a cyclothymic patient during a pe-
riod of 12 months. Ann Intern Med 41:798–815, 1954
Rothschild AJ, Schatzberg AF: Theoretical basis for response to steroid suppres-
sion in major depression (letter; comment). J Clin Psychopharmacol 12(2):
142–144, 1992
Rothschild AJ, Benes F, Hebben N, et al: Relationships between brain CT scan
findings and cortisol in psychotic and nonpsychotic depressed patients. Biol
Psychiatry 26(6):565–575, 1989
Rothschild AJ, Samson JA, Bond TC, et al: Hypothalamic-pituitary-adrenal axis
activity and 1-year outcome in depression. Biol Psychiatry 34(6):392–400,
1993
Rubin RT, Mandell AJ: Adrenal cortical activity in pathological emotional state:
a review. Am J Psychiatry 123(4):387–400, 1966
Sachar EJ: Corticosteroids in depressive illness. Arch Gen Psychiatry 17:544–553,
1967
Sachar EJ, Hellman L, Roffwarg HP, et al: Disrupted 24-hour patterns of cortisol
secretion in psychotic depression. Arch Gen Psychiatry 28:19–24, 1973
Sajous CED: The future of internal secretions. Endocrinology 1(1):1–11, 1917
Sawyer CH: Anterior pituitary neuronal control concepts, in Endocrinology: Peo-
ple and Ideas. Edited by McCann SM. Bethesda, MD, American Physiologi-
cal Society, 1988, pp 23–40
Schatzberg AF, Rothschild AJ: The roles of glucocorticoid and dopaminergic sys-
tems in delusional (psychotic) depression. Ann N Y Acad Sci 537:462–471,
1988
Schatzberg AF, Rothschild AJ, Langlais PJ, et al: A corticosteroid/dopamine hy-
pothesis for psychotic depression and related states. J Psychiatr Res 19(1):
57–64, 1985
Selye H: Stress and the general adaptation syndrome. Br Med J, June 17, 1950, pp
1383–1392
Stokes PE, Stoll PM, Koslow SH, et al: Pretreatment DST and hypothalamic-
pituitary-adrenocortical function in depressed patients and comparison groups:
a multicenter study. Arch Gen Psychiatry 41(3):257–267, 1984
Tattersall RB: Charles-Edouard Brown-Sequard: double-hyphenated neurologist
and forgotten father of endocrinology. Diabet Med 11(8):728–731, 1994
Tourney G: History of biological psychiatry in America. Am J Psychiatry 126:29–
42, 1969
Tower DB: Neurochemistry in historical perspective, in Basic Neurochemistry,
3rd Edition. Edited by Siegel GJ, Albers RW, Agranoff BW, et al. Boston,
MA, Little, Brown, 1981, pp 1–16
Historical Roots of Psychoneuroendocrinology 25
29
30 PSYCHONEUROENDOCRINOLOGY
Corticotropin-Releasing Hormone
one (Campbell et al. 1989; Casner et al. 1996; Herman et al. 1987). How-
ever, there are some negative reports (Beckwith et al. 1986; Szymanski et
al. 1987). A few reports document the efficacy of naltrexone in diminish-
ing self-injurious behaviors in patients with borderline personality disor-
der as well (Roth et al. 1996). With minor exception, these reports are
generally limited by open-label design, a relatively brief duration of treat-
ment, small numbers of patients, characterization of patients by behavior
rather than etiology, or a retrospective perspective (Casner et al. 1996).
It has been hypothesized that such self-injury results in pain-induced en-
dorphin release with continued stereotyped behaviors by the patient in an
attempt to maintain increased endogenous opioid levels. In concordance
with this hypothesis, investigators have reported increased cerebrospinal
fluid endorphin concentrations in self-injurious autistic children com-
pared with autistic patients without such behaviors (Gillberg et al. 1985).
In fact, increased plasma concentrations of b-endorphin (Sandman 1988)
and met-enkephalin (Coid et al. 1983) have been detected in self-injurious,
developmentally disabled individuals in comparison with control sub-
jects. Although the aforementioned results are very preliminary, they cer-
tainly serve as an impetus for further scrutiny.
Vasopressin
It is thought that AVP and the other well-known posterior pituitary hor-
mone, the nonapeptide oxytocin, play a role in modulating neural activ-
ity in hypothalamic, limbic, and autonomic circuits.
Osmotic and chemoreceptor stimulation, hemorrhage, and hypoten-
sion activate the magnocellular neurons of the paraventricular nucleus
and increase secretion of AVP from the neurohypophysis and extrahypo-
thalamic brain regions (Cunningham and Sawchenko 1991). AVP allows
the reabsorption of water back into the body by increasing the permeabil-
ity of the distal and collecting ducts of the kidney tubules. The normal,
narrow reference range of osmolality in humans is 280–295 mOsm/kg.
To protect the body from a hyperosmolar state, maximal stimulation of
AVP occurs at 295 mOsm/kg; antidiuretic hormone is not secreted as
hypo-osmolarity approaches (i.e., near 280 mOsm/kg). In humans an
increase in plasma osmolality as minute as 2% stimulates a twofold to
threefold surge in plasma levels of AVP. When plasma osmolality is nor-
mal, AVP is secreted in large amounts during hypovolemia and hypoten-
sion. However, approximately 40 times more AVP is required to increase
blood pressure compared with antidiuresis.
Chronic stress or adrenalectomy increases the activity of the parvo-
cellular AVP system (DeGoeij et al. 1992; Whitnall 1989). Interestingly,
AVP and CRH are the major hypothalamic secretagogues for ACTH re-
lease. AVP administered together with CRH produces a synergistic release
of pituitary POMC-derived peptides, that is, ACTH and b-endorphin in
humans (DeBold et al. 1984) and animals (Plotsky 1991). CRH and AVP
are co-localized in the parvocellular cells of the human hypothalamus
and may be secreted together into the human hypothalamic-hypophyseal
portal circulation (Mouri et al. 1993). The ratio of AVP to CRH in the
hypothalamic-hypophyseal portal circulation varies in different species
(Plotsky 1991) and according to the nature of the stress (Canny et al.
1989; Caraty et al. 1990).
Similar to the clinical investigations regarding CRH, a variety of pa-
tient groups have been studied. Alterations of cerebrospinal fluid AVP
have been reported in patients with major depression, bipolar disorder,
schizophrenia, anorexia, obesity, alcoholism, Alzheimer’s disease, and
Parkinson’s disease (Demitrack et al. 1989; Legros et al. 1993). Cerebro-
spinal fluid AVP concentrations in patients with major depression are
reportedly reduced in comparison with control subjects, although the
source of cerebrospinal fluid AVP is likely extrahypothalamic and not, in
contrast to its purported hypersecretion, from the paraventricular nu-
cleus in major depression (Gjerris et al. 1984, 1985; Linkowski et al.
1984). Basal plasma concentrations of AVP (secreted from the magnocel-
lular neurons of the paraventricular nucleus after osmotic or barorecep-
Neuropeptides and Hypothalamic Releasing Factors 45
Cholecystokinin
Neurotensin
Neuropeptide Y
Substance P
Other Peptides
Clinical Implications
References
Abelson JL, Nesse RM: Cholecystokinin-4 and panic (letter). Arch Gen Psychia-
try 47:395, 1990
Adams JB, Pyke RE, Costa J, et al: A double-blind, placebo-controlled study of a
CCK-B receptor antagonist, CI-988, in patients with generalized anxiety dis-
order. J Clin Psychopharmacol 15:428–434, 1995
Adinoff B, Anton R, Linnoila M, et al: Cerebrospinal fluid concentrations of cor-
ticotropin-releasing hormone (CRH) and diazepam-binding inhibitor (DBI)
during alcohol withdrawal and abstinence. Neuropsychopharmacology
15:288–295, 1996
Agren H, Lundqvist G: Low levels of somatostatin in human CSF mark depres-
sive episodes. Psychoneuroendocrinology 9:233–248, 1984
Aguilera G, Wynn PC, Harwood JP, et al: Receptor-mediated actions of corti-
cotropin-releasing factor in pituitary gland and nervous system. Neuroendo-
crinology 43:79–88, 1986
Allen JM, Balbi D: Structure and expression of the neuropeptide Y gene, in The
Biology of Neuropeptide Y and Related Peptides. Edited by Colmers WF,
Wahlestedt C. Totowa, NJ, Humana, 1993, pp 43–64
Altemus M, Pigott T, Kalogeras KT, et al: Abnormalities in the regulation of va-
sopressin and corticotropin releasing factor secretion in obsessive-compulsive
disorder. Arch Gen Psychiatry 49:9–20, 1992
Altemus M, Swedo SE, Leonard HL, et al: Changes in cerebrospinal fluid neuro-
chemistry during treatment of obsessive-compulsive disorder with clomipra-
mine. Arch Gen Psychiatry 51:794–803, 1994
Ambrosi B, Bochicchio D, Fadin C, et al: Failure of somatostatin and octreotide
to acutely affect the hypothalamic-pituitary-adrenal function in patients
with corticotropin hypersecretion. J Endocrinol Invest 13:257–261, 1990
Neuropeptides and Hypothalamic Releasing Factors 61
Black PM, Ballantine HT Jr, Carr DB, et al: Beta-endorphin and somatostatin con-
centrations in the ventricular cerebrospinal fluid of patients with affective
disorder. Biol Psychiatry 21:1077–1081, 1986
Bloom F, Segal D, Ling N, et al: Endorphins: profound behavioral effects in rats
suggest new etiological factors in mental illness. Science 194:630–632, 1976
Boyd AE, Levovitz HE, Pfeiffer JB: Stimulation of growth hormone secretion by
L-dopa. N Engl J Med 283:1425–1429, 1970
Bradwejn J, Koszycki D, Meterissian G: Cholecystokinin tetrapeptide induces
panic attacks in patients with panic disorder. Can J Psychiatry 35:83–85,
1990
Bradwejn J, Koszycki D, Bourin M: Dose ranging study of the effects of chole-
cystokinin in healthy volunteers. J Psychiatry Neurosci 16:91–95, 1991a
Bradwejn J, Koszycki D, Shriqui C: Enhanced sensitivity to cholecystokinin tetra-
peptide in panic disorder. Arch Gen Psychiatry 48:603–610, 1991b
Bradwejn J, Koszycki D, Payeur R: Replication of action of cholecystokinin tet-
rapeptide in panic disorder: clinical and behavioral findings. Am J Psychiatry
149:962–964, 1992
Bradwejn J, Koszycki D, Couetoux du Tertre A, et al: The panicogenic effects of
cholecystokinin-tetrapeptide are antagonized by L-365,260, a central chole-
cystokinin receptor antagonist, in patients with panic disorder. Arch Gen
Psychiatry 51: 486–493, 1994
Brambilla F, Cavagnini F, Invitti C, et al: Neuroendocrine and psychopathological
measures in anorexia nervosa: resemblances to primary affective disorders.
Psychiatry Res 16:165–176, 1985
Brambilla F, Petraglia F, Facchinetti F, et al: Abnormal beta-endorphin and beta-
lipotropin responses to TRH and LRH administration in primary and sec-
ondary affective disorders. Acta Endocrinol 112:481–486, 1986
Brawman-Mintzer O, Lydiard RB, Bradwejn J, et al: Effects of the cholecystokinin
agonist pentagastrin in patients with generalized anxiety disorder. Am J Psy-
chiatry 154:700–702, 1997
Breier A: AE Bennett award paper: experimental approaches to human stress re-
search: assessment of neurobiological mechanisms of stress in volunteers and
psychiatric patients. Biol Psychiatry 26:438–462, 1989
Bremner JD, Licinio J, Darnell A, et al: Elevated cerebrospinal fluid corticotro-
pin-releasing factor concentrations in posttraumatic stress disorder. Am
J Psychiatry 154:624–629, 1997
Breslin NA, Suddath RL, Bissette G, et al: CSF concentrations of neurotensin
in schizophrenia: an investigation of clinical and biochemical correlates
Schizophr Res 12:35–41, 1994
Campbell M, Overall JE, Small AM, et al: Naltrexone in autistic children: an
acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry
28:200–206, 1989
Canny BJ, Funder JW, Clarke IJ: Glucocorticoids regulate ovine hypophyseal por-
tal levels of corticotrophin-releasing factor and arginine vasopressin in a
stress specific manner. Endocrinology 125:2532–2539, 1989
64 PSYCHONEUROENDOCRINOLOGY
Geracioti TD Jr, Loosen PT, Orth DN: Low cerebrospinal fluid corticotropin-
releasing hormone concentrations in eucortisolemic depression. Biol Psychi-
atry 42:165–174, 1997
Gerner RH, Sharp B: CSF beta-endorphin immunoreactivity in normal, schizo-
phrenic, depressed, manic, and anorexic subjects. Brain Res 237:244–247,
1982
Gerner RH, Yamada T: Altered neuropeptide concentrations in cerebrospinal
fluid of psychiatric patients. Brain Res 238:298–302, 1982
Gerner RH, Van Kammen DP, Ninan PH: Cerebrospinal fluid cholecystokinin,
bombesin and somatostatin in schizophrenia and normals. Prog Neuropsy-
chopharmacol Biol Psychiatry 9:73–82, 1985
Gibbons JL, McHugh PR: Plasma cortisol in depressive illness. J Psychiatr Res
1:162–171, 1962
Gillberg C, Terenius L, Lonnerholm G: Endorphin activity in childhood psycho-
sis: spinal fluid levels in 24 cases. Arch Gen Psychiatry 4:780–783, 1985
Gillman MA, Sandyk R: Opiatergic and dopaminergic function and Lesch-Nyhan
syndrome (letter). Am J Psychiatry 142:1226, 1985
Gispen-de-Wied CC, Westenberg HG, Thijssen JH, et al: The dexamethasone
and cortisol suppression test in depression: beta-endorphin as a useful
marker. Psychoneuroendocrinology 12:355–366, 1987
Gjerris A, Rafaelsen OJ, Vendsborg P, et al: Vasoactive intestinal peptide de-
creased in cerebrospinal fluid (CSF) in atypical depression. J Affect Disord
7:325–337, 1984
Gjerris A, Hummer M, Vendsborg P, et al: Cerebrospinal fluid vasopressin
changes in depression. Br J Psychiatry 147:696–701, 1985
Gold PW, Goddwin FK, Post RM, et al: Vasopressin function in depression and
mania. Psychopharmacol Bull 17:7–9, 1981
Gold PW, Kaye WH, Robertson GL, et al: Abnormalities in plasma and cere-
brospinal fluid vasopressin in patients with anorexia nervosa. N Engl J Med
308:1117–1112, 1983
Gold PW, Chrousos GP, Kellner C, et al: Psychiatric implications of basic and
clinical studies with corticotropin-releasing factor. Am J Psychiatry 141:
619–627, 1984
Gold PW, Gwirtsman HE, Avgerinos PC, et al: Abnormal hypothalamic-
pituitary-adrenal function in anorexia nervosa. N Engl J Med 314:1335–
1342, 1986a
Gold PW, Loriaux DL, Roy A, et al: Responses to corticotropin-releasing hor-
mone in the hypercortisolism of depression and Cushing’s disease. N Engl
J Med 314:1329–1334, 1986b
Goldstein A, Tachibana S, Lowney LI, et al: Dynorphin (1–13) an extraordinarily
potent opioid peptide. Proc Natl Acad Sci U S A 76:6666–6670, 1979
Govoni S, Hong JS, Yang H-YT, et al: Increase of neurotensin content elicited by
neuroleptics in nucleus accumbens. J Pharmacol Exp Ther 215:413–417, 1980
Graf MV, Kastin AJ: Delta-sleep-inducing peptide (DSIP): an update. Peptides
7:1165–1187, 1986
68 PSYCHONEUROENDOCRINOLOGY
Lovenberg TW, Chalmers DT, Liu C, et al: CRH2 alpha and CRH2 beta receptor
mRNAs are differentially distributed between the rat central nervous system
and peripheral tissues. Endocrinology 136:4139–4142, 1995
Lowe SL, Francis PT, Procter AW, et al: Gamma-aminobutyric acid concentration
in brain tissue at two stages of Alzheimer’s disease. Brain 111:785–799, 1988
Lucassen PJ, Ravid R, Gonatas NK, et al: Activation of the human supraoptic and
paraventricular nucleus neurons with aging and in Alzheimer’s disease as
judged from increasing size of the Golgi apparatus. Brain Res 632:105–111,
1993
Lucassen PJ, Van Heerikhuize JJ, Guldenaar SE, et al: Unchanged amounts of va-
sopressin mRNA in the supraoptic and paraventricular nucleus during aging
and in Alzheimer’s disease. J Neuroendocrinol 9:297–305, 1997
Lydiard RB, Ballenger JC, Laraia MT, et al: CSF cholecystokinin concentrations
in patients with panic disorder and in normal comparison subjects. Am
J Psychiatry 149:691–693, 1992
Maes M, Jacobs MP, Suy E, et al: An augmented escape of beta-endorphins to
suppression by dexamethasone in severely depressed patients. J Affect Dis-
ord 18:149–156, 1990
Magoul R, Onteniente B, Benjelloun W, et al: Tachykinergic afferents to the rat
arcuate nucleus. A combined immunohistochemical and retrograde tracing
study. Peptides 14:275–286, 1993
Manberg PJ, Youngblood WW, Nemeroff CB, et al: Regional distribution of neu-
rotensin in human brain. J Neurochem 38:1777–1780, 1982
Mansbach RS, Brooks EN, Chen YL: Antidepressant-like effects of CP-154,526,
a selective CRH1 receptor antagonist. Eur J Pharmacol 323:21–26, 1997
Martensson B, Nyberg S, Toresson G, et al: Fluoxetine treatment of depression:
clinical effects, drug concentrations and monoamine metabolites and N-termi-
nally extended substance P in cerebrospinal fluid. Acta Psychiatr Scand 79:
586–596, 1989
Martignoni E, Petraglia F, Costa A, et al: Dementia of the Alzheimer type and the
hypothalamus-pituitary-adrenocortical axis: changes in cerebrospinal fluid
corticotropin releasing factor and plasma cortisol levels. Acta Neurol Scand
81:452–456, 1990
Matussek N, Ackenheil M, Hippius H, et al: Effects of clonidine on growth hor-
mone release in psychiatric patients and controls. Psychiatry Res 2:25–36, 1980
Mazurek MF, Beal MF, Bird ED, et al: Vasopressin in Alzheimer’s disease: a study
of postmortem brain concentrations. Ann Neurol 20:665–670, 1986a
Mazurek MF, Growdon JH, Beal MF, et al: CSF vasopressin concentration is re-
duced in Alzheimer’s disease. Neurology 36:1133–1137, 1986b
Meador-Woodruff JH, Haskett RF, Grunhaus L, et al: Postdexamethasone plasma
cortisol and beta-endorphin levels in depression: relationship to severity of
illness. Biol Psychiatry 22:1137–1150, 1987
Meller WH, Kathol RG, Jaeckle RS, et al: Stimulation of the pituitary-adrenal
axis with arginine vasopressin in patients with depression. J Psychiatr Res 21:
267–277, 1987
74 PSYCHONEUROENDOCRINOLOGY
Nemeroff CB, Kizer JS, Reynolds GP, et al: Neuropeptides in Alzheimer’s dis-
ease: a postmortem study. Regul Pept 25:123–130, 1989b
Nemeroff CB, Bissette G, Akil H, et al: Neuropeptide concentrations in the cere-
brospinal fluid of depressed patients treated with electroconvulsive therapy:
corticotropin-releasing factor, beta-endorphin and somatostatin. Br J Psychi-
atry 158:59–63, 1991
Nemeroff CB, Krishnan KKR, Reed D, et al: Adrenal gland enlargement in major
depression: a computed tomographic study. Arch Gen Psychiatry 49:384–
387, 1992
Nemeroff CB, Krishnan KKR, Dunnick NR: The adrenal gland and depression:
reply to a letter. Arch Gen Psychiatry 50:834–835, 1993
Nishino S, Mignot E, Benson KL, et al: Cerebrospinal fluid prostaglandins and
corticotropin releasing factor in schizophrenics and controls: relationship to
sleep architecture. Psychiatry Res 78:141–150, 1998
Nutt D: Substance-P antagonists: a new treatment for depression? Lancet 352:
1644–1646, 1998
Oram JJ, Edwardson J, Millard PH: Investigation of cerebrospinal fluid neuropep-
tides in idiopathic senile dementia. Gerontology 27:216–223, 1981
Patel YC: General aspects of the biology and function of somatostatin, in Basic
and Clinical Aspects of Neuroscience, Vol 4. Edited by Weil C, Muller EE,
Thorner MO. Berlin, Springer-Verlag, 1992, pp 1–16
Payan DG, Brewster DR, Goetzl EJ: Stereospecific receptors for substance
P on cultured human IM-9 lymphoblasts. J Immunol 133:3260–3265,
1984
Pelletier G, Steinbusch HWM, Verhofstad AAJ: Immunoreactive substance P and
serotonin present in the same dense-core vesicles. Nature 293:71–72, 1981
Pernow B: Substance P. Pharmacol Rev 35:85–141, 1983
Perrin M, Donaldson C, Chen R, et al: Identification of a second corticotropin-
releasing factor receptor gene and characterization of a cDNA expressed in
heart. Proc Natl Acad Sci U S A 92:2969–2973, 1995
Peskind ER, Wingerson D, Pascualy M, et al: Oral physostigmine in Alzheimer’s
disease: effects on norepinephrine and vasopressin in cerebrospinal fluid and
plasma. Biol Psychiatry 38:532–538, 1995
Pickar D, Bunney WE Jr, Kieholtz P, et al: Acute naloxone administration in
schizophrenic patients: a World Health Organization collaborative study.
Arch Gen Psychiatry 39:508–511, 1981a
Pickar D, Bunney WE Jr, Kieholtz P, et al: The endogenous opioid system and
psychiatric illness: effects of naloxone administration in schizophrenic and
manic patients. Biol Psychiatry 16:394–497, 1981b
Pickar D, Naber D, Post RM, et al: Endorphins in the cerebrospinal fluid of psy-
chiatric patients. Ann N Y Acad Sci 398:399–412, 1982a
Pickar D, Vartanian F, Bunney WE Jr, et al: Short-term naloxone administration
in schizophrenic and manic patients: a World Health Organization collabo-
rative study. Arch Gen Psychiatry 39:313–319, 1982b
76 PSYCHONEUROENDOCRINOLOGY
Richardson JS, Zaleski WA: Naloxone and self-mutilation. Biol Psychiatry 18:99–
101, 1983
Rimon R, Le Greves P, Nyberg F, et al: Elevation of substance P-like peptides in
the CSF of psychiatric patients. Biol Psychiatry 19:509–516, 1984
Risch SC: AE Bennett award paper: beta-endorphin hypersecretion in depres-
sion: possible cholinergic mechanisms. Biol Psychiatry 17:1071–1079, 1982
Risch SC, Cohen RM, Janowsky DS, et al: Mood and behavioral effects of phys-
ostigmine on humans are accompanied by elevations in plasma beta-endorphin
and cortisol. Science 209:1545–1546, 1982
Risch SC, Lewine RJ, Kalin NH, et al: Limbic-hypothalamic-pituitary-adrenal
axis activity and ventricular-to-brain ratio studies in affective illness and
schizophrenia. Neuropsychopharmacology 6:95–100, 1992
Ritchie J, Belkin BM, Krishnan KRR, et al: Plasma dexamethasone concentration
and the dexamethasone suppression test. Biol Psychiatry 27:159–173, 1990
Robertson GL, Shelton RL, Athar S: The osmoregulation of vasopressin. Kidney
Int 10:25–37, 1976
Roth AS, Ostroff RB, Hoffman RE: Naltrexone as a treatment for repetitive self-
injurious behavior: an open-label trial. J Clin Psychiatry 57:233–237, 1996
Roy A, Pickar D, Doran A, et al: The corticotropin releasing hormone stimulation
test in chronic schizophrenia. Am J Psychiatry 143:1393–1397, 1986
Roy A, Pickar D, Paul S, et al: CSF corticotropin-releasing hormone in depressed
patients and normal control subjects. Am J Psychiatry 144:641–645, 1987
Roy A, Pickar D, Gold P, et al: Diazepam-binding inhibitor and corticotropin-
releasing hormone in cerebrospinal fluid. Acta Psychiatr Scand 80:287–291,
1989
Roy A, DeJong J, Gold P, et al: Cerebrospinal fluid levels of somatostatin, corti-
cotropin-releasing hormone and corticotropin in alcoholism. Acta Psychiatr
Scand 82:44–48, 1990
Roy-Byrne PP, Uhde T, Post R, et al: The corticotropin-releasing hormone stimula-
tion tests in patients with panic disorder. Am J Psychiatry 143:896–899, 1986
Rubin RT, Phillips JJ, Sadow TF, et al: Adrenal gland volume in major depression:
increase during the depressive episode and decrease with successful treat-
ment. Arch Gen Psychiatry 52:213–218, 1995
Rubin RT, Phillips JJ, McCracken JT, et al: Adrenal gland volume in major depres-
sion: relationship to basal and stimulated pituitary-adrenal cortical axis func-
tion. Biol Psychiatry 40:89–97, 1996
Rubinow DR, Post RM, Pickar D, et al: Relationship between urinary free cortisol
and CSF opioid binding activity in depressed patients and normal volunteers.
Psychiatry Res 5:87–93, 1981
Rubinow DR, Gold PW, Post RM, et al: CSF somatostatin in affective illness.
Arch Gen Psychiatry 40:409–412, 1983
Rubinow DR, Gold PW, Post RM, et al: Somatostatin in patients with affective
illness and in normal volunteers, in Neurobiology of Mood Disorders. Ed-
ited by Post RM, Ballenger JC. Baltimore, MD, Williams & Wilkins, 1984,
pp 369–387
78 PSYCHONEUROENDOCRINOLOGY
Rubinow DR, Davis CL, Post RM: Somatostatin in the central nervous system, in
Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom
FE, Kupfer DJ. New York, Raven, 1995, pp 553–562
Rubinow DR, Davis CL, Post RM: Somatostatin in neuropsychiatric disorders, in
Basic and Clinical Aspects of Neuroscience, Vol 4: Somatostatin. Edited by
Weil C, Muller EE, Thorner MO. Berlin, Springer-Verlag, 1992, pp 29–42
Rupprecht R, Barocka A, Beck G, et al: Pre- and post-dexamethasone plasma
ACTH and beta-endorphin levels in endogenous and non-endogenous de-
pression. Biol Psychiatry 23:531–535, 1988
Sachar E, Hellman L, Fukushima D, et al: Cortisol production in depressive ill-
ness. Arch Gen Psychiatry 23:289–298, 1970
Sadoul JL, Checler F, Kitabgi P, et al: Loss of high affinity neurotensin receptors
in substantia nigra from parkinsonian subjects. Biochem Biophys Res Com-
mun 125:395–404, 1984
Sahu A, Kalra PS, Kalra SP: Food deprivation and ingestion induce reciprocal
changes in neuropeptide Y concentrations in the paraventricular nucleus.
Peptides 9:83–86, 1988
Saito A, Sankaran H, Goldine ID, et al: Cholecystokinin receptors in the brain:
characterization and distribution. Science 208:1155–1156, 1980
Sandman CA: Beta-endorphin dysregulation in autistic and self-injurious behav-
ior: a neurodevelopmental hypothesis. Synapse 2:193–199, 1988
Sandman CA, Datta PC, Barron J, et al: Naloxone attenuates self-abusive behav-
ior in developmentally disabled clients. Appl Res Ment Retard 4:5–11, 1983
Sandman CA, Barron JL, Crinella FM, et al: Influence of naloxone on brain and
behavior of a self-injurious woman. Biol Psychiatry 22:899–906, 1987
Sandyk R: Naloxone abolishes self-injuring in a mentally retarded child (letter).
Ann Neurol 17:520, 1985
Sawchenko PE, Swanson LW: Immunohistochemical identification of neurons in
the paraventricular nucleus of the hypothalamus that project to the medulla
or to the spinal cord in the rat. J Comp Neurol 205:260–272, 1982
Schilkrut R, Chandra O, Osswald M, et al: Growth hormone during sleep and
with thermal stimulation in depressed patients. Neuropsychobiology 1:70–
79, 1975
Schneider-Helmert D: DSIP in insomnia. Eur Neurol 23:346–352, 1984a
Schneider-Helmert D: Effects of DSIP on narcolepsy. Eur Neurol 23:353–357,
1984b
Schneider-Helmert D, Schoenenberger GA: Effects of DSIP in man. Multifunc-
tional psychophysiological properties besides induction of natural sleep.
Neuropsychobiology 9:197–206, 1983
Schneider-Helmert D, Gnirss F, Monnier M, et al: Acute and delayed effects of
DSIP (delta sleep-inducing peptide) on human sleep behavior. Int J Clin
Pharmacol Ther Toxicol 19:341–345, 1981
Schoenenberger GA, Maier PF, Tober KJ, et al: The delta-EEG (sleep)-inducing
peptide (DSIP), XI: amino-acid analysis, sequence, synthesis and activity of
the nonapeptide. Pflugers Arch 376:119–129, 1978
Neuropeptides and Hypothalamic Releasing Factors 79
Schultz DW, Mansbach RS, Sprouse J, et al: CP-154,526: a potent and selective
nonpeptide antagonist of corticotropin releasing factor receptors. Proc Natl
Acad Sci U S A 93:10477–10482, 1996
Shoyab M, Gentry GE, Marquardt H, et al: Isolation and characterization of a pu-
tative endogenous benzodiazepinoid (endozepine) from bovine and human
brain. J Biol Chem 261:11968–11973, 1986
Siever LJ: Role of noradrenergic mechanisms in the etiology of the affective dis-
orders, in Psychopharmacology: The Third Generation of Progress. Edited by
Meltzer HY. New York, Raven, 1987, pp 493–504
Siever LJ, Uhde TW, Silberman EK, et al: Growth hormone response to clonidine
as a probe of noradrenergic receptor responsiveness in affective disorder pa-
tients and controls. Psychiatry Res 6:171–183, 1982
Smith AI, Funder JW: Proopiomelanocortin processing in the pituitary, central
nervous system, and peripheral tissues. Endocr Rev 9:159–179, 1988
Smith MA, Davidson J, Ritchie JC, et al: The corticotropin-releasing hormone test
in patients with posttraumatic stress disorder. Biol Psychiatry 26:349–355, 1989
Soininen HS, Jolkkonen JT, Reinikainen KJ, et al: Reduced cholinesterase activity
and somatostatin-like immunoreactivity in the cerebrospinal fluid of patients
with dementia of the Alzheimer’s type. J Neurol Sci 63:167–172, 1984
Stanley BG: Neuropeptide Y in multiple hypothalamic sites controls eating be-
havior, endocrine, and autonomic systems for body energy balance, in The
Biology of Neuropeptide Y and Related Peptides. Edited by Colmers WF,
Wahlestedt C. Totowa, NJ, Humana, 1993, pp 457–509
Suemaru S, Suemaru K, Hashimoto K, et al: Cerebrospinal fluid corticotropin-
releasing hormone and ACTH, and peripherally circulating choline-containing
phospholipid in senile dementia. Life Sci 53:697–706, 1993
Suemaru S, Suemaru K, Kawai K, et al: Cerebrospinal fluid corticotropin-releasing
hormone in neurodegenerative diseases: reduction in spinocerebellar degen-
eration. Life Sci 57:2231–2235, 1995
Sundler F, Bottcher G, Ekblad E, et al: PP, PYY and NPY—occurrence and distri-
bution in the periphery, in The Biology of Neuropeptide Y and Related Pep-
tides. Edited by Colmers WF, Wahlestedt C. Totowa, NJ, Humana, 1993,
pp 157–196
Swanson LW: The hypothalamus, in Handbook of Chemical Neuroanatomy. Edited
by Bjorklund A, Hokfelt T, Swanson LW. New York, Elsevier, 1987; 5:1–124
Swanson LW, Sawchenko PE, Rivier J, et al: Organization of ovine corticotropin-
releasing factor immunoreactive cells and fibers in the rat brain: an immuno-
histochemical study. Neuroendocrinology 36:165–186, 1983
Szymanski L, Kedesdy J, Sulkes S, et al: Naltrexone in treatment of self-injurious
behavior: a clinical study. Res Dev Disabil 8:179–190, 1987
Tang F, Man SY: The regional distribution of thyrotropin releasing hormone,
LEU-enkephalin, MET-enkephalin, substance P, somatostatin and cholecys-
tokinin in the rat brain and pituitary. Neuropeptides 19:287–282, 1991
Toivola PTK, Gale CC, Goodner CJ, et al: Central a-adrenergic regulation of
growth hormone and insulin. Hormones 3:192–213, 1972
80 PSYCHONEUROENDOCRINOLOGY
Tsagarakis S, Rees LH, Besser GM, et al: Neuropeptide Y stimulates CRH-41 re-
lease from rat hypothalami in vitro. Brain Res 502:167–170, 1989
Uhl GR, Whitehouse PJ, Price DL, et al: Parkinson’s disease: depletion of sub-
stantia nigra neurotensin receptors. Brain Res 308:186–190, 1984
Vaccarino FJ, Rankin J: Nucleus accumbens cholecystokinin (CCK) can either at-
tenuate or potentiate amphetamine-induced locomotor activity: evidence
for rostral-caudal differences in accumbens CCK function. Behav Neurosci
103:831–836, 1989
Vale W, Spiess J, Rivier C, et al: Characterization of a 41 residue ovine hypotha-
lamic peptide that stimulates secretion of corticotropin of beta-endorphin.
Science 213:1394–1397, 1981
Vallet PG, Charnay Y, Bouras, et al: Distribution and colocalization of delta
sleep inducing peptide (DSIP) with corticotropin-like intermediate lobe
peptide (CLIP) in the human hypophysis. Neurosci Lett 90:78–82, 1988
Vanderhaeghen JJ, Signeau JC, Gepts LO: New peptide in the vertebrate CNS
reacting with gastrin antibodies. Nature 257:604–605, 1975
Van der Woude PF, Goudsmit E, Wierda M, et al: No vasopressin cell loss in the
human hypothalamus in aging and Alzheimer’s disease. Neurobiol Aging 16:
11–18, 1995
Van Kammen DP, Waters RN, Gold P: Spinal fluid vasopressin, angiotensin I and
II, beta-endorphin and opioid activity in schizophrenia: a preliminary evalu-
ation, in Biological Psychiatry. Edited by Perris C, Strume G, Jansson B. Am-
sterdam, Elsevier North Holland, 1981, pp 339–344
Van Kammen DP, Widerlov E, Neylan TC, et al: Delta sleep-inducing-peptide-
like immunoreactivity (DSIP-LI) and delta sleep in schizophrenic volun-
teers. Sleep 15:519–525, 1992
van Megen HJ, Den Boer HJGM, Westenberg HGM: Pentagastrin induced panic
attacks: enhanced sensitivity in panic disorder patients. Psychopharmacology
114:449–455, 1994
Van Ree JM, Gaffori O, DeWied D: In rats, the behavioral profile of CCK-8 re-
lated peptides resembles that of antipsychotic agents. Eur J Pharmacol 93:
63–78, 1983
van Zwieten EJ, Ravid R, Swaab DF. Differential vasopressin and oxytocin inner-
vation of the human parabrachial nucleus: no changes in Alzheimer’s disease.
Brain Res 711:146–152, 1996
Vaughan J, Donaldson C, Bittencourt J, et al: Urocortin, a mammalian neuropep-
tide related to fish urotensin I and to corticotropin-releasing factor. Nature
378:287–292, 1995
Vecsei L, Widerlov E: Effects of somatostatin-28 and some of its fragments and
analogs on open-field behavior, barrel rotation, and shuttle box learning in
rats. Psychoneuroendocrinology 15:139–145, 1990
Veith RC, Lewis N, Langohr JI, et al: Effect of desipramine on cerebrospinal fluid
concentrations of corticotropin-releasing factor in human subjects. Psychia-
try Res 46:1–8, 1992
Neuropeptides and Hypothalamic Releasing Factors 81
Wynn PC, Harwood JP, Catt KJ, et al: Corticotropin-releasing factor (CRH) in-
duces desensitization of the rat pituitary CRH receptor-adenylate cyclase
complex. Endocrinology 122:351–358, 1988
Yehuda R: Sensitization of the hypothalamic-pituitary-adrenal axis in posttrau-
matic stress disorder. Ann N Y Acad Sci 821:57–75, 1997
Young EA, Watson SJ, Kotun J, et al: Beta-lipotropin–beta-endorphin response to
low-dose ovine corticotropin releasing factor in endogenous depression: pre-
liminary studies. Arch Gen Psychiatry 47:449–457, 1990
Zis KD, Zis A: Increased adrenal weight in victims of violent suicide. Am J Psy-
chiatry 144:1214–1215, 1987
Zobel AW, Yassouridis A, Frieboes RM, et al: Prediction of medium-term out-
come by cortisol response to the combined dexamethasone-CRH test in pa-
tients with remitted depression. Am J Psychiatry 156:949–951, 1999
Chapter 4
An earlier version of this chapter (Sack RL, Lewy AJ, Hughes RJ, et al.: “Mela-
tonin as a Chronobiotic Drug”) was originally published in Drug News and Per-
spectives 9(6):325–332, 1996. Copyright 1996, Prous Science Publishers. Used
with permission.
83
84 PSYCHONEUROENDOCRINOLOGY
optimal timing and dosage, are currently being worked out. Meanwhile,
scientific research on melatonin has been overshadowed by a melatonin
fad in the United States, where it is sold in health food stores as a dietary
supplement. Although melatonin is not classified as a drug, those who
produce it for the health food market make implied claims that it is an
effective treatment for insomnia. Proponents of the fad also extend the
highly speculative hopes that melatonin has anti-aging effects, bolsters
the immune system, and can augment cancer therapy. We do not attempt
to review these claims in this chapter; instead we concentrate on the cir-
cadian phase-resetting and hypnotic actions of melatonin. The principles
discussed will presumably also apply to melatonin analogs and perhaps to
other chronobiotics that are under active development.
The word circadian is derived from the Greek roots circa, meaning
“about,” and dies, meaning “day.” Circadian rhythms have evolved as an
adaptation to the alternating light-dark cycle caused by the rotation of
the earth (for a very readable overview of circadian rhythm physiology,
see Moore-Ede et al. 1982). Circadian rhythms are not passive responses
but are actively generated by an internal pacemaker that operates to main-
tain synchrony with the light-dark cycle. The endogenous nature of these
rhythms can be demonstrated by placing an organism in an isolated envi-
ronment and then observing variations in behavior or physiology that
continue to oscillate about every 24 hours, even in the absence of any
external time cues (zeitgebers, from the German for “time-givers”). The
circadian system provides a mechanism for anticipatory adaptation to
predictable changes in the environment; for example, core body temper-
ature rises in the second half of the night, presumably preparing an indi-
vidual for activity on awakening in the morning.
In mammals, the circadian clock is located in the hypothalamus within
the suprachiasmatic nucleus (SCN) (Klein et al. 1991) (Figure 4–1). The
SCN acts as the master circadian pacemaker and controls the timing of
most circadian rhythms, including melatonin secretion, sleepiness, core
body temperature, and cortisol secretion. If this tiny area of the brain is
destroyed in laboratory animals, circadian rhythms in body temperature
and hormonal secretion are lost, and sleep occurs in short bouts evenly
distributed throughout the 24-hour day. Circadian rhythms can be re-
stored in SCN-lesioned animals by transplanting fetal SCN tissue into the
third ventricle of the brain (Ralph 1991). The intrinsic rhythm of the
86 PSYCHONEUROENDOCRINOLOGY
SCN is not exactly a 24-hour cycle but ranges from about 23 to 25 hours
(in humans, about 24.5 hours). When subjects are isolated from all time
cues, circadian rhythms express a cycle that is slightly longer (or shorter)
than 24 hours. For circadian rhythms to be synchronized to a precise 24-
hour day, the circadian clock must be regularly adjusted (reset) by expo-
sure to 24-hour time cues. Thus, circadian phase resetting is a normal, on-
going process; the resynchronization that occurs after a challenge to the
system such as transmeridian flight is an extension of an intrinsic process
that occurs normally every day in nontravelers.
The process of adjustment through interaction with time cues in the
environment is called entrainment. In nature the primary time cue is the
solar light-dark cycle, although other timing signals may play a role. Light
information is delivered directly to the SCN via the retinohypothalamic
tract, which is anatomically distinct from the visual imaging circuitry (see
Figure 4–1).
Chronobiology and Melatonin 87
The SCN stimulates the pineal gland to secrete melatonin during the
nighttime hours. A functional feedback loop between the pineal and the
SCN (see Figure 4–1) is mediated by highly specific melatonin receptors
(Reppert et al. 1994, 1995) concentrated in the SCN. This feedback loop
appears to regulate the timing, but not the amplitude, of melatonin se-
cretion. Melatonin receptors in the SCN are the probable target for the
clock-resetting effects of exogenously administered melatonin.
Both the potency and the direction of environmental time cues are de-
pendent on the time of day they are presented. In chronobiology, this
88 PSYCHONEUROENDOCRINOLOGY
the next few years (Sack and Lewy 1988; Sack et al. 1990, 1991). The
strategy of treatment was based on the animal experiments of Armstrong
and co-workers (Armstrong and Chesworth 1987; Redman and Arm-
strong 1988; Redman et al. 1983). Five totally blind males with con-
sistent free-running (non-24-hour) melatonin rhythms were given
exogenous melatonin (5 mg by mouth at bedtime) for up to 3 weeks.
Four of the five subjects showed significant cumulative advances (7–16
hours) in the phase of melatonin rhythm compared with phase projec-
tions derived from their pretreatment rhythms (Sack et al. 1991). Corti-
sol rhythms were advanced in parallel with the melatonin rhythms. In
blind subjects, the treatment-induced phase advances were unconstrained
by the light-dark cycle and therefore accumulated over the 3-week period.
In these early studies, we were not able to entrain the subjects’ circadian
rhythms to a 24-hour cycle, perhaps because the duration of treatment
was limited to 3 weeks.
We have readdressed the issue of melatonin treatment of blind peo-
ple. Using a higher dose (10 mg), we have been able to entrain six of
seven subjects treated (Sack et al. 1999, 2000). Placebo treatment had no
effect. Figure 4–2 shows representative data from one of the blind sub-
jects. Entrainment of free-running rhythms in blind people is a clear-cut
demonstration of the clock-resetting potency of melatonin. Recently, we
found that 0.5 mg can be effective in these individuals (Lewy et al.
2001).
After our initial demonstration of phase resetting in blind people with
free-running rhythms, we proceeded with studies in sighted people. We
administered melatonin at all phases of the circadian cycle, evaluating de-
laying as well as advancing effects, and derived a PRC (Lewy et al. 1992).
For each trial, subjects were given a daily 0.5-mg dose of melatonin or
placebo at the same time each day for 4 days, and circadian phase was as-
sessed on the fifth day by measuring the timing of endogenous melatonin
rhythm (dim light melatonin onset [DLMO]). Sleep times were held rel-
atively constant. The difference in DLMO between active treatment and
placebo was used as the measure of phase shift. Figure 4–3 presents the
melatonin PRC developed by this strategy. Advance responses (shifts to
an earlier time) are most likely to occur after melatonin administration
in the late afternoon and evening (just before the onset of endogenous
melatonin secretion), whereas delay responses (shifts to a later time) are
most likely to occur after melatonin administration in the morning (coin-
cident with the decline in endogenous secretion).
The strategy for using melatonin and light to shift circadian rhythms
according to their respective PRCs is summarized schematically in
Figure 4–4. As shown in the upper panel, melatonin administration in
90 PSYCHONEUROENDOCRINOLOGY
FIGURE 4–2. Data from entrainment of a totally blind man with free-
running rhythms by melatonin 10 mg given nightly at bedtime.
Total blindness is associated with circadian rhythms that run on a non-24-hour, “free-running”
cycle (see text). Recurrent insomnia and daytime sleepiness result when endogenous circa-
dian rhythms are out of phase with the desired sleep-wake cycle. The subject is a 57-year-
old man who was totally blinded at age 26 from trauma. His 24-hour melatonin profiles
were assessed at 2- to 4-week intervals to detect his melatonin onset (MO), the time when
concentrations rose above 10 pg/mL. His circadian period (tau) was determined by fitting
the MOs to a linear regression. MOs assessed during a diagnostic assessment (open circles)
revealed a free-running melatonin rhythm with a tau of 24.6 hours. The tau was unchanged
by placebo treatment (open squares). MOs assessed on melatonin treatment days 42 and
52 (closed squares) were at a slightly delayed but consistent phase of 1:00 and 12:45 A.M.,
6.8 hours and 13.2 hours (respectively) earlier than predicted by extrapolation of the free-
running rhythm (shown as the dotted line).
Source. Reprinted from Sack RL, Brandes RL, deJongh L, et al.: “Melatonin Entrains Free-
Running Circadian Rhythms in a Totally Blind Person.” Sleep 22(suppl):S138–S139, 1999.
Used with permission.
the evening (or light in the morning ) will shift circadian rhythms earlier
(i.e., cause a phase advance). As shown in the lower panel, melatonin ad-
ministration in the morning (or light in the evening) will shift the circa-
dian rhythms later (i.e., cause a phase delay). The most critical times for
Chronobiology and Melatonin
FIGURE 4–3. Melatonin phase response curve (PRC) derived from repeated trials of melatonin administration.
Advance responses are most likely in the late afternoon and evening (just before the onset of endogenous melatonin secretion), whereas delay responses are
most likely to occur in the morning (coincident with the decline in endogenous secretion).
Source. Reprinted from Lewy et al. 1998. Used with permission.
91
92 PSYCHONEUROENDOCRINOLOGY
FIGURE 4–4. The strategy for using melatonin and light to shift circadi-
an rhythms according to their respective phase response curves (PRCs),
shown schematically (see text for details).
Source. Reprinted from Lewy AJ, Sack RL: “The Role of Melatonin and Light in the Hu-
man Circadian System.” Progress in Brain Research 111(205):205–216, 1996. Copyright
1996, with permission from Elsevier Science.
phase shifting in nature are dawn and dusk. Melatonin given in the mid-
dle of the night and light exposure in the middle of the day (so-called
dead zones of the PRCs) have minimal phase-shifting effects.
no phase shift in their DLMO with the placebo treatment, but they
shifted at least 3 hours with melatonin. Subjects 17 through 24 delayed
their DLMO substantially with placebo alone, and melatonin did not
augment the shift. Subjects 1, 2, and 4 advanced their DLMO equally
with melatonin and placebo. Subjects 5–8 had no shift with either treat-
ment. Several subjects seemed to be atypical. For example, subject 3 was
at distinctly different phases on two off-week determinations. Perhaps
because of his differing starting phase, he advanced on the placebo trial
and delayed on his melatonin trial. Subject 16 had a larger delay in her
96 PSYCHONEUROENDOCRINOLOGY
ing the day (when endogenous levels are lowest) (Hughes and Badia
1997), but such an effect does not necessarily occur when it is given at
night (James et al. 1987). Furthermore, an increase in nocturnal sleep has
been reported in elderly persons with insomnia, who may have low en-
dogenous levels (Haimov et al. 1995).
Another hypothesis currently undergoing testing is that soporific ef-
fects are associated with pharmacologic doses (although some groups insist
that physiological doses are equally potent). Several studies illustrate this
conclusion: for example, in the initial trials of melatonin with healthy el-
derly subjects completed to date, a 50-mg dose improved some parameters
of sleep (Singer et al. 1995a), whereas a 0.2-mg sustained-release formu-
lation showed no benefit (Singer et al. 1995b). The numbers of subjects
were small, and, given the variability of sleep in the elderly, firm conclu-
sions await additional data. In a study of young subjects, Hughes et al.
(1995) assessed the hypnotic efficacy of three doses of melatonin (1 mg,
10 mg, and 40 mg) given at 10:00 A.M. before enforced bed rest and a sleep
opportunity from 12:00 until 4:00 P.M. Melatonin increased sleep duration
during the 4-hour nap, with a suggestion of a dose-response effect.
We have attempted to integrate the findings on melatonin and sleep
by proposing that melatonin does not produce sleepiness per se; rather, it
releases accumulated sleep drive by antagonizing the daytime alerting sig-
nal generated by the SCN. This model is schematically portrayed in
Figure 4–7. The upper panel illustrates the dynamics of the opponent
process of sleep regulation (after Edgar et al. 1993). According to this
model, sleep drive builds up during the waking hours and is discharged
at night. However, the buildup of daytime sleep drive is usually unex-
pressed, because it is opposed by an alerting process generated in the
SCN. At bedtime there is a rather sudden transition to sleepiness (some-
times referred to as the opening of the sleep gate [Shochat et al. 1997]),
which coincides with the abrupt diminution in the SCN-dependent
alerting process. The lower panel of Figure 4–7 shows how melatonin
might promote sleep by attenuating the SCN-dependent alerting pro-
cess, thereby releasing the built-up sleep drive. If melatonin is given just
before sleep time (A), this action will shorten sleep latency. If given in
the middle of the night (B), there will be little effect on sleep because
sleep drive is in the process of discharging and the alerting process is qui-
escent (i.e., the sleep gate is already open). According to the model, me-
latonin can promote daytime naps (C), depending on the amount of
underlying sleep drive.
Melatonin appears to have no anxiolytic effects. Therefore, it may be
of little benefit to persons with insomnia who cannot sleep because of
tension, anxiety, or depression.
98 PSYCHONEUROENDOCRINOLOGY
tonin taken in the morning may promote daytime sleep and also shift the
circadian clock to a later time. In clinical practice, a more potent sedative
drug might be combined with melatonin. For example, in the treatment
of jet lag, it may take several days for the circadian rhythms to synchro-
nize with local time, even if melatonin administration speeds up the
adaptive process. During this transition, a hypnotic drug may help to pro-
mote sleep. Combining melatonin with a hypnotic agent might be justi-
fied in the treatment of other circadian rhythm sleep disorders as a
transitional aid. The need for a hypnotic would naturally diminish as
rhythms came into alignment with desired sleep times. Treatment rec-
ommendations using melatonin, light exposure, and hypnotic medica-
tions for jet lag are presented in Table 4–2. A clinical vignette illustrating
combination treatment for delayed sleep-phase syndrome is provided
below.
until 2 or 3 A.M. He would set several alarm clocks but would often sleep
through the alarms. When he did not wake up in time, he missed his bus,
so he stayed home and slept until late morning. Unexcused absences re-
sulted in declining grades and demoralization about school.
A diagnosis of delayed sleep-phase syndrome was made. Considerable
time was spent with the patient and his mother explaining the circadian
system, specifically 1) how the “body clock” tended to run on a longer
than 24-hour cycle, especially in teenagers; 2) how sleeping in on the
weekend could result in a rhythm that was so delayed that it was not pos-
sible to adjust it during the school week; and 3) how appropriately timed
light exposure and melatonin administration could be used to reset and
stabilize the sleep propensity rhythm. A treatment plan was developed in
which a very specific sleep, light exposure, and medication schedule was
written out using a computer spreadsheet. The schedule started with the
patient’s current preferred wakeup time (10 A.M.). The goal of treatment
was to advance wakeup time by 15 minutes every other day. Bedtime was
set at 8 hours before wakeup time. The patient was prescribed melatonin
3 mg to take 3 hours before bedtime. If he did not fall asleep within 20
minutes, he was to get up and take zolpidem (a sedative-hypnotic) 10 mg
and go back to bed. On arising, he was to go outside in the daylight for at
least 15 minutes. He was warned not to advance the schedule any faster
than prescribed and to keep on schedule during the weekends.
At the end of 3 weeks, the patient was able to wake up in time to
make the bus. He stopped taking the zolpidem but continued to take me-
latonin and to go outside in the morning. He was able to maintain a reg-
ular schedule, and with time he was more successful at school, resulting
in improved self-esteem.
Melatonin Analogs
Safety Concerns
prion disease. Therefore, unregulated use of melatonin for sleep has re-
minded some clinicians of the experience with tryptophan, in which im-
purities caused an eosinophilic syndrome; however, there is no evidence
for this problem so far with melatonin.
References
Ralph MR: Suprachiasmatic nucleus transplant studies using the tau mutation in
golden hamsters, in Suprachiasmatic Nucleus: The Mind’s Clock. Edited by
Klein DC, Moore RY, Reppert SM. New York, Oxford University Press,
1991, pp 341–348
Redman JR, Armstrong SM: Re-entrainment of rat circadian activity rhythms: ef-
fects of melatonin. J Pineal Res 5:203–215, 1988
Redman JR, Armstrong S, Ng KT: Free-running activity rhythms in the rat: en-
trainment by melatonin. Science 219:1089–1091, 1983
Reppert SM, Weaver DR, Ebisawa T: Cloning and characterization of a mamma-
lian melatonin receptor that mediates reproductive and circadian responses.
Neuron 13:1177–1185, 1994
Reppert SM, Godson C, Mahle CD, et al: Molecular characterization of a second
melatonin receptor expressed in human retina and brain: the Mel1b melato-
nin receptor. Proc Natl Acad Sci U S A 92:8734–8738, 1995
Sack RL, Lewy AJ: Melatonin administration phase advances endogenous rhythms
in humans. Sleep Research 17:396, 1988
Sack RL, Lewy AJ: Melatonin as a chronobiotic: treatment of circadian desyn-
chrony in night workers and the blind. J Biol Rhythms 12(6):595–603, 1997
Sack RL, Lewy AJ, Hoban TM: Free-running melatonin rhythms in blind people:
phase shifts with melatonin and triazolam administration, in Temporal Dis-
order in Human Oscillatory Systems. Edited by Rensing L, an der Heiden U,
Mackey MC. Heidelberg, Springer-Verlag, 1987, pp 219–224
Sack RL, Stevenson J, Lewy AJ: Entrainment of a previously free-running blind
human with melatonin administration. Sleep Research 19:404, 1990
Sack RL, Lewy AJ, Blood ML, et al: Melatonin administration to blind people:
phase advances and entrainment. J Biol Rhythms 6(3):249–261, 1991
Sack RL, Brandes RW, deJongh L, et al: Melatonin entrains free-running circadian
rhythms in a totally blind person. Sleep 22 (suppl):S138–S139, 1999
Sack RL, Brandes RW, Kendall AR, et al: Entrainment of free-running circadian
rhythms by melatonin in blind people. New Engl J Med 343:1070–1077, 2000
Sharkey KM, Eastman CI: Melatonin phase shifts human circadian rhythms in a
placebo-controlled simulated night-work study. Am J Physiol Regul Integr
Comp Physiol 282:R454–R463, 2002
Shochat T, Luboshitsky R, Lavie P: Nocturnal melatonin onset is phase locked to
the primary sleep gate. Am J Physiol 273:R364–R370, 1997
Simpson HW: Chronobiotics: selected agents of potential value in jet lag and
other desynchronisms, in Chronobiology: Principles and Applications to
Shifts in Schedules. Edited by Scheving LE, Halberg F. Netherlands, Sijthoff
& Noordhoff, 1980, pp 433–446
Singer C, McArthur A, Hughes R, et al: High dose melatonin administration and
sleep in the elderly. Sleep Research 24A:151, 1995a
Singer C, McArthur A, Hughes R, et al: Physiologic melatonin administration and
sleep in the elderly. Sleep Research 24A:152, 1995b
Tamarkin L, Baird CJ, Almeida OFX: Melatonin: a coordinating signal for mam-
malian reproduction? Science 227:714–720, 1985
Chronobiology and Melatonin 105
107
108 PSYCHONEUROENDOCRINOLOGY
Schizophrenia
Although basal prolactin levels are within the normal range in most non-
medicated schizophrenic patients, some studies have shown an inverse re-
lationship between prolactin concentrations and positive symptoms (T.J.
Crow et al. 1986). Basal prolactin level in nonmedicated patients with
acute schizophrenia is also slightly greater compared with basal levels in
patients with chronic schizophrenia or control subjects (Garver 1988).
Hyperprolactinemia and associated findings of galactorrhea, menstrual
dysfunction, decreased libido, and infertility occur commonly in women
responding to typical antipsychotic agents (Canuso et al. 1998). With the
exception of risperidone, newer atypical antipsychotic agents appear to
avoid elevation of prolactin level (Goodnick et al. 2002; Remington and
Kapur 2000). The prolactin-increasing effect is partly related to the potency
of blockade at the dopamine type 2 receptor in the tuberoinfundibulum.
Although the majority of evidence indicates that such side effects do not
appear to interfere with therapeutic response, patient compliance with
medication regimens associated with such consequences may be compro-
Hormones: Psychobiological and Clinical Implications 111
Anxiety Disorders
Very little information has been collected regarding changes in prolactin
level in simple and social phobia, and most of this information does not
show a correlation (Curtis and Glitz 1988). Support for serotonergic
hypersensitivity, as evidenced by prolactin hyperresponsiveness to sero-
tonin agonists such as m-chlorophenylpiperazine (mCPP), has been seen
in some studies of patients with panic disorder (Klein et al. 1991). How-
ever, central serotonergically mediated prolactin responses in obsessive-
compulsive disorder (OCD) seem to be more similar to the blunted re-
sponses seen in patients with MDD, even after accounting for depressive
comorbidity (Lucey et al. 1992), and may correlate with response to in-
travenous clomipramine treatment in patients with treatment-refractory
OCD (Mathew et al. 2001).
Anxiety Disorders
Panic disorder, OCD, and social phobia have been linked to disturbances
of the growth hormone system. Basal growth hormone levels are elevated
in some studies of patients with panic disorder (Nesse et al. 1984). In addi-
tion, blunted growth hormone responses have been consistently observed
in patients with panic disorder following administration of a2-adrenergic
agonists (Charney and Heninger 1986; Coplan et al. 1995). As with ma-
jor depression, the reduced growth hormone response to clonidine is
thought to reflect reduced sensitivity of a2-adrenergic receptors in the
CNS, especially in the hypothalamus. This fits with the hypothesized
overactivation of presynaptic noradrenergic neurons in the locus coeru-
leus in panic disorder, which theoretically contributes to downregulation
of postsynaptic a2 receptors (Curtis and Glitz 1988).
The assessment of neuroendocrine function in patients with OCD is
complicated by frequent comorbidity with depressive disorders. Up to
50% of patients with OCD have coexisting MDD, but neuroendocrine
findings, though often similar to those seen in depressed populations, can
also occur in patients with OCD uncomplicated by any depressive symp-
toms. Blunted growth hormone response to clonidine in patients with
OCD, a nonspecific finding also occurring in MDD and panic disorder,
reflects reduced a2-adrenergic receptor responsiveness (Insel et al. 1984;
Siever et al. 1983).
Schizophrenia
Although basal growth hormone levels have been noted to be normal in
acute and chronic schizophrenia (Ferrier 1987), abnormal responses to
Hormones: Psychobiological and Clinical Implications 115
Alzheimer’s Disease
Although two studies of patients with Alzheimer’s disease suggested ab-
normal growth hormone system functioning (Christie et al. 1987; Thien-
haus et al. 1986), the vast majority of studies in this population indicate
little change in growth hormone responses (Davidson et al. 1988; Davis
et al. 1985; Heuser et al. 1992; McKhann et al. 1984). Effects of gender
and severity of illness may account for the few studies in which dif-
ferences in growth hormone responses to a2-adrenergic or cholinergic
agonists were observed between patients with Alzheimer’s disease and
control subjects without dementia (Davidson et al. 1988; Heuser et al.
1992).
lenge tests are discussed in the section on growth hormone above. Abnor-
malities in hypoglycemic responses to insulin tolerance testing in various
psychiatric populations are discussed briefly below.
Eating Disorders
Bulimic patients were found to have increased depression, fatigue, anxiety,
and bewilderment as assessed by self-report following glucose challenge in
a double-blind, placebo-controlled trial, whereas control subjects did not
differ in symptoms reported after glucose challenge. These mood changes
were correlated with blood glucose level in the bulimic group but not in
the control subjects, although no differences in insulin response could be
detected between groups (Blouin et al. 1993).
Conclusion
References
Ack M, Miller I, Weil WB: Intelligence of children with diabetes mellitus. Pedi-
atrics 28:764–770, 1961
Adamis D, Ball C: Physical morbidity in elderly psychiatric inpatients: prevalence
and possible relations between the major mental disorders and physical ill-
ness. Int J Geriatr Psychiatry 15:248–253, 2000
Aleyassine H, Lee SH: Inhibition of insulin release by substrates and inhibitors of
monoamine oxidase. Am J Physiol 222:565–569, 1972
Amsterdam JD, Maislin G: Hormonal responses during insulin-induced hypogly-
cemia in manic-depressed, unipolar depressed and healthy control subjects.
J Clin Endocrinol Metab 73:541–548, 1991
Amsterdam JD, Schweizer E, Winokur A: Multiple hormonal responses to insulin-
induced hypoglycemia in depressed patients and normal volunteers. Am J
Psychiatry 144:170–175, 1987
Amsterdam JD, Garcia-Espana F, Goodman D, et al: Breast enlargement during
chronic antidepressant therapy. J Affect Disord 46:151–156, 1997
Andreoli TE, Carpenter CCJ, Plum F, et al (eds): Diabetes mellitus, in Cecil Es-
sentials of Medicine. Philadelphia, PA, WB Saunders, 1986, pp 485–495
Antonijevic I, Murck H, Frieboes R, et al: Elevated nocturnal profiles of serum
leptin in patients with depression. J Psychiatr Res 32:403–410, 1998
128 PSYCHONEUROENDOCRINOLOGY
Hall RCW, Gardner ER, Popkin ER, et al: Unrecognized physical illness prompt-
ing psychiatric admission: a prospective study. Am J Psychiatry 138:629–
643, 1981
Hamner MB, Arvanitis LA, Miller BG, et al: Plasma prolactin in schizophrenia
subjects treated with Seroquel (ICI 204,636). Psychopharmacol Bull 32:
107–110, 1996
Harris MI, Hadden WC, Knowler WC, et al: Prevalence of diabetes and impaired
glucose tolerance and plasma glucose levels in U.S. population aged 20–74
yr. Diabetes 36:523–534, 1987
Haskett RF, Rose RM: Neuroendocrine disorders and psychopathology. Psychiatr
Clin North Am 4:239–252, 1981
Heninger GR, Charney DS, Sternberg DE: Serotonergic function in depression:
prolactin response to intravenous tryptophan in depressed patients and healthy
subjects. Arch Gen Psychiatry 41:398–402, 1984
Hershey T, Bhargava N, Sadler M, et al: Conventional versus intensive diabetes
therapy in children with type 1 diabetes: effects on memory and motor speed.
Diabetes Care 22:1318–1324, 1999
Heuser IJ, Baronti F, Marin CA, et al: Growth hormone secretion in Alzheimer’s
disease: 24-hour profile of basal levels and response to stimulation and sup-
pression studies. Neurobiol Aging 13:255–260, 1992
Hinkle LE, Wolf S: Importance of life stress in course and management of diabe-
tes mellitus. JAMA 148:513–520, 1952
Hoffman AR, Leiberman SA, Ceda GP: Growth hormone therapy in the elderly:
implications for the aging brain. Psychoneuroendocrinology 17:327–333, 1992
Holmes SJ, Shalet SM: Factors influencing the desire for long-term growth hor-
mone replacement in adults. Clin Endocrinol (Oxf) 43:151–157, 1995
Insel TR, Mueller EA III, Gillin JC, et al: Biological markers in obsessive-compul-
sive and affective disorders. J Psychiatr Res 18:407–423, 1984
Iwatani N, Miike T, Kai Y, et al: Glucoregulatory disorders in school refusal stu-
dents. Clin Endocrinol (Oxf) 47:273–278, 1997
Jeffcoate WJ, Silverstone JR, Edwards CRW, et al: Psychiatric manifestations of
Cushing’s syndrome: response to lowering of plasma cortisol. Q J Med 191:
465–472, 1979
Kaplan SM, Maas JW, Pixley JM, et al: Use of imipramine in diabetics. JAMA
174:511–517, 1960
Kathol RG, Gehris TL, Carroll BT, et al: Blunted ACTH response to hypoglyce-
mic stress in depressed patients but not in patients with schizophrenia.
J Psychiatr Res 26:103–116, 1992
Kawakami N, Takatsuka N, Shimizu H, et al: Depressive symptoms and occur-
rence of type 2 diabetes among Japanese men. Diabetes Care 22:1071–1076,
1999
Kitis G: Sheehan syndrome with psychosis. Proc R Soc Med 69:43–44, 1976
Klein E, Zohar J, Geraci MF, et al: Anxiogenic effects of m-CPP in patients with
panic disorder: comparison to caffeine’s anxiogenic effects. Biol Psychiatry
30:973–984, 1991
132 PSYCHONEUROENDOCRINOLOGY
Lynch S, Merson S, Beshyah SA, et al: Psychiatric morbidity in adults with hy-
popituitarism. J R Soc Med 87:445–447, 1994
Martin JB, Reichlin S, Brown GM: Clinical Neuroendocrinology. Philadelphia,
PA, FA Davis, 1977
Mathew SJ, Coplan JD, Perko KA, et al: Neuroendocrine predictors of response
to intravenous clomipramine therapy for refractory obsessive-compulsive
disorder. Depress Anxiety 14:199–208, 2001
McCrimmon RJ, Ewing FM, Frier BM, et al: Anger state during acute insulin-
induced hypoglycaemia. Physiol Behav 67:35–39, 1999
McKhann G, Drachman D, Folstine F, et al: Clinical diagnosis of Alzheimer’s
disease: report of the NINCDS-ADRDA work group under the auspices of
Department of Health and Human Services Task Force on Alzheimer’s Dis-
ease. Neurology 34:485–490, 1984
Meltzer HY, Maes M: Effects of buspirone on plasma prolactin and cortisol levels
in major depressed and normal subjects. Biol Psychiatry 35:316–323, 1994
Mendelson WB, Sitaram N, Wyatt RU, et al: Methylscopolamine inhibition of
sleep-related GH secretion. J Clin Invest 61:1683–1690, 1978
Mendleweicz J, Linkowski P, Kerhofs M, et al: Diurnal hypersecretion of growth
hormone in depression. J Clin Endocrinol Metab 60:505–511, 1985
Michelson D, Amsterdam JD, Quitkin FM, et al: Changes in weight during a 1-
year trial of fluoxetine. Am J Psychiatry 156:1170–1176, 1999
Mitchell PB, Bearn JA, Corn TH, et al: The growth hormone response to cloni-
dine after recovery in patients with endogenous depression. Br J Psychiatry
152:34–38, 1988
Mitchell P, Smythe G, Parker G, et al: Hormonal responses to fenfluramine in de-
pressive subtypes. Br J Psychiatry 157:551–557, 1990
Moeller FG, Steinberg JL, Fulton M, et al: A preliminary neuroendocrine study
with buspirone in major depression. Neuropsychopharmacology 10:75–83,
1994
Mueller PS, Heninger GR, McDonald RK: Intravenous glucose tolerance test in
depression. Arch Gen Psychiatry 21:470–477, 1968
Nesse RM, Cameron OG, Curtis GC, et al: Adrenergic function in patients with
panic anxiety. Arch Gen Psychiatry 41:771–776, 1984
Nicholas LM, Tancer ME, Silva SG, et al: Short stature, growth hormone defi-
ciency, and social anxiety. Psychosom Med 59:372–375, 1997
Okamoto T, Gerstein HC, Obara T: Psychiatric symptoms, bone density and non-
specific symptoms in patients with mild hypercalcemia due to primary hy-
perparathyroidism: a systematic overview of the literature. Endocr J 44:367–
374, 1997
Okamura F, Tashiro A, Utsumi A, et al: Insulin resistance in patients with depres-
sion and its changes in the clinical course of depression: a report on three
cases using the minimal model analysis. Intern Med 38:257–260, 1999
O’Keane V, McLoughlin D, Dinan TG: D-Fenfluramine–induced prolactin and
cortisol release in major depression: response to treatment. J Affect Disord
26:143–150, 1992
134 PSYCHONEUROENDOCRINOLOGY
The Hypothalamic-Pituitary-Adrenal
Axis and Psychiatric Illness
Measurement
Dexamethasone Suppression Test
The cortisol response after a challenge with an exogenous glucocorticoid,
dexamethasone, distinguishes many psychiatrically ill (particularly de-
139
140 PSYCHONEUROENDOCRINOLOGY
Sampling Times
For convenience, often only an afternoon sample is obtained from outpa-
tients, but this does result in a loss of test sensitivity (APA Task Force on
Laboratory Tests in Psychiatry 1987; Rush et al. 1996). The combination
of 4:00 and 11:00 P.M. samples provides greater sensitivity than the combi-
nation of 8:00 A.M. and 4:00 P.M. samples (Rush et al. 1996). The greatest
sensitivity is obtained if all three samples are collected (Rush et al. 1996).
Definition of Nonsuppression
The criterion level to define normal plasma concentration of cortisol
under the test conditions described earlier was defined in Carroll’s 1981
paper (Carroll et al. 1981b) as 5.0 mg/dL, using a modified Murphy com-
petitive protein binding technique (Murphy 1968) (see Chapter 17 in
this volume). Rubin and colleagues (1987) suggested a cutoff of 3.5 mg/
dL when using the more specific radioimmunoassay techniques. Others
have suggested a cutoff of 4.0 mg/dL, citing data showing that the speci-
ficity of the DST is 96% at this threshold (Rush et al. 1996). The APA
Task Force on Laboratory Tests in Psychiatry (1987) argued that using a
cutoff of 7 mg/dL would enhance the utility of the DST in the clinical set-
ting. In 1982, our group (Rothschild et al. 1982) suggested a threshold of
15 mg/dL might be more specific and predictive for psychotic depression
(see below), an observation that has been noted in several other studies
(Meyers et al. 1993; J.C. Nelson and Davis 1997). It also remains unclear
whether the cortisol abnormality (as determined by the DST) is perhaps
better viewed as a spectrum of cortisol levels rather than a binary, all-or-
none, nonsuppression versus suppression classification.
Salivary Cortisol
The measurement of salivary cortisol has been shown to provide an ac-
curate and valid measure of biologically active free cortisol (Kirschbaum
142 PSYCHONEUROENDOCRINOLOGY
and Hellhammer 1994). The ease of sampling is one of the most obvious
advantages of the saliva cortisol test. Although whole saliva sampled in
wide disposable containers provides adequate material for analysis, some
investigators have used swabs that the subjects chew on to stimulate sa-
liva flow to a rate that provides sufficient material within 30–60 seconds
(Kirschbaum and Hellhammer 1994). Salivary cortisol measurements are
closely correlated with cortisol levels in serum and plasma before and af-
ter administration of exogenous cortisol or dexamethasone (Kirschbaum
and Hellhammer 1994).
Salivary cortisol levels normally range from 1 to 25 nmol/L. Different
cutoff values on the DST for salivary cortisol levels have been used, often
leading to conflicting results. Mean salivary cortisol levels at a specific
time of day (due to diurnal variation) are usually used when reporting re-
sults.
Age
Several studies have reported increased rates of nonsuppression on the
DST with age (Baumgartner et al. 1986; Davis et al. 1984; Halbreich et
al. 1984; D.A. Lewis et al. 1984; W.H. Nelson et al. 1984; Stokes et al.
1984; Weiner 1989; Whiteford et al. 1987), whereas others have not ob-
served a relationship (Aguilar et al. 1984; Carroll et al. 1981b; Ferrier et
al. 1988; Greden et al. 1986; Schweitzer et al. 1991; Tourigny-Rivard et
al. 1981). Rush and colleagues (1996) suggested that the apparent in-
crease in DST nonsuppression in depressed patients older than age 69 (or
younger than age 20) may be due to a higher proportion of endogenous
patients in this age range. However, in healthy older subjects an associa-
tion between advancing age and higher cortisol levels on the DST has
been observed (O’Brien et al. 1994).
Age may play a key role in the effects of cortisol hypersecretion on
cognitive functioning. Rubinow and colleagues (1984) observed a signif-
icant relationship between performance on the Halstead Category Test
and mean UFC excretion in depressed patients but not in control sub-
jects. Although an even more robust correlation was observed between
144 PSYCHONEUROENDOCRINOLOGY
age and test errors in the depressed patients, it appeared that age and
depression interacted to produce severe cognitive impairment. Other
studies (e.g., Lupien et al. 1997) have reported significant relationships
between stress-induced declarative memory impairment and cortisol in
healthy elderly subjects.
Mood Disorders
Psychotic Depression
It is in patients with psychotic depression (PD) that one of the most rep-
licable findings in the HPA axis literature exists: high rate of DST non-
suppression, markedly elevated postdexamethasone cortisol levels, and
high levels of 24-hour UFC. In 1983, our group (Schatzberg et al. 1983)
reported that patients with major depression and very high plasma corti-
sol levels (15 mg/dL or more at 4:00 P.M.) had a propensity for exhibiting
mood-congruent psychotic features at the time of study. For example, of
the 9 patients with major depression who had plasma cortisol levels of 15
mg/dL or more, 7 showed psychotic features, and all 6 with plasma cor-
tisol levels of 17 mg/dL or more at 4:00 P.M. were psychotic. In contrast,
of the remaining 36 patients with major depression whose plasma corti-
sol levels were less than 15 mg/dL, only 7 showed psychotic features
(c2 =11.4; df=1; P<0.001). (Schatzberg et al. 1983). In this study the fre-
quency of nonsuppression (10 of 14, or 71.4%) was higher in the PD
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 145
Dysthymic Disorder
Several studies have investigated the rate of nonsuppression on the DST
in dysthymic disorder. Generally, the rate of DST nonsuppression is less
than in major depression and is similar to what is observed in control sub-
jects without dysthymic disorder. For example, in a meta-analysis of 10
studies that used DSM-III criteria comparing DST results in dysthymic
disorder, major depression, and other psychiatric disorders in adults
(Howland and Thase 1991), the rate of nonsuppression on the DST in
subjects with dysthymic disorder (14%) was found to be lower than in
subjects with major depression (59%) and not significantly different from
the rate in psychiatrically healthy control subjects (6%). In a more recent
study (Ravindran et al. 1994), primary dysthymic patients had a rate of
nonsuppression on the DST of 7%. In contrast, another study (Rihmer
and Szadoczky 1993) reported a 50% rate of abnormal response on the
DST in patients with dysthymic disorder, similar to that reported in pa-
tients with major depression. Our group reported a rate of DST non-
suppression in patients with either dysthymic disorder or borderline
personality of 16% compared with a rate of DST nonsuppression of 61%
in the major depression group (Schatzberg et al. 1983). We also found
that the mean (±SD) 4:00 P.M. postdexamethasone cortisol level for pa-
tients with major depression (8.8±6.7 mg/dL) was significantly higher
than that seen in the dysthymic disorder–borderline personality group
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 147
major depression, raising interesting questions for future research. For ex-
ample, would there be an HPA axis abnormality (and of what type?) in
patients who concurrently have major depression and PTSD or major de-
pression with psychotic features and PTSD? In the clinical setting, there
are often patients in whom the specific diagnosis is unclear. For example,
some patients have major depression with psychotic features and also
have a history of abuse or trauma. Should they be considered PTSD patients
who exhibit psychotic symptoms, or should they be treated as patients
with major depression with psychotic features who happen to have a his-
tory of trauma? The low-dose DST (i.e., 0.5 mg instead of 1.0 mg) may
be a potentially useful clinical and research tool for distinguishing what
is primarily a PTSD disorder from major depression with psychotic fea-
tures.
Schizophrenia
Most studies using the DST have focused on the frequency of nonsup-
pression within a specific diagnostic category. Certainly within a specific
diagnosis some patients exhibit hypercortisolemia and some do not, lead-
ing to confusion as to the relevance of the elevated cortisol levels to the
pathophysiology of the illness. And yet, why do some patients have this
measurable abnormality? Using an interesting approach to this question,
Reus (1982) examined whether suppression and nonsuppression on the
DST was associated with specific behavioral symptom clusters indepen-
dent of diagnosis. Nonsuppressors on the DST exhibited an increase in
classic endogenous signs of depression—including increased symptoms of
anxiety, sleep disturbance, attentional difficulty, and anergy—compared
with suppressors on the DST (Reus 1982). In patients with schizophre-
nia (as discussed above), higher cortisol levels were associated with a
greater frequency of negative and depressive symptoms in most studies.
Because it has been known for many years that endogenous hypercorti-
solemia or the administration of exogenous glucocorticoids can be dele-
terious for animals and human beings, one would expect that chronic
hypercortisolemia may play a role in the pathophysiology and outcome
of psychiatric illness. Prolonged elevation of cortisol levels in depressed
patients, as evidenced by failure to convert to normal suppression on the
DST (even after an apparently adequate initial clinical response to treat-
ment), has been reported in many studies to be a warning sign of in-
creased risk for relapse (Ribeiro et al. 1993). In a meta-analysis of studies
of the long-term outcome of depressed patients who were nonsuppres-
sors of cortisol on the DST at posttreatment evaluation, a significantly
poorer outcome was observed in the nonsuppressors compared with the
suppressors (c2 =32.54; df=1; P<0.0001) (Ribeiro et al. 1993). We have
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 151
Antiglucocorticoid Strategies
Several years ago our group hypothesized that the development of de-
lusions in depressed patients is secondary to the effects of hyper-
cortisolemia (Schatzberg et al. 1985) and that acute improvement in
psychotic symptoms in major depression with psychotic features may oc-
cur after cortisol levels are lowered or the effects are blocked with corti-
sol receptor antagonists in the brain (Schatzberg and Rothschild 1988).
The hypothesis that endogenous hypercortisolemia may play a role in
the pathophysiology of psychiatric illness can be tested by the adminis-
tration of antiglucocorticoid medication. Several studies (Amsterdam et
al. 1994; Anand et al. 1995; Arana et al. 1995; Chouinard et al. 1996;
Ghadirian et al. 1995; Iizuka et al. 1996; Murphy 1991; Murphy and
Wolkowitz 1993; O’Dwyer et al. 1995; Raven et al. 1996; Sovner and
Fogelman 1996; Thakore and Dinan 1995; Wolkowitz et al. 1992, 1996a,
1996b) have reported antidepressant effects in some patients when anti-
glucocorticoid medication was administered. Antiglucocorticoid medi-
cations used in these studies include the cortisol synthesis inhibitors
aminoglutethimide, metyrapone, and ketoconazole. The use of antigluco-
corticoid strategies in the treatment of depression have been superbly
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 153
Conclusion
References
Devanand DP, Pandurangi AK, Dewan MJ: False-positive dexamethasone test re-
sults related to antipsychotic drug withdrawal: case report. J Clin Psychiatry
45:275–276, 1984
Devanand DP, Sackeim HA, Lo ES, et al: Serial dexamethasone suppression tests
and plasma dexamethasone levels: effects of clinical response to electrocon-
vulsive therapy in major depression. Arch Gen Psychiatry 48:525–533, 1991
Ettigi P, Brown GM: Psychoneuroendocrinology of affective disorders: an over-
view. Am J Psychiatry 134:493–501, 1977
Evans DL, Nemeroff CB: The dexamethasone suppression test in mixed bipolar
disorder. Am J Psychiatry 140:615–617, 1983
Ferrier IN, Pascual J, Charlton BG, et al: Cortisol, ACTH, and dexamethasone
concentrations in a psychogeriatric population. Biol Psychiatry 23:252–260,
1988
Ghadirian AM, Englesmann F, Dhar V, et al: The psychotropic effects of inhibi-
tors of steroid biosynthesis in depressed patients refractory to treatment. Biol
Psychiatry 37:369–375, 1995
Godwin CD: The dexamethasone suppression test in acute mania. J Affect Dis-
order 7:281–286, 1984
Goldman MB, Blake L, Marks RC, et al: Association of nonsuppression of cortisol
on the DST with primary polydipsia in chronic schizophrenia. Am J Psychi-
atry 150:653–655, 1993
Greden JF, Flegel P, Haskett R, et al: Age effects in serial hypothalamic-pituitary-
adrenal monitoring. Psychoneuroendocrinology 11:195–204, 1986
Gustafsson JA, Eneroth P, Hokfelt T, et al: Central control of hepatic steroid me-
tabolism and “lactogenic” receptor. J Steroid Biochem 12:1–15, 1980
Halbreich U, Asnis GM, Zumoff B, et al: Effect of age and sex on cortisol secre-
tion in depressives and normals. Psychiatry Res 13:221–229, 1984
Halbreich U, Asnis GM, Shindledecker R, et al: Cortisol secretion in endogenous
depression, I: basal plasma levels. Arch Gen Psychiatry 42:904–908, 1985
Herz MI, Fava GA, Molnar G, et al: The dexamethasone suppression test in newly
hospitalized schizophrenic patients. Am J Psychiatry 142:127–129, 1985
Holsboer F, Wiedemann K, Boll E: Shortened dexamethasone half-life in de-
pressed dexamethasone nonsuppressors. Arch Gen Psychiatry 43:813–815,
1986a
Holsboer F, Wiedemann K, Gerken A, et al: The plasma dexamethasone variable
in depression: test-retest studies and early biophase kinetics. Psychiatry Res
17:97–103, 1986b
Holsboer-Trachsler E, Buol C, Wiedemann K, et al: Dexamethasone suppression
test in severe schizophrenic illness: effects of plasma dexamethasone and caf-
feine levels. Acta Psychiatr Scand 75:608–613, 1987
Howland RH, Thase ME: Biological studies of dysthymia. Biol Psychiatry 30:
283–304, 1991
Iizuka H, Kishimotor A, Nakamura J, et al: [Clinical effects of cortisol synthesis
inhibition on treatment-resistant depression.] Nihon Shinkei Seishin Yaku-
rigaku Zasshi 16:33–36, 1996
158 PSYCHONEUROENDOCRINOLOGY
Ismail K, Murray RM, Wheeler MJ, et al: The dexamethasone suppression test in
schizophrenia. Psychol Med 28:311–317, 1998
Johnson GF, Hunt G, Kerr K, et al: Dexamethasone suppression test and plasma
dexamethasone levels in depressed patients. Psychiatry Res 13:305–313,
1984
Jones JS, Stein DJ, Stanley B, et al: Negative and depressive symptoms in suicidal
schizophrenics. Acta Psychiatr Scand 89:81–87, 1994
Kellner CH, Rubinow DR, Gold PW, et al: Relationship of cortisol hypersecre-
tion to brain CT scan alternations in depressed patients. Psychiatry Res 8:
191–197, 1983
Kirschbaum C, Hellhammer DH: Salivary cortisol in psychoneuroendocrine re-
search: recent developments and applications. Psychoneuroendocrinology
19:313–333, 1994
Kraus RF, Graf P, Brown M: Drugs and the DST: need for reappraisal. Am J Psy-
chiatry 145:666–674, 1988
Krishnan RR, Maltbie AA, Davidson JR, et al: Abnormal cortisol suppression in
bipolar patients with simultaneous manic and depressive symptoms. Am
J Psychiatry 140:203–205, 1983
Kumar A, Alcser K, Grunhaus L, et al: Relationships of the dexamethasone sup-
pression test to clinical severity and degree of melancholia. Biol Psychiatry
21:436–444, 1986
Lamberts SW, Bons EG, Vitterlinden PP: Studies on the glucocorticoid receptor
blocking action of RU 486 in cultured ACTH-secreting human pituitary tu-
mor cells and normal rat pituitary cells. Acta Endocrinol Metab 59:25–31,
1984
Lewis CF, Tandon R, Shipley JE, et al: Biological predictors of suicidality in
schizophrenia. Acta Psychiatr Scand 94:416–420, 1996
Lewis DA, Pfohl B, Schlechte J, et al: Influence of age on the cortisol response to
dexamethasone. Psychiatry Res 13:213–220, 1984
Lupien SJ, Gaudreau S, Tchiteya BM, et al: Stress-induced declarative memory
impairment in healthy elderly subjects: relationship to cortisol reactivity.
J Clin Endocrinol Metab 82(7):2070–2075, 1997
Maguire KP, Tuckwell VM, Schweitzer I, et al: Dexamethasone kinetics in de-
pressed patients before and after clinical response. Psychoneuroendocrinol-
ogy 15(2):113–123, 1990
Mason JW, Giller EL, Kosten TR, et al: Urinary-free cortisol in posttraumatic
stress disorder. J Nerv Ment Dis 174:145–149, 1986
McEwen BS: Steroid hormones are multifunctional messengers of the brain.
Trends Endocrinol Metab 2:62–67, 1991
McEwen BS, Davis PG, Parsons B, et al: The brain as target for steroid hormone
action. Annu Rev Neurosci 2:65–112, 1979
McGauley GA, Aldridge CR, Fahy TA, et al: The dexamethasone suppression
test and negative symptoms of schizophrenia. 80:548–553, 1989
Meyers BS, Alpert S, Gabriele M, et al: State specificity of DST abnormalities in
geriatric depression. Biol Psychiatry 34:108–114, 1993
The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 159
Rubinow DR, Post RM, Savard R, et al: Cortisol hypersecretion and cognitive im-
pairment in depression. Arch Gen Psychiatry 41:279–283, 1984
Rush AJ, Giles DE, Schlesser MA, et al: The dexamethasone suppression test in
patients with mood disorders. J Clin Psychiatry 57(10):470–484, 1996
Sachar EJ, Hellman L, Fukushima DK: Cortisol production in depressive illness:
a clinical and biochemical clarification. Arch Gen Psychiatry 23:289–298,
1970
Saffer D, Metcalfe M, Coppen A: Abnormal dexamethasone suppression test in
type II schizophrenia. Br J Psychiatry 147:721–723, 1985
Sapolsky RM: Glucocorticoids endanger hippocampal neurons, in Stress, the Ag-
ing Brain and the Mechanisms of Neuron Death. Edited by Sapolsky RM.
Cambridge, MA, MIT Press, 1992, pp 119–258
Sapolsky RM, Krey LC, McEwen BS: Prolonged glucocorticoid exposure reduces
hippocampal neuron number: implications for aging. J Neurosci 5:1222–
1227, 1985
Sapolsky RM, Uno H, Rebert CS, et al: Hippocampal damage associated with
prolonged glucocorticoid exposure in primates. J Neurosci 10(9):2897–
2902, 1990
Sawyer J, Jeffries JJ: The dexamethasone suppression test in residual schizophre-
nia. J Clin Psychiatry 45:399–402, 1984
Schatzberg AF, Rothschild AJ: The roles of glucocorticoid and dopaminergic systems
in delusional (psychotic) depression. Ann N Y Acad Sci 537:462–471, 1988
Schatzberg AF, Rothschild AJ: Psychotic (delusional) major depression: should it
be included as a distinct syndrome in DSM-IV? Am J Psychiatry 149:733–
745, 1992
Schatzberg AF, Rothschild AJ, Stahl JB, et al: The dexamethasone suppression
test: identification of subtypes of depression. Am J Psychiatry 140:88–91,
1983
Schatzberg AF, Rothschild AJ, Langlais PJ, et al: A corticosteroid/dopamine hy-
pothesis for psychotic depression and related states. J Psychiatr Res 19:57–
64, 1985
Schweitzer I, Tucknell VM, Maguire KP, et al: Plasma cortisol and 11-deoxycor-
tisol activity in depressed patients and normal volunteers. Psychoneuroendo-
crinology 16:375–382, 1991
Sheline YI, Wang PW, Gado MH, et al: Hippocampal atrophy in recurrent major
depression. Proc Natl Acad Sci U S A 93(9):3908–3913, 1996
Shima S, Kitamura T, Takahashi Y, et al: Dexamethasone suppression test and
negative symptoms of schizophrenics. Keio J Med 35:203–207, 1986
Sikes CR, Stokes PE, Lasley BJ: Cognitive sequelae of hypothalamic-pituitary-
adrenal (HPA) dysregulation in depression (abstract). Biol Psychiatry 25(7A):
148A–149A, 1989
Sovner R, Fogelman S: Ketoconazole therapy for atypical depression. J Clin Psy-
chiatry 57:227–228, 1996
Starkman MN: Hippocampal formation volume, memory dysfunction and cortisol
levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765, 1992
162 PSYCHONEUROENDOCRINOLOGY
Psychiatric Manifestations of
Hyperadrenocorticism and
Hypoadrenocorticism
(Cushing’s and Addison’s Diseases)
This chapter was adapted from Starkman MN: “The HPA Axis and Psychopa-
thology: Cushing’s Syndrome.” Psychiatric Annals, 23:691–701, 1993. Used with
permission.
165
166 PSYCHONEUROENDOCRINOLOGY
al. 1981). In fact, the majority of patients with Cushing’s syndrome were
found to meet DSM-III (American Psychiatric Association 1980) criteria
for MDD (except for the exclusion of an organic mental disorder) (Has-
kett 1985; Starkman et al. 1981).
From a theoretical point of view, defining and exploring the clinical
and biochemical similarities between patients with spontaneous Cush-
ing’s syndrome and patients with primary depression provides a unique
opportunity to examine in greater detail the relationship between HPA
axis dysregulation and abnormalities in mood and cognition. For the cli-
nician, however, these similarities may lead to a problem in differential
diagnosis, particularly early in the course of Cushing’s syndrome when the
characteristic physical stigmata are less prominent.
Similarly, the converse condition exists: primary adrenal insufficiency
(Addison’s disease) also produces behavioral symptoms that can lead to
difficulties in distinguishing this condition from primary psychiatric ill-
ness. This chapter examines the behavioral effects of abnormalities in
adrenal steroid secretion and points out parameters that may assist in dif-
ferential diagnosis.
Under normal conditions, the secretion of cortisol from the adrenal gland
is regulated by a system extraordinarily sensitive to changes within the or-
ganism and changes in its environment. Hypothalamic neurosecretory
cells produce corticotropin-releasing hormone (CRH), and neurotrans-
mitter pathways modulate its release. CRH, in turn, acts on the adreno-
corticotropic hormone (ACTH)–producing cells of the anterior pituitary,
and ACTH is secreted into the systemic circulation acting on the adrenal
cortex to elicit the secretion of corticosteroids, including cortisol. (Regu-
lation of the HPA axis is discussed in greater detail in Chapter 3.)
Regulatory mechanisms are present at various levels along the axis.
Cortisol feedback occurs at pituitary, hypothalamic, and suprahypotha-
lamic brain levels. An endogenous timer superimposes a circadian and ul-
tradian pattern on CRH, and thereby on ACTH and cortisol secretion.
The suprachiasmatic nucleus is a major anatomical component of the
timer, regulating the periodicity of other physiological functions such as
body temperature, eating, drinking, and activity. In addition, central ner-
vous system centers regulate CRH release in response to environmental
and endogenous inputs such as emotional and physical stress, infection,
and the metabolic milieu.
Cushing’s and Addison’s Diseases 167
Addison’s Disease
Etiology
Insufficient secretion of corticosteroids may arise in two different ways.
Secondary adrenal insufficiency results when ACTH secretion by the pitu-
itary is inadequate, and the normal adrenal gland responds by decreasing
its secretion accordingly. Primary adrenocortical insufficiency, referred
to as Addison’s disease, results from destruction of the adrenal gland. In
the past, tuberculosis was the most frequent cause of this disorder. Cur-
rently, 80% of new cases are idiopathic, and most are thought to arise
from autoimmune destruction of the adrenal gland. Many such patients
also manifest autoimmune attack on other endocrine glands as well, lead-
ing to multiple endocrine deficiencies such as hypothyroidism, hypopar-
athyroidism, and premature ovarian failure. Additional causes of adrenal
insufficiency include fungal disease (such as histoplasmosis), blood-borne
bacterial infections, disorders such as sarcoidosis, and adrenal hemorrhage
due to anticoagulant treatment. Patients with acquired immunodefi-
ciency syndrome (AIDS) can also develop primary adrenal insufficiency,
possibly as a result of cytomegalic virus infection of the adrenal gland. In
contrast to Cushing’s disease, which occurs primarily in women, men and
women are equally affected with Addison’s disease.
Diagnosis
Once Addison’s disease is suspected, diagnosis is readily established. Lab-
oratory abnormalities include hyponatremia and hyperkalemia, although
these may be normal in the earlier phase of the disease. Hypercalcemia
occurs in 10%–20% of patients. Patients with adrenal insufficiency sec-
ondary to primary hypothalamic or pituitary abnormalities do not exhibit
hyperkalemia.
The diagnosis is supported by a low 8:00 A.M. serum cortisol concen-
tration and by decreased 24-hour excretion of urinary free cortisol or
17-hydroxysteroids. The diagnosis is further strengthened by using exog-
enous synthetic ACTH to stimulate the adrenal glands. A normal re-
sponse to a rapid stimulation by ACTH excludes the diagnosis of primary
or secondary adrenal insufficiency. An abnormal response must be con-
firmed by a more extended ACTH infusion. Radioimmunoassays for
ACTH are now commercially available. These assays can document the
elevated serum ACTH levels that exist in primary adrenal insufficiency.
(A detailed description of tests of HPA axis function is provided in Chap-
ter 17 of this volume.)
Treatment
Correction of the electrolyte imbalance alone does not alter psychiatric
symptoms appreciably. Treatment requires replacement of both gluco-
corticoids and mineralocorticoids. Recently, it has been shown that re-
placement of dehydroepiandrosterone (which is also low in patients with
untreated Addison’s disease) confers added benefit, improving well-
being, mood, energy, and libido in women (Arlt et al. 1999). Because pa-
tients remain extremely sensitive to declines in blood levels of steroids,
multidose administration of steroids throughout the day is preferable to
170 PSYCHONEUROENDOCRINOLOGY
enous steroids in that they are exposed to sustained elevated cortisol lev-
els for months to years and are less subject to sudden acute shifts and
rapid rates of change of steroid levels that occur during short-term treat-
ment with high-dose corticosteroids. (Neuropsychiatric effects of pred-
nisone and other exogenous glucocorticoids are further discussed in
Chapter 8.)
What patients with Cushing’s syndrome do manifest is a consistent
constellation of symptoms that includes impairments in affect (irritabil-
ity and depressed mood), vegetative functions (decreased libido and mid-
dle insomnia), and cognitive functions (decreased concentration and
memory) (Starkman et al. 1981). Some authors view the symptom pro-
file as being characteristic of endogenous depression (Haskett 1985),
whereas others consider that the profile represents atypical depression
(Dorn et al. 1995).
Biological Drives
Abnormalities in four areas of basic biological vegetative drives are
present:
Cognition
Cognitive symptoms are a prominent part of the clinical picture. Inatten-
tion, distractibility, difficulty with concentration, and shortened atten-
tion span are reported by most patients (Starkman et al. 1981). Difficulty
with reasoning ability, comprehension, and processing of new informa-
tion is often reported. Some patients report episodes of rapid scattered
thinking, whereas others complain of slow and ponderous thinking.
Thought blocking may occur in more severe instances. Patients complain
of using incorrect words while speaking and of misspelling simple words.
Impairment of memory is one of the most frequent symptoms, re-
ported by 80% of patients (Starkman et al. 1981). Patients report prob-
Cushing’s and Addison’s Diseases 177
physiological systems and make the central nervous system more vulner-
able to the effects of increases in ACTH and other neuroactive substances
(Starkman 1987). Currently, evidence indicates that relevant neuroactive
substances include excitatory amino acids such as glutamic acid (Sapol-
sky 1990).
longer sleep latency, less total sleep time, and lower sleep efficiency than
did the healthy subjects. In both Cushing’s disease patients and MDD pa-
tients, rapid eye movement (REM) latency was significantly shortened,
and REM density in the first REM period was significantly increased
compared with control subjects (Shipley et al. 1992a, 1992b).
One procedure that holds some promise as a possible tool for helping
to distinguish between patients with Cushing’s disease and those with
MDD is the administration of CRH to stimulate ACTH secretion (Gold
et al. 1986). (See also Chapter 17 in this volume.) At present, however,
there is still a substantial overlap in the ACTH secretory responses be-
tween the two groups, impairing the clinical utility of the test. Further
refinements will be required. One modification includes taking both the
pre-CRH plasma cortisol level and the peak ACTH response to CRH into
account (Gold et al. 1987). Further improvement in diagnostic accuracy
is achieved when CRH is administered 2 hours after completion of the
classic endocrine 2-day low-dose dexamethasone suppression test (Yan-
ovski et al. 1993). As research continues to provide greater understand-
ing of HPA axis pathophysiology and its associations with the depressive
syndromes, the development of better tools to provide the discriminatory
power necessary can be anticipated.
Some patients with MDD continue to have an abnormal overnight
1-mg dexamethasone suppression test after treatment. Although this
may reflect an increased risk of poor outcome or relapse, if any clinical
manifestations consistent with Cushing’s disease develop, such patients
should receive endocrine evaluation, including the standard 2-mg and
8-mg dexamethasone suppression tests (Schlechte et al. 1986).
References
Jacquet YF: Dual action of morphine on the central nervous system: parallel ac-
tions of beta-endorphin and ACTH. Ann N Y Acad Sci 398:272–290, 1983
Jeffcoate WJ, Silverstone JT, Edwards CR, et al: Psychiatric manifestations of
Cushing’s syndrome: response to lowering of plasma cortisol. Q J Med
48:465–472, 1979
Kadekaro M, Ito M, Gross PM: Local cerebral glucose utilization is increased in
acutely adrenalectomized rats. Neuroendocrinology 47:329–334, 1988
Kelly WF: Psychiatric aspects of Cushing’s syndrome. Q J Med 89(7):543–551, 1996
Kelly WF, Checkley SA, Bender DA: Cushing’s syndrome, tryptophan and de-
pression. Br J Psychiatry 136:125–132, 1980
Kelly WF, Checkley SA, Bender DA, et al: Cushing’s syndrome and depression—
a prospective study of 26 patients. Br J Psychiatry 142:16–19, 1983
Kelly WF, Kelly MJ, Faragher B: A prospective study of psychiatric and psycho-
logical aspects of Cushing’s syndrome. Clin Endocrinol (Oxf) 45(6):715–
720, 1996
Kling MA, Roy A, Doran AR, et al: Cerebrospinal fluid immunoreactive corti-
cotropin-releasing hormone and adrenocorticotropin secretion in Cushing’s
disease and major depression: potential clinical implications. J Clin Endo-
crinol Metab 72(2):260–271, 1991
Krieger DT: The central nervous system and Cushing’s syndrome. Mt Sinai J Med
39:416–428, 1972
Krieger DT: Cyproheptadine-induced remission of Cushing’s disease. N Engl
J Med 293:893–896, 1975
Krieger DT: Rhythms in CRF, ACTH and corticosteroids, in Endocrine Rhythms.
Edited by Krieger DT. New York, Raven, 1979
Krystal A, Krishnan KR, Raitiere M, et al: Differential diagnosis and pathophysi-
ology of Cushing’s syndrome and primary affective disorder. J Neuropsychi-
atry Clin Neurosci 2:34–43, 1990
Loosen PT, Chambliss B, DeBold CR, et al: Psychiatric phenomenology in Cush-
ing’s disease. Pharmacopsychiatry 25:192–198, 1992
Majewska M: Actions of steroids on neuron: role in personality, mood, stress and
disease. Integrative Psychiatry 5:258–273, 1987
McEwen BS: Possible mechanisms for atrophy of the human hippocampus. Mol
Psychiatry 2:255–262, 1997
Mobley PL, Sulser F: Adrenal corticoids regulate sensitivity of noradrenaline re-
ceptor-coupled adenylate cyclase in brain. Nature 286:608–609, 1980
Ostroff R, Giller E, Bonese K, et al: Neuroendocrine risk factors of suicidal be-
havior. Am J Psychiatry 139:1323–1325, 1982
Pfohl B, Rederer M, Coryell W, et al: Association between post-dexamethasone
cortisol level and blood pressure in depressed inpatients. J Nerv Ment Dis
179:44–47, 1991
Reus VI: Pituitary-adrenal disinhibition as the independent variable in the assess-
ment of behavioral symptoms. Biol Psychiatry 17:317–326, 1982
Reus VI, Miner C: Evidence for physiologic effects of hyper-cortisolemia in psy-
chiatric patients. Psychiatry Res 14:47–55, 1985
Cushing’s and Addison’s Diseases 187
189
190 PSYCHONEUROENDOCRINOLOGY
ory, which are mediated by the frontal cortex, may also be affected by
steroid treatment (Lupien et al. 1999). In rare cases, steroid-induced cog-
nitive impairment can be so severe as to mimic a stupor or dementia-like
syndrome (Doherty et al. 1991) and can be a source of considerable mor-
bidity (Reckart and Eisendrath 1990; Wolkowitz and Rapaport 1989;
Wolkowitz et al. 1997, 2001). In six patients studied by Varney et al.
(1984), the steroid-induced dementia was characterized by deficits in
memory retention, attention, concentration, mental speed and efficiency,
IQ, and occupational performance.
Apart from the acute behavioral reactions seen during steroid treatment,
a “steroid withdrawal syndrome,” during steroid withdrawal or after dis-
continuation of steroid treatment, has been described in approximately
21% of patients (Freyberg et al. 1951). This syndrome may occur even
in the absence of biochemical evidence of deficient adrenal secretion
(Miller and Tyrell 1995). Symptoms of this syndrome may include low-
ered sense of well-being, discouragement, depression, irritability, leth-
argy, malaise, anorexia and weight loss, nausea, arthralgias and myalgias,
skin desquamation, headache, fever, depersonalization, confusion, poor
concentration, and impaired memory (Freyberg et al. 1951; Glaser 1953;
Hassanyeh et al. 1991; Judd et al. 1983; Miller and Tyrell 1995; Wolko-
witz and Rapaport 1989; Wolkowitz et al. 1997, 2001). Vomiting, pos-
tural hypotension, psychosis, obsessiveness, and suicidality also occur,
but less commonly.
In medically ill patients, it is important to differentiate such symp-
toms from a recurrence of the condition for which the steroids were
being prescribed and from symptoms of frank adrenal insufficiency. Al-
though prolonged adrenal insufficiency lasting more than a few days is
rare after short-term steroid treatment, long-term or high-dose steroid
treatment may impair adrenal function for months to a year or longer.
Persistent adrenal suppression is often discernible with the ACTH stim-
ulation test. An excellent clinical and laboratory approach to the diagno-
sis and treatment of adrenal insufficiency is presented by Miller and
Tyrell (1995).
The causes of the steroid withdrawal syndrome are unknown (Wolko-
witz and Rapaport 1989). Steroid withdrawal–related symptoms typi-
cally resolve by 6–8 weeks (Freyberg et al. 1951; Wolkowitz and Rapa-
port 1989), but they may persist for considerably longer periods in some
Psychiatric Effects of Glucocorticoid Hormone Medications 195
Conclusion
References
Arana GW, Santos AB, Laraia MT, et al: Dexamethasone for the treatment of de-
pression: a randomized, placebo-controlled, double-blind trial. Am J Psychi-
atry 152:265–267, 1995
Beale MD, Arana GW: Dexamethasone for treatment of major depression in pa-
tients with bipolar disorder (letter). Am J Psychiatry 152:959–960, 1995
Beck SG, Choi KC, List TJ, et al: Corticosterone alters 5-HT1A receptor-
mediated hyperpolarization in area CA1 hippocampal pyramidal neurons.
Neuropsychopharmacology 14:27–33, 1996
Beckwith BE, Petros TV, Scaglione C, et al: Dose-dependent effects of hydrocor-
tisone on memory in human males. Physiol Behav 36:283–286, 1986
Bender BG, Lerner JA, Poland JE: Association between corticosteroids and psy-
chologic change in hospitalized asthmatic children. Ann Allergy 66:414–
417, 1991
Beshay H, Pumariega AJ: Sertraline treatment of mood disorder associated with
prednisone: a case report. J Child Adolesc Psychopharmacol 8:187–193, 1998
Bick PA: Obsessive-compulsive behavior associated with dexamethasone treat-
ment. J Nerv Ment Dis 171:253–254, 1983
Biegon A: Effects of steroid hormones on the serotonergic system. Ann N Y Acad
Sci 600:427–432, 1990
Bloch M, Gur E, Shalev AS: Chlorpromazine prophylaxis of steroid-induced psy-
chosis. Gen Hosp Psychiatry 16:42–44, 1994
Bobele GB, Bodensteiner JB: The treatment of infantile spasms by child neurol-
ogists. J Child Neurol 9:432–435, 1994
Boston Collaborative Drug Surveillance Program: Acute adverse reactions to
prednisone in relation to dosage. Clin Pharmacol Ther 13:694–698, 1972
Braunig P, Bleistein J, Rao ML: Suicidality and corticosteroid-induced psychosis.
Biol Psychiatry 26:209–210, 1989
Cade R, Spooner G, Schlein E, et al: Comparison of azathioprine, prednisone and
heparin alone or combined in treating lupus nephritis. Nephron 10:37–56,
1973
Cameron OG, Addy RO, Malitz D: Effects of ACTH and prednisone on mood:
incidence and time of onset. Int J Psychiatry Med 15:1985–1986, 1985
Carroll BJ: Psychiatric disorders and steroids, in Neuroregulators and Psychiatric
Disorders. Edited by Usdin E, Hamburg DA, Barchas JD. New York, Oxford
University Press, 1977, pp 276–283
Chauloff F: Physiopharmacological interactions between stress hormones and
central serotonergic systems. Brain Res Brain Res Rev 18:1–32, 1993
Clark LD, Bauer W, Cobb S: Preliminary observations on mental disturbances oc-
curring in patients under therapy with cortisone and ACTH. N Engl J Med
246:205–216, 1952
Coirini H, Flores D, Vega MC, et al: Binding of the anti-inflammatory steroid de-
flazacort to glucocorticoid receptors in brain and peripheral tissues. In vivo
and in vitro studies. J Steroid Biochem Mol Biol 49:42–49, 1994
Dawson KL, Carter ER: A steroid-induced acute psychosis in a child with
asthma. Pediatr Pulmonol 26:362–364, 1998
200 PSYCHONEUROENDOCRINOLOGY
Goodwin GM, Muir WJ, Seckl JR, et al: The effects of cortisol infusion upon hor-
mone secretion from the anterior pituitary and subjective mood in depres-
sive illness and in controls. J Affect Disord 26:73–83, 1992
Goolker P, Schein J: Psychic effects of ACTH and cortisone. Psychosom Med
6:590–613, 1953
Greenberg DB, Younger Y, Kaufman SD: Management of lithium in patients with
cancer. Psychosomatics 34:388–394, 1993
Greeves JA: Rapid-onset steroid psychosis with very low dosage of prednisolone.
Lancet 1:1119–1120, 1984
Hall RCW, Popkin MK, Kirkpatrick B: Tricyclic exacerbation of steroid psychosis.
J Nerv Ment Dis 166:738–742, 1978
Hall RCW, Popkin MK, Stickney SK, et al: Presentation of the steroid psychoses.
J Nerv Ment Dis 167:229–236, 1979
Halmi KA, Noyes R, Millard SA: Effect of lithium on plasma cortisol and adrenal
response to adrenocorticotropin in man. Clin Pharmacol Ther 13:699–703,
1972
Hassanyeh F, Murray RB, Rodgers H: Adrenocortical suppression presenting with
agitated depression, morbid jealousy, and a dementia-like state. Br J Psychi-
atry 159:870–872, 1991
Joels M, de Kloet ER: Control of neuronal excitability by corticosteroid hor-
mones. Trends Neurosci 15:25–30, 1992
Joseph MS, Brewerton TD, Reus VI, et al: Plasma L-tryptophan/neutral amino
acid ratio and dexamethasone suppression in depression. Psychiatry Res 11:
185–192, 1984
Judd FK, Burrows GD, Norman TR: Psychosis after withdrawal of steroid ther-
apy. Med J Aust 2:350–351, 1983
Kawata M: Roles of steroid hormones and their receptors in structural organiza-
tion in the nervous system. Neurosci Res 24:1–46, 1995
Keenan PA, Jacobson MW, Soleymani RM, et al: The effect on memory of chronic
prednisone treatment in patients with systemic disease. Neurology 47:1396–
1402, 1996
Kershner P, Wang-Cheng R: Psychiatric side effects of steroid therapy. Psycho-
somatics 30:135–138, 1989
Kimball CP: Psychological dependency on steroids? Ann Intern Med 75:111–
113, 1971
Kohen M, Asherson RA, Gharavi AE, et al: Lupus psychosis: differentiation from
the steroid-induced state. Clin Exp Rheumatol 11:323–326, 1993
Koo E, Katalin F, Gyorgy EF: Experiences with dehydroepiandrosterone therapy
in steroid-dependent intrinsic bronchial asthma. Orv Hetil 38:1995–1997,
1987
Landfield PW: The role of glucocorticoids in brain aging and Alzheimer’s disease:
an integrative physiological hypothesis. Exp Gerontol 29:3–11, 1994
Lesch KP, Lerer B: The 5-HT receptor–G protein–effector system complex in de-
pression, I: effect of glucocorticoids. J Neural Transm Gen Sect 84:3–18,
1991
202 PSYCHONEUROENDOCRINOLOGY
Dehydroepiandrosterone in
Psychoneuroendocrinology
205
206
PSYCHONEUROENDOCRINOLOGY
FIGURE 9–1. Biosynthetic pathway of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S).
Dehydroepiandrosterone in Psychoneuroendocrinology 207
the first adequately controlled clinical trial (Morales et al. 1994), fostered
the hope that DHEA might increase well-being in humans and the hope
(or the wish) that it could extend life, protect the brain, and retard the
ravages of aging.
Coincident with this burst of scientific activity, consumer interest in
DHEA was enlivened by the passage, in the United States, of the Dietary
Supplement Health and Education Act of 1994 (P.L. 103-417), which al-
lowed the marketing and sale of DHEA as a “food supplement” (not sub-
ject to the usual U.S. Food and Drug Administration regulations) rather
than as a hormonal medication. Shortly thereafter, popular mass-market
books began promoting DHEA with titles such as The DHEA Break-
through: Look Younger, Live Longer, Feel Better (Cherniske 1998) and
DHEA: The Miracle Hormone That Can Help You Boost Immunity, Increase
Energy, Lighten Your Mood, Improve Your Sex Drive, and Lengthen Your
Lifespan (Callahan 1997). Such claims, as well as the widespread unreg-
ulated use of DHEA, have concerned many medical investigators and
practitioners, because preclinical data may not readily extrapolate to
clinical situations, and because the full risk-benefit ratio of long-term
DHEA usage remains unknown (Katz and Morales 1998; van Vollen-
hoven 1997).
The purpose of this chapter is to put into scientific context the possi-
ble role of DHEA as a psychotropic agent and to review clinical data re-
garding its use in neuropsychiatric illnesses. The main focus is on clinical
efficacy, feasibility, and safety in neuropsychiatric conditions. More exten-
sive discussions of pertinent preclinical studies are available elsewhere
(Baulieu 1997; Baulieu and Robel 1996, 1998; Majewska 1992, 1995; Re-
gelson and Kalimi 1994; Regelson et al. 1990; Roberts 1990; Roberts et al.
1987; Svec 1997; Svec and Porter 1998; Wolkowitz and Reus 2000;
Wolkowitz et al. 2000, 2001), as are reviews of the possible uses of DHEA
in nonpsychiatric conditions (Arlt et al. 1999; Katz and Morales 1998; van
Vollenhoven 1997) and in healthy aging individuals (Barnhart et al. 1999;
Flynn et al. 1999; Hinson and Raven 1999; Kroboth et al. 1999).
DHEA as a Neurosteroid
DHEA and its metabolite DHEA sulfate (DHEA-S) are the most plenti-
ful adrenal corticosteroids in humans, yet their physiological roles remain
uncertain. Important actions in the central nervous system, however, have
been inferred from the fact that DHEA and DHEA-S are synthesized in
situ in the brain; indeed, it has been termed a neurosteroid for this reason
208 PSYCHONEUROENDOCRINOLOGY
(Baulieu 1997; Zwain and Yen 1999). Highlighting the potential impor-
tance of DHEA and DHEA-S for brain functioning, accumulation of
DHEA and DHEA-S in rat brain is largely independent of adrenal and
gonadal synthesis, remaining constant after gonadectomy, adrenal-
ectomy, and dexamethasone administration and increasing in response to
acute stress independently of changes in plasma levels (Corpechot et al.
1981a; Robel and Baulieu 1995).
By necessity, much of the data about the effects of DHEA and DHEA-S
derive from animal or tissue culture–based studies. Species typically
studied, such as rats and mice, have significant concentrations of brain
DHEA and DHEA-S, but minimal peripheral (adrenally derived) levels,
challenging the relevance of such preclinical data to effects in humans.
Nonetheless, such studies have provided valuable leads for designing
clinical trials and have suggested possible mechanisms of the behavioral
effects of DHEA and DHEA-S.
DHEA and DHEA-S generally have memory-enhancing effects in an-
imals. They can restore learning performance in old male mice and rats
to the levels seen in young animals (Flood and Roberts 1988; Tejkalova
et al. 1998) and can reverse pharmacologically induced amnesia in mice
(Flood et al. 1988; Melchior and Ritzmann 1996; Roberts 1990). DHEA-
S can reverse amnesia induced by scopolamine, an anticholinergic drug,
and by anisomysin, a protein synthesis inhibitor (Flood et al. 1988; Rob-
erts 1990).
DHEA-S also has antidepressant-like effects in mice tested in the Por-
solt forced swim test, significantly decreasing immobility time (Reddy et
al. 1998). The nonsulfated parent compound, DHEA, also has antide-
pressant effects in this test, but interestingly, only in high-anxiety rats
(Prasad et al. 1997). Anti-anxiety effects of DHEA and DHEA-S have
also been demonstrated in mice using the elevated plus maze test (Mel-
chior and Ritzmann 1994). However, whereas DHEA augments the anx-
iolytic effect of ethanol in this model, DHEA-S blocks it (Melchior and
Ritzmann 1994). Consistent with possibly different effects of DHEA
versus DHEA-S in animal models of anxiety, DHEA-S has been found to
be anxiogenic in the mirrored chamber test, another test of anxiety in
mice (Reddy and Kulkarni 1997). Administration of DHEA, but not
DHEA-S, also decreases mouse aggressive behavior in certain paradigms
(e.g., the attack by group-housed triads of castrated male mice on lactat-
ing female mouse intruders) (Robel and Baulieu 1995). The specificity of
DHEA versus DHEA-S in these models of depression, anxiety, and
aggression may be related to differential effects of the two hormones at
brain g-aminobutyric acid A (GABA-A) receptors (with DHEA-S having
a stronger antagonist or inverse agonist effect) (Corpechot et al. 1981b;
Demirgoren et al. 1991; Robel and Baulieu 1995), although, physiologi-
cally, DHEA and DHEA-S are readily interconvertible in the circulation.
DHEA-S also affects eating behavior, producing hypophagia in food-
deprived male mice (Reddy and Kulkarni 1998). This effect may, at least
210 PSYCHONEUROENDOCRINOLOGY
Several studies have suggested that DHEA and DHEA-S have neuro-
trophic potential. For example, DHEA and DHEA-S enhance neuronal
and glial survival and differentiation in dissociated cultures of mouse em-
bryo brain (Bologa et al. 1987; Roberts et al. 1987) and induce the for-
mation of hypertrophic cells in hippocampal slice cultures derived from
orchiectomized adult male rats (Del Cerro et al. 1995). These hyper-
trophic cells appear similar to the reactive astroglia that may be involved
in restorative events following brain injury (Del Cerro et al. 1995).
DHEA and DHEA-S also modulate the astrogliosis that usually accom-
panies myelin breakdown, lessening the formation of astroglial scar
(Muntwyler and Bologa 1989). DHEA and DHEA-S have also been
shown to prevent or reduce hippocampal neurotoxicity induced by the
glutamate agonist NMDA (Kimonides et al. 1998), by corticosterone
(Kimonides et al. 1999), by the oxidative stressors hydrogen peroxide
and sodium nitroprusside (Bastianetto et al. 1999), and by transient but
severe forebrain ischemia (Li et al. 2001). In a provocative recent study
using explants of adult human cortical brain tissue (obtained from neu-
rosurgical samples), DHEA-S, in synergy with recombinant fibroblast
growth factor, significantly improved neuronal survival (Brewer et al.
2001). It is possible that decreased levels of DHEA and DHEA-S con-
tribute to the increased vulnerability of the aging or stressed human brain
to neurotoxic damage, because 1) glutamate release has been implicated
in neural damage resulting from cerebral ischemia and other neuronal in-
sults; 2) excessive corticosterone exposure has been linked to hippocam-
pal atrophy; and 3) oxidative stress has been implicated in degenerative
changes in the hippocampus (Bastianetto et al. 1999; Hechter et al.
1997; Herbert 1997, 1998; Kimonides et al. 1998, 1999; Leblhuber et al.
1992; Wolkowitz et al. 1992). Such effects may be related to the obser-
vations that in normal aging and in Alzheimer’s disease, hippocampal
perfusion (Murialdo et al. 2000b) and volume (Magri et al. 2000) are
positively related to serum levels of DHEA and DHEA-S and to the
ratios of DHEA and DHEA-S to cortisol.
Dehydroepiandrosterone in Psychoneuroendocrinology 211
470 ng/dL, proposed by Erb and colleagues (1981), Brophy and col-
leagues determined the mean serum DHEA level in their sample of
schizophrenic patients to be 405 ng/dL compared with 506 ng/dL in
their sample of control subjects. In a recently completed study, D. S.
Harris and colleagues (in press) noted that morning serum DHEA levels
and ratios of DHEA to cortisol were directly correlated with aspects of
memory performance and were inversely correlated with ratings of
psychosis and parkinsonian movements in medicated, institutionalized
patients with chronic schizophrenia. These findings cumulatively raise
the possibility that low DHEA levels (or low ratios of DHEA to cortisol)
identify a particularly impaired subgroup of chronic schizophrenic pa-
tients.
Three recent studies have also demonstrated low basal or stimulated
DHEA and DHEA-S levels in patients with chronic fatigue syndrome
(CFS) (De Becker et al. 1999; Kuratsune et al. 1998; Salahuddin et al.
1997). De Becker et al. (1999) found no basal difference in DHEA levels
in CFS patients but found a blunted DHEA response to intravenous in-
jection of adrenocorticotropic hormone (ACTH). Scott et al. (2000)
found no difference in DHEA response to a low-dose ACTH stimulation
test but found evidence for a divergence in DHEA versus cortisol re-
sponses in comparison with a control group. Kuratsune and colleagues
(1998) speculated that decreases in DHEA and DHEA-S levels are di-
rectly responsible for the neuropsychiatric aspects of this condition. Such
a hypothesis would be consistent with reports that exogenous DHEA ad-
ministration alleviates fatigue in healthy subjects (Morales et al. 1994) as
well as in medically ill patients (Calabrese et al. 1990). To our knowl-
edge, DHEA has not been formally tested as a treatment for CFS, al-
though infusions of DHEA along with high doses of vitamin C have been
reported to alleviate CFS in a series of uncontrolled studies in Japan
(Kodama et al. 1996a, 1996b).
Many studies have also assessed the relationship of DHEA and
DHEA-S levels to overall well-being and cognitive and general function-
ing. In many population-based studies, cognitive and general functional
abilities have been shown to be positively correlated with DHEA and
DHEA-S levels in elderly persons (Abbasi et al. 1998; Berkman et al.
1993; Berr et al. 1996; Cawood and Bancroft 1996; Kalmijn et al. 1998;
Morrison et al. 1998; Ravaglia et al. 1996, 1997; Reus et al. 1993; Rud-
man et al. 1990) as well as in the young (Klinteberg et al. 1992), but in
some studies, the relationships were gender specific. Based on the data in
elderly populations, some investigators have proposed that DHEA and
DHEA-S play a role in “successful aging” (Ravaglia et al. 1996, 1997) as
well as in “brain aging” (Magri et al. 2000).
Dehydroepiandrosterone in Psychoneuroendocrinology 215
In early clinical trials, DHEA was found to rapidly improve energy, in-
sight, self-confidence, emotionality, vitality, adjustment to the environ-
ment, and school and occupational performance and to decrease anxiety,
depression, apathy, and withdrawal in patients with schizophrenia, inad-
equate personality, or emotional immaturity (Sands 1954; Sands and
Chamberlain 1952; Strauss and Stevenson 1955; Strauss et al. 1952) and
in patients with phobic-obsessive psychoneuroses, neuropsychasthenia,
psychopathic personality, involutive syndromes, and depressive psycho-
ses (Pelliccioni et al. 1981; Scali et al. 1980; Serra 1953). Although these
studies were largely uncontrolled, in several cases the improvements
dissipated on single-blind crossover to placebo and returned with single-
blind crossover back to DHEA. In the first double-blind, placebo-
controlled clinical trial of DHEA, eight patients with depression, anxiety,
social phobia, shyness, lack of confidence, hyposexuality, and so forth
(classified by the authors as having vulnerable personalities) showed
slightly more global positive assessments and slightly fewer negative glo-
bal assessments when taking DHEA compared with placebo, but these
improvements were not interpreted as being significant by the authors
(Forrest et al. 1960).
After a 30- to 40-year hiatus, clinical trials with DHEA resumed. Pa-
tients with multiple sclerosis and systemic lupus erythematosus, for
example, showed increased energy, libido, and sense of well-being in
open-label trials (Calabrese et al. 1990; Roberts and Fauble 1990; van
Vollenhoven et al. 1994). In another study, DHEA was administered to
healthy middle-aged and elderly subjects in a randomized, placebo-
controlled, double-blind crossover study (Morales et al. 1994). Subjects,
ages 40–70 years old, received 50 mg of DHEA or placebo every evening
for 3 months. This dosing schedule restored DHEA and DHEA-S levels
to youthful levels within 2 weeks, and levels were sustained for the entire
3-month period. DHEA-treated subjects showed significant increases in
perceived physical and psychological well-being with no change in li-
bido. Reported improvements included increased energy, deeper sleep,
improved mood, feeling more relaxed, and having enhanced ability to
handle stressful events. These results generated considerable interest in
the possible behavioral effects of DHEA, but the global subjective
measure used to assess behavioral change in this study was relatively
crude.
Dehydroepiandrosterone in Psychoneuroendocrinology 217
Labrie and Diamond and colleagues (P. Diamond et al. 1996; Labrie
et al. 1997) treated women ages 60–70 with daily percutaneous appli-
cations of a 10% DHEA cream for 12 months. This was preceded or
followed by 6 months of placebo cream, although it is not stated if the
protocol was open label, single blind, or double blind. These researchers
noted, as did Morales and colleagues (1994), that 80% of the women re-
ported improved “well-being and an increase in energy” during DHEA
treatment. Unfortunately, these behavioral changes were assessed via
nonstandardized daily diaries. Vogiatzi and colleagues (1996) adminis-
tered micronized DHEA (40 mg) or placebo twice daily sublingually in
a double-blind manner to 13 morbidly obese adolescents. The researchers
reported no change in sense of well-being in these subjects, but their as-
sessment method was not specified, and the sample size was too small to
meaningfully gauge this effect. Piketty and colleagues (1998) adminis-
tered DHEA, 50 mg/day for 4 months, to patients with advanced HIV
disease in a randomized, controlled study. They found significant im-
provement in ratings of mental function in the DHEA-treated patients
compared with the placebo-treated patients. An additional double-blind
study examined the effects of 2 weeks’ treatment with DHEA, 50 mg/
day, compared with 2 weeks of placebo in healthy elderly men and
women (Kudielka et al. 1998; Wolf et al. 1997b). Only women tended
to report an increase in well-being (P=0.11) and mood (P=0.10), as as-
sessed with questionnaires. They also showed better performance in one
of six cognitive tests (picture memory) after DHEA treatment. However,
after post hoc correction for multiple comparisons, this difference was no
longer significant. No such trends were observed in the male subjects
(P>0.20). This study employed reliable neuropsychological test instru-
ments and had an adequate sample size, but the duration of treatment
was likely too short for behavioral changes to be manifested (Polleri et al.
1998).
Most recently, Baulieu and colleagues (2000) reported preliminary
results of a 1-year double-blind trial of DHEA (50 mg/day) versus pla-
cebo in a large group of healthy elderly patients recruited from a geriatric
clinic. Most of these patients were being seen for problems such as mild
anxiety, memory complaints, pain, and asthenia but did not qualify for
diagnoses of major depressive or dementing disorders. Significant im-
provements in libido, sexual function, and sexual satisfaction were noted
in the women but not in the men; effects were more prominent after 12
months of treatment compared with 6 months of treatment. Data from
this study on changes in cognitive performance and quality of life had not
been presented at the time of this writing. In another recent study, peri-
menopausal women with complaints of “altered mood and well-being”
218 PSYCHONEUROENDOCRINOLOGY
were treated with DHEA (50 mg/day) or placebo in a blind manner for
3 months (Barnhart et al. 1999). DHEA had no significant effects on per-
imenopausal symptoms, mood, dysphoria, libido, cognition, memory, or
well-being, but, as suggested by Baulieu et al. (2000), such effects may
progressively develop over more extended periods of time. Consistent
with this possibility, a recent study in which postmenopausal women
were treated with DHEA (50 mg/day) for 6 months found significant im-
provements in a measure of psychological and vasomotor symptoms
(Stomati et al. 2000).
Perhaps the strongest evidence to date of an improvement in well-
being with DHEA replacement (at least in individuals with pathologi-
cally low levels of DHEA and DHEA-S at baseline) comes from a study
utilizing well-validated psychological outcome measures in women with
adrenal insufficiency secondary to Addison’s disease (Arlt et al. 1999).
Twenty-four patients were treated daily with DHEA (50 mg orally) or
placebo for 4 months in a double-blind crossover study. Treatment with
DHEA, but not placebo, resulted in significant improvements in well-
being, mood, anxiety, obsessive-compulsive traits, hostility, and exhaus-
tion. These improvements were seen after 4 months of treatment but not
after 1 month, supporting assertions that the psychological effects of
DHEA may take several months to develop (Baulieu et al. 2000; Polleri
et al. 1998). In a similar study, men and women with Addison’s disease
showed significant improvements in self-esteem, mood, and fatigue, but
not in cognitive function, with 3 months of DHEA treatment (Hunt et
al. 2000).
Other studies have specifically assessed the effect of DHEA on mood
in depressed or dysthymic subjects. In an initial small-scale (N=6) open-
label pilot study, Wolkowitz and colleagues (1997) reported antidepres-
sant effects of DHEA in middle-aged and elderly patients with major de-
pression. Dosages of DHEA were individually adjusted between 30 and
90 mg/day for 4 weeks to achieve circulating DHEA and DHEA-S levels
in the mid-to-high normal range for healthy young adults. Subjects demon-
strated highly significant improvements in scores on the Hamilton Rating
Scale for Depression (Ham-D) and the Hopkins Symptom Checklist–90
and showed a significant improvement in “automatic” cognitive process-
ing at week 3 of DHEA treatment. Mood improvements were signifi-
cantly related to increases in circulating levels of DHEA and DHEA-S
and to their ratios with cortisol; changes in cortisol concentrations alone
were not correlated with behavioral changes. One subject from this
study, an elderly woman with previously treatment-resistant depression,
received extended open-label treatment with DHEA (60 mg/day for
4 months followed by 90 mg/day for an additional 2 months). Her
Dehydroepiandrosterone in Psychoneuroendocrinology 219
bert 1997; Holsboer et al. 1994; Leblhuber et al. 1992; Svec and Lopez
1989; Wolkowitz et al. 1992, 1997). Antagonism of glucocorticoid ef-
fects by DHEA or by certain of its metabolites has been demonstrated in
multiple model systems in peripheral tissue (Attal-Khemis et al. 1998;
Ben-Nathan and Feuerstein 1990; Blauer et al. 1991; Browne et al. 1992;
Fleshner et al. 1997; Loria 1997; Morfin and Chmielewski 1997; Padgett
et al. 1997; Riley et al. 1990; Svec and Lopez 1989) and in brain (Kimo-
nides et al. 1999). Antiglucocorticoid effects could, in theory, account for
both antidepressant (Dubrovsky 1997; Goodyer et al. 1998; Hechter et
al. 1997; Herbert 1997; Murphy and Wolkowitz 1993; Reus et al. 1997;
Wolkowitz et al. 2001) and neuroprotective (Herbert 1998; Kimonides
et al. 1999; Leblhuber et al. 1992; Sapolsky 1986; Wolkowitz et al. 1992)
effects of DHEA.
Miscellaneous other mechanisms that could contribute to the neuro-
psychiatric effects of DHEA include increased serum levels and bioavail-
ability of insulin-like growth factor I (Morales et al. 1994); inhibition of
the formation of proinflammatory brain cytokines (e.g., interleukin-1,
interleukin-6, and tumor necrosis factor a) and free radicals, which have
been implicated in neurodegeneration (Aragno et al. 1997; Danenberg
et al. 1992; Daynes et al. 1993; Griffin et al. 1989; Solerte et al. 1999;
Straub et al. 1998; Tamagno et al. 1998); elevation of a kB-dependent
transcription factor (which has been associated with neuroprotection)
(Mao and Barger 1998); and increases in brain calcium-ATPase activity
224 PSYCHONEUROENDOCRINOLOGY
With news of the effects of DHEA entering the lay media and with the
ready availability of commercial DHEA in health food stores nationwide,
many consumers are already purchasing and self-prescribing this hor-
mone. Many medical authorities and researchers in this field, including
ourselves, believe this enthusiasm remains premature until more is learned
about the benefit-risk ratio of long-term DHEA supplementation (Gold-
berg 1998; Katz and Morales 1998; Svec 1997; van Vollenhoven 1997).
This admonition may change as additional studies emerge in the near fu-
ture.
Human studies to date—typically involving 6–12 months or less of
treatment with DHEA—suggest that DHEA treatment is generally well
tolerated and not associated with significant group mean changes in phys-
ical examination; hepatic, thyroid and hematologic tests; urinalysis and
prostate-specific antigen levels; or prostatic or urinary function (Baulieu
et al. 2000; Morales et al. 1994; Reiter et al. 1999; van Vollenhoven
1997; Wolkowitz et al., in press). Long-term and other unforeseen side
effects remain possible, however, and DHEA cannot yet be recommended
for clinical use (van Vollenhoven 1997), with the possible exceptions of
treating Addison’s disease (Arlt et al. 1999; Hunt et al. 2000) or systemic
lupus erythematosus (van Vollenhoven et al. 1998) or as an adjunctive
therapy in certain patients receiving long-term glucocorticoid therapy
(Straub et al. 2000). Relatively common minor side effects that are seen
with DHEA treatment (even with treatment periods less than 6 months)
include acne, oily skin, nasal congestion, and headache. Less commonly
reported side effects include insomnia, overactivation (including disinhi-
bition, aggression, mania, or psychosis), hirsutism, increased body odor,
itching, irregular menstrual cycles, and voice deepening (Dean 2000;
Strauss et al. 1952; van Vollenhoven 1997; Wolkowitz et al., in press).
Proarrhythmogenic and antiarrhythmogenic effects (Sahelian and Borken
1998) have also been reported, as have (in animal models) pro-tumor and
antitumor effects. Tumorigenic effects in humans remain controversial
Dehydroepiandrosterone in Psychoneuroendocrinology 225
Clinical Considerations
For patients who are interested in trying DHEA, and for physicians inter-
ested in prescribing it, despite the cautions just listed, the following rec-
ommendations seem prudent; additional recommendations are outlined
by van Vollenhoven (1997). Most of the following recommendations are
derived from an informed reading of the scientific literature and from
common sense and anecdotal experience rather than from empirical clin-
ical studies:
• The current state of knowledge about the effects of DHEA and about
its potential side effects should be reviewed with patients, with partic-
ular emphasis on diminishing any unrealistic expectations about its
anti-aging effects.
• Patients should be monitored for the occasional development of hy-
pomanic, aggressive, psychotic, or disinhibited behavior (Dean 2000;
Howard 1992; Markowitz et al. 1999; Strauss and Stevenson 1955;
Strauss et al. 1952; Wolkowitz et al., in press).
• Patients at increased risk for hormonally sensitive tumors (e.g., cancer
of the breast, ovary, uterus, cervix, or prostate or malignant mela-
noma) should be advised not to take DHEA (until more is known
about its potential risks), although certain antitumor as well as pro-
tumor effects have been reported in animal studies (Comstock et al.
1993; Dorgan et al. 1997; Goldberg 1998; Jones et al. 1997; McNeil
1997; Schwartz et al. 1986). For other patients, baseline and follow-up
assessments, such as prostate-specific antigen measurements (Goldberg
1998), mammograms, uterine ultrasounds, and Pap smears, may be pru-
dent (van Vollenhoven 1997). For nonhysterectomized women con-
templating long-term DHEA treatment (e.g., more than 3 months),
periodic progesterone treatment aimed at shedding the uterine lining
226 PSYCHONEUROENDOCRINOLOGY
Conclusion
References
Callahan M: DHEA: The Miracle Hormone That Can Help You Boost Immunity,
Increase Energy, Lighten Your Mood, Improve Your Sex Drive, and Lengthen
Your Lifespan. New York, Signet, 1997
Carette B, Poulain P: Excitatory effect of dehydroepiandrosterone, its sulphate es-
ter and pregnenolone sulphate, applied by iontophoresis and pressure, on
single neurones in the septo-preoptic area of the guinea pig. Neurosci Lett
45:205–210, 1984
Cawood EH, Bancroft J: Steroid hormones, the menopause, sexuality and well-
being of women. Psychol Med 26:925–936, 1996
Cherniske S: The DHEA Breakthrough: Look Younger, Live Longer, Feel Better.
New York, Ballantine Books, 1998
Clark DG, Tomas FM, Withers RT, et al: Differences in substrate metabolism be-
tween self-perceived “large-eating” and “small-eating” women. Int J Obes
Relat Metab Disord 19:245–252, 1995
Comstock GW, Gordon GB, Hsing AW: The relationship of serum dehydroepi-
androsterone and its sulfate to subsequent cancer of the prostate. Cancer Ep-
idemiol Biomarkers Prev 2:219–221, 1993
Corpechot C, Robel P, Axelson M, et al: Characterization and measurement of
dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci U S A 78:
4704–4707, 1981a
Corpechot C, Robel P, Lachapelle N, et al: Dehydroepiandrosterone libre et
sulfo-conjugee dans le cerveau du souris dysmyeliniques. C R Acad Sci III
292:231–234, 1981b
Cuckle H, Stone R, Smith D, et al: Dehydroepiandrosterone sulphate in Alzhei-
mer’s disease. Lancet 2:449–450, 1990
Danenberg HD, Alpen G, Lustig S, et al: Dehydroepiandrosterone protects mice
from endotoxin toxicity and reduces tumor necrosis factor production. Anti-
microb Agents Chemother 36:2275–2279, 1992
Daynes RA, Araneo BA, Ershler WB, et al: Altered regulation of IL-6 production
with normal aging. Possible linkage to the age-associated decline in dehydro-
epiandrosterone and its sulfated derivative. J Immunol 150:5219–5230, 1993
Dean CE: Prasterone (DHEA) and mania. Ann Pharmacother 34:1419–1422,
2000
De Becker P, De Meirleir K, Joos E, et al: Dehydroepiandrosterone (DHEA) re-
sponse to i.v. ACTH in patients with chronic fatigue syndrome. Horm Metab
Res 31:18–21, 1999
Del Cerro S, Garcia-Estrada J, Garcia-Segura LM: Neuroactive steroids regulate
astroglia morphology in hippocampal cultures from adult rats. Glia 14:65–
71, 1995
Demirgoren S, Majewska MD, Spivak CE, et al: Receptor binding and electro-
physiological effects of dehydroepiandrosterone sulfate, an antagonist of the
GABAA receptor. Neuroscience 45:127–135, 1991
Diamond DM, Branch BJ, Fleshner M, et al: Effects of dehydroepiandrosterone
sulfate and stress on hippocampal electrophysiological plasticity. Ann N Y
Acad Sci 774:304–307, 1995
Dehydroepiandrosterone in Psychoneuroendocrinology 231
Diamond P, Brisson GR, Candas B, et al: Trait anxiety, submaximal physical ex-
ercise and blood androgens. Eur J Appl Physiol 58:699–704, 1989
Diamond P, Cusan L, Gomez JL, et al: Metabolic effects of 12-month percutane-
ous dehydroepiandrosterone replacement therapy in postmenopausal women.
J Endocrinol 150 (suppl):S43–50, 1996
Dilbaz N, Guz H, Arikazan M: Comparison of serum gonadal sex hormones of early
onset schizophrenics with adult onset schizophrenics (Abstract PT10010),
in Proceedings of the XXIst Collegium Internationale Neuro-Psychophar-
macologicum Congress, Glasgow, UK, 1998
Dmitrieva TN, Oades RD, Hauffa BP, et al: Dehydroepiandrosterone sulphate
and corticotropin levels are high in young male patients with conduct dis-
order: comparisons for growth factors, thyroid and gonadal hormones. Neu-
ropsychobiology 43:134–140, 2001
Dorgan JF, Stanczyk FZ, Longcope C, et al: Relationship of serum dehydroepi-
androsterone (DHEA), DHEA sulfate, and 5-androstene-3 beta, 17 beta-
diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol
Biomarkers Prev 6:177–181, 1997
Dubrovsky B: Natural steroids counteracting some actions of putative depres-
sogenic steroids on the central nervous system: potential therapeutic bene-
fits. Med Hypotheses 49:51–55, 1997
Dukoff R, Molchan S, Putnam K, et al: Dehydroepiandrosterone administration
in demented patients and non-demented elderly volunteers (abstract). Biol
Psychiatry 43:55S, 1998
Erb JL, Kadane JB, Tourney G, et al: Discrimination between schizophrenic and
control subjects by means of plasma dehydroepiandrosterone measurements.
J Clin Endocrinol Metab 52:181–186, 1981
Fava M, Littman A, Halperin P: Neuroendocrine correlates of the type A behav-
ior pattern: a review and new hypothesis. Int J Psychiatry Med 17:289–307,
1987
Fava M, Rosenbaum JF, MacLaughlin RA, et al: Dehydroepiandrosterone-sulfate/
cortisol ratio in panic disorder. Psychiatry Res 28:345–350, 1989
Fava M, Littman A, Lamon-Fava S, et al: Psychological, behavioral and biochem-
ical risk factors for coronary artery disease among American and Italian male
corporate managers. Am J Cardiol 70:1412–1416, 1992
Ferguson HC, Bartram ACG, Fowlie HC, et al: A preliminary investigation of ste-
roid excretion in depressed patients before and after electroconvulsive ther-
apy. Acta Endocrinologica 47:58–66, 1964
Ferrari E, Borri R, Casarotti D, et al: Major depression in elderly patients: a chrono-
neuroendocrine study (abstract). Aging Clin Exp Res 9:83, 1997
Ferrari E, Arcaini A, Gornati R, et al: Pineal and pituitary-adrenocortical function
in physiological aging and in senile dementia. Exp Gerontol 35:1239–1250,
2000
Ferrari E, Cravello L, Muzzoni B, et al: Age-related changes of the hypothalamic-
pituitary-adrenal axis: pathophysiological correlates. Eur J Endocrinol 144:
319–329, 2001
232 PSYCHONEUROENDOCRINOLOGY
Reddy DS, Kulkarni SK: The role of GABA-A and mitochondrial diazepam-
binding inhibitor receptors on the effects of neurosteroids on food intake in
mice. Psychopharmacology 137:391–400, 1998
Reddy DS, Kaur G, Kulkarni SK: Sigma (sigma1) receptor mediated anti-depressant-
like effects of neurosteroids in the Porsolt forced swim test. Neuroreport
9:3069–3073, 1998
Regelson W, Kalimi M: Dehydroepiandrosterone (DHEA)—the multifunctional
steroid, II: effects on the CNS, cell proliferation, metabolic and vascular, clin-
ical and other effects. Mechanism of action? Ann N Y Acad Sci 719:564–
575, 1994
Regelson W, Kalimi M, Loria R: DHEA: some thoughts as to its biologic and clin-
ical action, in The Biologic Role of Dehydroepiandrosterone (DHEA). Ed-
ited by Kalimi M, Regelson W. Berlin, Walter de Gruyter, 1990, pp 405–445
Reiter WJ, Pycha A, Schatzl G, et al: Dehydroepiandrosterone in the treatment
of erectile dysfunction: a prospective, double-blind, randomized, placebo-
controlled study. Urology 53:590–594, 1999
Reus VI, Wolkowitz OM, Roberts E, et al: Dehydroepiandrosterone (DHEA)
and memory in depressed patients (abstract). Neuropsychopharmacology 9:
66S, 1993
Reus VI, Wolkowitz OM, Frederick S: Antiglucocorticoid treatments in psychia-
try. Psychoneuroendocrinology 22 (suppl 1):S121–S124, 1997
Rhodes ME, Li PK, Flood JF, et al: Enhancement of hippocampal acetylcholine
release by the neurosteroid dehydroepiandrosterone sulfate: an in vivo mi-
crodialysis study. Brain Res 733:284–286, 1996
Rhodes ME, Li PK, Burke AM, et al: Enhanced plasma DHEAS, brain acetylcho-
line and memory mediated by steroid sulfatase inhibition. Brain Res 773:28–
32, 1997
Riley V, Fitzmaurice MA, Regelson W: DHEA and thymus integrity in the mouse,
in The Biologic Role of Dehydroepiandrosterone (DHEA). Edited by Kalimi
M, Regelson W. Berlin, Walter de Gruyter, 1990, pp 131–155
Robel P, Baulieu EE: Dehydroepiandrosterone (DHEA) is a neuroactive neuro-
steroid. Ann N Y Acad Sci 774:82–110, 1995
Roberts E: Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) as neural
facilitators: effects on brain tissue in culture and on memory in young and
old mice. A cyclic GMP hypothesis of action of DHEA and DHEAS in ner-
vous system and other tissues, in The Biologic Role of Dehydroepiandroster-
one (DHEA). Edited by Kalimi M, Regelson W. Berlin, Walter de Gruyter,
1990, pp 13–42
Roberts E, Fauble T: Oral dehydroepiandrosterone in multiple sclerosis. Results
of a phase one, open study, in The Biologic Role of Dehydroepiandrosterone
(DHEA). Edited by Kalimi M, Regelson W. Berlin, Walter de Gruyter, 1990,
pp 81–94
Roberts E, Bologa L, Flood JF, et al: Effects of dehydroepiandrosterone and its
sulfate on brain tissue in culture and on memory in mice. Brain Res 406:357–
362, 1987
Dehydroepiandrosterone in Psychoneuroendocrinology 239
245
246 PSYCHONEUROENDOCRINOLOGY
each of these conditions separately and pose questions that help define
the possible relationships between mood changes, the menstrual cycle,
and the perimenopause. Finally, for each condition, we provide several
recommendations for evaluation and treatment.
Normal Cycling
The first day of menstruation is, by convention, the first day of the men-
strual cycle. Gonadotropin-releasing hormone (GnRH) is secreted in a
pulsatile fashion from the hypothalamus and stimulates the secretion of
follicle-stimulating hormone (FSH) from the pituitary. FSH stimulates
the secretion of estrogen from the ovarian follicles, resulting in the pro-
liferation of the uterine lining. At the end of the first menstrual cycle
week, one follicle is selected and becomes the predominant follicle. That
follicle undergoes maturation and secretes increasing amounts of estro-
gen. The release of the egg from the follicle, ovulation, marks the end of
the follicular phase.
After ovulation and under the influence of luteinizing hormone (LH)
stimulation, the corpus luteum (the remains of the ovarian follicle) se-
cretes large amounts of progesterone (P4) and, to a smaller extent, estra-
diol (E2). This phase of the menstrual cycle is the luteal phase. If fertili-
zation and implantation of the egg do not take place, the corpus luteum
atrophies. Progesterone levels precipitously decline, and that decline ini-
tiates the shedding of the uterine lining—menstruation—within approx-
imately 14 days of ovulation.
FIGURE 10–1. Levels of the ovarian steroids estradiol (E2) and proges-
terone (Prog) and the pituitary gonadotropic hormones follicle-stimulating
hormone (FSH) and luteinizing hormone (LH) at three phases of repro-
ductive life.
The illustrated hormonal patterns for the climacteric do not reflect intraindividual and in-
terindividual variability in frequency of ovulation and length of menstrual cycle during this
phase. Ov=ovulation; M=menses.
Source. Reprinted from Schmidt PJ, Rubinow DR: “Menopause-Related Affective Disor-
ders: A Justification for Further Study.” American Journal of Psychiatry 148:844–952, 1991.
Copyright 1991, American Psychiatric Association. Used with permission.
strual cycle, ovulatory cycles are fewer, and menstrual cycle irregularity
ensues (Judd and Fournet 1994). However, in contrast to the postmeno-
pause, episodic (not tonic) gonadotropin secretion is present and both
ovulation and normal (or at times increased) estradiol secretion may occur
(Burger et al. 1995; Santoro et al. 1996). The late perimenopause is char-
acterized endocrinologically by persistent elevations of plasma FSH levels,
sustained menstrual cycle irregularity with periods of amenorrhea, and hy-
poestrogenism. However, the levels of several other hormones that may
impact mood and behavior also decrease with aging (concomitant with
changes in reproductive function): androgens (testosterone and andros-
tenedione) (Adashi 1994; Burger et al. 1995; Davis and Burger 1996);
dehydroepiandrosterone (Morley et al. 1997); and insulin-like growth fac-
tors and binding proteins (Klein et al. 1996; Morley et al. 1997).
248 PSYCHONEUROENDOCRINOLOGY
Defining Questions
Are There Luteal Phase–Specific Mood Disturbances?
If women’s daily moods are studied over three or more cycles, a subgroup
can be identified in which mood clearly varies in a menstrual cycle–
dependent fashion, with increasing symptoms during the luteal phase and
elimination of symptoms at or soon after the onset of menses. (See
Figure 10–2 for three examples of women’s self-ratings.) The fact that
fewer than 50% of women presenting with a history of PMS will show a
cycle-dependent pattern, however, illustrates the need to obtain longitu-
dinal ratings in addition to a history of PMS before making a diagnosis.
This requirement for prospective ratings has been incorporated into both
sets of diagnostic guidelines for PMS: those for premenstrual dysphoric
disorder, a diagnosis appearing in Appendix B of DSM-IV-TR (American
Psychiatric Association 2000) (Table 10–1), and those of the National In-
stitute of Mental Health (NIMH Premenstrual Syndrome Research Work-
shop Guidelines. Rockville, MD, National Institute of Mental Health,
unpublished, 1983). According to these criteria (which also contain an
impairment requirement), about 5% of women of reproductive age
would be diagnosed with PMS (Rivera-Tovar and Frank 1990). In an at-
tempt to operationalize the definition of PMS, the National Institute of
Mental Health PMS Research Workshop (in Rockville, MD, 1983) spec-
ified the degree of change (30%) in symptom severity during the luteal
phase required for a syndromal diagnosis. These and other operational
criteria for PMS are reviewed and compared by Schnurr (1989).
For our studies, PMS is operationally defined as follows: Each woman
has an increase of at least 30% (relative to the range of the scale em-
ployed) in her mean self-ratings of negative moods (depression, anxiety,
and irritability) in the 7 days before menses, compared with the ratings
for the 7 days afterward, in at least two of three cycles during the
3-month baseline. As described by Schnurr (1988, 1989), this method
correlates highly with the effect-size method used to establish that sever-
ity criteria for PMS have been met. Women are excluded from the study
if they have mood symptoms during the follicular phase of the cycle, that
is, postmenstrual mean mood ratings beyond the midpoint of the rating
scale. All women with PMS come to our clinic or are referred by their
personal physician because their PMS symptoms interfere with daily
function. Additional criteria include the following: regular menstrual
cycles (e.g., 22–34 days), normal gynecologic examinations, and do not
meet criteria for a current DSM-IV Axis I diagnosis. Approximately 30%
of the women presenting to our clinic with symptoms of PMS meet these
diagnostic criteria.
Menstrual Cycle–Related Affective Disorders 251
255
256 PSYCHONEUROENDOCRINOLOGY
receiving mifepristone and placebo entered the follicular phase after the
mifepristone-induced menses. Results demonstrated that women with
prospectively confirmed PMS experienced their characteristic premen-
strual mood state after the mifepristone-induced menses, at a time when
the peripheral endocrine profile was that of the early follicular phase
(Figures 10–4 and 10–5).
The observation that, as a group, women with prospectively con-
firmed PMS showed no alterations of their symptoms despite the re-
setting of the menstrual cycle could support either of two conclusions.
Premenstrual syndrome may represent an autonomous, cyclic disorder
that is linked to, but can be dissociated or desynchronized from, the
menstrual cycle. Alternatively, symptoms may be triggered by hormonal
events before the late luteal phase, consistent with reports that the sup-
pression of ovulation results in a remission of PMS symptoms (Casson et
al. 1990). To test the latter possibility, we suppressed ovarian steroid pro-
duction and created a temporary, reversible menopause by administering
the GnRH superagonist leuprolide acetate (Lupron). Suppression of the
ovarian cycle prevented the appearance of PMS symptoms, a finding that
was also observed in other studies (Bancroft et al. 1987; Muse et al.
1984).
To determine whether gonadal steroids were the factors that when re-
moved resulted in the elimination of PMS, we added back estradiol and
progesterone separately to women who continued to take leuprolide and
for whom leuprolide alone successfully eliminated symptoms of PMS.
Both estradiol and progesterone were associated with the return of symp-
toms typical of PMS (Schmidt et al. 1998) (Figure 10–6). It does appear,
therefore, that gonadal steroids can trigger symptoms of PMS, an obser-
vation that at first glance appears discordant with the lack of differences
in gonadal steroid levels between women with PMS and control subjects.
In the second part of this study, women with confirmed absence of PMS
received the same protocol of leuprolide and hormone addback. The con-
trol women showed no perturbation of mood during leuprolide-induced
hypogonadism and, significantly, no perturbation of mood during hormone
addback with either progesterone or estradiol, despite achieving hor-
mone levels comparable to those seen in the women with PMS. Women
with PMS, therefore, are differentially sensitive to gonadal steroids such
that they experience mood destabilization with levels or changes in go-
nadal steroids that are absolutely without effect on mood in women lack-
ing a history of PMS. These results indicate that gonadal steroids are
necessary but not sufficient for PMS. They can trigger PMS, but only in
women, who, for undetermined reasons, are otherwise vulnerable to ex-
periencing mood state destabilization (Schmidt et al. 1998).
Menstrual Cycle–Related Affective Disorders 257
FIGURE 10–4. Absence of the effect of truncation of the late luteal phase
with RU 486 on the appearance of premenstrual syndrome symptoms.
Data show group means plus standard deviation. Analysis of variance with repeated mea-
sures showed significant increases in anxiety symptoms from day 5 through day 11 after the
administration of RU-486 or placebo (open bars) compared with the ratings from the 7 days
before the luteinizing hormone (LH) surge (the follicular phase) (shaded bars). No signifi-
cant effects in the treatment group were observed. hCG=human chorionic gonadotropin.
Source. Reprinted from Schmidt PJ, Nieman LK, Grover GN, et al.: “Lack of Effect of
Induced Menses on Symptoms in Women With Premenstrual Syndrome.” New England
Journal of Medicine 324:1174–1179, 1991. Copyright 1991, Massachusetts Medical Soci-
ety. Used with permission.
258
PSYCHONEUROENDOCRINOLOGY
FIGURE 10–5. Appearance of premenstrual syndrome (PMS) symptoms during an RU 486–induced follicular phase in one
woman.
Sadness ratings ranged from 1 (none) to 6 (extreme). After the administration of RU 486, the woman had typical PMS symptoms during the drug-induced
follicular phase of the menstrual cycle, confirmed by the plasma levels of gonadal steroids shown. LH=luteinizing hormone.
Source. Reprinted from Schmidt PJ, Nieman LK, Grover GN, et al.: “Lack of Effect of Induced Menses on Symptoms in Women With Premenstrual Syn-
drome.” New England Journal of Medicine 324:1174–1179, 1991. Copyright 1991, Massachusetts Medical Society. Used with permission.
Menstrual Cycle–Related Affective Disorders 259
There are various ways in which the menstrual cycle may modulate
mood and behavior disturbances independent of the presence of PMS:
1) the menstrual cycle may modify the severity of appearance of certain
psychiatric illnesses; 2) the menstrual cycle may trigger the recrudes-
cence of a previously experienced psychiatric illness. In general, these
phenomena may be readily distinguished from PMS during longitudinal
confirmation of the diagnosis.
261
262 PSYCHONEUROENDOCRINOLOGY
263
264 PSYCHONEUROENDOCRINOLOGY
Treatment Approaches
Perimenopause-Related Depression
Defining Questions
How Is the Perimenopause Defined and Characterized?
In the past, several different criteria have been employed to define the
reproductive status of women participating in studies of the relationship
between menopause and mood. First, an age window of 45–55 years has
been used to select perimenopausal subjects. Although the average age
of the menopause is 51 years, there is considerable individual variation in
the age at onset of the menopause, ranging from the early 40s to the late
50s. Adopting an age window as the sole selection criteria will inevitably
result in the selection of a heterogeneous sample of women in different
266 PSYCHONEUROENDOCRINOLOGY
Irritability 70
Tearfulness 70
Excessive worry 67
Anxiety 67
Mood more fragile; easily upset by life events 64
Depressed mood 61
Mood instability 61
Increased appetite, cravings 58
Unmotivated 56
Decreased energy 53
Poor concentration 53
Early-morning waking 50
Interrupted sleep 50
Emotionally detached from important people in life 50
Note. Subjects met criteria for major or minor depression after administration of the
Structured Clinical Interview for DSM-IV (Spitzer et al. 1990) and the modified Schedule
for Affective Disorders and Schizophrenia—Lifetime Version (Spitzer et al. 1978), respec-
tively.
Treatment Recommendations
The management of mood and behavioral disturbances during the peri-
menopause requires the determination of the symptoms experienced and
the hormonal context in which they appear. As a complement to the
usual dicta regarding careful neuropsychiatric evaluation, longitudinal
monitoring of symptoms on a daily basis may provide invaluable infor-
mation about the severity, stability, and pattern of symptom experience.
Both affective and relevant somatic symptoms (e.g., vaginal dryness, hot
flushes) should be followed up. If it was not previously done, the pres-
ence of the perimenopause and hypoestrogenism should be documented
with FSH and estradiol measures. As part of our operational criteria, we
have required three of four serial FSH levels to be greater than 20 IU/L
(depending on the laboratory) for the perimenopause and greater than 40
IU/L for the menopause. Although estradiol levels below 60 pg/mL are
consistent with decreased ovarian function, levels above 60 pg/mL may
nonetheless appear in the presence of markedly elevated FSH levels that
suggest ovarian insensitivity.
The therapy selected for a major depressive disorder during the peri-
menopause will depend on the nature and severity of the somatic symp-
toms and the presence (or absence) and type of hormone replacement
therapy. In perimenopausal women presenting with depression, the pres-
ence of distressing signs of estrogen deficiency such as vaginal dryness and
hot flushes should lead to consideration of a trial of estrogen therapy, un-
less contraindications to estrogen treatment exist (e.g., history of breast
cancer). Alternatively, if perimenopausal somatic symptoms are mild or
272 PSYCHONEUROENDOCRINOLOGY
References
Kaufert PA, Gilbert P, Tate R: Defining menopausal status: the impact of longi-
tudinal data. Maturitas 9:217–226, 1987
Kaufert PA, Gilbert P, Tate R: The Manitoba project: a re-examination of the link
between menopause and depression. Maturitas 14:143–155, 1992
Kessler RC, McGonagle KA, Swartz M, et al: Sex and depression in the National
Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. J Af-
fect Disord 29:85–96, 1993
Kirkham C, Hahn PM, VanVugt DA, et al: A randomized, double-blind, placebo-
controlled, cross-over trial to assess the side effects of medroxyprogesterone
acetate in hormone replacement therapy. Obstet Gynecol 78:93–97, 1991
Klein NA, Battaglia DE, Miller PB, et al: Circulating levels of growth hormone,
insulin-like growth factor-I and growth hormone binding protein in normal
women of advanced reproductive age. Clin Endocrinol (Oxf) 44:285–292,
1996
Kraepelin E: Psychiatrie: ein Lehrbuch für Studirende und Aerzte (1896). New
York, Arno Press, 1975
Kritz-Silverstein D, Wingard D, Barrett-Connor E, et al: Hysterectomy, oophor-
ectomy and depression in older women, in Abstracts of the 4th Annual
Meeting of the North American Menopause Society, San Diego, CA, Sep-
tember 2–4, 1993, p 83 (#S6)
Kukopulos A, Reginaldi D, Laddomada P, et al: Course of the manic-depressive
cycle and changes caused by treatments. Pharmakopsychiatr Neuropsycho-
pharmakol 13:156–167, 1980
Lee KA, Shaver JF, Giblin EC, et al: Sleep patterns related to menstrual cycle
phase and premenstrual affective symptoms. Sleep 13:403–409, 1990
Magos AL, Brewster E, Singh R, et al: The effects of norethisterone in postmeno-
pausal women on oestrogen replacement therapy: a model for the premen-
strual syndrome. Br J Obstet Gynaecol 93:1290–1296, 1986
Malikian JE, Hurt S, Endicott J, et al: Premenstrual dysphoric changes in de-
pressed patients, in 1989 New Research and Program and Abstracts of the
American Psychiatric Association 142nd Annual Meeting, San Francisco,
CA, May 6–11, 1989. Washington, DC, American Psychiatric Association,
1989, p 128
Malmgren R, Collins A, Nilsson CG: Platelet serotonin uptake and effects of
vitamin B6-treatment in premenstrual tension. Neuropsychobiology 18:83–
88, 1987
Mandell AJ, Mandell MP: Suicide and the menstrual cycle. JAMA 200:792–793,
1967
McEwen BS, Alves SE: Estrogen actions in the central nervous system. Endocr
Rev 20:279–307, 1999
Merson J: The climacteric period in relation to insanity. West Riding Lunatic Asy-
lum Reports (London) 6:85–107, 1876
Mezrow G, Shoupe D, Spicer D, et al: Depot leuprolide acetate with estrogen and
progestin add-back for long-term treatment of premenstrual syndrome. Fer-
til Steril 62:932–937, 1994
276 PSYCHONEUROENDOCRINOLOGY
Montgomery JC, Brincat M, Tapp A, et al: Effect of oestrogen and testosterone im-
plants on psychological disorders in the climacteric. Lancet 1:297–299, 1987
Morley JE, Kaiser F, Raum WJ, et al: Potentially predictive and manipulable
blood serum correlates of aging in the healthy human male: progressive de-
creases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the
ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci
U S A 94:7537–7542, 1997
Mortola JF, Girton L, Fischer U: Successful treatment of severe premenstrual syn-
drome by combined use of gonadotropin-releasing hormone agonist and es-
trogen/progestin. J Clin Endocrinol Metab 71:252A–252F, 1991
Muse KN, Cetel NS, Futterman LA, et al: The premenstrual syndrome: effects of
“medical ovariectomy.” N Engl J Med 311:1345–1349, 1984
Myers JK, Weissman MM: Use of a self-report symptom scale to detect depres-
sion in a community sample. Am J Psychiatry 137:1081–1084, 1980
Oldenhave A, Jaszmann LJB, Everaerd WT, et al: Hysterectomized women with
ovarian conservation report more severe climacteric complaints than do nor-
mal climacteric women of similar age. Am J Obstet Gynecol 168:765–771,
1993
Paddison PL, Gise LH, Lebovits A, et al: Sexual abuse and premenstrual syn-
drome: comparison between a lower and higher socioeconomic group. Psy-
chosomatics 31:265–272, 1990
Parry BL, Mendelson WB, Duncan WB, et al: Longitudinal sleep EEG, tempera-
ture, and activity measurements across the menstrual cycle in patients with
premenstrual depression and in age-matched controls. Psychiatry Res 30:
285–303, 1989
Parry BL, Berga SL, Kripke DF, et al: Altered waveform of plasma nocturnal me-
latonin secretion in premenstrual syndrome. Arch Gen Psychiatry 47:1139–
1146, 1990
Prior JC, Alojado N, McKay DW, et al: No adverse effects of medroxyprogester-
one treatment without estrogen in postmenopausal women: double-blind,
placebo-controlled, crossover trial. Obstet Gynecol 83:24–28, 1994
Rabin DS, Schmidt PJ, Campbell G, et al: Hypothalamic-pituitary-adrenal func-
tion in patients with the premenstrual syndrome. J Clin Endocrinol Metab
71:1158–1162, 1990
Rapkin AJ, Morgan M, Goldman L, et al: Progesterone metabolite allopreg-
nanolone in women with premenstrual syndrome. Obstet Gynecol 90:709–
714, 1997
Rausch JL, Parry BL: Treatment of premenstrual mood symptoms. Psychiatr Clin
North Am 16:829–839, 1993
Reame NE: Gonadotropin changes in the perimenopause, in Proceedings of the
International Symposium on Perimenopause. Edited by Lobo RA. New York,
Springer-Verlag, 1997, pp 157–169
Reame NE, Marshall JC, Kelch RP: Pulsatile LH secretion in women with pre-
menstrual syndrome (PMS): evidence for normal neuroregulation of the
menstrual cycle. Psychoneuroendocrinology 17:205–213, 1992
Menstrual Cycle–Related Affective Disorders 277
Sherwin BB, Gelfand MM: The role of androgen in the maintenance of sexual
functioning in oophorectomized women. Psychosom Med 49:397–409, 1987
Sherwin BB, Gelfand MM, Brender W: Androgen enhances sexual motivation in
females: a prospective, crossover study of sex steroid administration in the
surgical menopause. Psychosom Med 47:339–351, 1985
Sherwood RA, Rocks BF, Stewart A, et al: Magnesium and the premenstrual syn-
drome. Ann Clin Biochem 23:667–670, 1986
Smith SL, Sauder C: Food cravings, depression, and premenstrual problems. Psy-
chosom Med 31:281–287, 1969
Soares CD, Almeida OP, Joffe H, et al: Efficacy of estradiol for the treatment of
depressive disorders in perimenopausal women: a double-blind, random-
ized, placebo-controlled trial. Arch Gen Psychiatry 58:529–534, 2001
Spitzer RL, Endicott J: Schedule for Affective Disorders and Schizophrenia
(Lifetime Version), 3rd Edition. New York, New York State Psychiatric In-
stitute, 1978
Spitzer RL, Williams JB, Gibbon M, et al: Structured Clinical Interview for
DSM-III-R, Patient Edition. New York, Biometrics Research Department,
New York State Psychiatric Institute, 1990
Stein MB, Schmidt PJ, Rubinow DR, et al: Panic disorder and the menstrual cycle:
panic disorder patients, healthy control subjects, and patients with premen-
strual syndrome. Am J Psychiatry 146:1299–1303, 1989
Steiner M, Steinberg S, Stewart D, et al: Fluoxetine in the treatment of premen-
strual syndrome. N Engl J Med 332:1529–1534, 1995
Stenstedt A: Involutional melancholia: an etiologic clinical and social study of en-
dogenous depression in later life, with special reference to genetic factors.
Acta Psychiatr Neurol Scand 127:1–71, 1959
Stone AB, Pearlstein TB, Brown WA: Fluoxetine in the treatment of premenstrual
syndrome. Psychopharmacol Bull 26:331–335, 1990
Stone AB, Pearlstein TB, Brown WA: Fluoxetine in the treatment of late luteal
phase dysphoric disorder. J Clin Psychiatry 52:290–293, 1991
Su T-P, Schmidt PJ, Danaceau MA, et al: Fluoxetine in the treatment of premen-
strual dysphoria. Neuropsychopharmacology 16:346–356, 1997
Sundblad S, Modigh K, Andersch B, et al: Clomipramine effectively reduces pre-
menstrual irritability and dysphoria: a placebo-controlled trial. Acta Psychi-
atr Scand 85:39–47, 1992
Sutherland H: Menstruation and insanity, in A Dictionary of Psychological Med-
icine. Edited by Tuke DH. Philadelphia, PA, P Blakistone, Son and Co, 1892,
pp 801–803
Taylor DL, Mathew RJ, Ho BT, et al: Serotonin levels and platelet uptake during
premenstrual tension. Neuropsychobiology 12:16–18, 1984
Tonks CM, Rack PH, Rose MJ: Attempted suicide in the menstrual cycle. J Psy-
chosom Res 11:319–323, 1968
Treolar AE: Menstrual cyclicity and the pre-menopause. Maturitas 3:249–264,
1981
Tulenheimo A, Laatikainen T, Salminen K: Plasma beta-endorphin immunoreac-
tivity in premenstrual tension. Br J Obstet Gynaecol 94:26–29, 1987
Menstrual Cycle–Related Affective Disorders 279
281
282 PSYCHONEUROENDOCRINOLOGY
Postpartum Depression
Postpartum depression represents a more severe form of puerperal mood
disturbance. Unlike blues, symptoms emerge slowly during the first few
weeks after delivery. Symptoms include those characteristic of other
major depressive episodes: dysphoric mood, loss of interest, decreased
energy and appetite, sleep changes, guilt, change in psychomotor activ-
ity, diminished concentration, and potential suicidality. Because some
symptoms of depression—such as sleep disturbance, fatigue, and appe-
tite changes—can be normative during the postpartum period, it may be
difficult to distinguish such vegetative symptoms of depression from
those more characteristic of a depressive episode. The severity of post-
partum depression ranges from mild to severe. Postpartum mood distur-
bance may also be classified as psychotic or nonpsychotic.
Prevalence rates of nonpsychotic postpartum major depression are es-
timated between 6.8% (Gotlib et al. 1989) and 16.5% (Whiffin 1988).
The extent to which pregnancy and the postpartum period constitute a
period of increased risk for affective disorder has been addressed in sev-
eral studies, with inconsistent results. Several studies have shown that the
risk of depression after delivery is higher than the risk of depression dur-
ing pregnancy (Kumar and Robson 1984; Watson et al. 1984). However,
studies that compare rates of depression during the postpartum period to
rates of depression in nonpuerperal women have not consistently shown
a significant difference in rates of mood disturbance (O’Hara 1986;
O’Hara et al. 1991). Although rates of postpartum mood disturbance
may not vary from those seen in a matched control group, other data sug-
Endogenous Gonadal Hormones in Postpartum Disorders 283
Postpartum Psychosis
Postpartum psychosis is the most severe form of postpartum mood distur-
bance. Typical symptoms include hallucinations or delusions, confusion,
and (occasionally) severely depressed mood. The incidence is estimated
at approximately 1 in 1,000 to 4 in 1,000 births (Brockington et al.
1982). Although nonpsychotic postpartum depressive episodes may typ-
ically emerge during the first 4 weeks after delivery, puerperal psychotic
episodes begin earlier in the immediate postpartum period—very often
within the first few days after delivery. Several studies suggest that the
first 30 days postpartum represent a period of increased risk for new-
onset psychosis (Kendell et al. 1987; McNeil 1987; Nott 1982). In a fre-
quently cited study by Kendell et al. (1987), it was described that the
number of psychiatric admissions in women during the first 30 days after
delivery was much higher than in a 30-day nonchildbearing period during
pregnancy or after 30 days postpartum.
Whether postpartum psychoses are distinct from psychotic episodes
that occur at other times has been debated. Many have suggested that
most postpartum psychosis is a form of affective disorder, specifically bi-
polar disorder. For example, a study by Brockington et al. (1981) deter-
mined that women with postpartum psychosis experienced higher levels
284 PSYCHONEUROENDOCRINOLOGY
Gonadotropin-Releasing Hormone
GnRH is a decapeptide produced by the hypothalamus and is responsible
for synthesis and release of LH and FSH from the pituitary. In nongravid
women, GnRH is released in a pulsatile fashion. Hypothalamic release of
GnRH is suppressed during pregnancy and early in the puerperium.
The relationship between GnRH and behavior has not been well stud-
ied. In animals, central administration of GnRH has been shown to en-
hance sexual behavior (Moss and McCann 1973). In humans, GnRH
cannot be easily measured in the systemic circulation. The extent to which
GnRH dysregulation might contribute to puerperal psychiatric disorders
has not been explored.
b-Endorphin
Circulating levels of b-endorphins increase during late pregnancy and
reach very high levels during delivery. Levels then drop rapidly during
the first few hours after delivery (Newnham et al. 1984). However, se-
rum b-endorphin does not cross the blood-brain barrier and does not re-
flect central nervous system concentration of b-endorphin.
Prolactin
Prolactin is a peptide hormone, made in the anterior pituitary (see Chap-
ter 5, this volume). Plasma concentrations in nonpregnant women are ap-
proximately 10 ng/mL. During pregnancy, maternal blood levels rise to
concentrations of 200 ng/mL. In nonlactating women, levels decline
postpartum over a period of approximately 2 weeks. In women who
breastfeed, levels remain above the nongravid range and increase in re-
sponse to suckling. If breastfeeding occurs 1–3 times a day, prolactin
returns to nongravid levels within 6 months; if breastfeeding occurs more
than 6 times a day, levels can remain high for up to 1 year postpartum
(Novy 1987). In the hypothalamus, increasing concentrations of pro-
lactin lead to increases in dopamine release, which then inhibits further
prolactin release. Studies of the effects of prolactin on other dopamine
systems of the brain have not consistently shown any specific effects of
prolactin on dopamine binding sites. One study showed hyperprolactine-
mia increasing striatal dopamine receptor binding sites (Hruska et al.
1982), but another series of studies failed to show an effect of hyperpro-
lactinemia on dopamine receptor binding sites in the striatum (Simpson
et al. 1986). In nonchildbearing women, hyperprolactinemia has been as-
sociated with depression, anxiety, and hostility (Simpson et al. 1986).
Estrogen
Estrogens are produced by both the placenta and the fetus during preg-
nancy. Estrone and estradiol are produced by the placenta through con-
version of the androgen dehydroepiandrosterone sulfate (DHEA-S),
which is produced by fetal and maternal adrenal glands. Estriol is also syn-
thesized by the placenta, but from the precursor 16a-hydroxy DHEA-S,
produced by the fetal liver from adrenal DHEA-S (Campbell and Wino-
ker 1985). Plasma levels of estrogens rise dramatically throughout preg-
Endogenous Gonadal Hormones in Postpartum Disorders 287
Progesterone
Progesterone is produced by the ovary during the first 6–7 weeks of preg-
nancy, and then production shifts to the placenta. At term, serum proges-
terone levels are approximately 170 times higher than levels seen in the
follicular phase of the menstrual cycle (Filer 1992). Levels fall precipitously
after delivery, and the half-life of progesterone is calculated in minutes
(Novy 1987). As the corpus luteum of pregnancy continues to produce
small amounts of progesterone during the first few days postpartum, levels
do not fall as precipitously as do estrogen levels (Filer 1992). However, by
postpartum day 3, plasma levels are lower than those observed in the luteal
phase of the menstrual cycle, and by the end of postpartum week 1, levels
are as low as those seen in the follicular phase (Filer 1992).
A progesterone metabolite, 3a-hydroxy-5a-dihydroxyprogesterone
(allopregnanolone) has been shown to bind to g-aminobutyric acid type
A (GABA-A) receptors in rat brain, mimicking the GABA-mediated in-
hibition produced by benzodiazepines and barbiturates (Majewska et al.
1986). Administration of micronized progesterone has been associated
with sedative and hypnotic effects similar to those seen with benzodiaz-
epines (Arafat et al. 1988; Freeman et al. 1992).
Androgens
Serum levels of testosterone increase throughout pregnancy and are signif-
icantly elevated in the third trimester. The increase is due to the increase
in estrogen, which causes an increase in the liver-synthesized binding
protein that binds both estrogen and testosterone. Although total test-
osterone levels increase throughout pregnancy, free testosterone concen-
trations remain stable. At delivery, testosterone levels drop secondary to
the drop in binding protein, but free levels again remain stable. Levels of
DHEA and DHEA-S decrease during pregnancy because they are uti-
lized to produce the large amounts of estrogens synthesized by the pla-
centa. After delivery there is a gradual return of DHEA and DHEA-S to
baseline levels (Filer 1992).
Thyroid Hormones
Rapid fluctuations in thyroid indices occur in the immediate postpartum
period. During pregnancy, there is an increase in total thyroxine (T4) and
Endogenous Gonadal Hormones in Postpartum Disorders 289
Corticosteroids
Plasma concentrations of both free and bound cortisol rise during late
pregnancy and peak during labor. Postpartum levels rapidly fall to those
seen in late pregnancy, and then gradually return to pregravid concentra-
tions (O’Hara 1991). By postpartum day 1, levels have returned to the
antepartum range. Return of both cortisol and 17-hydroxycorticosteroid
to nonpregnant levels occurs by the end of the first postpartum week
(Novy 1987).
Hypercortisolemia and nonsuppression with dexamethasone have
been associated with depression (see Chapter 6, this volume). In addi-
tion, a reduced metabolite of deoxycorticosterone, 3a-5a-tetrahydrode-
oxycorticosterone, has been shown to modulate the GABA-A receptor
complex, interacting at a site close to or identical with that of barbitu-
rates (Majewska et al. 1986).
Postpartum Blues
Etiology
Endocrine factors. Systematic study of the relationship between endo-
crine factors and postpartum blues has yielded conflicting and incon-
clusive results. Nott et al. measured levels of LH, FSH, estrogen and
progesterone in women during the six weeks postpartum. They found no
consistent evidence of an association between specific changes in hor-
mone levels and changes in mood. However, a correlation was noted be-
tween irritability and antepartum estrogen levels (Nott 1982). Feksi et al.
(1984) describe a relationship between maternity blues and elevated
concentrations of salivary progesterone and estrogen. A study by Heid-
rich et al. (1994), however, failed to show significant differences in free
hormone levels of estradiol and progesterone between women with and
without postpartum blues. Gard et al. (1986) also found no difference in
estrogen or progesterone in the first 5 days postpartum between women
with or without maternity blues. No consistent relationship between cor-
tisol levels and postpartum blues has been found.
A few studies have looked at b-endorphin levels and postpartum
mood, but results have been inconsistent. One investigation noted a re-
lationship between low levels of b-endorphin at 36 weeks gestation and
severe symptoms of blues (Newnham et al. 1984). Another study showed
no association between b-endorphin levels and blues (Brinsmead et al.
1985).
Nonendocrine factors. Biological factors which have been investigated
as potential causes of postpartum blues include plasma tryptophan levels,
platelet monoamine oxidase (MAO), and platelet alpha receptors. Two
studies have noted an absence of normal increase in plasma tryptophan seen
typically in the first 2 days postpartum in association with postpartum blues
(Gard et al. 1986; Handley et al. 1980). However, tryptophan supplemen-
tation during the first 10 days postpartum did not reduce the incidence of
blues. One study showed that women with postpartum blues had more
platelet alpha 2 receptors than women without blues (Metz et al. 1983).
Psychosocial and demographic factors have been investigated in the
etiology of postpartum blues. First pregnancy and past history of PMS
appear to be risk factors for postpartum blues (Nott et al. 1976; Yalom
et al. 1968).
Treatment
Postpartum blues are generally considered to be a transient, self-limited,
and normal consequence of pregnancy. There is some evidence that blues
Endogenous Gonadal Hormones in Postpartum Disorders 291
may predict risk for later postpartum depression. However, the majority
of women with postpartum blues recover without any negative sequelae
(O’Hara 1987). Appropriate treatment includes anticipation, support,
reassurance, and follow-up to ensure that symptoms have in fact remit-
ted by 2 weeks postpartum. Symptoms that continue beyond this time
frame may reflect an evolving mood disturbance.
Consequences
There have been no studies suggesting that postpartum blues has any
long-term negative effects on mother or child.
Postpartum Depression
Etiology
Endocrine factors. As is the case for postpartum blues, there is little
consistent evidence suggesting that a specific hormonal imbalance or ab-
normality is the cause of postpartum depression. Pedersen et al. (1993)
found higher cortisol levels during the puerperium in women with post-
partum dysphoria. O’Hara et al. (1991) did not find any difference in
plasma or urinary cortisol levels between depressed and nondepressed
women in the early postpartum period. Studies of dexamethasone sup-
pression have not shown a distinction between postpartum depressed
and nondepressed women in the early postpartum period (Greenwood
and Parker 1984; Singh et al. 1986).
O’Hara et al. (1991) did find significantly lower levels of estradiol at
gestation week 36 and postpartum day 2 among postpartum depressed
women. Studies examining the relationship between postpartum depres-
sion and progesterone levels have failed to show a consistent relationship
between level of depression and levels of progesterone (Ballinger et al.
1982; Kuevi et al. 1983). A study by Harris et al. (1989) reported lower
levels of progesterone in depressed breastfeeding women than in nonde-
pressed breastfeeding women, with the opposite effect seen in bottle-
feeding women. A study by Buckwalter et al. (1999) found that although
mood disturbances during pregnancy were associated with higher levels
of progesterone and lower levels of DHEA, in the postpartum period el-
evated testosterone levels were associated with greater mood disturbance.
Studies of thyroid function and postpartum mood have produced in-
consistent results as well. One study failed to show evidence of thyroid
disturbance associated with postpartum mood disturbance (Grimmel
and Larsen 1965). Two more recent studies did show an association
between thyroid dysfunction and postpartum mood disturbance (Harris
292 PSYCHONEUROENDOCRINOLOGY
et al. 1989; Pop et al. 1991). Pedersen et al. (1993) found that women
with higher levels of postpartum dysphoria had lower free T4 levels and
higher T3 uptake at 38 weeks of pregnancy.
Nonendocrine factors. A number of studies describe risk factors that
appear to increase risk for postpartum depression. However, these stud-
ies tend not to be particularly consistent. No data suggest that age, parity,
or marital status are consistently associated with increased risk for post-
partum depression.
The extent to which certain psychosocial factors have been impli-
cated in the etiology of (or contribute risk for) postpartum depression has
also been explored. Some studies have noted an association between neg-
ative or stressful life events during pregnancy or during the postpartum
period and increased probability of postpartum depression. For example,
poor marital relationships have been associated with depression during
the postpartum period in some but not all studies (Blair et al. 1970; Feg-
getter and Gath 1981; Hopkins et al. 1987; O’Hara 1986; O’Hara et al.
1983). In contrast, poor social support has been associated quite consis-
tently with increased risk for postpartum depression (O’Hara et al. 1983;
Paykel et al. 1980).
Most studies have suggested that history of depression is a risk factor
for postpartum depression (Martin 1977; Nilsson and Almgren 1970;
O’Hara 1986; O’Hara et al. 1983, 1991; Paykel et al. 1980; Playfair and
Gowers 1981; Tod 1964; Uddenberg 1974; Watson et al. 1984). In ad-
dition, family history of depression also appears to be a risk factor for
postpartum depression (Nilsson and Almgren 1970; O’Hara et al. 1984;
Watson et al. 1984). Although history or family history of mood disorder
appears to be highly associated with postpartum depression, a small
number of studies have failed to demonstrate this association (Blair et al.
1970; Dalton 1971; Kumar and Robson 1984; O’Hara et al. 1991; Pitt
1968).
No factor has been identified as singularly driving the risk for post-
partum depression. However, history of depression and family history of
depression appear to increase the risk of postpartum depression most
consistently in studies that have examined this issue. In addition, depres-
sion during pregnancy and poor psychosocial support do appear to con-
sistently increase the risk of postpartum depression (O’Hara 1986;
O’Hara et al. 1991).
Treatment
There are few treatment studies of postpartum depression. Research into
prevention of postpartum depression has shown that prenatal education
Endogenous Gonadal Hormones in Postpartum Disorders 293
(including relaxation training and advice to avoid stressors and seek sup-
port) may decrease postpartum distress. Because women with histories
of depression appear to be at increased risk for postpartum depression,
prophylactic strategies to reduce the risk of postpartum depression are
indicated. In women with histories of chronic or recurrent depression,
consideration of continuation of pharmacotherapy during pregnancy and
the postpartum period is appropriate. Given evidence that depression
during pregnancy is a strong predictor of postpartum depression, avoid-
ance of recurrence of depression during pregnancy may decrease the like-
lihood of a postpartum depressive episode. Women must be informed of
the risks to the fetus of pharmacotherapy during pregnancy, and a careful
weighing of risks to the fetus against risks of untreated depression in the
mother must be undertaken to come up with appropriate treatment
strategies for individual patients. Risks to the fetus associated with use of
pharmacotherapy during pregnancy may include specific risks of certain
congenital anomalies when specific medications are used during the first
trimester, unknown risks of neurodevelopmental problems associated
with exposing the developing fetal brain to psychotropic medications
throughout the pregnancy, and potential risks of toxicity and withdrawal
associated with maternal use of medications at time of delivery (Alt-
shuler et al. 1996).
Appropriate treatment of postpartum depression is like treatment of
depression in other settings. Patients who have profound depression with
suicidality, or those who are unable to take care of themselves, benefit in
almost all cases from hospitalization. Evaluation to rule out medical
causes of depression, such as Sheehan’s syndrome or postpartum thyroid
dysfunction, is important. Treatment of postpartum depression may in-
clude pharmacotherapy in conjunction with psychotherapy and other
support when necessary. Only a few studies of the treatment of postpar-
tum depression with specific agents have been published. These agents
include antidepressants such as sertraline, venlafaxine, and fluoxetine, all
of which have demonstrated efficacy (Appelby et al. 1997; Cohen et al.
2001; Stowe et al. 1995). Estrogen, administered either transdermally or
sublingually, has been reported to have a small effect on improvement of
postpartum depressive symptoms (Ahokas et al. 1998; Gregoire et al.
1996). However, in the study of transdermal estrogen (Gregoire et al.
1996), many subjects received antidepressants in conjunction with estro-
gen, thus calling into question the effect of estrogen alone. Further inves-
tigation is needed into the possible use of estrogen in the treatment of
postpartum depression before it can be considered a first-line therapy.
Both cognitive-behavioral therapy and interpersonal therapy have
been shown to be helpful in the treatment of postpartum depression
294 PSYCHONEUROENDOCRINOLOGY
(Appelby et al. 1997; Stuart et al. 1995). Services such as home health
aides or visiting nurses who can help with baby care, thus allowing moth-
ers to catch up on rest, are often quite helpful. Enlisting family members
to take over some of the numerous chores involved with care of a new
baby also may allow a mother with depression to recover more quickly.
If pharmacotherapy is initiated, safety of breastfeeding may be raised
as an issue of concern. The use of lithium is generally contraindicated
during breastfeeding, as breast milk levels of this drug are relatively con-
sistent and may reach 50% of serum levels (Llewellyn and Stowe 1998;
Schou and Amdisen 1973). Other psychotropic medications may be se-
creted into breast milk; however, the amount may be small or unmeasur-
able by standard laboratory tests. Mothers should be advised that if they
wish to breastfeed when using psychotropic medications, the baby’s se-
rum should be measured for presence of drug approximately 2 weeks af-
ter medication is initiated. If medication is not detected in the infant’s
plasma, then mothers may elect to continue to breastfeed. However, they
should be cautioned that standard laboratory assays may not be suffi-
ciently sensitive to detect trace amount of drug. On the other hand moth-
ers may be reassured that the likelihood of neonatal toxicity in the setting
of a nondetectable infant plasma level of drug is extremely small (Birn-
baum et al. 1999; Stowe et al. 1997).
Consequences
Follow-up studies of women who have experienced postpartum depres-
sion have shown that women with postpartum depression often continue
to experience depression up to 3.5 years after delivery (O’Hara et al.
1991). Risk for recurrent postpartum depression has been estimated to
be 50%, and risk for recurrent nonpostpartum depression is also elevated
(O’Hara 1995). Studies of children of mothers who have had postpartum
depression have shown more problems in these children than in children
of nondepressed mothers, including behavior problems, poorer cognitive
performance as toddlers, and patterns of insecure attachment with moth-
ers (Cogill et al. 1986).
Postpartum Psychosis
Etiology
Endocrine factors. There has been little research concerning the rela-
tionship between endocrine status and postpartum psychosis. A study by
Kumar et al. (1993) found that women with histories of bipolar or schizo-
affective disorder who went on to have a postpartum recurrence of illness
Endogenous Gonadal Hormones in Postpartum Disorders 295
Treatment
Few studies of treatment of postpartum psychosis have been reported.
Postpartum psychosis should be considered a psychiatric and obstetric
emergency. Postpartum psychosis has been associated with infanticide
(O’Hara 1995). Treatment should include hospitalization, and accepted
somatic treatments have included antipsychotic medications and mood
stabilizers, as well as electroconvulsive therapy. In the United Kingdom,
specialized mother-baby units have been established that allow psychotic
mothers to be hospitalized along with the infant. This allows the mother
to continue to take as much responsibility as she is able for care of the
infant while she is undergoing treatment. Children hospitalized with
their psychotic mothers do not appear to be at increased risk of physical
injury (Margison and Brockington 1982).
Consequences
Women who experience a postpartum psychotic episode appear to be at
increased risk for subsequent episodes of both nonpuerperal and postpar-
tum psychosis. Estimates of risk of postpartum psychotic episodes in sub-
296 PSYCHONEUROENDOCRINOLOGY
Conclusion
References
Blair RA, Gilmore JS, Playfair HR, et al: Puerperal depression: a study of predic-
tive factors. J R Coll Gen Pract 19:22–25, 1970
Blum M, McEwen BS, Roberts J: Transcriptional analysis of tyrosine hydroxylase
gene expression in the tubero-infundibular dopaminergic neurones of the rat
arcuate nucleus after oestrogen treatment. J Biol Chem 262:817–821, 1987
Brinsmead M, Smith R, Singh B, et al: Peripartum concentrations of beta endor-
phin and cortisol and maternal mood states. Aust N Z J Obstet Gynecol 25:
194–197, 1985
Brockington IF, Cernik KF, Schofield EM, et al: Puerperal psychosis: phenomena
and diagnosis. Arch Gen Psychiatry 38:829–833, 1981
Brockington IF, Winokur G, Dean C: Puerperal psychosis, in Motherhood and
Mental Illness. Edited by Brockington IF, Kumar R. New York, Grune &
Stratton, 1982, pp 37–69
Buckwalter J, Stanczyk F, McCleary C, et al: Pregnancy, the postpartum, and ste-
roid hormones: effects on cognition and mood. Psychoneuroendocrinology
24:69–84, 1999
Campbell JL, Winoker G: Post-partum affective disorders: selected biological as-
pects, in Recent Advances in Postpartum Psychiatric Disorders. Edited by In-
wood DG. Washington, DC, American Psychiatric Press, 1985, pp 19–40
Cantazarite VA, Perkins RP, Pernoll ML: Assessment of fetal wellbeing, in Cur-
rent Obstetric and Gynecologic Diagnosis and Treatment, 6th Edition. Ed-
ited by Pernoll ML, Benson RC. Norwalk, CT, Appleton & Lange, 1987, pp
279–302
Carsten ME: Endocrinology of pregnancy and parturition, in Essentials of Obstet-
rics and Gynecology. Edited by Hacker NF, Moore JG. Philadelphia, PA, WB
Saunders, 1986
Cogill SR, Caplan HL, Alexandra H, et al: Impact of maternal depression on cog-
nitive development of young children. Br Med J 292:1165–1167, 1986
Cohen L: Ob/gyn patients, in Massachusetts General Hospital Handbook of Gen-
eral Hospital Psychiatry, 4th Edition. Edited by Cassem NH, Stern TA,
Rosenbaum JF, et al. St Louis, MO, CV Mosby, 1997, pp 487–501
Cohen LS, Viguera AC, Bouffard SM, et al: Venlafaxine in the treatment of post-
partum depression. J Clin Psychiatry 62:592–596, 2001
Cohler BJ, Grunebaum HU, Weis JL, et al: Disturbance of attention among schizo-
phrenic, depressed, and well mothers and their young children. J Child Psy-
chol Psychiatry 18:115–135, 1977
Cox JL, Connor Y, Kendell RE: Prospective study of the psychiatric disorders of
childbirth. Br J Psychiatry 140:111–117, 1982
Dalton K: Prospective study into puerperal depression. Br J Psychiatry 118:689–
692, 1971
Dean C, Williams RJ, Brockington IF: Is puerperal psychosis the same as bipolar
manic-depressive disorder? a family study. Psychol Med 19:637–647, 1989
Emery R, Weintraub S, Neale JM: Effects of marital discord on the school behav-
ior of children with schizophrenic, affectively disordered, and normal par-
ents. J Abnorm Child Psychol 10:215–228, 1982
298 PSYCHONEUROENDOCRINOLOGY
O’Hara MW: Social support, life events, and depression during pregnancy and the
puerperium. Arch Gen Psychiatry 43:569–573, 1986
O’Hara MW: Postpartum blues, depression, and psychosis: a review. J Psychosom
Obstet Gynaecol 7:205–227, 1987
O’Hara MW: Postpartum mental disorders, in Gynecology and Obstetrics, Vol 6,
Chapter 84. Edited by Sciarra JJ. Philadelphia, PA, Harper & Row, 1991
O’Hara MW: Postpartum Depression: Causes and Consequences. New York,
Springer-Verlag, 1995
O’Hara MW, Rehm LP, Campbell SB: Postpartum depression: a role for social
network and life stress variables. J Nerv Ment Dis 171:336–341, 1983
O’Hara MW, Neunaber DJ, Zekoski EM: A prospective study of postpartum de-
pression: prevalence, course, and predictive factors. J Abnorm Psychol 93:
158–171, 1984
O’Hara MW, Schlechte JA, Lewis DA, et al: Controlled prospective study of
postpartum mood disorders: psychological, environmental, and hormonal
factors. J Abnorm Psychol 100:63–73, 1991
Paykel ES, Emms EM, Fletcher J: Life events and social support in puerperal de-
pression. Br J Psychiatry 136:339–346, 1980
Pedersen CA, Stern RA, Pate J, et al: Thyroid and adrenal measures during late
pregnancy and the puerperium in women who have been major depressed
or who become dysphoric postpartum. J Affect Disord 29:201–211, 1993
Pitt B: “Atypical” depression following childbirth. Br J Psychiatry 114:1325–
1335, 1968
Playfair HR, Gowers JI: Depression following childbirth—a search for predictive
signs. J R Coll Gen Pract 31:201–208, 1981
Pop VJM, de Rooy HAM, Vader HL, et al: Postpartum thyroid dysfunction and
depression in an unselected population. N Engl J Med 324:1815–1816, 1991
Reich T, Winokur G: Postpartum psychosis in patients with manic depressive dis-
ease. J Nerv Ment Dis 151:60–68, 1970
Schou M, Amdisen A: Lithium and pregnancy, III: lithium ingestion by children
breast-fed by women on lithium treatment. Br Med J 2:138, 1973
Simpson MD, Jenner P, Mardson CD: Hyperprolactinaemia does not alter spe-
cific striatal 3H-spiperone binding in the rat. Biochem Pharmacol 35:3203–
3208, 1986
Singh B, Gilhotra M, Smith R, et al: Postpartum psychoses and the dexametha-
sone suppression test. J Affect Disord 11:173–177, 1986
Snyder SH: The dopamine hypothesis of schizophrenia: focus on a dopamine re-
ceptor. Am J Psychiatry 134:138–143, 1977
Stowe ZN, Casarella J, Landrey J, et al: Sertraline in the treatment of women with
postpartum major depression. Depression 3:49–55, 1995
Stowe ZN, Owens MJ, Landry JC, et al: Sertraline and desmethylsertraline in hu-
man breast milk and nursing infants. Am J Psychiatry 154:1255–1260, 1997
Tetlow C: Psychoses of childbearing. Journal of Mental Science 101:629–639, 1955
Tod EDM: Puerperal depression: a prospective epidemiological study. Lancet 2:
1264–1266, 1964
Endogenous Gonadal Hormones in Postpartum Disorders 301
303
304 PSYCHONEUROENDOCRINOLOGY
The secretion and activity of gonadal hormones are regulated via the hy-
pothalamic-pituitary-gonadal (HPG) system. Inputs and circuits from
the cortex and several internal brain regions influence the hypothalamus,
which secretes gonadotropin-releasing hormone (GnRH) in a pulsatile
fashion. GnRH causes the secretion of the pituitary hormones, follicle-
stimulating hormone (FSH) and luteinizing hormone (LH), which are in-
volved in the process leading to ovulation and which regulate the female
gonadal hormones estrogen and progesterone. A series of feedback mech-
anisms maintain a very delicate homeostasis of the HPG system and its
interactions with other hormonal and biological systems. This homeosta-
sis can be impaired in response to environmental stimuli, pharmacologic
interventions, and a variety of physical and mental disorders.
The interaction between the brain and gonadal hormones is bidirec-
tional. The peripheral gonadal hormones exert two main types of actions
on the central nervous system: organizational/genomic effects and activa-
tional/nongenomic effects (McEwen 1991). The organizational/genomic
effects are trophic and occur early during development of the brain. They
are permanent and control neural architecture and future activity. Among
other influences, organizational effects of gonadal hormones or their ab-
sence are responsible for gender differences in brain and behavior. Acti-
vational/nongenomic effects of gonadal hormones occur mostly during
postnatal life and throughout the entire life cycle. They are reversible and
include alterations of normal electrical and biochemical functions and
structure. They can add to, and support, gender-differentiated brain
functions. Activational/nongenomic effects include many functions that
are considered to be involved in the continuous regulation of behavior
and mood, are putatively impaired in mental disorders, and are in-
fluenced by psychotropic medications. These activities include receptor
Gonadal Hormone Medications in Women 305
however, there are few studies showing any direct comparison of effects
on well-being and cognition of esterified estrogen or estradiol with and
without methyl testosterone (Sherwin and Gelfand 1985). In fact, this
preparation might cause some androgenic side effects.
1982b). Three to eight percent of women meet criteria for severe dys-
phoric PMS or premenstrual dysphoric disorder (American Psychiatric
Association 2000); such diagnoses require impaired functioning and war-
rant treatment (American College of Obstetricians and Gynecologists
1989; Rivera-Tovar and Frank 1990). Even though the exact etiology and
pathobiology of PMS are still obscure, most researchers in the field be-
lieve that gonadal hormones play a major role in the disorder. It is sug-
gested that the etiology of PMS involves a compilation of vulnerability
factors; environmental, social, and personality inputs; and biological de-
terminants. The biological determinants probably involve an interplay
between steroids, gonadal hormones, other hormonal systems, neu-
rotransmitters, and intraneural mechanisms (Gold and Severino 1994;
Halbreich 1995, 1996, 1999; Halbreich and Endicott 1985; Halbreich et
al. 1986, 1988, 1995; Smith and Schiff 1993). The role of ovulation or
ovulation-related mechanisms and processes in the pathophysiology of
PMS is underscored by reports that women with PMS did not have symp-
toms during anovulatory menstrual cycles (Backstrom et al. 1983, 1989).
Hysterectomy and ovariectomy were shown to eliminate PMS, whereas
symptoms continued when hysterectomy alone was performed (Back-
strom et al. 1983; Casper and Hearn 1990; Casson et al. 1990). Indeed,
one of the most effective treatments for PMS is elimination of ovulation
with GnRH analogs or with danazol (Bancroft et al. 1985, 1987; Halbreich
et al. 1991; Muse et al. 1984).
Suppression of ovulation interferes with multiple processes as well as
with their cyclicity, and even though the main change is probably in the
decreased levels and elimination of cyclicity of gonadal hormones, the in-
fluence of other parameters cannot be ignored. This is also the case when
GnRH analogs or other ovulation suppressants are administered as treat-
ment for other disorders (e.g., endometriosis or polycyclic ovaries).
Ovulation might be suppressed by danazol (Danocrine), which is a
synthetic derivative of 17a-ethinyl testosterone. It inhibits the midcycle
gonadotropin surge. It has been shown (Day 1979; Gillomere et al. 1985)
to be effective for treatment of PMS in a marginal dosage of 200 mg/day.
It is effective only when ovulation is suppressed (Halbreich et al. 1991).
Even though it has been reported that danazol is also effective when
given following ovulation at the beginning of the luteal phase, this has
probably not been confirmed. Danazol might cause a myriad of side ef-
fects, mostly androgenic, and is not well tolerated by many women. Ovu-
lation suppression by several GnRH analogs (e.g., buserelin) has been
widely shown to be effective in treatment of a wide range of premen-
strual syndromes, including dysphoric PMS (Bancroft et al. 1985, 1987;
Hammerback and Backstrom 1988). The most convenient way to sup-
314 PSYCHONEUROENDOCRINOLOGY
another group (Shariff et al. 1995), which found that 12% of breast can-
cer patients taking tamoxifen had moderately elevated scores for anxiety
and dysthymia. When given as a chemopreventive therapy to healthy
women, only 2% (3/141) reported depression, a rate that was quite sim-
ilar to that of placebo (2/138) (Powles et al. 1990). In a small study of
males taking tamoxifen, 4 of 24 patients reported depression (Anelli et
al. 1994).
Our own impression is that tamoxifen does not usually cause depres-
sion by itself. However, if a woman with a lifetime history of a major de-
pressive disorder becomes depressed again as part of her usual pattern
while taking tamoxifen, her response to antidepressants might be altered.
She might not respond to medications to which she responded well in the
past, or she might need higher dosages of these medications.
It is intriguing (and distressing) that despite the relatively extensive
use of other antiestrogens, such as clomiphene (which is used for stimu-
lation of secretion of gonadotropins and induction of ovulation) (Ameri-
can Medical Association 1994) and recently raloxifene (which is used for
HRT and breast cancer), the effects of these medications on the central
nervous system, mood, and behavior have not yet been properly studied.
However, alertness to possible alteration of mood in women treated with
these medications is advisable.
A recent study of women with PMS (Wang et al. 1996) showed a sig-
nificant menstrually related cyclic variation of pregnenolone and preg-
nenolone sulfate, which was correlated with progesterone levels and
variation. These authors found that higher luteal-phase levels of 5a-preg-
nane-3,20-dione (5a-dihydroprogesterone [5a-DHP]) and 3a-hydroxy-
5a-pregnan-20-one (3a,5a-tetrahydroprogesterone [3a,5a-THP]) were
associated with improved PMS symptoms, whereas higher levels of preg-
nanolone sulfate and pregnanolone (as well as estradiol) were associated
with worsened negative dysphoric symptoms. This might suggest that
different metabolic pathways of progesterone might exist in different
women and in different situations, resulting in different anxiolytic or
anxiogenic effects. In women with dysphoric PMS, or any other dys-
phoric state, the dominant pathway is the one leading to the anxiogenic
metabolites. It is of interest whether these not-yet-confirmed hypotheses
are also pertinent to the central nervous system. Another interesting and
generalizable finding of the same study (Wang et al. 1996) is that dys-
phoric symptoms correlate with plasma levels of progesterone, preg-
nenolone, 5a-DHP and 3a,5a-THP, with a delay of 3–4 days between
hormonal peaks and symptoms formation. This finding confirms pre-
vious reports by Halbreich et al. (1986) and Redei and Freeman (1995)
and might have implications for the understanding of the clinical time-
line of progestogens as well as for the elucidation of their pathophysi-
ology.
References
Ahdieh HB, Mayer AD, Rosenblatt JS: Effects of brain antiestrogen implants on
maternal behavior and on postpartum estrus in pregnant rats. Neuroendocri-
nology 46:522–531, 1987
American College of Obstetricians and Gynecologists: Premenstrual Syndrome.
Committee Opinion No 66. Washington, DC, American College of Obste-
tricians and Gynecologists, 1989
American Medical Association: Drug Evaluations Annual. Milwaukee, WI,
American Medical Association, 1994
American Medical Association: Drug Evaluations Annual. Milwaukee, WI,
American Medical Association, 1995
American Psychiatric Association: Diagnostic and Statistical Manual of Mental
Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiat-
ric Association, 2000
Amsterdam J, Garcia-Espana F, Fawcett J, et al: Fluoxetine efficacy in meno-
pausal women with and without estrogen replacement. J Affect Disord 55:
11–17, 1999
Gonadal Hormone Medications in Women 323
Cullberg J: Mood changes and menstrual symptoms with different estrogen com-
binations. Acta Psychiatry Scand Suppl 236:1–86, 1972
Daly E, Gray A, Barlow D, et al: Measuring the impact of menopausal symptoms
on quality of life. BMJ 307:836–840, 1993
Day J: Danazol and the premenstrual syndrome. Postgrad Med J 55 (suppl 5):87–
89, 1979
Ditkoff EC, Crary WG, Cristo M, et al: Estrogen improves psychological function
in asymptomatic postmenopausal women. Obstet Gynecol 78:991–995, 1991
Dorner G, Poppe I, Stahl F, et al: Gene- and environment-dependent neuroendo-
crine etiogenesis of homosexuality and transsexualism (review). Exp Clin
Endocrinol 98(2):141–150, 1991
Dorner G, Rohde W, Schott G, et al: On the LH response to oestrogen and LH-
RH in transsexual men. Exp Clin Endocrinol 82(3):257–267, 1993
Drake EB, Henderson VW, Stanczyk FZ, et al: Associations between circulating
sex steroid hormones and cognition in normal elderly women. Neurology
54:599–603, 2000
Estrogens, in Drug Facts and Comparisons, 54th Edition. St Louis, MI, Facts and
Comparisons Publishing Group, 2000, pp 217–224
Etgen AM: Antiestrogens: effects of tamoxifen, nafoxidine, and CI-628 on sexual
behavior, cytoplasmic receptors, and nuclear binding of estrogen. Horm Be-
hav 13:97–112, 1979
Fedor-Freybergh P: The influence of oestrogens on the wellbeing and mental per-
formance in climacteric and postmenopausal women. Acta Obstet Gynecol
Scand Suppl 64:1–91, 1977
Finn DA, Gee KW: A comparison of RO 16-6028 with benzodiazepine receptor “full
agonists” on GABAa receptor function. Eur J Pharmacol 247(3):233–237, 1993a
Finn DA, Gee KW: The influence of estrus cycle on neurosteroid potency at the
GABAa receptor complex. J Pharmacol Exp Ther 265(3):1374–1379, 1993b
Finn DA, Gee KW: The estrus cycle, sensitivity to convulsants and the anticonvulsant
effect of a neuroactive steroid. J Pharmacol Exp Ther 271(1):164–170, 1994
Freeman E, Rickels K, Sondheimer S, et al: Ineffectiveness of progesterone sup-
pository treatment for premenstrual syndrome. JAMA 264:349–353, 1990
Freeman EW, Purdy RH, Coutifaris C, et al: Anxiolytic metabolites of progester-
one: correlation with mood and performance on measures following oral
progesterone administration to healthy female volunteers. Neuroendocrinol-
ogy 58:478–484, 1993
Furuhjelm M, Carlstrom K: Treatment of climacteric and postmenopausal
women with 17-B-estradiol and norethisterone acetate. Acta Obstet Gyn-
ecol Scand 56:351–361, 1977
Furuhjelm M, Fedor-Freybergh P: The influence of estrogens on the psyche in
climacteric and post-menopausal women, in Consensus on Menopause Re-
search. Edited by van Keep PA, Greenblatt RB, Albeaux-Fernet M. Balti-
more, MD, University Park Press, 1976, pp 84–93
Gee KW: Steroid modulation of the GABA/benzodiazepine receptor-linked chlo-
ride ionophore. Mol Neurobiol 2:291–317, 1988
326 PSYCHONEUROENDOCRINOLOGY
Gillomere DH, Hawthorne RJ, Hart DM: Danazol for premenstrual syndrome: a
preliminary report of a placebo-controlled double-blind study. J Int Med Res
13:129–130, 1985
Gold JH, Severino SK: Premenstrual Dysphorias, Myths and Realities. Washing-
ton, DC, American Psychiatric Press, 1994
Graham GA, Sherwin BB: The relationship between retrospective premenstrual
symptom reporting and present oral contraceptive use. J Psychosom Res 31:
45–53, 1987
Gray JM, Schrock S, Bishop M: Estrogens and antiestrogens: actions and interac-
tions with fluphenazine on food intake and body weight in rats. Am J Physiol
264:R1214–R1218, 1993
Hackman BW, Galbraith D: Replacement therapy with piperazine oestrone sul-
fate (“Harmogen”) and its effect on memory. Curr Med Res Opin 4(4):303–
306, 1976
Halbreich U: Menstrually related disorders: what we do know, what we only be-
lieve we know, and what we know that we do not know. Crit Rev Neurobiol
9(2 and 3):163–175, 1995
Halbreich U: Premenstrual syndromes, in Psychiatric Issues in Women. Edited by
Halbreich U. London, Bailliere Tindall, 1996, pp 667–700
Halbreich U: Role of estrogen in postmenopausal depression. Neurology 8 (suppl 7):
S16–S20, 1997
Halbreich U: Premenstrual syndromes: closing the 20th century chapters. Curr
Opin Obstet Gynecol 11:265–270, 1999
Halbreich U, Endicott J: The relationship of dysphoric premenstrual changes to
depressive disorders. Acta Psychiatr Scand 71:331–338, 1985
Halbreich U, Endicott J, Goldstein S, et al: Premenstrual changes and changes in
gonadal hormones. Acta Psychiatr Scand 74:576–586, 1986
Halbreich U, Alt IH, Paul L: Premenstrual changes: impaired hormonal homeo-
stasis. Neurol Clin 6:173–194, 1988
Halbreich U, Rojansky N, Palter S: Elimination of ovulation and menstrual cyclic-
ity (with danazol) improves dysphoric premenstrual syndromes. Fertil Steril
56: 1066–1069, 1991
Halbreich U, Piletz JE, Carson S, et al: Increased imidazoline and alpha-2 adren-
ergic binding in platelets of women with dysphoric premenstrual syndromes.
Biol Psychiatry 34:676–686, 1993
Halbreich U, Rojansky N, Palter S, et al: Estrogen augments serotonergic activity
in postmenopausal women. Biol Psychiatry 37:434–441, 1995
Hammerback S, Backstrom T: Induced anovulation as treatment of premenstrual
tension syndrome: a double-blind crossover study with GnRH-agonist versus
placebo. Acta Obstet Gynecol Scand 67:159–166, 1988
Hammerback S, Backstrom T, Holst J, et al: Cyclical changes produced by se-
quential estrogen progestagen therapy. J Psychosom Obstet 23:201, 1983
Hasan SA, Brain PF, Castano D: Studies on effects of tamoxifen (ICI 46474) on ag-
onistic encounters between pairs of intact mice. Horm Behav 22:178–185, 1988
Gonadal Hormone Medications in Women 327
Haugen MM, Evans CB, Kim MH: Patient satisfaction with a levonorgestrel-
releasing contraceptive implant. Reasons for and patterns of removal. J Re-
prod Med 41:849–854, 1996
Henderson VW: The epidemiology of estrogen replacement therapy and Alzhei-
mer’s disease. Neurology 48 (suppl 7):S27–S35, 1997
Honjo H, Ogino Y, Natitoh K, et al: In vivo effects by estrone sulphate on the
central nervous system on senile dementia (Alzheimer’s type). J Steroid Bio-
chem 34:521–525, 1989
Honjo H, Tanaka K, Kashiwagi T, et al: Senile dementia-Alzheimer’s type and es-
trogen. Horm Metab Res 27(4):204–207, 1995
Kampen D, Sherwin B: Estrogen use and verbal memory in healthy postmeno-
pausal women. Obstet Gynecol 83:979–983, 1994
Kaunitz A: Long-acting hormonal contraception: assessing impact on bone den-
sity, weight, and mood. Int J Fertil 44(2):110–117, 1999
Kirkman RJ, Bromham DR, O’Connor TP, et al: Prospective multicentre study
comparing levonorgestrel implants with a combined contraceptive pill: final
results. Br J Fam Plann 25:36–40, 1999
Landgren BM, Aedo AR, Diczfalusy E: Hormonal changes associated with ovu-
lation and luteal function, in The Gonadotropins: Basic Science and Clinical
Aspects in Females. Edited by Flamigni C, Givens JR. New York, Academic
Press, 1982, pp 187–201
Limouzin-Lamothe M, Mairon N, LeGal J, et al: Quality of life after the meno-
pause: influence of hormonal replacement therapy. Am J Obstet Gynecol
170:618–624, 1994
Lindsay R: Why do estrogens prevent bone loss? Baillieres Clin Obstet Gynaecol
5(4):837–852, 1991
Lobo R, McCormick W, Singer F, et al: Depo-medroxyprogesterone acetate com-
pared with conjugated estrogens for the treatment of postmenopausal women.
Obstet Gynecol 63(1):1–5, 1984
Luine VN, Khylchevskaya RJ, McEwen BS: Effect of gonadal steroids on activities of
monoamine oxidase and choline acetylase in rat brain. Brain Res 86:293–306, 1975
Magos AL, Colins WP, Studd JWW: Management of the premenstrual syndrome by
subcutaneous implants of oestradiol. J Psychosom Obstet Gynecol 3:93–99, 1984
Magos AL, Brewster E, Singh R, et al: The effects of norethisterone in postmeno-
pausal women on estrogen replacement therapy: a model for the premen-
strual syndrome. Br J Gynaecol 93:1290–1296, 1986a
Magos AL, Brincat M, Studd JWW: Treatment of the premenstrual syndrome by
subcutaneous oestradiol implants and cyclical oral norethisterone: placebo
controlled study. Br Med J 292:1629–1633, 1986b
Majewska MD: Neurosteroids: endogenous bimodal modulators of the GABA-A
receptor mechanism of action and physiological significance. Prog Neurobiol
38:379–395, 1992
Majewska MD, Schwartz RD: Pregnenolone sulfate: an endogenous antagonist of
the gamma-aminobutyric acid receptor complex in brain? Brain Res 404:
355–360, 1987
328 PSYCHONEUROENDOCRINOLOGY
Majewska MD, Harrison NL, Schwartz RD, et al: Metabolites of steroid hor-
mones are barbiturate-like modulators of the aminobutyric acid receptors.
Science 232:1004–1007, 1986
McEwen BS: Non-genomic and genomic effects of steroids on neural activity.
Trends Pharmacol Sci 12:141–147, 1991
McEwen BS, Alves SE, Bulloch K: Ovarian steroids and the brain: implications
for cognition and aging. Neurology 48 (suppl 7):S8–S15, 1997
Meyer WJ, Webb A, Stuart CA, et al: Physical and hormonal evaluation of trans-
sexual patients: a longitudinal study. Arch Sex Behav 15(2):121–138, 1986
Meyer-Bahlburg HFL: Intersexuality and the diagnosis of gender identity disor-
der. Arch Sex Behav 23:21–41, 1994
Michael C, Kantor H, Shore H: Further psychometric evaluation of older
women—the effect of estrogen administration. J Gerontol 25(4):337–341,
1970
Milsom I, Sundell G, Andersch B: A longitudinal study of contraception and preg-
nancy outcome in a representative sample of young Swedish women. Con-
traception 43(2)111–119, 1991
Mortel KF, Meyer JS: Estrogen replacement therapy and risk of dementia (ab-
stract). Neurology 44(S2):A208, 1994
Mortel KF, Meyer JS: Lack of postmenopausal estrogen replacement therapy
and the risk of dementia. J Neuropsychiatry Clin Neurosci 7(3):334–337,
1995
Mortola JF, Girton L, Fischer U: Successful treatment of premenstrual syndrome
by combined use of gonadotropin-releasing hormone agonist and estrogen/
progestin. J Clin Endocrinol Metab 72:252A–252F, 1991
Mulnard RA, Cotman CW, Kawas C, et al: Estrogen replacement therapy for
treatment of mild to moderate Alzheimer disease: a randomized controlled
trial. Alzheimer’s Disease Cooperative Study (comments). JAMA 283:
1007–1015, 2000
Muse K, Cetel N, Futterman L, et al: The premenstrual syndrome: effects of
“medical ovariectomy.” N Engl J Med 311:1345–1349, 1984
National Surgical Adjuvant Breast and Bowel Project (NSABP): NSABP Protocol
P-1: A Clinical Trial to Determine the Worth of Tamoxifen for Preventing
Breast Cancer. Pittsburgh, PA, National Surgical Adjuvant Breast and Bowel
Project, January 24, 1992
Norberg L, Wahlström G, Backström T: The anaesthetic potency of 3 alpha-
hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-
one determined with an intravenous EEG-threshold method in male rats.
Pharmacol Toxicol 61:42–47, 1987
Ohkura T, Isse K, Akazawa K, et al: Low-dose estrogen replacement therapy for
Alzheimer disease in women. Menopause: The Journal of the North Ameri-
can Menopause Society. 1(3):125–130, 1994
Ohkura T, Isse K, Akazawa K, et al: Long-term estrogen replacement therapy in
female patients with dementia of the Alzheimer’s type: 7 case reports. De-
mentia 6(2):99–107, 1995
Gonadal Hormone Medications in Women 329
AASs. Although various AASs may differ in their relative degree of ana-
bolic versus androgenic effects, no AAS even approaches being purely an-
abolic or purely androgenic.
Since the 1970s, AASs have come into widespread use, first among
elite athletes, and subsequently among amateur bodybuilders, football
players, and other athletes seeking gains in muscle mass and strength.
However, research suggests that many men who use these drugs illicitly
do not have any particular athletic aspirations at all, but simply wish to
improve their physical appearance (Pope et al. 1988, 2000a). Epidemio-
logical studies in the United States suggest that more than 1 million
Americans have used AASs at some time in their lives (Buckley et al.
1988; Durant et al. 1993; Faigenbaum et al. 1998; Johnston et al. 2002;
Pope et al. 2000a; Radokovich et al. 1993; Yesalis et al. 1990, 1993, 1997).
Partially in recognition of the magnitude of this problem, the U.S. Con-
gress has reclassified AASs as schedule III substances (Anabolic Steroids
Control Act of 1990 [P.L. 101-647]; U.S. Senate 1990).
AASs are well known to produce important physiological side effects
in addition to their anabolic properties. These include, for example, acne,
hypertension, gynecomastia (as mentioned above), testicular atrophy,
and unfavorable alterations in the ratio of total cholesterol to high-
density lipoproteins (Brower 2002; Catlin 1998; Friedl and Yesalis 1989;
Glazer 1991; Haupt and Rovere 1984; Kouri et al. 1996; Lenders et al.
1988; Lombardo and Sickles 1992; Yesalis 2000). These effects have
been well documented in the literature and are not reviewed here. Less
extensively studied, however, are the psychiatric effects of AASs; it has
only recently been recognized that AASs may produce prominent psy-
chiatric changes in some illicit users and that these effects may represent
a public health problem. In this chapter, we review studies that have ex-
amined the psychiatric effects of AASs and offer some general impres-
sions to assist the clinician who may encounter patients who exhibit
these effects.
Studies that have examined the psychiatric effects of AASs include
1) clinical studies of AASs in the treatment of psychiatric or medical dis-
orders, 2) laboratory studies of the effects of AASs in normal volunteers,
and 3) naturalistic field studies of athletes using AASs illicitly.
Clinical Studies
dosage used in their study was far lower than that used by most athletes
in the field (Pope and Katz 1994).
Naturalistic Studies
As can be seen from the above review, most medical and laboratory stud-
ies of AASs have used only physiological or modestly supraphysiological
doses of AASs, and in addition have only rarely measured psychiatric ef-
fects in a systematic way. Therefore, these studies provide little evidence
regarding the effects to be expected of athletes who may frequently self-
administer combinations of several AASs simultaneously (a practice
known as “stacking”), such that their total weekly dosage of AASs may be
5–10 times greater than that typically administered in laboratory studies
(Brower 1991, 2002; Pope and Brower 2000; Pope and Katz 1988, 1994).
To assess these effects, one must examine naturalistic studies of actual il-
licit AAS users in the field.
Before 1988, only a few anecdotal reports had appeared describing
psychiatric effects of AASs in athletes (Annitto and Layman 1980; Fre-
inhar and Alvarez 1985; Tennant et al. 1988). Since 1988, however, many
studies have appeared in which investigators have assessed groups of
AAS-using athletes using psychiatric interviews or rating scales. These stud-
ies are summarized below.
In 1988, Pope and Katz (1987, 1988) interviewed 41 AAS users (39
men and 2 women), recruited from gymnasiums in Boston and Los An-
geles, using the Structured Clinical Interview for DSM-III-R (SCID). The
authors found that 5 (12.2%) of the subjects reported manic syndromes
during AAS use, compared with none of the subjects during periods
when they were not taking AASs (P=0.06). Five (12.2%) of the subjects
reported psychotic symptoms (paranoid or grandiose delusions, and in
one case, auditory hallucinations) during the on-AAS periods, compared
with none of the subjects during the off-AAS periods (P=0.06). Also,
5 (12.2%) of the subjects reported an episode of major depression on
stopping AASs; however, 2 of these subjects had also experienced a ma-
jor depressive episode at some other time in their lives.
Choi and colleagues (1990) compared 6 men, of whom 3 were AAS
users and three nonusers, in a longitudinal design. Subjects rated them-
selves repeatedly on several scales, including the Buss-Durkee Hostility
Inventory (BDHI), the Profile of Mood States (POMS), and the Rosen-
zweig Picture-Frustration Study. They also received unstructured in-
terviews. On both the BDHI and the POMS, users showed increased
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 337
hostility when taking AASs compared with when they were not taking
AASs or compared with nonusers. One AAS user in the study admitted
to attempted murder during a previous period of AAS use.
Lefavi and colleagues (1990) compared 13 current users of AASs, 18
former users, and 14 nonusers. On the Multidimensional Anger Inven-
tory (MDAI), users scored significantly higher than nonusers on two sub-
scales: Anger-Arousal and Hostile Outlook. The MDAI was not employed
in assessing the former users, but this group also reported increases in ag-
gression in association with their past AAS use.
Perry and colleagues (1990) compared 20 weightlifters who were
currently using AASs with a comparison group of 20 weightlifters who
had never used AASs. On the Symptom Checklist–90 (SCL-90), users
reported significantly higher scores during the periods when they were
taking AASs than did the nonusers on the Depression, Anxiety, and Hos-
tility subscales. Scores on the Depression, Somatization, and Paranoid
Ideation subscales were also significantly higher in the users while taking
AASs compared with these same users during periods when they were
not taking AASs. No significant differences were found on any subscale
when comparing the users at times when they were not taking AASs with
the nonusers. However, in contrast to these robust differences on the
SCL-90, the authors did not find an increased incidence of major psychi-
atric disorders among the AAS users when interviewing them using the
Diagnostic Interview Schedule.
Moss and colleagues (1992) sought personality pathology in 50 cur-
rent or past AAS users compared with 25 nonuser athletes, using the
Multidimensional Personality Questionnaire. No significant differences
were found on this instrument, except a trend toward slightly higher ag-
gression scores among the users compared with the nonusers. The au-
thors also used the POMS, the BDHI, and the SCL-90 to compare the 25
current AAS users with the 25 nonusers. In general agreement with the
studies of Choi et al. (1990) and Perry et al. (1990), described above,
Moss and colleagues (1992) found that current AAS users displayed sig-
nificantly higher ratings of hostility on the POMS and significantly higher
scores on the Somatization and Hostility subscales of the SCL-90. On the
BDHI, the Verbal Aggression subscale significantly differentiated users
from nonusers, and trends approaching significance were also found on
the Irritability and Guilt subscales. However, the authors reported that
they were unable to confirm the presence of specific psychiatric disorders
in association with AAS use.
Bahrke and colleagues (1992) reported almost entirely negative find-
ings in a comparison of 12 current AAS users, 14 former users, and 24
nonusers. In this study, both the current users and the former users de-
338 PSYCHONEUROENDOCRINOLOGY
In addition to the hypomanic symptoms associated with AAS use and the
depressive symptoms associated with AAS withdrawal in many of the
studies described above, several specific syndromes have been described
in association with AAS use. These include AAS dependence, “muscle
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 343
Muscle Dysmorphia
The speculations outlined above regarding psychological mechanisms for
AAS dependence are supported by the observation that many individuals
using AASs display a sort of “reverse anorexia nervosa” in which they per-
ceive themselves to be small and weak even when they are in fact large
and muscular. In recent studies from our laboratory, we have called this
syndrome muscle dysmorphia and described its characteristics in greater
detail (Olivardia et al. 2000; Phillips et al. 1997; Pope et al. 1993, 1997).
Other investigators have also found that feeling “not big enough” may
represent a risk factor for use of AASs (Bahrke et al. 2000; Brower et al.
1994; Kanayama et al. 2001; Pope et al. 2000a). The role of this syn-
drome of body image distortion in weightlifters who use AASs clearly
deserves further investigation.
344 PSYCHONEUROENDOCRINOLOGY
Violence
Several reports have noted that occasional users of AASs become unchar-
acteristically violent when taking these drugs (Choi et al. 1990; Con-
acher and Workman 1989; Dalby 1992; Pope and Katz 1990; Pope et al.
1996; Stanley and Ward 1994). In two of these reports (Pope and Katz
1990; Stanley and Ward 1994), the individuals displayed psychotic
symptoms apparently associated with AAS use. Although it is difficult to
confirm in retrospective observations that the violence was specifically
attributable to AAS use, many of the individuals described in these re-
ports exhibited no premorbid history of violence, no criminal record, and
no apparent history of psychiatric disorder prior to AAS use—observa-
tions suggesting that AASs represented the principal etiologic factor in
the violent behavior.
Our anecdotal experience suggests that AAS-induced violence is fre-
quently directed at women (Pope et al. 2000a). In an examination of this
hypothesis, Choi and Pope (1994) studied 23 AAS users and 14 nonus-
ers, recruited in the course of a study described earlier (Pope and Katz
1994), using the Dyadic Adjustment Scale and the Conflict Tactics Scale
to assess users’ relationships with wives or girlfriends. Although the
former scale did not detect effects of AASs, the Conflict Tactics Scale re-
vealed several significant differences between the AAS users when taking
the drug versus not taking the drug and between the users taking the drug
versus the nonusers. Several users described striking incidents of violence
toward women while taking AASs: for example, one reported that he
threw a brick at his girlfriend, and another reportedly fractured several
bones in his girlfriend’s hand by squeezing it. Neither of these subjects
reported comparable behavior toward women when they were not taking
AASs.
During the last several years, we have also consulted on approxi-
mately 20 legal cases in which individuals were charged with various vi-
olent crimes that appeared to have been committed at times when the
individuals were taking AASs. Several of these cases involved murder or
attempted murder. We described this experience, and presented an ex-
ample of a particularly striking murder case, in a paper (Pope et al. 1996).
Again, it is not possible to conclude with certainty that AASs played an
etiologic role in these crimes. It is noteworthy, however, that most of
these men reported no history of any DSM-IV psychiatric disorder before
their AAS exposure, and most also displayed no prior history of criminal
convictions or violent activity. In several of the cases, however, the indi-
vidual had used alcohol as well as AASs at the time of the crime, which
suggests a possible additive effect. In many of these cases, the role of
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 345
AASs was raised as an issue in the legal defense, either under the rubric
of “involuntary intoxication” or, less frequently, insanity. We are not
aware of any case in which an “AAS defense” has led to a verdict of not
guilty by reason of insanity, but there have been several cases in which
the evidence of AAS use may have acted as a mitigating factor, apparently
leading to a more lenient sentence. Three of these criminal cases are de-
scribed in a separate publication (Pope and Katz 1990); a more detailed
discussion of the forensic issues surrounding AASs and criminal behavior
has also appeared (Bidwell and Katz 1989).
stantial data suggest that some women have experimented with AASs
as well. However, the number of women using AAS is almost certainly
much lower than the number of men. Admittedly, some anonymous
student surveys have suggested that rates of AAS use in girls may be at
least 1.5%—or about one-third the rate in boys (Durant et al. 1993;
Middleman et al. 1995), and one survey found a rate of 2.8% in girls as
opposed to only 2.6% in boys (Faigenbaum et al. 1998). However, since
these estimates were based on anonymous survey responses, they must
be regarded with some caution, because of the risk of false positive re-
sponses by students who had used either corticosteroids or nutritional
supplements that they misidentified as “steroids” (Pope et al. 2000a).
Studies in which subjects were interviewed personally, such as the Na-
tional Household Survey (1994), thus probably provide somewhat
more reliable estimates—and in that survey the ratio of women to men
is much lower. In the 1994 survey (the most recent to collect AAS
data), the number of American men estimated to have used AAS in the
past 3 years was 413,458, as compared with 31,316 women—a ratio of
13 to 1 (National Household Survey 1994). With subjects who re-
ported that they had ever used a needle to inject AAS (perhaps a better
measure of serious AAS use), the survey estimated 205,499 men versus
8,404 women—a ratio of 25 to 1. In the only large interview study that
recruited subjects of both sexes, Malone and colleagues (1995) ob-
tained 71 male AAS users and 6 female users—a ratio of 12 to 1.
Because of the relative infrequency of female AAS users, few studies
have examined the psychiatric effects of AASs in women. One anecdotal
report described 10 women athletes who had used AASs (Strauss et al.
1985); these women described various masculinizing effects and, in some
cases, increases in aggression. However, given the small sample size and
lack of a control group in this study, it is difficult to generalize from these
findings. Other more recent studies have documented adverse effects on
lipoprotein profiles (Moffat et al. 1990) and neuroendocrine measures
(Malarkey et al. 1991) in small groups of women using AASs, but they
have not systematically sought psychiatric symptoms. More recently, our
group reported a comparison of 25 women athletes who had used AASs
with 50 who had not (Gruber and Pope 2000). None of the AAS-using
women in this study described a frank episode of mania or major depres-
sion in association with AAS use or withdrawal, probably because the
doses that they used were lower than those frequently used by male us-
ers. However, a majority of these women reported increases in irritability
and aggression during AAS use and depressive symptoms after discon-
tinuing AASs.
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 347
Clinical Implications
limitations (Aguilera et al. 1996, 1999; Catlin and Cowan 1992; Catlin
et al. 1987). A less expensive screening test that may be of some value
is to determine the plasma testosterone level. If it is well above the nor-
mal range, this finding would suggest that the patient may have been
illicitly taking exogenous testosterone. If it is well below the normal
range, then the patient may very likely have been using some other ex-
ogenous AAS, thus suppressing his own endogenous testosterone pro-
duction.
Episodes of major depression following AAS withdrawal may also re-
quire psychiatric intervention. One report described successful treat-
ment of four such episodes with fluoxetine (Malone and Dimeff 1992).
Another report described an AAS user whose withdrawal depression did
not respond to desipramine or fluoxetine but ultimately responded to
electroconvulsive therapy (Allnut and Chaimowitz 1994). Given the risk
of suicide in some individuals withdrawing from large doses or long
courses of AASs, such intervention may be important.
At present, it is not clear why some individuals develop manic or de-
pressive symptoms in association with AAS use while the majority of us-
ers do not. There is little evidence in the various retrospective studies
reviewed above to suggest that a prior history of psychiatric disorder or a
family history of psychiatric disorder increases the risk of these syn-
dromes, although further investigation is clearly required to resolve this
question. Similarly, there is little reason to assume that the prior person-
ality of the user, his history of aggressive or violent behavior, or his expec-
tations regarding the effects of AASs are particularly predictive of a
AAS-induced mood syndrome. Presumably, individuals who have dis-
played a mood syndrome in association with a previous course of AAS
use will be at increased risk to display a similar syndrome on using AASs
in the future, but even this is not certain. In the retrospective study cited
earlier (Pope and Katz 1994), we noted anecdotally that individuals dis-
playing adverse responses to AASs on one occasion were likely to do so
on another, but this was not invariably the case. Assessment of this ques-
tion is complicated by the fact that individuals may use different combi-
nations and doses of AASs on different occasions, making comparison
difficult. In short, therefore, it seems most likely that AAS-induced mood
syndromes represent an idiosyncratic response that is largely unpredict-
able, although such syndromes probably do become more likely with in-
creasing dosages.
Treatment of AAS use and dependence may be difficult in many cases,
because athletes exhibiting this syndrome rarely seek treatment (Pope et
al. 2000a). However, preliminary recommendations, based on models de-
veloped from treatment of other types of substance dependence, have
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 349
been published (Brower 1992, 1994, 2002; Corcoran and Longo 1992;
Goldberg et al. 1991, 1996a, 1996b, 2000). Pharmacotherapy for de-
pression during AAS withdrawal and pharmacotherapy or psychotherapy
to deal with body image disorders such as muscle dysmorphia (Neziroglu
et al. 1997; Phillips 2001; Phillips et al. 1997; Rosen et al. 1995) may be
useful elements in such a treatment program. It is not clear whether AAS
users will benefit from treatment in mixed groups with other types of
substance abusers, because many AAS users scrupulously avoid abuse of
other substances and pay close attention to their health while using AASs
(Pope and Katz 1994). Thus, in our experience, AAS users do not inte-
grate easily into groups of other substance abusers. Similarly, we are not
aware of a 12-step type of program that has been employed successfully
with AAS users. Individual therapy, ideally with a therapist who is famil-
iar with AASs and with the gymnasium subculture, may therefore be the
treatment of choice.
Finally, forensic psychiatrists should be aware of the possibility that
AASs may be involved in acts of violence. In cases where an athlete or
an unusually muscular individual has committed a violent crime, the
possibility of AAS use should always be considered and, if possible, as-
sessed via urine testing. The psychiatrist’s index of suspicion should be
particularly high in instances where the individual abruptly becomes
very depressed, with prominent vegetative features such as anhedonia
and psychomotor retardation, immediately after being incarcerated, but
then seems to regain his normal personality several weeks later. This
pattern, which we (Pope and Katz 1990) and others (Stanley and Ward
1994) have noted in men who were incarcerated in the midst of a course
of AAS use, likely reflects the abrupt syndrome of AAS withdrawal,
during which hypothalamic-pituitary-testicular function is grossly at-
tenuated, followed by return of more normal mood as testicular func-
tion reverts to baseline. Of course, even in cases where it is established
beyond doubt that an individual has committed violence under the in-
fluence of AASs, the forensic implications may vary, depending on pre-
vailing laws regarding “voluntary intoxication” or “diminished capacity”
caused by a substance that the individual has intentionally ingested.
In conclusion, studies regarding the clinical effects of AASs and
clinical treatment of AAS users remain limited. Virtually all of the rel-
evant literature has appeared just within the last 10 years. With in-
creased attention now being directed at the psychiatric syndromes
associated with AAS use, the understanding of the epidemiology, na-
ture, and treatment of these syndromes will doubtless expand rapidly
in the near future.
350 PSYCHONEUROENDOCRINOLOGY
References
Bidwell M, Katz DL: Injecting new life into an old defense: anabolic steroid-
induced psychosis as a paradigm of involuntary intoxication. University of
Miami Entertainment and Sports Law Review 7:1–63, 1989
Blumberg A, Keller H: [Erythropoiesis in anephric patients.] Schweiz Med
Wochenschr 101:1887–1893, 1971
Brower KJ: Anabolic-androgenic steroids, in Comprehensive Handbook of Drug
and Alcohol Addiction. Edited by Miller NS. New York, Marcel Dekker,
1991, pp 521–536
Brower KJ: Addictive potential of anabolic steroids. Psychiatric Annals 22:30–34,
1992
Brower KJ: Withdrawal from anabolic steroids. Curr Ther Endocrinol Metab
5:291–296, 1994
Brower KJ: Withdrawal from anabolic steroids. Curr Ther Endocrinol Metab 6:
338–343, 1997
Brower KJ: Anabolic steroid abuse and dependence. Curr Psychiatry Rep 4:377–
383, 2002
Brower KJ, Blow FC, Beresford TP, et al: Anabolic-androgenic steroid depen-
dence. J Clin Psychiatry 50:31–33, 1989a
Brower KJ, Blow FC, Eliopulos GA, et al: Anabolic androgenic steroids and sui-
cide (letter). Am J Psychiatry 146:1075, 1989b
Brower KJ, Eliopulos GA, Blow FC, et al: Evidence for physical and psychological
dependence on anabolic steroids in eight weight lifters. Am J Psychiatry 147:
510–512, 1990
Brower KJ, Blow FC, Hill EM: Risk factors for anabolic androgenic steroid use in
men. J Psychiatr Res 28:369–380, 1994
Buckley WA, Yesalis CE, Friedl KE, et al: Estimated prevalence of anabolic ste-
roid use among male high school seniors. JAMA 260:3441–3445, 1988
Burnett KF, Kleiman ME: Psychological characteristics of adolescent steroid us-
ers. Adolescence 29:81–89, 1994
Catlin DH: Effects and complications of anabolic androgenic steroids, in Hand-
book on Drug Abuse. Edited by Karch SB. Boca Raton, FL, CRC Press, 1998,
pp 653–662
Catlin DH, Cowan DA: Detecting testosterone administration. Clin Chem 38:
1685–1686, 1992
Catlin DH, Kammerer RC, Hatton CK, et al: Analytical chemistry at the games
of the XXIIIrd Olympiad in Los Angeles, 1984. Clin Chem 33:319–327,
1987
Cherrier MM, Asthana S, Plymate S, et al: Testosterone supplementation im-
proves spatial and verbal memory in healthy older men. Neurology 57:80–
88, 2001
Choi PYL, Pope HG Jr: Violence towards women and illicit androgenic-anabolic
steroid use. Ann Clin Psychiatry 6:21–25, 1994
Choi PYL, Parrott AC, Cowan D: High-dose anabolic steroids in strength ath-
letes: effects upon hostility and aggression. Human Psychopharmacology 5:
349–356, 1990
352 PSYCHONEUROENDOCRINOLOGY
Conacher GN, Workman DG: Violent crime possibly associated with anabolic
steroid use (letter). Am J Psychiatry 146:679, 1989
Cooper CJ, Noakes TD: Psychiatric disturbances in users of anabolic steroids.
S Afr Med J 84:509–512, 1994
Corcoran JP, Longo ED: Psychological treatment of anabolic-androgenic steroid-
dependent individuals. J Subst Abuse Treat 9:229–235, 1992
Crist DM, Peake GT, Egan PA, et al: Body composition response to exogenous GH
during training in highly conditioned adults. J Appl Physiol 65:579–584, 1988
Croxson TS, Chapman WE, Miller LK, et al: Changes in the hypothalamic-pituitary-
gonadal axis in human immunodeficiency virus–infected homosexual men.
J Clin Endocrinol Metab 68:317–321, 1989
Dalby JT: Brief anabolic steroid use and sustained behavioral reaction. Am J Psy-
chiatry 149:271–272, 1992
Daly RC, Su TP, Schmidt PJ, et al: Cerebrospinal fluid and behavioral changes af-
ter methyltestosterone administration: preliminary findings. Arch Gen Psy-
chiatry 58:172–177, 2001
Danziger L, Schroeder HT, Unger A: Androgen therapy for involutional melan-
cholia. Archives of Neurology and Psychiatry 51:457–461, 1944
David K, Dingemanse E, Freud J, et al: Uber Krystallinisches mannliches Hormon
Hoden (Testosteron), wirksamer als aus Harn oder aus Cholesterin Berei-
tetes Androsteron. Zeit Physiol Chem 233:281–282, 1935
Davidoff E, Goodstone GL: Use of testosterone propionate in treatment of invo-
lutional psychosis in the male. Archives of Neurology and Psychiatry 48:
811–817, 1942
Davidson JM, Cavhargo CA, Smith ER: Effects of androgen on sexual behavior
in hypogonadal men. J Clin Endocrinol Metab 48:955–958, 1979
Dowben RM, Perlstein MA: Muscular dystrophy treated with norethandrolone.
Arch Intern Med 107:245–251, 1961
Durant RH, Rickert VI, Ashworth CS, et al: Use of multiple drugs among adoles-
cents who use anabolic steroids. N Engl J Med 328:922–926, 1993
Elashoff JD, Jacknow AD, Shain SG, et al: Effects of anabolic androgenic steroids
on muscular strength. Ann Intern Med 115:387–393, 1991
Elofson G, Elofson S: Steroids claimed our son’s life. Physician Sportsmedicine
18:15–16, 1990
Faigenbaum AD, Zaichkowsky LD, Gardner DE, et al: Anabolic steroid use by
male and female middle school students. Pediatrics 101:E6, 1998
Forbes GB, Porta CR, Herr BE, et al: Sequence of changes in body composition
induced by testosterone and reversal of changes after drug is stopped. JAMA
267:397–399, 1992
Freinhar JP, Alvarez W: Androgen-induced hypomania. J Clin Psychiatry 46:354–
355, 1985
Fried W, Jonasson O, Lang G, et al: The hematologic effect of androgen in uremic
patients. Ann Intern Med 79:823–827, 1973
Friedl K, Yesalis CE: Self-treatment of gynecomastia in bodybuilders who use an-
abolic steroids. Physician Sportsmedicine 17:67–79, 1989
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 353
Friedl KE, Jones RE, Hannan CJ, et al: The administration of pharmacological
doses of testosterone or 19-nortestosterone to normal men is not associated
with increased insulin secretion or impaired glucose tolerance. J Clin Endo-
crinol Metab 68:971–975, 1989
Friedl KE, Dettori JR, Hannan CJ, et al: Comparison of the effect of high-dose
testosterone and 19-nortestosterone to a replacement dose of testosterone
on strength and body composition in normal men. J Steroid Biochem Mol
Biol 40:607–612, 1991
Fudala PJ, Calarco JS, Weinrieb R, et al: A pilot evaluation of anabolic steroid
users across and between cycles of use, in Problems of Drug Dependence
1995: proceedings of the 57th Annual Scientific Meeting, College on
Problems of Drug Dependence, Scottsdale, AZ, June 10–15, 1995 (NIDA
Res Monogr 162). Bethesda, MD, National Institutes of Health, 1996,
p 48
Glazer G: Atherogenic effects of anabolic steroids on serum lipid levels. Arch In-
tern Med 151:1925–1933, 1991
Goldberg L, Bents R, Bosworth E, et al: Anabolic steroid education and adoles-
cents: do scare tactics work? Pediatrics 87:283–286, 1991
Goldberg L, Elliot DL, Clarke GN, et al: The Adolescents Training and Learn-
ing to Avoid Steroids (ATLAS) prevention program. Background and re-
sults of a model intervention. Arch Pediatr Adolesc Med 150:713–721,
1996a
Goldberg L, Elliot D, Clarke GN, et al: Effects of a multidimensional anabolic ste-
roid prevention intervention: The Adolescents Training and Learning to
Avoid Steroids (ATLAS) Program. JAMA 276:1555–1562, 1996b
Goldberg L, MacKinnon DP, Elliot DL, et al: The Adolescents Training and Learn-
ing to Avoid Steroids Program: preventing drug use and promoting health be-
haviors. Arch Pediatr Adolesc Med 154:332–338, 2000
Griggs RC, Pandya S, Florence JM, et al: Randomized controlled trial of testoster-
one in myotonic dystrophy. Neurology 39:219–222, 1989
Grinspoon S, Corcoran C, Stanley T, et al: Effects of hypogonadism and testoster-
one administration on depression indices in HIV-infected men. J Clin Endo-
crinol Metab 85:60–65, 2000
Gruber AJ, Pope HG Jr: Psychiatric and medical effects of anabolic-androgenic
steroid use in women. Psychother Psychosom 69:19–26, 2000
Guirdham A: Treatment of mental disorders with male sex hormone. Br Med J
1:10–12, 1940
Halpern DF: Sex Differences in Cognitive Ability. Hillsdale, NJ, Erlbaum, 1992
Hannan CJ, Friedl KE, Zold A, et al: Psychological and serum homovanillic acid
changes in men administered androgenic steroids. Psychoneuroendocrinol-
ogy 16:335–343, 1991
Haupt HA, Rovere GD: Anabolic steroids: a review of the literature. Am J Sports
Med 12:469–484, 1984
Janowsky JS, Oviatt SK, Orwoll ES: Testosterone influences spatial cognition in
older men. Behav Neurosci 108:325–332, 1994
354 PSYCHONEUROENDOCRINOLOGY
Johnston LD, O'Malley PM, Bachman JG: Monitoring the Future: National Sur-
vey Results on Drug Use, 1975–2001, Vol 1: Secondary School Students
(NIH Publ No 02-5106). Bethesda, MD, National Institute on Drug Abuse,
2002
Kanayama G, Pope HG Jr, Hudson JI: “Body image” drugs: a growing psycho-
somatic problem. Psychother Psychosom 70:61–65, 2001a
Kanayama G, Pope HG Jr, Gruber AJ, et al: Over-the-counter drug use in gym-
nasiums: an underrecognized substance abuse problem? Psychother Psycho-
som 70:137–140, 2001b
Kanayama G, Cohane G, Weiss RD, et al: Past anabolic-androgenic steroid use
among men admitted for substance abuse treatment: an underrecognized
problem? J Clin Psychiatry (in press)
Kashkin KB, Kleber HD: Hooked on hormones? an anabolic steroid addiction
hypothesis. JAMA 262:3166–3170, 1989
Kouri E, Pope HG, Katz DL, et al: Fat-free mass index in users and non-users of
anabolic-androgenic steroids. Clin J Sport Med 5:223–228, 1995
Kouri EM, Pope HG Jr, Oliva PS: Changes in lipoprotein-lipid levels in normal
men following administration of increasing doses of testosterone cypionate.
Clin J Sport Med 6:152–157, 1996
Kutscher EC, Lund BC, Perry PJ: Anabolic steroids: a review for the clinician.
Sports Med 32:285–296, 2002
Lefavi RG, Reeve TG, Newland MC: Relationship between anabolic steroid use
and selected psychological parameters in male bodybuilders. Journal of Sport
Behavior 13:157–166, 1990
Lenders JWM, Demacher PNM, Vos JA, et al: Deleterious effects of anabolic ste-
roids on serum lipoproteins, blood pressure and liver function in amateur
bodybuilders. Int J Sports Med 9:19–23, 1988
Lombardo JA, Sickles RT: Medical and performance-enhancing effects of ana-
bolic steroids. Psychiatric Annals 22:19–23, 1992
Luisi M, Franchi F: Double-blind group comparative study of testosterone unde-
canoate and mesterolone in hypogonadal male patients. J Endocrinol Invest
3:305–308, 1980
Malarkey WB, Strauss RH, Leizman DJ, et al: Endocrine effects in female weight
lifters who self-administer testosterone and anabolic steroids. Am J Obstet
Gynecol 165:1385–1390, 1991
Malone DA Jr, Dimeff RJ: The use of fluoxetine in depression associated with
anabolic steroid withdrawal: a case series. J Clin Psychiatry 53:130–132,
1992
Malone DA Jr, Dimeff R, Lombardo JA, et al: Psychiatric effects and psychoac-
tive substance use in anabolic-androgenic steroid users. Clin J Sports Med 5:
25–31, 1995
Matsumoto AM: Effects of chronic testosterone administration in normal men:
safety and efficacy of high-dosage testosterone and parallel dose-dependent
suppression of luteinizing hormone, follicle-stimulating hormone, and sperm
production. J Clin Endocrinol Metab 70:282–287, 1990
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 355
Pope HG Jr, Katz DL: Psychiatric and medical effects of anabolic-androgenic ste-
roid use. Arch Gen Psychiatry 51:375–382, 1994
Pope HG Jr, Katz DL, Champoux R: Anabolic-androgenic steroid use among
1010 college men. The Physician and Sports Medicine 16:75–81, 1988
Pope HG Jr, Katz DL, Hudson JI: Anorexia nervosa and “reverse anorexia” among
108 male bodybuilders. Compr Psychiatry 34:406–409, 1993
Pope HG Jr, Kouri EM, Powell KF, et al: Anabolic-androgenic steroid use among
133 prisoners. Compr Psychiatry 37:322–327, 1996
Pope HG Jr, Gruber AJ, Choi PY, et al: Muscle dysmorphia: an underrecognized
form of body dysmorphic disorder. Psychosomatics 38:548–557, 1997
Pope HG Jr, Phillips KA, Olivardia R: The Adonis Complex: The Secret Crisis of
Male Body Obsession. New York, Free Press, 2000a
Pope HG Jr, Kouri EM, Hudson JI: The effects of supraphysiologic doses of test-
osterone on mood and aggression in normal men: a randomized controlled
trial. Arch Gen Psychiatry 57:133–140, 2000b
Pope HG Jr, Cohane G, Kanayama G, et al: Testosterone gel supplementation in
treatment-refractory depressed men: a randomized placebo-controlled trial.
Am J Psychiatry (in press)
Rabkin JG, Wagner GJ, Rabkin R: A double-blind, placebo-controlled trial of tes-
tosterone therapy for HIV-positive men with hypogonadal symptoms. Arch
Gen Psychiatry 57:141–147, 2000
Radokovich J, Broderick P, Pickell G: Rates of anabolic-androgenic steroid abuse
among students in junior high school. J Am Board Fam Pract 6:341–345, 1993
Riem KE, Hursey KG: Using anabolic-androgenic steroids to enhance physique
and performance: effects on moods and behavior. Clin Psychol Rev 15:235–
256, 1995
Rosen JC, Reiter J, Orosan P: Cognitive/behavioral body image therapy for body
dysmorphic disorder. J Consult Clin Psychol 63:263–269, 1995
Ross J, Winters F, Hartmann K, et al: 1988–89 Survey of Substance Abuse Among
Maryland Adolescents. Baltimore, MD, Maryland Department of Health and
Mental Hygiene, Alcohol and Drug Abuse Administration, 1989
Rubinow DR, Schmidt PJ: Androgens, brain, and behavior. Am J Psychiatry 153:
974–984, 1996
Salmimies P, Kockett G, Pirk KM: Effects of testosterone replacement on sexual
behavior in hypogonadal men. Arch Sex Behav 11:345–353, 1982
Sands R, Studd J: Exogenous androgens in postmenopausal women. Am J Med
98(suppl):76S–79S, 1995
Scott DM, Wagner JC, Barlow TW: Anabolic steroid use among adolescents in
Nebraska schools. Am J Health Syst Pharm 53:2068–2072, 1996
Shahidi NT, Diamond LK: Testosterone-induced remission in aplastic anemia of
both acquired and congenital types: further observations in 24 cases. N Engl
J Med 264:953–967, 1961
Sherwin BB, Gelfand MM: Sex steroids and affect in the surgical menopause: a
double-blind, cross-over study. Psychoneuroendocrinology 10:325–335,
1985
Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 357
Shifren JL, Braunstein GD, Simon JA, et al: Transdermal testosterone treatment
in women with impaired sexual function after oophorectomy. N Engl J Med
343:682–688, 2000
Skakkebaek NE, Bancroft J, Davidson DW, et al: Androgen replacement with oral
testosterone undecanoate in hypogonadal men: a double-blind controlled
study. Clin Endocrinol (Oxf) 14:49–61, 1981
Stanley A, Ward M: Anabolic steroids—the drugs that give and take away
manhood. A case with an unusual physical sign. Med Sci Law 34:82–83,
1994
Strauss R, Liggett M, Lanese R: Anabolic steroid use and perceived effects in ten
weight-trimmed women athletes. JAMA 253:2871–2873, 1985
Su T-P, Pagliaro M, Schmidt PJ, et al: Neuropsychiatric effects of anabolic steroid
in male normal volunteers. JAMA 269:2760–2764, 1993
Tennant F, Black DL, Voy RO: Anabolic steroid dependence with opioid-type
features (letter). N Engl J Med 319:578, 1988
Thiblin I, Finn A, Ross SB, et al: Increased dopaminergic and 5-hydroxytryptaminergic
activities in male rat brain following long-term treatment with anabolic an-
drogenic steroids. Br J Pharmacol 126:1301–1306, 1999
Tierney R, McLain LG: The use of anabolic steroids in high school students. Am
J Dis Child 144:99–103, 1990
Tricker R, Casaburi R, Storer TW, et al: The effect of supraphysiological doses of
testosterone on angry behavior in healthy eugonadal men. J Clin Endocrinol
Metab 81:3754–3758, 1996
U.S. Senate, Committee on the Judiciary: On the Steroid Abuse Problem in Amer-
ica, Focusing on the Use of Steroids in College and Professional Football Today
(congressional hearing). Washington, DC, U.S. Government Printing Office,
1990
Van Goozen SH, Cohen-Kettenis PT, Gooren LJ, et al: Activating effects of an-
drogens on cognitive performance: causal evidence in a group of female-to-
male transsexuals. Neuropsychologia 32:1153–1157, 1994
Vogel W, Klaiber EL, Braverman DM: A comparison of the antidepressant effect
of a synthetic androgen (mesterolone) and amitriptyline in depressed men.
J Clin Psychiatry 46:6–8, 1985
Wang C, Alexander G, Berman N, et al: Testosterone replacement therapy im-
proves mood in hypogonadal men: a clinical research center study. J Clin
Endocrinol Metab 81:3578–3583, 1996
Wettstein A: Uber die kunstliche Herstellung des Testikelhormons Testosteron.
Schweiz Med Wochenschr 16:912, 1935
Wilson IC, Prange AJ Jr, Lara PP: Methyltestosterone with imipramine in men:
conversion of depression to paranoid reaction. Am J Psychiatry 131:21–24,
1974
Wines JD Jr, Gruber AJ, Pope HG Jr, et al: Nalbuphine hydrochloride depen-
dence in anabolic steroid users. Am J Addict 8:161–164, 1999
Yates WR, Perry P, MacIndoe J, et al: Psychosexual effects of three doses of test-
osterone in cycling and normal men. Biol Psychiatry 45:254–260, 1999
358 PSYCHONEUROENDOCRINOLOGY
Yesalis CE (ed): Anabolic Steroids in Sport and Exercise, 2nd Edition. Cham-
paign, IL, Human Kinetics, 2000
Yesalis CE, Buckley WA, Wang MO, et al: Athletes’ projections of anabolic ste-
roid use. Clin Sports Med 2:155–171, 1990
Yesalis CE, Kennedy NJ, Kopstein AN, et al: Anabolic-androgenic steroid use in
the United States. JAMA 270:1217–1221, 1993
Yesalis CE, Barsukiewicz CK, Kopstein AN, et al: Trends in anabolic-androgenic
steroid use among adolescents. Arch Pediatr Adolesc Med 151:1197–1206,
1997
Zeifert M: Massive dose testosterone therapy in male involutional psychosis. Psy-
chiatr Q 16:319–332, 1942
Part V
Thyroid Hormones
This page intentionally left blank
Chapter 14
Thyroid Function in
Psychiatric Disorders
Thyroid Physiology
361
362 PSYCHONEUROENDOCRINOLOGY
Weinberg and Katzell 1977 50 T4 increased 6 Mental state improved after remission of the thyrotoxicosis.
Caplan et al. 1983 100 FT4I increased 6
Cohen and Swigar 1979 480 Estimated 18 In half of the patients, return to normal within several weeks.
FT4I increased or
PSYCHONEUROENDOCRINOLOGY
decreased
Spratt et al. 1982 645 T4 increased 33 No difference between schizophrenic and depressed patients.
Thyroid function without therapy in 22 patients serially followed.
FT4 increased 18
Morley and Shafer 1982 386 FT4 or FT3I increased 19 Elevations particularly common in patients with paranoid
Total T3 increased 17 schizophrenia (38%) and in patients with amphetamine abuse
(32%). Return to normal levels on retesting 2 or 3 weeks later.
Roca et al. 1990 45 One or more thyroid 49 Significant positive correlations between psychiatric symptom
hormones increased severity and FT4I among depressed and schizophrenic patients.
Chopra et al. 1990 84 T4 increased 24 On repeat testing 7–21 days after admission, serum TSH (and/or T4)
FT4I increased 16 normalized in 3 of the 5 patients studied.
Total T3 increased 20
FT3I increased 13
TSH increased 17
Levy et al. 1981 150 Thyroid hormones 7 Euthyroid sick syndrome in 7% of patients; when blood was sampled
serially, 27%.
McLarty et al. 1978 1,206 Thyroid hormones 0.5–0.7 Hypothyroidism (0.5%), hyperthyroidism (0.7%).
Note. FT4 =free thyroxine; FT3I=free triiodothyronine index; FT4I=free thyroxine index; T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone.
Thyroid Function in Psychiatric Disorders 365
Bipolar Disorder
Serum concentrations of thyroid hormones have been shown to be in-
creased in some acutely ill adult (Mason et al. 1989; Muller and Boning
1988; Southwick et al. 1989; Styra et al. 1991) and adolescent (Sokolov
et al. 1994) patients with bipolar disorder. Other investigators found
reduced thyroid hormone concentrations in acutely ill bipolar patients
(Bartalena et al. 1990a; Chang et al. 1998; Rybakowski and Sowinski
1973), and normal concentrations in euthymic (Kjellman et al. 1985)
bipolar patients. In contrast to depression, changes in serum T4 concen-
Thyroid Function in Psychiatric Disorders 367
trations are not common during recovery from mania (Bauer and Why-
brow 1988). The relationships between bipolar disorder and various
forms of hypothyroidism are discussed under “Thyrotropin, Subclinical
Hypothyroidism, and Antithyroid Antibodies” below.
Depression
The following TSH and autoimmune dysfunctions are not uncommon in
depression: a blunted TSH response to TRH, an abnormal circadian TSH
rhythm, elevated basal TSH concentrations, and elevated titers of anti-
thyroid antibodies. The latter two findings are frequently seen together
in subclinical hypothyroidism.
Abnormal circadian TSH rhythm. Depression is often associated with
disturbances in various circadian behavioral rhythms (e.g., changes in
emotional well-being during the day, frequently worsening in the early
morning) and biological rhythms (e.g., abnormalities in body tempera-
ture and cortisol secretion). To these circadian dysfunctions we can add
an abnormal diurnal TSH rhythm, most commonly a lack of the noctur-
nal TSH surge (Table 14–4). In addition to depression and anorexia ner-
vosa (discussed under “Thyroid Function in Eating Disorders” below),
this abnormality can be found in central hypothyroidism (Adriaanse et al.
1993), in euthyroid patients with suprasellar extensions of pituitary le-
sions (Adriaanse et al. 1993), and after naloxone administration (Samuels
et al. 1994). The latter, of course, suggests that endogenous opioids have
significant stimulatory effects on TSH secretion, predominantly during
the nocturnal TSH surge.
Subclinical hypothyroidism. Between 1% and 4% of patients with a
variety of affective illnesses show evidence of overt hypothyroidism, and
between 4% and 40% show evidence of subclinical hypothyroidism (see
Table 14–5).
Subtle, but not overt, thyroid dysfunctions are therefore rather com-
mon in depressed patients, and they are not clinically innocuous. Comorbid
subclinical hypothyroidism can lower the threshold for the occurrence of
both depression (Haggerty et al. 1993) and panic disorder (Joffe and Lev-
itt 1992) and can be associated with cognitive dysfunction (Haggerty et
TABLE 14–4. Circadian variation in thyroid function in depression
Study N Diagnosis Thyroid measure Comment
Weeke and Weeke 12 ED T4, T3, FT4, FT3, TSH 0200h and 2400h Absence of diurnal TSH variation and free
1978 hormones related to symptom severity
Weeke and Weeke 4 ED T3, TSH q1h for 24h No difference from control subjects
369
370
TABLE 14–5. Hypothyroidism in affectively ill patients
Study N Diagnosis Prevalence (%) Comment
Gold et al. 1981 250 Depression and/or anergia 1 (grade 1) Of the 20 patients with some degree of hypothyroidism, 6 were
4 (grade 2) later discharged after thyroid replacement alone.
4 (grade 3)
Gold et al. 1982 100 Depression and/or anergia 15 (grades 1–3) Of these 15 patients, 60% had detectable antimicrosomal antibodies.
PSYCHONEUROENDOCRINOLOGY
Targum et al. 1984 21 Refractory depression 24 (grade 3) Five of 7 patients who responded to combined thyroid hormone-
antidepressant treatment had grade 3 hypothyroidism.
Haggerty et al. 1987 102 Affective disorder 10 (grade 3) Dexamethasone nonsuppressors were significantly more likely to
have elevated TSH levels than suppressors. 20% of patients had
antithyroid antibodies.
Tappy et al. 1987 157 Psychogeriatric admissiona 4 (grade 1) 15% of 27 patients with neurotic depression had grade 1
104 Medical-surgical admissions 2 (grade 1) hypothyroidism.
Joffe et al. 1992 139 Unipolar depression 14 (grade 3) Depression with grade 3 hypothyroidism differed from depression
without grade 3 hypothyroidism by the presence of a concurrent
panic disorder and a poorer antidepressant response.
Gewirtz et al. 1988 15 Refractory depression 40 (grades 2, 3) The 6 women with hypothyroidism all responded behaviorally to
thyroid substitution.
Maes et al. 1993 62 Minor depression 8.8 (grade 3) Diagnoses made by use of ultrasensitive TSH assay. Of the
101 Major depression melancholic patients, 8.8% showed some degree of subclinical
57 Melancholic hypothyroidism.
Custro et al. 1994 75 Mood disturbance (in 56 (grade 3) Five of 9 endogenously depressed women were subclinically
women) hypothyroid, but none of the 66 patients with minor depression.
All five women were positive for antithyroid antibodies.
TABLE 14–5. Hypothyroidism in affectively ill patients (continued)
Study N Diagnosis Prevalence (%) Comment
Ordas and Labbate 260 Major and minor depression 3.1 (grade 3) Eight of 260 patients showed subclinical hypothyroidism.
1995
Fava et al. 1995 200 Depression (in outpatients) 2.6 (grade 3) TSH concentration was slightly elevated in 2.6% of patients; no
relationship to response rate was found.
371
372 PSYCHONEUROENDOCRINOLOGY
Bipolar Disorder
When examining thyroid function in bipolar illness, it is useful to distin-
guish between rapid-cycling and non–rapid-cycling bipolar disorder. By
definition, rapid cyclers experience four or more affective episodes per
year (American Psychiatric Association 1994). Approximately 10%–15%
of bipolar patients experience rapid cycling; although they are similar to
other bipolar patients nosologically and demographically, they tend to
TABLE 14–6. Antithyroid antibodies in affectively ill patients
Prevalence
Study N Diagnosis (%) Comment
Gold et al. 1982 100 Depression and/or 9 Of 15 patients with some form of thyroid abnormality, 60% had positive
anergia antibody titers.
373
374 PSYCHONEUROENDOCRINOLOGY
Linnoila et al. 1983 34 MDD rT3 increased rT3 increased in unipolar depression
11 BPD
Kirkegaard and Faber 12 MDD FT4, FrT3 increased Decrease in both hormones with recovery
1991
PSYCHONEUROENDOCRINOLOGY
Kirkegaard et al. 1979 15 MDD TRH increased TRH higher in depressed patients, both before and after
20 Neurological disease recovery, than in neurological disease
Banki et al. 1988 14 MDD TRH increased TRH markedly higher in depressed patients than in the other
4 Somatization patient groups
disorder
12 Neurological disease
Gjerris et al. 1985 21 ED TRH No significant difference among patient groups
13 Non-ED
8 Mania
9 Schizophrenia
Roy et al. 1994 17 MDD TRH No significant difference between patients and control subjects
Roy et al. 1990 51 Alcoholism TRH No significant difference between patients and control subjects
Adinoff et al. 1991 13 Abstinent alcoholics TRH Inverse correlation between TRH-induced TSH response and
cerebrospinal fluid TRH concentrations
Fossey et al. 1993 45 Anxiety disorder TRH TRH levels in patients with panic disorder, generalized anxiety
disorder, or obsessive-compulsive disorder not different from
those of control subjects
Note. BPD=bipolar disorder; ED=endogenous depression; FrT3 =free reverse triiodothyronine; FT4 =free thyroxine; MDD=major depressive disorder;
rT3 =reverse triiodothyronine; TSH=thyroid-stimulating hormone.
Thyroid Function in Psychiatric Disorders 377
MAOIs
To date, only one study has evaluated whether MAOIs can adversely af-
fect thyroid function. Joffe and Singer (1987) treated depressed patients
with phenelzine for 4 weeks and reported no change in thyroid function.
378 PSYCHONEUROENDOCRINOLOGY
Although the study suggests that MAOIs do not have a noticeable effect
on thyroid function, one may caution against the use of MAOIs in the
presence of hyperthyroidism. Increased thyroid hormone concentration
results in increased myocardial sensitivity to a number of central and pe-
ripheral mediators of cardiac activity, including catecholamines and in-
doleamines. Therefore, cardiac toxicity could result from the use of
MAOIs in patients with hyperthyroidism (Larsen and Ingbar 1992).
TCAs
Although TCA toxicity is increased in the presence of hyperthyroidism
(Loosen and Prange 1984; Prange et al. 1969), there appear to be no mor-
phologic or functional changes in the HPT axis during TCA administra-
tion in healthy volunteers (Kirkegaard et al. 1977; Widerlov et al. 1978)
or in depressed patients (Coppen et al. 1974; Karlberg et al. 1978). (The
change in serum T4 concentrations during antidepressant treatment noted
above does not appear to be specific to TCAs, as it is seen during a wide
range of antidepressant treatments, including TCAs, selective serotonin
reuptake inhibitors, sleep deprivation, and ECT.) Hoeflich et al. (1992)
treated 41 depressed patients with either maprotiline or fluvoxamine for
4 weeks. Serum T4 levels and body temperature decreased and serum
TSH increased significantly during treatment, but there were no signifi-
cant differences between treatment groups or between responders and
nonresponders. Shelton et al. (1993) treated 39 depressed patients with
either desipramine or fluoxetine. Twenty-six percent showed some ab-
normality in baseline thyroid hormone levels. There were no demonstra-
ble differences for any of the thyroid indices from baseline to the 3- or 6-
week samples for the total group or for either drug. There was a signifi-
cant group-by-time interaction for total T4 between the drug treatment
groups, which was caused by a small but significant increase in T4 in the
desipramine sample. Correlations between the change in hormones over
the 6-week period and treatment response were calculated. There was a
significant association between a decline in T3 levels and response to flu-
oxetine but not desipramine.
Brady et al. (1994) assessed the comparative efficacy of fluvoxamine
and imipramine in patients with major depressive disorder. Although se-
rum thyroid hormone concentrations were normal at baseline, both T4
and T3 levels decreased significantly in the imipramine group but not in
the fluvoxamine group. In the imipramine group, decreases in depression
scores were also significantly correlated with decreases in T3 concen-
trations. McCowen and colleagues (1997) found elevated serum TSH
concentrations in nine T4-substituted patients with hypothyroidism (with
Thyroid Function in Psychiatric Disorders 379
duration of the illness ranging from 1 to 23 years) who were treated with
sertraline. FT4I values decreased in all patients in whom they were mea-
sured. No patient had symptoms of hypothyroidism. The effects of ser-
traline were not due to changes in T4 absorption or serum concentrations
of TBG; sertraline may increase the clearance of T4.
Taken together, the data suggest that routine monitoring of thyroid
function in patients with major depressive disorder taking TCAs is not
necessary. However, TCAs—and, to a lesser degree, selective serotonin
reuptake inhibitors—should be used with caution in patients with overt
thyroid disease, particularly hyperthyroidism, because they may promote
tachycardia and cardiac arrhythmias in this condition. The theoretical
basis for these effects is similar to that described above for MAOIs. The
effects of sertraline in hypothyroid patients substituted with T4 described
above (McCowen et al. 1997) also need to be considered.
ECT
The effects of ECT on hormones of the HPT axis are remarkably consis-
tent. Most (Aperia et al. 1985; Dykes et al. 1987; Papakostas et al. 1991;
Scott et al. 1989) but not all (Deakin et al. 1983) studies reported that
serum TSH levels rise acutely during ECT; the TSH rise seems to atten-
uate after a series of ECT treatments (Aperia et al. 1985; Hofmann et al.
1994). A blunted TSH response to TRH during ECT has also been re-
ported (Decina et al. 1987), although not all studies agree (Hofmann et
al. 1994; Papakostas et al. 1981). In rats, ECT can induce synthesis of
TRH in multiple subcortical limbic and frontal cortical regions, which are
known to be involved in depression (Sattin 1998).
Seizure activity (Papakostas et al. 1991; Scott et al. 1989) and seizure
duration (Dykes et al. 1987; Scott et al. 1989) are associated with these
dynamic changes in HPT axis function during ECT, but not treatment re-
sponse (Decina et al. 1987; Dykes et al. 1987; Papakostas et al. 1991),
treatment modality (i.e., unilateral vs. bilateral ECT) (Decina et al. 1987),
or psychopathology (i.e., diagnosis of depression or schizophrenia) (Pa-
pakostas et al. 1991).
Prange et al. (1990), studying 50 patients with major depressive dis-
order, first reported that baseline thyroid hormone concentrations were
inversely related to ratings of ECT-induced organicity. This finding, sug-
gesting that the course of ECT may be beneficially affected by thyroid
hormones, was confirmed when the same investigators demonstrated
that patients given a small amount of T3 required fewer ECT treatments
than patients receiving placebo, although the percentage decrease was
not different among groups (Stern et al. 1991).
Thyroid Function in Psychiatric Disorders 381
Sleep Deprivation
The antidepressant effects of one night of sleep deprivation have been
well documented (Kuhs and Toelle 1991; Leibenluft and Wehr 1991).
Changes in serum thyroid hormone and TSH concentrations during par-
tial or total sleep deprivation are very common. Although study designs
and methodologies differed, all studies reported that serum TSH levels
increased significantly during total (Baumgartner et al. 1990a, 1990c;
Kaschka et al. 1989; Kasper et al. 1988, 1992; Leibenluft et al. 1993;
Parekh et al. 1998) or partial (Baumgartner et al. 1990b, 1993) sleep
deprivation; the TSH rise did correlate with clinical response in some
(Baumgartner et al. 1990a; Kaschka et al. 1989; Kasper et al. 1992;
Parekh et al. 1998) but not other (Baumgartner et al. 1990b, 1990c;
Kasper et al. 1988; Leibenluft et al. 1993) studies. Increases in serum
thyroid hormone levels during sleep deprivation have also been reported
(Baumgartner et al. 1990a, 1990b, 1990c; Kaschka et al. 1989; Kasper
et al. 1992; Parekh et al. 1998); the thyroid hormone increase did
(Kasper et al. 1992) or did not (Baumgartner et al. 1990b) correspond
with clinical response. In patients with rapid-cycling bipolar disorder,
the normal nocturnal circadian increase in serum TSH was absent, and
sleep deprivation failed to increase TSH concentration (Sack et al.
1988).
Phototherapy
There is no evidence that thyroid function plays a role in the response of
winter depressive symptoms to light treatment (Bauer et al. 1993; Joffe
et al. 1991).
Bipolar Disorder
Bipolar disorders are often associated with various forms of hypothyroid-
ism. As in depression, such comorbidity is seen more frequently in female
patients. As in depression, such comorbidity seems to negatively affect
the course of the illness (by predisposing the individual patient to a rapid-
cycling course). As in depression, substitution with T4 has proved useful
in some patients, but often high doses are necessary to induce clinical
response (Bauer and Whybrow 1988; Baumgartner et al. 1994a). Con-
ceptually, these findings have led to the hypothesis that a relative central
thyroid hormone deficit may predispose to the marked and frequent
mood swings that characterize rapid-cycling bipolar disorder. However,
there are several confounding issues in studies involving rapid cycling and
thyroid function (Bauer et al. 1990). First, because of their more severe
course, rapid-cycling patients are more likely to have received thyroid
hormone treatment and may then be erroneously classified as hypothy-
roid in retrospective studies. Second, the female preponderance in rapid-
cycling bipolar disorder may elevate the rate of hypothyroidism, because
both disorders are more common in women. Last, the use of lithium and
carbamazepine, known goitrogens, is not examined in some studies. It
also remains to be determined whether the alleged central thyroid
hormone deficit serves only as a risk factor for the development of rapid
cycling in a known bipolar patient, or whether it can predispose most af-
fectively ill patients to any major behavioral change (e.g., the switch from
depression into recovery or from depression into mania).
nificance. The most likely factor contributing to elevated basal TSH lev-
els and, possibly, absence of a blunted TSH response, is the reduced
serum T3 concentration noted above. Other possible factors are a de-
creased TSH clearance, increased serum estrogen levels (which are not
unusual in patients with liver damage and which could potentiate TSH
release), or a combination thereof. Estrogens do acutely inhibit the rate
of hormone release from the thyroid in adults, but any effect appears to
be transient because thyroid function is similar in healthy women and
men (Gambert 1991), and both men and women taking long-term estro-
gen therapy have normal serum FT4, FT3, and TSH levels (Gambert
1991).
with PTSD and 24 male control subjects, reported that PTSD patients
showed moderately elevated T4 levels and normal FT4 levels, marked and
sustained elevation in levels of both T3 and FT3, as well as elevated T3:T4
ratios and normal TSH levels.
T4 AN in normal range 5 Brown et al. 1977; Burman et al. 1977; Collu 1979; Moore and Mills 1979; Moshang et al.
1975
T4 AN<matched controls 3 Kokei et al. 1986; Miyai et al. 1975; Tamai et al. 1986
FT4 AN<matched controls 2 Kokei et al. 1986; Tamai et al. 1986
391
triiodothyronine; T3 =triiodothyronine; T4 =thyroxine; TBG=thyroxin-binding globulin; TSH=thyroid-stimulating hormone; TRHDTSH=Thyrotropin response to TRH.
392 PSYCHONEUROENDOCRINOLOGY
Lobkov 1990; Jung et al. 1985), and in obese patients (Portnay et al. 1974;
Vagenakis et al. 1975). The pattern of low normal T4, diminished T3, and
normal TSH concentrations is known as the low T3 syndrome or the eu-
thyroid sick syndrome (Carter et al. 1974; Chopra et al. 1983). There is
evidence that the peripheral signs of hypothyroidism (i.e., bradycardia,
hypercholesterolemia) are related to the diminished T3 seen in anorexia
nervosa (Bannai et al. 1988). Both low thyroid indices and TBG abnor-
malities demonstrated in anorexia nervosa and in protein-calorie malnu-
trition are corrected after weight gain (Table 14–8). In anorexic patients,
T3 levels may even increase into the hyperthyroid range during the weight
gain phase of treatment (Moore and Mills 1979). This increase in T3 se-
cretion may be partially responsible for the diet-induced thermogenesis
and increased resting energy expenditure observed in anorexia nervosa
patients, which enhances their adaptive resistance to refeeding (Moukad-
dem et al. 1997).
Reverse T3, the metabolically inactive enantiomer of T3, has been
found to be increased in experimentally starved control subjects (Komaki
et al. 1986; Vagenakis et al. 1975), in patients with anorexia nervosa
(Table 14–8), and in obese individuals. It has also been found in protein-
calorie malnutrition and other disease states (Chopra et al. 1975; Kokei
et al. 1986). It is thought that the tissue conversion of T4 and T3 to rT3
represents a physiological adaptation to malnutrition and decreased ca-
loric intake, with the goal of preserving energy and preventing the (un-
necessary and potentially harmful) further burning of calories. There is
also evidence that the thyroid gland secretes less T3 in anorexia nervosa
and that this mechanism is another contributor of the low T3 reported in
this illness (Kiyohara et al. 1989).
Baseline levels of TSH in anorexia nervosa are in the normal range in
all studies but one, in which decreased TSH levels were found (Table 14–8).
In anorexia nervosa TSH secretion may be more predominantly regulated
by normal FT4 than by T3 levels (Bannai et al. 1988; Haraguchi et al.
1986), because high TSH levels have been reported in the presence of
low FT4 concentrations (Matsubayashi et al. 1988). TSH levels also do
not seem to be altered in acutely starved control subjects or overweight
patients (Portnay et al. 1974). TSH has a circadian rhythm in healthy in-
dividuals (Azukizawa et al. 1976; Vagenakis 1979), with a peak occur-
ring during or after the onset of sleep, and a nadir in the late afternoon.
Both indirect (Croxson and Ibbertson 1977) and direct (Gwirtsman et al.
1988) measurements of these circadian rhythms in anorexia nervosa in-
dicate a loss of the nighttime surge, with a general resetting of the curve
upward. Although these data are preliminary and require replication, it
is noteworthy that in experimental animals both hypothyroidism and
Thyroid Function in Psychiatric Disorders 393
Bulimia Nervosa
Several studies have examined thyroid function and RMR in bulimic pa-
tients, with equivocal results. Some investigators found RMR (Devlin et
al. 1990; Obarzanek et al. 1991) and serum T3 levels (Kiyohara et al.
1988; Obarzanek et al. 1991; Pirke et al. 1985b) to be significantly re-
duced in bulimic patients with normal weight, especially when patients
394 PSYCHONEUROENDOCRINOLOGY
were studied during abstinence from binge eating, whereas other investi-
gators found thyroid indices, including basal TSH, to be normal (Devlin
et al. 1990; Gwirtsman et al. 1983; Mitchell and Bantle 1983). Two stud-
ies conducted at the National Institutes of Health reported that bulimic
patients studied shortly after admission had either normal thyroid indices
or slightly diminished T3 levels. However, after 3 weeks of abstinence
from binge eating and purging, T4 and T3 levels declined significantly,
whereas TSH levels increased modestly (Spalter et al. 1993). After 7 weeks
of abstinence, all thyroid indices, including FT4, FT3, rT3, and TBG levels
were reduced compared with the acute binge-eating phase and compared
with control subjects. The nocturnal TSH surge in the bulimic patients
was similar to that of control subjects and was unaffected by changes in
thyroid indices (Altemus et al. 1996). The authors concluded that this
represented a form of subclinical hypothyroidism during abstinence,
with an impaired feedback on the pituitary or the hypothalamus. In one
study (Spalter et al. 1993), levels of T3 were directly correlated with ca-
loric intake and were inversely correlated with body weight. RMR has
also been reported to decline significantly during abstinence from binge
eating and purging (Altemus et al. 1991; T. Leonard et al. 1996), com-
pared with the same patients during active binge eating. The data suggest
that binge-purge behavior may transiently increase thyroid indices and
RMR, whereas decreases in thyroid indices following abstinence from
binge eating and purging behaviors are probably related to either dimin-
ished caloric consumption or else may reflect hypothalamic-pituitary
dysregulation. Thus, normal-weight bulimic subjects who are abstinent
from binge-purge cycles may have a variant of the euthyroid sick syn-
drome (Spalter et al. 1993).
Binge-Eating Disorder
Binge-eating disorder is a newly described eating disorder in which in-
dividuals engage in binge eating episodes but do not purge their food,
leading inevitably to obesity (American Psychiatric Association 1994).
Recent epidemiological surveys indicate that this disorder is highly prev-
alent among the obese, perhaps exceeding 30% (Spitzer et al. 1992).
RMR or baseline thyroid indices do not differ in binge-eating and non-
binging obese patients (Wadden et al. 1993). However, a low RMR can
be a predictor of certain forms of obesity (Astrup et al. 1996; Ravussin
and Gautier 1999). Furthermore, the physiological role of leptin on energy
intake may be through a modulatory effect on the HPT axis—specifi-
cally, by regulating pro-TRH gene expression in the paraventricular nu-
cleus (Ahima et al. 1996; Legradi et al. 1997).
Thyroid Function in Psychiatric Disorders 395
Conclusion
The literature provides much support for the notion that there are many
associations between thyroid hormones and behavior, although the exact
nature of these associations remains unknown. The effects of thyroid hor-
mones (or the lack thereof) during early human development on brain
function, their use to supplement the treatment regimen of some pa-
tients who respond poorly to standard antidepressants, and their often
marked psychological effects in patients with thyroid disorders are be-
yond the scope of this review and have been discussed elsewhere (Ahmed
Smith and Loosen 1998; Bauer and Whybrow 1988; Loosen 1986).
The clinical studies of thyroid function in mental illness discussed
here have brought forward a plethora of findings; some are clinically rel-
evant. First, abnormal thyroid function is often observed in mood disor-
ders. In a similar way, mood disturbances are among the most prominent
psychological sequelae of overt thyroid disease. In both depression and
bipolar disorder, comorbid thyroid dysfunctions are not clinically innoc-
uous; they can negatively affect short-term and long-term outcome and
can complicate treatment. (Routine thyroid function tests are not indi-
cated in psychiatric patients, because only a very small percentage of
patients show even such mild thyroid abnormalities as subclinical hypo-
thyroidism. However, if thyroid dysfunction exists as a comorbid condi-
tion in mood disorders, early aggressive treatment is warranted.) Second,
the euthyroid sick syndrome and mild, transient hyperthyroxinemia are
common among acutely hospitalized psychiatric patients; both are dis-
ease nonspecific and usually normalize on recovery. Thyroid function
tests obtained at admission therefore need to be interpreted with caution.
Third, lithium and carbamazepine (but not valproic acid) decrease thy-
roid function; careful, repeated thyroid status assessments are therefore
necessary during the course of treatment. Fourth, abnormal thyroid func-
tion can be associated with a symptom of a disease rather than with the
disease itself. The effects of starvation on thyroid function are well known;
starvation and symptoms leading to starvation (e.g., loss of appetite,
weight loss) therefore need to be considered when interpreting results. In
a similar way, disease complications can lead to false-negative results. In al-
coholic patients without liver disease a blunted TSH response to TRH is
common. However, in those with liver disease TSH responses are nor-
mal, possibly due to decreased T3 concentrations (which, in turn, are
thought to be the direct result of alcohol-induced liver damage). Fifth,
there appears to be no direct causal relationship between thyroid func-
tion and various clinical states. Rather, changes in thyroid function can fa-
398 PSYCHONEUROENDOCRINOLOGY
References
Adinoff B, Nemeroff CB, Bissette G, et al: Inverse relationship between CSF TRH
concentrations and the TSH response to TRH in abstinent alcohol-dependent
patients. Am J Psychiatry 148:1586–1588, 1991
Adriaanse R, Brabant G, Endert E, et al: Pulsatile thyrotropin release in patients
with untreated pituitary disease. J Clin Endocrinol Metab 77:205–209, 1993
Agner T, Hagen C, Nyboe Andersen B, et al: Pituitary-thyroid function and thy-
rotropin, prolactin and growth hormone responses to TRH in patients with
chronic alcoholism. Acta Med Scand 220:57–62, 1986
Ahima RS, Prabakaran D, Mantzoros C, et al: Role of leptin in the neuroendo-
crine response to fasting. Nature 382:250–252, 1996
Ahmed Smith N, Loosen PT: Thyroid hormones in major depressive and bipolar dis-
orders, in Women’s Health: Hormones, Emotions and Behavior. Edited by
Casper RC. Cambridge, England, Cambridge University Press, 1998, pp 83–108
Altemus M, Hetherington MM, Flood M, et al: Decrease in resting metabolic rate
during abstinence from bulimic behavior. Am J Psychiatry 148:1071–1072,
1991
Altemus M, Hetherington M, Kennedy B, et al: Thyroid function in bulimia ner-
vosa. Psychoneuroendocrinology 21:249–261, 1996
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Dis-
orders, 4th Edition. Washington, DC, American Psychiatric Association, 1994
Thyroid Function in Psychiatric Disorders 399
Anderson DL, Nelson JC, Haviland MG, et al: Thyroid stimulating hormone and
prolactin responses to thyrotropin releasing hormone in nondepressed alco-
holic inpatients. Psychiatry Res 43:121–128, 1992
Aperia B, Thoren M, Wetterberg L: Prolactin and thyrotropin in serum during
electroconvulsive therapy in patients with major depressive illness. Acta Psy-
chiatr Scand 72:302–308, 1985
Astrup A, Buemann B, Toubro S, et al: Low resting metabolic rate in subjects pre-
disposed to obesity: a role for thyroid status. Am J Clin Nutr 63:879–883,
1996
Atterwill CK, Bunn SJ, Atkinson DJ, et al: Effects of thyroid status on presynaptic
alpha-2 adrenoreceptor function and beta-adrenoreceptor binding in the rat
brain. J Neural Transm 59:43–55, 1984
Azukizawa M, Pekary AE, Hershman JM, et al: Plasma thyrotropin, thyroxine,
and triiodothyronine relationships in man. J Clin Endocrinol Metab 43:533–
542, 1976
Banki CM, Arato M, Papp Z: Thyroid stimulation test in healthy subjects and psy-
chiatric patients. Acta Psychiatr Scand 70:295–303, 1984
Banki CM, Bissette G, Arato M, et al: Elevation of immunoreactive CSF TRH in
depressed patients. Am J Psychiatry 145:1526–1531, 1988
Bannai C, Kuzuya N, Koide Y, et al: Assessment of the relationship between se-
rum thyroid hormone levels and peripheral metabolism in patients with an-
orexia nervosa. Endocrinol Jpn 35:455–462, 1988
Baptista T, Molina MG, Martinez JL, et al: Effects of the antipsychotic drug sulpi-
ride on reproductive hormones in healthy premenopausal women: relation-
ship with body weight regulation. Pharmacopsychiatry 30:256–262, 1997
Bartalena L, Pellegrini L, Meschi M, et al: Evaluation of thyroid function in pa-
tients with rapid-cycling and non-rapid-cycling bipolar disorder. Psychiatry
Res 34:13–17, 1990a
Bartalena L, Placidi GF, Martino E, et al: Nocturnal serum thyrotropin
(TSH) surge and the TSH response to TSH-releasing hormone: dissociated
behavior in untreated depressives. J Clin Endocrinol Metab 71:650–655,
1990b
Bauer MS, Whybrow PC: Thyroid hormones and the central nervous system in
affective illness: interactions that may have clinical significance. Integr Psy-
chiatry 6:75–100, 1988
Bauer MS, Whybrow PC: Rapid cycling bipolar affective disorder, II: treatment
of refractory rapid cycling with high-dose levothyroxine: a preliminary study.
Arch Gen Psychiatry 47:435–440, 1990
Bauer MS, Whybrow PC, Winokur A: Rapid cycling bipolar affective disorder, I:
association with grade I hypothyroidism. Arch Gen Psychiatry 47:427–432,
1990
Bauer MS, Kurtz J, Winokur A, et al: Thyroid function before and after four-week
light treatment in winter depressives and controls. Psychoneuroendocrinol-
ogy 18:437–443, 1993
400 PSYCHONEUROENDOCRINOLOGY
Chopra IJ, Chopra U, Smith SR, et al: Reciprocal changes in serum concentra-
tions of 3,3¢,5- triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol
Metab 41:1043–1049, 1975
Chopra IJ, Hershman JM, Pardridge WM, et al: Thyroid function in nonthyroidal
illnesses (review). Ann Intern Med 98:946–957, 1983
Chopra IJ, Solomon DH, Huang TS: Serum thyrotropin in hospitalized psychiat-
ric patients: evidence for hyperthyrotropinemia as measured by an ultrasen-
sitive thyrotropin assay. Metabolism 39:538–543, 1990
Cohen K, Swigar M: Thyroid function screening in psychiatric patients. JAMA
242:254–257, 1979
Coiro V, Volpi R, Marchesi C, et al: Lack of seasonal variation in abnormal TSH
secretion in patients with seasonal affective disorder. Biol Psychiatry 35:36–
41, 1994
Collu R: Abnormal pituitary hormone response to thyrotropin-releasing hor-
mone: an index of central nervous system dysfunction, in Clinical Neuro-
endocrinology: A Pathophysiological Approach. Edited by Tolis G. New
York, Raven, 1979, pp 129–137
Coppen A, Peet M, Montgomery S, et al: Thyrotropin-releasing hormone in the
treatment of depression. Lancet 2:433–435, 1974
Cowdry RW, Wehr TA, Zis AP, et al: Thyroid abnormalities associated with rapid-
cycling bipolar illness. Arch Gen Psychiatry 40:414–420, 1983
Croxson MS, Ibbertson HK: Low serum triiodothyronine (T3) and hypothyroid-
ism in anorexia nervosa. J Clin Endocrinol Metab 44:167–174, 1977
Custro N, Scafidi V, Lo BR, et al: Subclinical hypothyroidism resulting from
autoimmune thyroiditis in female patients with endogenous depression.
J Endocrinol Invest 17:641–646, 1994
Dackis CA, Bailey J, Pottash AL, et al: Specificity of the DST and the
TRH test for major depression in alcoholics. Am J Psychiatry 141:680–683,
1984
Deakin JF, Ferrier IN, Crow TJ, et al: Effects of ECT on pituitary hormone re-
lease: relationship to seizure, clinical variables and outcome. Br J Psychiatry
143:618–624, 1983
Decina P, Sackeim HA, Kahn DA, et al: Effects of ECT on the TRH stimulation
test. Psychoneuroendocrinology 12:29–34, 1987
de la Fuente JR, Morse RM, Niven RG, et al: Thyroid function in the alcoholic.
Rev Invest Clin 34:211–214, 1982
DeLisi LE, Boccio AM, Riordan H, et al: Familial thyroid disease and delayed lan-
guage development in first admission patients with schizophrenia. Psychia-
try Res 38:39–50, 1991 (Published erratum appears in Psychiatry Res 41(2):
189, 1992.)
Devlin MJ, Walsh BT, Kral JG, et al: Metabolic abnormalities in bulimia nervosa.
Arch Gen Psychiatry 47:144–148, 1990
Dewhurst KE, El Kabir DJ, Exley D, et al: Blood levels of TSH, protein-bound
iodine, and cortisol in schizophrenia and affective states. Lancet 2:1160–
1162, 1968
Thyroid Function in Psychiatric Disorders 403
Garbutt JC, Miller LP, Karnitschnig JS, et al: Thyrotropin response to thyrotropin-
releasing hormone in young men at high or low risk for alcoholism. Ann N Y
Acad Sci 708:129–133, 1994
Garbutt JC, Miller LP, Mundle L, et al: Thyrotropin and prolactin responses to
thyrotropin-releasing hormone in young men at high or low risk for alcohol-
ism. Alcohol Clin Exp Res 19:1133–1140, 1995
Geurts J, Demeester-Mirkinje N, Glinoer D, et al: Alterations in circulating thy-
roid hormones and thyroxine binding globulin in chronic alcoholism. Clin
Endocrinol (Oxf) 14:113–118, 1981
Gewirtz GR, Malaspina D, Hatterer JA, et al: Occult thyroid dysfunction
in patients with refractory depression. Am J Psychiatry 145:1012–1014,
1988
Gibbons JL, Gibson JG, Maxwell AE: An endocrine study of depressive illness.
J Psychosom Res 5:32–41, 1960
Gillette GM, Garbutt JC, Quade DE: TSH response to TRH in depression with
and without panic attacks. Am J Psychiatry 146:743–748, 1989
Girdler SS, Pedersen CA, Light KC: Thyroid axis function during the menstrual
cycle in women with premenstrual syndrome. Psychoneuroendocrinology
20:395–403, 1995
Gjerris A, Hammer M, Vendsborg P, et al: Cerebrospinal fluid vasopressin—
changes in depression. Br J Psychiatry 147:696–701, 1985
Gjessing LR: A review of periodic catatonia. Biol Psychiatry 8:23–45, 1974
Gold MS, Pottash AL, Martin DM, et al: Thyroid stimulating hormone and
growth hormone responses to thyrotropin releasing hormone in anorexia
nervosa. Int J Psychiatry Med 10:51–55, 1980
Gold MS, Pottash ALC, Extein I: Hypothyroidism and depression. JAMA 245:
1919–1922, 1981
Gold MS, Pottash ALC, Extein I: “Symptomless” autoimmune thyroiditis in de-
pression. Psychiatry Res 6:261–269, 1982
Golstein J, VanCauter E, Linkowski P, et al: Thyrotropin nyctohemeral pattern in
primary depression: differences between unipolar and bipolar women. Life
Sci 27: 1695–1703, 1980
Gorozhanin VS, Lobkov VV: [Hormonal and metabolic reactions in the human
body during prolonged starvation]. Kosm Biol Aviakosm Med 24:47–50,
1990
Green JRB, Snitcher EJ, Mowat NAG, et al: Thyroid function and thyroid regu-
lation in euthyroid men with chronic liver disease. Clin Endocrinol (Oxf)
7:453–461, 1977
Grunder G, Wetzel H, Hillert A, et al: The neuroendocrinological profile of rox-
indole, a dopamine autoreceptor agonist, in schizophrenic patients. Psycho-
pharmacology (Berl) 117:472–478, 1995
Grunder G, Wetzel H, Schlosser R, et al: Neuroendocrine response to antipsy-
chotics: effects of drug type and gender. Biol Psychiatry 45:89–97, 1999
Gwirtsman HE, Roy-Byrne P, Yager J, et al: Neuroendocrine abnormalities in bu-
limia. Am J Psychiatry 140:559–563, 1983
Thyroid Function in Psychiatric Disorders 405
Israel Y, Orrego H: Hypermetabolic state and hypoxic liver damage. Recent Dev
Alcohol 2:119–133, 1984
Israel Y, Walfish PG, Orrego H, et al: Thyroid hormones in alcoholic liver disease.
Gastroenterology 76:116–122, 1979
Jackson IM: The thyroid axis and depression. Thyroid 8:951–956, 1998
Joffe RT: Anti-thyroid antibodies in major depression. Acta Psychiatr Scand 76:
598–599, 1987
Joffe RT, Levitt AJ: Major depression and subclinical (grade 2) hypothyroidism.
Psychoneuroendocrinology 17:215–221, 1992
Joffe RT, Levitt AJ: The thyroid and depression, in The Thyroid Axis and Psychi-
atric Illness. Edited by Joffe RT, Levitt AJ. Washington, DC, American Psy-
chiatric Press, 1993, pp 195–253
Joffe RT, Singer W: Effect of phenelzine on thyroid function in depressed pa-
tients. Biol Psychiatry 22:1033–1035, 1987
Joffe RT, Singer W: The effect of tricyclic antidepressants on basal thyroid hor-
mone levels in depressed patients. Pharmacopsychiatry 23:67–69, 1990
Joffe RT, Swinson RP: Thyroid function in obsessive-compulsive disorder. Psychi-
atr J Univ Ott 13:215–216, 1988
Joffe RT, Gold PW, Uhde TW, et al: The effects of carbamazepine on the thyro-
tropin response to thyrotropin-releasing hormone. Psychiatry Res 12:161–
166, 1984
Joffe RT, Blank DW, Post RM, et al: Decreased triiodothyronines in depression: a
preliminary report. Biol Psychiatry 20:922–925, 1985
Joffe RT, Kutcher S, MacDonald C: Thyroid function and bipolar affective disor-
der. Psychiatry Res 25:117–121, 1988
Joffe RT, Levitt AJ, Kennedy SH: Thyroid function and phototherapy in seasonal
affective disorder (letter). Am J Psychiatry 148:393, 1991 (Published erra-
tum appears in Am J Psychiatry 148(6):819, 1991.)
Joffe RT, Singer W, Levitt AJ: Methimazole in treatment-resistant depression.
Biol Psychiatry 31:1235–1237, 1992
Johnstone EC, Macmillan JF, Crow TJ: The occurrence of organic disease of pos-
sible or probable aetiological significance in a population of 268 cases of first
episode schizophrenia. Psychol Med 17:371–379, 1987
Jung RT, Rosenstock J, Wood SM, et al: Dopamine in the pituitary adaptation to
starvation in man. Postgrad Med J 717:571–574, 1985
Kallner G: Assessment of thyroid function in chronic alcoholics. Acta Med Scand
209:93–96, 1981
Karlberg BE, Kjellman BF, Kagedol B: Treatment of endogenous depression with
oral thyrotropin. Acta Psychiatr Scand 58:389–400, 1978
Kaschka WP, Fluegel D, Negele-Anetsberger J, et al: Total sleep deprivation and
thyroid function in depression. Psychiatr Res 29:231–234, 1989
Kasper S, Sack DA, Wehr TA, et al: Nocturnal TSH and prolactin secretion dur-
ing sleep deprivation and prediction of antidepressant response in patients
with major depression. Biol Psychiatry 24:631–641, 1988
Thyroid Function in Psychiatric Disorders 407
Loosen PT, Wilson IC, Dew BW, et al: Thyrotropin-releasing hormone (TRH) in
abstinent alcoholic men. Am J Psychiatry 140:1145–1149, 1983
Loosen PT, Garbutt JC, Prange AJ Jr: Evaluation of the diagnostic utility of the
TRH-induced TSH response in psychiatric disorders. Pharmacopsychiatry
20:90–95, 1987a
Loosen PT, Marciniak R, Thadani K: TRH-induced TSH response in healthy vol-
unteers: relationship to psychiatric history. Am J Psychiatry 144:455–459,
1987b
Lundberg PO, Walinder J, Werner I, et al: Effects of thyrotropin-releasing hor-
mone on plasma levels of TSH, FSH, LH and GH in anorexia nervosa. Eur
J Clin Invest 2:150–153, 1972
Macaron C, Wilber JF, Green O, et al: Studies of growth hormone (GH), thyro-
tropin (TSH) and prolactin (PRL) secretion in anorexia nervosa. Psycho-
neuroendocrinology 3:181–185, 1978
MacSweeney D, Timms P, Johnson A: Thyro-endocrine pathology, obstetric mor-
bidity and schizophrenia: survey of a hundred families with a schizophrenic
proband. Psychol Med 8:151–155, 1978
Maes M: TRH test in depression and use of an ultrasensitive TSH assay. Biol Psy-
chiatry 34:122–123, 1993
Maes M, Meltzer HY, Cosyns P, et al: An evaluation of basal hypothalamic-
pituitary-thyroid axis function in depression: results of a large-scaled and
controlled study. Psychoneuroendocrinology 18:607–620, 1993
Maes M, D’Hondt P, Blockx P, et al: A further investigation of basal HPT axis
function in unipolar depression: effects of diagnosis, hospitalization, and
dexamethasone administration. Psychiatry Res 51:185–201, 1994
Marangell LB, George MS, Bissette G, et al: Carbamazepine increases cerebro-
spinal fluid thyrotropin-releasing hormone levels in affectively ill patients.
Arch Gen Psychiatry 51:625–628, 1994
Marangell LB, Ketter TA, George MS, et al: Inverse relationship of peripheral thy-
rotropin-stimulating hormone levels to brain activity in mood disorders. Am
J Psychiatry 154:224–230, 1997
Marchesi C, Campanini T, Govi A, et al: Abnormal thyroid stimulating hormone,
prolactin, and growth hormone responses to thyrotropin releasing hormone
in abstinent alcoholic men with cerebral atrophy. Psychiatry Res 28:89–96,
1989
Markianos M, Hatzimanolis J, Stefanis C: Prolactin and TSH responses to TRH
and to haloperidol in schizophrenic patients before and after treatment. Eur
Neuropsychopharmacol 4:513–516, 1994
Mason JW, Kennedy JL, Kosten TR, et al: Serum thyroxine levels in schizophre-
nic and affective disorder diagnostic subgroups. J Nerv Ment Dis 177:351–
358, 1989
Mason J, Southwick S, Yehuda R, et al: Elevation of serum free triiodothyronine,
total triiodothyronine, thyroxine-binding globulin, and total thyroxine levels
in combat-related posttraumatic stress disorder. Arch Gen Psychiatry 51:
629–641, 1994
Thyroid Function in Psychiatric Disorders 411
Myers DH, Carter RA, Burns BH, et al: A prospective study of the effects of lith-
ium on thyroid function and on the prevalence of anti-thyroid antibodies.
Psychol Med 15:55–61, 1985
Naber D, Steinbock H, Greil W: Effects of short- and long-term neuroleptic treat-
ment on thyroid function. Prog Neuropsychopharmacol Biol Psychiatry 4:
199–206, 1980
Natori Y, Yamaguchi N, Koike S, et al: [Thyroid function in patients with anorexia
nervosa and depression]. Rinsho Byori 42:1268–1272, 1994
Nemeroff CB, Simon JS, Haggerty JJ Jr, et al: Anti-thyroid antibodies in depressed
patients. Am J Psychiatry 142:840–843, 1985
Nikolai TF, Mulligan GM, Gribble RK, et al: Thyroid function and treatment in
premenstrual syndrome. J Clin Endocrinol Metab 70:1108–1113, 1990
Nomura S, Pittman CS, Chambers JB Jr, et al: Reduced peripheral conversion of
thyroxine to triiodothyronine in patients with hepatic cirrhosis. J Clin Invest
56:643–652, 1975
Obarzanek E, Lesem MD, Goldstein DS, et al: Reduced resting metabolic rate in
patients with bulimia nervosa. Arch Gen Psychiatry 48:456–462, 1991
O’Hanlon M, Barry S, Clare AW, et al: Serum thyrotropin responses to thyrotropin-
releasing hormone in alcohol-dependent patients with and without depres-
sion. J Affect Disord 21:109–115, 1991
Ordas DM, Labbate LA: Routine screening of thyroid function in patients hospi-
talized for major depression or dysthymia? (see comments). Ann Clin Psy-
chiatry 7:161–165, 1995
Orenstein H, Peskind A, Raskind MA: Thyroid disorders in female psychiatric pa-
tients with panic disorder or agoraphobia. Am J Psychiatry 145:1428–1430,
1988
Orrego H, Blake JE, Blendis LM, et al: Long-term treatment of alcoholic liver dis-
ease with propylthiouracil. N Engl J Med 317:1421–1427, 1987
Orsulak PJ, Crowley G, Schlesser MA, et al: Free triiodothyronine (T3) and thy-
roxine (T4) in a group of unipolar depressed patients and normal subjects.
Biol Psychiatry 20:1047–1054, 1985
O’Shanick GJ, Ellinwood EH Jr: Persistent elevation of thyroid-stimulating hor-
mone in women with bipolar affective disorder. Am J Psychiatry 139:513–
514, 1982
Othman SS, Abdul KK, Hassan J, et al: High prevalence of thyroid function test
abnormalities in chronic schizophrenia (see comments). Aust N Z J Psychi-
atry 28:620–624, 1994
Papakostas Y, Fink M, Lee J, et al: Neuroendocrine measures in psychiatric pa-
tients: course and outcome with ECT. Psychiatry Res 4:55–64, 1981
Papakostas Y, Markianos M, Papadimitriou G, et al: Thyrotropin and prolactin re-
sponses to ECT in schizophrenia and depression. Psychiatry Res 37:5–10,
1991
Parekh PI, Ketter TA, Altshuler L, et al: Relationships between thyroid hormone
and antidepressant responses to total sleep deprivation in mood disorder pa-
tients. Biol Psychiatry 43:392–394, 1998
Thyroid Function in Psychiatric Disorders 413
Pienaar WP, Roberts MC, Emsley RA, et al: The thyrotropin releasing hormone
stimulation test in alcoholism. Alcohol Alcohol 30:661–667, 1995
Pirke KM, Fichter MM, Pahl J: Noradrenaline, triiodothyronine, growth hor-
mone, and prolactin during weight gain in anorexia nervosa. Int J Eat Disord
4:493–499, 1985a
Pirke KM, Pahl J, Schweiger U, et al: Metabolic and endocrine indices of starva-
tion in bulimia: a comparison with anorexia nervosa. Psychiatry Res 15:33–
39, 1985b
Plunkett ER, Rangecroft G, Heagy PC: Thyroid function in patients with sex
chromosomal abnormalities. J Ment Defic Res 8:25–34, 1964
Poirier MF, Loo H, Galinowski A, et al: Sensitive assay of thyroid stimulating hor-
mone in depressed patients. Psychiatry Res 57:41–48, 1995
Portnay GI, O’Brian JT, Bush J, et al: The effect of starvation on the concentration
and binding of thyroxine and triiodothyronine in serum and on the response
to TRH. J Clin Endocrinol Metab 39:191–194, 1974
Post RM, Kramlinger KG, Joffe RT, et al: Rapid cycling bipolar affective disorder:
lack of relation to hypothyroidism. Psychiatry Res 72:1–7, 1997
Prange AJ Jr, Wilson IC, Rabon AM, et al: Enhancement of imipramine anti-
depressant activity by thyroid hormone. Am J Psychiatry 126:457–469,
1969
Prange AJ Jr, Loosen PT, Wilson IC, et al: Behavioral and endocrine responses of
schizophrenic patients to TRH (protirelin). Arch Gen Psychiatry 36:1086–
1093, 1979
Prange AJ Jr, Haggerty JJ Jr, Browne JL, et al: Marginal hypothyroidism in mental
illness: preliminary assessments of prevalence and significance, in Neuropsy-
chopharmacology. Edited by Bunney WE, Hippius H, Laakmann G, et al.
Berlin, Springer-Verlag, 1990, pp 352–361
Radouco-Thomas S, Garcin F, Murphy MRV, et al: Biological markers in major
psychosis and alcoholism: phenotypic and genotypic markers. J Psychiatr Res
18:513–539, 1984
Raitiere MN: Clinical evidence for thyroid dysfunction in patients with seasonal
affective disorder. Psychoneuroendocrinology 17:231–241, 1992
Rao ML, Gross G, Huber G: Altered interrelationship of dopamine, prolactin,
thyrotropin and thyroid hormone in schizophrenic patients. Eur Arch Psy-
chiatry Neurol Sci 234:8–12, 1984
Rao ML, Strebel B, Halaris A, et al: Circadian rhythm of vital signs, norepineph-
rine, epinephrine, thyroid hormones, and cortisol in schizophrenia. Psychia-
try Res 57:21–39, 1995
Ravussin E, Gautier JF: Metabolic predictors of weight gain. Int J Obes Relat
Metab Disord 23 (suppl 1):37–41, 1999
Rinieris PM, Christodoulou GN, Souvatzoglou A, et al: Free thyroxine index in
mania and depression. Compr Psychiatry 19:561–564, 1978a
Rinieris PM, Christodoulou GN, Souvatzoglou A, et al: Free-thyroxine index
in psychotic and neurotic depression. Acta Psychiatr Scand 58:56–60,
1978b
414 PSYCHONEUROENDOCRINOLOGY
Scott AI, Milner JB, Shering PA: Diminished TSH release after a course of ECT:
altered monoamine function or seizure activity? Psychoneuroendocrinology
14:425–431, 1989
Segerson TP, Kauer J, Wolfe HC, et al: Thyroid hormone regulates TRH biosyn-
thesis in the paraventricular nucleus of the rat hypothalamus. Science 238:
78–80, 1987
Sellman JD, Joyce PR: The clinical significance of the thyrotropin-releasing hor-
mone test in alcoholic men. Aust N Z J Psychiatry 26:577–585, 1992
Shelton RC, Winn S, Ekhatore N, et al: The effects of antidepressants on the thy-
roid axis in depression. Biol Psychiatry 33:120–126, 1993
Simpson GM, Cooper TB: Thyroid indices in chronic schizophrenia. J Nerv Ment
Dis 142:58–62, 1966
Sokolov ST, Kutcher SP, Joffe RT: Basal thyroid indices in adolescent depression
and bipolar disorder. J Am Acad Child Adolesc Psychiatry 33:469–475, 1994
Souetre E, Salvati E, Wehr TA, et al: Twenty-four-hour profiles of body temper-
ature and plasma TSH in bipolar patients during depression and during re-
mission and in normal control subjects. Am J Psychiatry 145:1133–1137,
1988
Souetre E, Salvati E, Belugou JL, et al: Circadian rhythms in depression and re-
covery: evidence for blunted amplitude as the main chronobiological abnor-
mality. Psychiatry Res 28:263–278, 1989
Southwick S, Mason JW, Giller EL, et al: Serum thyroxine change and clinical re-
covery in psychiatric inpatients. Biol Psychiatry 25:67–74, 1989
Spalter AR, Gwirtsman HE, Demitrack MA, et al: Thyroid function in bulimia
nervosa. Biol Psychiatry 33:408–414, 1993
Spitzer RL, Devlin M, Walsh BT: Binge eating disorder: a multisite field trial of
the diagnostic criteria. Int J Eat Disord 11(3):191–203, 1992
Spratt DI, Pont A, Miller MB, et al: Hyperthyroxinemia in patients with acute
psychiatric disorders. Am J Med 73:41–48, 1982
Stein MB, Uhde TW: Thyroid indices in panic disorder. Am J Psychiatry 145:
745–747, 1988
Stein MB, Uhde TW: Autoimmune thyroiditis and panic disorder. Am J Psychia-
try 146:259–260, 1989
Stein MB, Uhde TW: Endocrine, cardiovascular, and behavioral effects of intrave-
nous protirelin in patients with panic disorder. Arch Gen Psychiatry 48:148–
156, 1991
Stein MB, Uhde TW: The thyroid and anxiety disorders, in The Thyroid Axis and
Psychiatric Illness. Edited by Joffe RT, Levitt AJ. Washington, DC, American
Psychiatric Press, 1993, pp 255–277
Stein MB, Muir-Nash J, Uhde TW: The QKd interval in panic disorder: an assess-
ment of end-organ thyroid hormone responsivity. Biol Psychiatry 29:1209–
1214, 1991
Stern RA, Nevels CT, Shelhorse ME, et al: Antidepressant and memory effects of
combined thyroid hormone treatment and electroconvulsive therapy: pre-
liminary findings. Biol Psychiatry 30:623–627, 1991
416 PSYCHONEUROENDOCRINOLOGY
Van Thiel DH, Smith WI Jr, Wright C, et al: Elevated basal and abnormal thyro-
tropin-releasing hormone–induced thyroid-stimulating hormone secretion
in chronic alcoholic men with liver disease. Alcohol Clin Exp Res 3:302–
308, 1979
Vieira AH, Ramos RT, Gentil V: Hormonal response during a fenfluramine-
associated panic attack. Braz J Med Biol Res 30:887–890, 1997 (Published
erratum appears in Braz J Med Biol Res 30(9):1145, 1997.)
Vigersky RA, Loriaux DL: Anorexia nervosa as a model of hypothalamic dysfunc-
tion, in Anorexia Nervosa. Edited by Vigersky R. New York, Raven, 1977,
pp 109–122
Vigersky RA, Loriaux DL, Andersen AE, et al: Delayed pituitary hormone re-
sponse to LRF and TRF in patients with anorexia nervosa and with secondary
amenorrhea associated with simple weight loss. J Clin Endocrinol Metab
43:893–900, 1976
Vinik AI, Kalk WJ, McLaren H, et al: Fasting blunts the TSH response to syn-
thetic thyrotropin-releasing hormone (TRH). J Clin Endocrinol Metab
40:509–511, 1975
Wadden TA, Foster GD, Letizia KA, et al: Metabolic, anthropometric, and psy-
chological characteristics of obese binge eaters. Int J Eat Disord 14:17–25,
1993
Wahby V, Ibrahim G, Friedenthal S, et al: Serum concentrations of circulating
thyroid hormones in a group of depressed men. Neuropsychobiology 22:8–
10, 1989
Wakeling A, de Souza VF, Gore MB, et al: Amenorrhoea, body weight and serum
hormone concentrations, with particular reference to prolactin and thyroid
hormones in anorexia nervosa. Psychol Med 9:265–272, 1979
Weeke A, Weeke J: Disturbed circadian variation of serum thyrotropin in patients
with endogenous depression. Acta Psychiatr Scand 57:281–289, 1978
Weeke A, Weeke J: The 24-hour pattern of serum TSH in patients with endog-
enous depression. Acta Psychiatr Scand 62:69–74, 1980
Wehr TA, Goodwin FK: Rapid cycling in manic-depressives induced by tricyclic
antidepressants. Arch Gen Psychiatry 36:555–559, 1979
Wehr TA, Sack DA, Rosenthal NE, et al: Rapid cycling affective disorder: con-
tributing factors and treatment responses in 51 patients. Am J Psychiatry
145:179–184, 1988
Weinberg AD, Katzell TD: Thyroid and adrenal functions among psychiatric pa-
tients. Lancet 1:1104–1105, 1977
Wenzel KW, Meinhold H, Herpach M: TRH Stimulationstest mit alters- und
geschlechtsabhaengigem TSH Anstieg bei Normalpersonen. Klin Wochenschr
52:722–727, 1974
Whybrow PC, Coppen A, Prange AJJ, et al: Thyroid function and the response to
liothyronine in depression. Arch Gen Psychiatry 26:242–245, 1972
Widerlov E, Wide L, Sjostrom R: Effects of tricyclic antidepressants on human
plasma levels of TSH, GH and prolactin. Acta Psychiatr Scand 58:449–456,
1978
418 PSYCHONEUROENDOCRINOLOGY
Willenbring ML, Anton RF, Spring WD Jr, et al: Thyrotropin and prolactin re-
sponse to thyrotropin-releasing hormone in depressed and nondepressed al-
coholic men. Biol Psychiatry 27:31–38, 1990
Yeragani VK, Rainey JM, Pohl R, et al: Thyroid hormone levels in panic disorder.
Can J Psychiatry 32:467–469, 1987
Ylikahri RH, Huttunen MO, Haerkonen M, et al: Acute effects of alcohol on an-
terior pituitary secretion of tropic hormones. J Clin Endocrinol Metab 46:
715–720, 1978
Chapter 15
Clinical Manifestations
The clinical manifestations of an excessive availability of thyroid hor-
mones are numerous and are found in all systems of the body, including
the brain. Usually the manifestations of the illness are insidious, and fam-
Hyperthyroidism and Hypothyroidism 423
scale (Artunkal and Togrol 1964), and increased depression and anxiety
on the MMPI (MacCrimmon et al. 1979). In addition, a study using the
Clyde Mood Scale also found an increased jittery score and reduced
score for clear thinking among thyrotoxic patients (Robbins and Vinson
1960).
Cognitive dysfunction, including decreased concentration and impaired
memory, are also correlated with the thyrotoxic state. Patients with thy-
rotoxicosis were found to resemble those with an organic brain syndrome
when assessed for neurotic and cognitive traits using standardized mea-
sures (Robbins and Vinson 1960). Performance on tasks requiring con-
centration and memory was also shown to decline in direct proportion to
the degree of increase in serum thyroxine (T4) (MacCrimmon et al.
Hyperthyroidism and Hypothyroidism 425
Laboratory Diagnosis
A biochemical diagnosis of (overt) thyrotoxicosis is easily obtained by
measurement of levels of FT4, FT3, or both (increased) and of serum TSH
levels (decreased). Subclinical thyrotoxicosis is defined as a low serum
TSH concentration and normal serum FT4 and FT3 concentrations asso-
ciated with few or no symptoms or signs of thyrotoxicosis (Ross 2000).
Mild overt thyrotoxicosis is diagnosed when asymptomatic patients show
low TSH concentrations but have slightly high serum free thyroid hor-
mone concentrations. Ultrasensitive TSH assays now permit detection of
subnormal TSH values. In the absence of pituitary disease, if serum TSH
values are less than 0.2 mU/L, hyperthyroidism is the likely diagnosis. In
cases of ambiguity, a TRH challenge test can be of substantial value in
quantifying the hyperthyroid state. In the standard TRH test, 500 mg of
TRH is given intravenously and TSH values are drawn at baseline and
at 15, 30, 45, and 60 minutes. Peak values in normal women are usually
more than 6 mU/L above baseline values. In normal men, TSH levels
usually rise more than 6 mU/L before age 30 and by more than 2 mU/L
after age 40. Suppressed responses in the absence of pituitary disease are
virtually diagnostic of thyrotoxicosis, but if subjects show normal re-
sponses to TRH infusion, thyrotoxicosis can be ruled out.
Kleinschmidt and Waxenberg 17 47% showed decreased mood and psychotic symptoms
1956
Robbins and Vinson 1960 10 Cognitive and neurosis scores improved
Artunkal and Togrol 1964 20 Minimal change
427
428 PSYCHONEUROENDOCRINOLOGY
increase the risk for severe dystonic reactions (Witschy and Redmond
1981). There is also a case report of thyroid storm coinciding with halo-
peridol administration in a 13-year-old girl (Weiner 1979). Hyperthyroid
rats are more sensitive than euthyroid rats to side effects of neuroleptics
and are more likely to develop psychomotor activation from phenothi-
azines. Furthermore, administration of triiodothyronine (T3) to humans
increases sensitivity to chlorpromazine (Prange 1985). Taken together,
these clinical and animal findings suggest that the anticholinergic effects
of neuroleptics theoretically may worsen the tachycardia and cardiac dys-
rhythmias in hyperthyroid persons, demanding careful monitoring of
heart rate and electrocardiography in such cases.
Hypothyroidism
Clinical Manifestations
In adults, the onset of hypothyroidism is usually insidious. Symptoms
may be present for a period of years before dramatic events occur. Phys-
ical symptoms include enlarged thyroid, constipation, cold intolerance,
weight increase with decreased appetite, fatigue, dry and rough skin, hair
loss, puffiness of the face, lethargy, and slowed motor activity (Braver-
man and Utiger 2000a). The behavioral presentation of thyroid hormone
deficiency varies considerably depending on the cause, duration, and se-
verity of the hypothyroid state. Characteristically there is a slowing of
mental and physical activity and a slowing of many organ functions.
symptoms after treatment with thyroxine indicates that they are second-
ary to the hormonal abnormality. A wide variety of neuropsychiatric
symptoms are associated with hypothyroidism, including impaired cogni-
tion, mood changes, anxiety, irritability, and psychotic symptoms. Vague
symptoms of inattentiveness, slowing of thought, weakness, fatigue, and
poor memory are prevalent in mild hypothyroidism. Depressive mood is
the most common mood change, but it may be accompanied by anxiety
and insomnia. Progressively, the patients’ ability to carry out daily activ-
ities or to interact with others deteriorates. In addition, impaired percep-
tion with paranoia and visual hallucinations may develop (Whybrow and
Bauer 2000a; Whybrow et al. 1969). The few studies examining behav-
ioral changes have confirmed these clinical impressions (Table 15–4). In
one study, 5 of 7 consecutive patients with hypothyroidism were de-
pressed and one was anxious (Whybrow et al. 1969). Of 30 consecutive
patients with hypothyroidism, 22 had some psychopathology; however,
the severity of the hypothyroidism and the psychiatric symptoms were
unrelated (Jain 1972). In this study, 33% had anxiety and 43% had de-
pression. In a study by Haggerty et al. (1993), of 31 persons at risk for
hypothyroidism with no manifestations of the disease, 16 were found to
have subclinical hypothyroidism; these patients were considerably more
likely to have a lifetime history of depression than a matched control
group of 15 euthyroid subjects.
Laboratory Diagnosis
In most cases of florid hypothyroidism, T4 level and FTI are below nor-
mal and TSH level is elevated (>4.7 mU/L). Frequently, patients with
primary hypothyroidism may also manifest hypercholesterolemia. How-
ever, as noted earlier, subtle cases of hypothyroidism that may not produce
physical abnormalities but are associated with psychiatric disturbance oc-
434 PSYCHONEUROENDOCRINOLOGY
cur when T4 and T3 serum levels are in the normal range. The TSH level
may be solely elevated or the pituitary thyrotrophs may be abnormally
sensitive to TRH stimulation in individuals with these psychiatric manifes-
tations. This suggests that the CNS may be more sensitive to the alteration
of the thyroid economy than are other organs. Therefore, in psychiatric
practice, it is important to measure TSH levels, after TRH challenge if
necessary.
Disorders of the thyroid gland are frequently associated with mental dis-
turbances. Hyperthyroidism and hypothyroidism can induce distur-
bances of mood and intellectual function, and in severe states there may
be a profound disturbance of behavior that can mimic melancholic de-
pression and dementia. The mental changes accompanying thyroid gland
dysfunction are usually reversed with return to euthyroid status.
The cellular and molecular mechanisms that can uniformly explain
the many psychiatric symptoms associated with thyroid illness are not yet
understood. The manifestations of both hypothyroidism and hyperthy-
roidism are manifold, from very mild cognitive deficits and dysphoria to
psychosis and delirium. Thyroid hormones are widely distributed in the
brain and have a multitude of effects on the CNS, and many of the limbic
438 PSYCHONEUROENDOCRINOLOGY
system structures where thyroid hormones are prevalent have been im-
plicated in the pathogenesis of mental disorders. The specific neuro-
chemical basis and functional pathways for the therapeutic effects of
thyroid hormones on mental functions are also unknown. The influence
of the thyroid system on neurotransmitters that putatively play a major
role in the regulation of mood and behavior, particularly serotonin and
norepinephrine, may contribute to the mechanisms of action (Bauer et
al. 2002a; Whybrow and Prange 1981). However, it is not clear whether
these are the seminal disturbances accounting for behavioral change. Fur-
thermore, within the CNS, the regulatory cascade through which the
thyroid hormones, particularly T3, exert their effects is not well under-
stood: deiodinase activity, nuclear binding to genetic loci, and ultimately
protein synthesis may all be involved. What is clear, however, is that
without optimal thyroid function, psychiatric and mood symptoms often
emerge. Therefore, despite the lack of understanding of fundamental
mechanisms, the evaluation of thyroid status is of vital concern to the
physician and especially to the psychiatrist. In addition to what has been
learned about the association of thyroid dysfunction with behavior and
mood, the adjunctive treatment of mood disorders with thyroid hormones
has become a valuable strategy (Bauer and Whybrow 2001). These issues
are addressed in detail in other chapters of this volume.
References
Kathol RG, Delahunt JW: The relationship of anxiety and depression to symp-
toms of hyperthyroidism using operational criteria. Gen Hosp Psychiatry 8:
23–28, 1986
Kathol RG, Delahunt JXV, Cooke R: Urinary free cortisol levels and dexametha-
sone suppression testing in organic affective disorder associated with hyper-
thyroidism. Am J Psychiatry 142:1193–1195, 1985
Kato R, Takanaka A, Takahashi A, et al: Species differences in the alterations of
drug metabolizing activity of liver microsomes by thyroxine therapy. Jpn J
Pharmacol 9:5–18, 1969
Kleinschmidt H, Waxenberg S: Psychophysiology and psychiatric management of
thyrotoxicosis: a two year follow up study. Mt Sinai J Med 23:131–153, 1956
Larsen PR, Davies TF, Hay ID: The thyroid gland, in Williams Textbook of En-
docrinology, 9th Edition. Edited by Wilson JD, Foster DW, Kronenberg HM,
et al. Philadelphia, PA, WB Saunders, 1998, pp 389–515
Lazarus JH: The effects of lithium therapy on thyroid and thyrotropin-releasing
hormone. Thyroid 8:909–913, 1998
Lazarus JH, Richard AR, Addison GM: Treatment of thyrotoxicosis with lithium
carbonate. Lancet 2:1160–1163, 1974
Lee S, Chow CC, Wing YK, et al: Mania secondary to thyrotoxicosis. Br J Psychi-
atry 159:712–713, 1991
Loosen P, Prange A: Serum thyrotropin response to thyrotropin-releasing hor-
mone in psychiatric patients. Am J Psychiatry 139:405–416, 1982
MacCrimmon DJ, Wallace JE, Goldberg WM, et al: Emotional disturbance and
cognitive deficits in hyperthyroidism. Psychosom Med 41:331–340, 1979
Mandelbrote BM, Wittkomer E: Emotional factors in Graves’ disease. Psychosom
Med 17:109–113, 1955
Marcocci C, Chiovato L: Thyroid-directed antibodies, in Werner and Ingbar’s The
Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braver-
man LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000,
pp 414–431
Mattson A, Seltzer R: MAOI-induced rapid cycling affective disorder in an ado-
lescent. Am J Psychiatry 13:677–679, 1981
McLachlan SM, Rapoport B: Genetic factors in thyroid disease, in Werner and In-
gbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited
by Braverman LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wil-
kins, 2000, pp 474–487
Nyström E, Caidahl K, Fager G, et al: A double-blind cross-over 12 month study
of L-thyroxine treatment of women with “subclinical” hypothyroidism. Clin
Endocrinol (Oxf) 29:63–76, 1988
Parry CH: Collections From the Unpublished Writings of the Late C. H. Parry,
Vol 2. London, Underwoods, 1825
Peake RL: Recurrent apathetic hyperthyroidism. Arch Intern Med 141:258–260,
1981
Prange AJ Jr: Psychotropic drugs and the thyroid axis: a review of interactions.
Adv Biochem Psychopharmacol 40:103–110, 1985
442 PSYCHONEUROENDOCRINOLOGY
Prange AJ Jr, Wilson IC, Rabon AM, et al: Enhancement of imipramine anti-
depressant activity by thyroid hormone. Am J Psychiatry 126:457–469,
1969
Prange AJ Jr, Meek JL, Lipton MA: Catecholamines: diminished rate of norepi-
nephrine biosynthesis in rat brain and heart after thyroxine pretreatment.
Life Sci 9:401–406, 1970
Reitan RM: Intellectual functions in myxoedema. Arch Neurol Psychiatry 69:
436–449, 1953
Reus VI, Gold P, Post R: Lithium-induced thyrotoxicosis. Am J Psychiatry 136:
724–725, 1979
Robbins LR, Vinson DB: Objective psychological assessment of the thyrotoxic
patient and the response to treatment. J Clin Endocrinol 20:120–129, 1960
Rockey P, Griep R: Behavioral dysfunction in hyperthyroidism: improvement
with treatment. Arch Intern Med 140:1194–1197, 1980
Rogers M, Whybrow PC: Clinical hyperthyroidism occurring during lithium
treatment: two case histories and a review of thyroid function in 19 patients.
Am J Psychiatry 128:158–163, 1971
Ross DS: Subclinical thyrotoxicosis, in Werner and Ingbar’s The Thyroid: A Fun-
damental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger
RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 1007–1012
Rosser R: Thyrotoxicosis and lithium. Br J Psychiatry 128:61–66, 1976
Russ MJ, Ackerman SH: Antidepressant treatment response in hypothyroid pa-
tients. Hosp Community Psychiatry 40:954–956, 1989
Schon M, Sutherland A, Rawson R: Hormones and neuroses—the psychological
effects of thyroid deficiency. Proceedings of the Third World Congress of
Psychiatry, Montreal, Vol 2. Toronto, Ontario, McGill University Press,
1961, pp 835–839
Segal RL, Rosenblatt S, Eliasoph I: Endocrine exophthalmos during lithium ther-
apy of manic-depressive disease. N Engl J Med 289:136–138, 1973
Silverman DHS, Geist CL, Van Herle K, et al: Abnormal regional brain metabo-
Lism in patients with hypothyroidism secondary to Hashimoto’s disease (ab-
stract). Society of Nuclear Medicine 49th Annual Meeting, Los Angeles, CA,
June 15–19, 2002. J Nucl Med 43 (5, suppl):254P, 2002
Smith CD, Ain KB: Brain metabolism in hypothyroidism studied with 31P mag-
netic-resonance spectroscopy. Lancet 345:619–620, 1995
Sokoloff L, Wechsler RL, Mangold R, et al: Cerebral blood flow and oxygen con-
sumption in hyperthyroidism before and after treatment. J Clin Invest 32:
202–208, 1953
Sonino N, Girelli ME, Boscaro M, et al: Life events in the pathogenesis of Graves’
disease. A controlled study. Acta Endocrinol 128:293–296, 1993
Strandjord RE, Aanderud, S, Myking O: Serum levels of thyroid hormones in pa-
tients treated with carbamazepine, in Advances in Epileptology. Twelfth Ep-
ilepsy International Symposium. Edited by Conger R, Angeleri F, Perry J.
New York: Raven, 1980, pp 439–443
Taylor JW: Depression in thyrotoxicosis. Am J Psychiatry 132:552–553, 1975
Hyperthyroidism and Hypothyroidism 443
Thompson CJ, Baylis PH: Asymptomatic Graves’ disease during lithium therapy.
Postgrad Med J 62:295–296, 1986
Tonks CM: Mental illness in hypothyroid patients. Int J Psychiatry 110:706–710,
1964
Treadway CR, Prange AJ Jr, Doehne EF, et al: Myxedema psychosis: clinical and
biochemical changes during recovery. J Psychiatr Res 5:289–296, 1967
Trzepacz PT, McCue M, Klein I, et al: Psychiatric and neuropsychological re-
sponse to propranolol in Graves’ disease. Biol Psychiatry 23:678–688, 1988a
Trzepacz PT, McCue M, Klein I, et al: A psychiatric and neuropsychological study
of patients with untreated Graves’ disease. Gen Hosp Psychiatry 10:49–55,
1988b
Tunbridge WMG, Evered DC, Hall R, et al: The spectrum of thyroid disease in
the community: the Whickham Survey. Clin Endocrinol (Oxf) 7:481–493,
1977
Vanderpump MP, Tunbridge WM, French JM, et al: The incidence of thyroid dis-
orders in the community: a twenty-year follow-up of the Whickham Survey.
Clin Endocrinol (Oxf) 43:55–68, 1995
Voth HM, Holzman PS, Katz JB, et al: Thyroid hot spots: their relationship to life
stress. Psychosom Med 32:561–568, 1970
Wallace I, MacCrimmon D, Goldberg W: Acute hyperthyroidism: cognitive and
emotional correlates. J Abnorm Psychol 89:519–527, 1980
Wallerstein RS, Holzman PS, Voth HM, et al: Thyroid hot spots: a psychophysi-
ological study. Psychosom Med 27:508–523, 1965
Wartofsky L: Thyrotoxic storm, in Werner and Ingbar’s The Thyroid: A
Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE,
Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp
679–684
Weetman AP: Chronic autoimmune thyroiditis, in Werner and Ingbar’s The Thy-
roid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman
LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000,
pp 721–732
Weiner M: Haloperidol, hyperthyroidism, and sudden death. Am J Psychiatry
136:717–718, 1979
Wenzel KW, Meinhold H, Raffenberg M, et al: Classification of hypothyroidism
in evaluating patients after radioiodine therapy by serum cholesterol, T3-uptake,
total T4, fT4-index, total T3, basal TSH and TRH test. Eur J Clin Invest
4:141–148, 1974
Wharton RN: Accidental lithium carbonate treatment of thyrotoxicosis as mania.
Am J Psychiatry 137:747–748, 1980
Whybrow PC: Sex differences in thyroid axis function: relevance to affective dis-
order and its treatment. Depression 3:33–42, 1995
Whybrow PC, Bauer M: Behavioral and psychiatric aspects of hypothyroidism, in
Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th
Edition. Edited by Braverman LE, Utiger RD. Philadelphia, Lippincott Wil-
liams & Wilkins, 2000a, pp 837–842
444 PSYCHONEUROENDOCRINOLOGY
445
446 PSYCHONEUROENDOCRINOLOGY
has been speculated that similar use in humans may enhance the thera-
peutic effect of antidepressants (Breese et al. 1974). Finally, data from
animal studies suggest that thyroid hormones may interact with biogenic
amines, in some instances potentiating the effects of the amines (Breese
et al. 1974).
Approaches undertaken in the use of thyroid hormones in psychiatric
illnesses include their use as monotherapy and in combination with other
psychotropic agents. Thyrotropin-releasing hormone (TRH), thyroid-
stimulating hormone (TSH), and the peripheral thyroid hormones thy-
roxine (T4) and triiodothyronine (T3) have been used and investigated in
various psychiatric illnesses, including major depression, bipolar disorder,
and anxiety disorders.
Major Depression
Thyrotropin-Releasing Hormone
TRH is a tripeptide released from the hypothalamus whose principal en-
docrine role is to regulate synthesis and secretion of TSH, which in turn
regulates thyroid hormone synthesis and release. TRH may also affect
brain function in a manner separate from its role within the thyroid axis
by acting as a neurotransmitter (Griffiths 1985). Effects of the adminis-
tration of exogenous TRH include reversal of drug-induced sedation or
anesthesia; stimulation of motor activity; and other effects on cardiac,
respiratory, gastrointestinal, and neurological function (Griffiths 1985;
Prange et al. 1978).
Use of TRH in antidepressant therapy was suggested by its apparently
widespread role in the central nervous system and by its potential for
stimulating the thyroid axis. The use of this hormone in combination
with ECT has been suggested on the basis of its beneficial effect on neu-
rological and cognitive function.
Thyroid Hormone Treatment of Psychiatric Disorders 447
Monotherapy
Thirteen double-blind studies have evaluated the effect of TRH on symp-
toms of major depression by intravenous, oral, or intrathecal admin-
istration (Coppen et al. 1974; Ehrensing et al. 1974; Furlong et al. 1976;
Hollister et al. 1974; Karlberg et al. 1978; Kastin et al. 1972; Kiely et al.
1976; Marangell et al. 1997; Mountjoy et al. 1974; Prange et al. 1972; Van
Den Burg et al. 1975, 1976; Vogle et al. 1977). The equivocal results of
the oral and intravenous TRH studies may be explained by the relatively
short half-life of TRH in serum (5.3±0.5 minutes after intravenous ad-
ministration) and by the impermeability of the blood-brain barrier to pe-
ripherally administered TRH (Marangell et al. 1997). To overcome these
limitations, Marangell and co-workers (1997) used a double-blind, pla-
cebo-controlled crossover design and administered TRH intrathecally in
a group of patients with highly refractory depression. Although robust
improvement was seen in the majority of subjects, the improvement was
short-lived.
Therefore, the fact that the majority of studies of TRH do not dem-
onstrate a significant antidepressant effect is likely accounted for by the
peripheral route of administration. When effects were demonstrated,
they were mostly either minimal or transient (Furlong et al. 1976; Kastin
et al. 1972; Prange et al. 1972; Van Den Burg et al. 1975, 1976). Although
robust effects were demonstrated in the one study using a central route
of administration, response was short-lived, and in clinical practice ad-
ministration of TRH intrathecally is impractical (Marangell et al. 1997).
On the basis of investigations to date, it cannot be concluded that TRH
monotherapy has a significant role in the treatment of depression.
ited evidence that TRH has some efficacy in preventing cognitive side
effects of ECT. Further replication using larger numbers of subjects is
required.
Thyroid-Stimulating Hormone
On the basis of the known physiological role of TSH in stimulation of
thyroid hormone synthesis and release, it was postulated that TSH ad-
ministration might have antidepressant effects. In the only study to ex-
amine antidepressant effects of TSH, Prange et al. (1969) administered
10 IU of TSH intravenously to 20 depressed women 24 hours before ini-
tiating imipramine therapy. The researchers observed that TSH-treated
women experienced a more rapid response than did patients who received
a saline injection. The precise mechanism of this effect is not clear, and
although these results are intriguing, replication of these data is required
before it can be concluded that TSH administration has substantial clin-
ical utility.
Thyroxine
The original studies evaluating thyroid hormone treatment of depression
used T3, on the basis of the observation that T3 is several times more bi-
ologically active than T4. However, it was assumed that in the treatment
of psychiatric illness, T4 would function similarly to T3 and that because
it had a considerably longer half-life than T3, its psychotropic effects
would be more enduring.
A number of studies, however, have attempted to evaluate T4 aug-
mentation (Bauer et al. 1998; Rudas et al. 1999; Targum et al. 1984). In
the earliest study, Targum et al. (1984) administered T4 as an augmenta-
tion agent in 21 patients who had not responded to treatment with a tri-
cyclic antidepressant. Although 7 patients responded, 5 of these had
evidence of subclinical hypothyroidism, as determined by a maximum
TSH response to TRH greater than 25 mIU/mL at baseline before thy-
roid hormone augmentation. Therefore, in this study, it appeared that T4
may have played a role as replacement therapy for subclinical hypothy-
roidism—a role presumably distinct from the use of T3 in augmentation
therapy of euthyroid depressed patients (see “Augmentation” under “Tri-
iodothyronine” below). Bauer et al. (1998) openly added supraphysiolog-
ical doses of T4 (mean, 482±72 mg/day) to antidepressant medication in
12 bipolar and 5 unipolar patients with highly refractory depression.
High-dosage T4 was generally well tolerated, with 10 patients responding
robustly and 7 of the 10 maintaining excellent response over the follow-
Thyroid Hormone Treatment of Psychiatric Disorders 449
Triiodothyronine
T3 has been used in the treatment of depression in four distinct ways: as
monotherapy; in combination with ECT; in conjunction with antidepres-
sants to produce a more rapid response (acceleration); and in conjunction
with antidepressants to potentiate response in patients who have not re-
sponded to adequate antidepressant treatment (augmentation).
Monotherapy
Two early anecdotal reports suggested that T3 might be effective in in-
creasing spontaneous motor activity and improvement in depression
symptoms in a mixed cohort of psychiatric patients (Feldmesser-Reiss
1958; Flach et al. 1958). Unfortunately, these data have not been repli-
cated using current methodological and diagnostic paradigms. Monother-
450 PSYCHONEUROENDOCRINOLOGY
Acceleration
There is some evidence to suggest that when used in combination with
antidepressant medication T3 is effective in accelerating the onset of an-
tidepressant response. Several studies undertaken more than 30 years ago
(Prange et al. 1969; Wheatley 1972; Wilson et al. 1970) examined the
use of 25–50 mg/day of T3 started simultaneously with tricyclic antide-
pressant treatment. In these studies, patients receiving T3 responded
more quickly to antidepressants than patients who did not receive T3. For
reasons that are not clear, this effect appeared to be more prominent in
women. Other reports (Feighner et al. 1972) suggest that the accelera-
tion effect of T3 may not be consistently observed.
Thyroid Hormone Treatment of Psychiatric Disorders 451
Augmentation
In addition to reports of the T3 acceleration effect, 11 studies (Banki
1975, 1977; Earle 1970; Gitlin et al. 1987; Goodwin et al. 1982; Joffe
and Singer 1990; Joffe et al. 1993b; Ogura et al. 1974; Schwarcz et al.
1984; Thase et al. 1989; Tsutsui et al. 1979) examined the addition of
small amounts of T3 to augment response in patients who did not re-
spond to a trial of tricyclic antidepressants. These studies are reviewed in
Table 16–1.
The six open studies (Banki 1975; Earle 1970; Ogura et al. 1974;
Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979) demon-
strated that of subjects who did not respond to tricyclic antidepressants,
approximately 25%–91% (weighted mean, 63.1%) had a response within
2–4 weeks after the addition of 5–50 mg of T3 to their antidepressant. The
one negative open trial (Thase et al. 1989) consisted of a study sample of
severely ill patients with highly recurrent major depressive illness, possi-
bly explaining the lack of response to T3.
The five controlled studies (Banki 1977; Gitlin et al. 1987; Goodwin
et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b) are generally sup-
portive of the results from the open studies, with rates of response ap-
proximating 50%. The one negative study (Gitlin et al. 1987) is difficult
to evaluate owing to several methodological issues (for example, it used
a 2-week crossover design, which may not be the most appropriate pro-
tocol for evaluating the efficacy of antidepressant treatment with a de-
layed onset and cessation of action of unknown duration). Across the six
studies, response to antidepressant augmentation with T 3 was not
affected by sex, bipolar/unipolar diagnosis, type of heterocyclic antide-
pressant used, or baseline thyroid status of the patients. A recent meta-
analysis of 292 patients treated in six studies suggests that T3 augmentation
is twice as likely to produce a response as control treatments (Aronson et
al. 1996).
Two of the controlled T3 augmentation studies warrant special note.
First, Joffe and Singer (1990) conducted the only study to directly com-
pare T3 augmentation to T4 augmentation. Using a double-blind design,
the researchers found that 9 of 17 patients responded significantly bet-
ter to T3 (P=0.026, Fisher exact test) than to T4 (4 of 21 patients). All
452
TABLE 16–1. Augmentation of tricyclic antidepressants with triiodothyronine (T3)
Dosage
Study N (mg/day) Tricyclic Design Response (%)
PSYCHONEUROENDOCRINOLOGY
Banki 1977 33 20 AMI Partially controlled 23 (69.7)
Tsutsui et al. 1979 11 5–25 Various Open 10 (90.9)
Goodwin et al. 1982 12 25–50 Various Double-blind 8 (66.7)
Schwarcz et al. 1984 8 25–50 DMI Open 4 (50.0)
Gitlin et al. 1987 16 25 IMI Double-blind, placebo T3 =placebo
Thase et al. 1989 20 25 IMI Open 5 (25.0)
Joffe and Singer 1990 38 37.5 DMI, IMI Double-blind vs. T4 9 of 17 (52.9) for T3, superior to T4
Joffe et al. 1993b 51 37.5 DMI, IMI Double-blind, placebo and lithium 10 of 17 (58.8) for T3, T3 >placebo, T3 =lithium
Note. AMI=amitriptyline; DMI=desipramine; IMI=imipramine; T4 =thyroxine.
Thyroid Hormone Treatment of Psychiatric Disorders 453
patients were euthyroid. Potential shortcomings of this study are the lack
of a placebo group and the possibility that there was a delayed (undetec-
ted) onset of effect of T4 owing to the short duration of the trial period
and the considerably longer half-life of T4 compared with T3. Second,
in a randomized, double-blind, placebo-controlled design, Joffe et al.
(1993b) directly compared T3 and lithium augmentation in 51 patients
who did not respond to adequate treatment with desipramine or imipra-
mine. Subjects received 2 weeks’ treatment with either 37.5 mg/day of
T3, 900–1,200 mg/day of lithium, or placebo in addition to their antide-
pressant. Lithium doses were adjusted by a nonblind overseer at the end
of the first week of treatment to standardize serum levels to 0.58 mmol/
L or above. Ten of 17 patients (58.8%) responded to T3, 9 of 17 (52.9%)
responded to lithium, and 3 of 16 (18.8%) responded to placebo. Both
T3 and lithium were significantly better than placebo (T3 versus placebo,
P=0.018; lithium versus placebo, P=0.038, Fisher exact test) and did not
differ from each other. These findings are interesting in light of clinical
lore suggesting that lithium is the “gold standard” for antidepressant aug-
mentation, and as such, the efficacy of T3 augmentation has been met
with skepticism (reviewed in Joffe et al. 1993b; Nemeroff 1991).
The open and controlled studies of T3 augmentation (Banki 1975,
1977; Earle 1970; Gitlin et al. 1987; Goodwin et al. 1982; Joffe and Singer
1990; Joffe et al. 1993b; Ogura et al. 1974; Schwarcz et al. 1984; Thase
et al. 1989; Tsutsui et al. 1979) suggest that the use of T3 augmentation
is effective in patients who do not respond to tricyclic antidepressants. In
general, rates of response in these studies are comparable to those re-
ported with lithium augmentation (reviewed in Joffe et al. 1993b). Fur-
thermore, when lithium augmentation and T3 augmentation are directly
compared (Joffe et al. 1993b), T3 may be at least comparable in efficacy.
However, although T3 and lithium augmentation may have comparable
response rates, they may not necessarily be effective in the same individ-
uals; several case series suggest that nonresponse to one does not predict
nonresponse to the other (Garbutt et al. 1986; Joffe 1988a).
Side effects and tolerability. T3 administration is generally considered a
well-tolerated treatment with few side effects. The likely low incidence of
side effects associated with T3 augmentation probably relates to the small
doses being used (25–50 mg), which are below what would be considered
physiological replacement doses. However, the studies to date have com-
mented only generally on side effects and have not systematically logged
adverse reactions (Banki 1975, 1977; Earle 1970; Gitlin et al. 1987; Good-
win et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b; Ogura et al.
1974; Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979).
454 PSYCHONEUROENDOCRINOLOGY
Bipolar Disorder
Non–Rapid Cycling
Baumgartner et al. (1994) reported on the use of high-dosage T4 in non–
rapid-cycling patients with treatment-refractory bipolar disorder. Six
458 PSYCHONEUROENDOCRINOLOGY
patients were treated with 250–500 mg/day of T4. Four of the six patients
obtained a significant response as measured by mean number of relapses
and mean length of hospitalizations during the follow-up period (12–46
months). However, four of the patients in the study had evidence of
subclinical hypothyroidism. Therefore, it is unclear whether the benefi-
cial effect of T4 was due to its being employed as thyroid replacement
therapy.
Rapid Cycling
Although the specificity of hypothyroidism in rapid-cycling bipolar dis-
order is not known, T4 has been used by several investigators in an at-
tempt to treat rapid-cycling bipolar illness. Reports to date have used
dosages of T4 up to 500 mg/day in combination with mood stabilizers—
high enough to induce a hypermetabolic state (Bauer and Whybrow 1990;
Leibow 1983; Stancer and Persad 1982). First, Stancer and Persad (1982)
openly treated 10 rapid-cycling patients whose illness had been refrac-
tory to conventional treatments (lithium, ECT, neuroleptics) with sup-
raphysiological thyroid hormone. Five of 7 women treated with 300–500
mg/day of T4 obtained complete remission of their illness (follow-up pe-
riod, 1.5–9 years), 2 women treated with 240–400 mg/day of T3 had tem-
porary or slight responses, and 2 men treated with T4 also responded
minimally. Subsequently, Leibow (1983) reported a single case of rapid
cycling that responded to 400 mg/day of T4. More recently, Bauer and
Whybrow (1990) openly treated 11 rapid-cycling patients with 150–400
mg/day of T4. Depressive symptoms improved in 10 of 11 patients, and
manic symptoms improved in 5 of the 7 patients who exhibited these
symptoms at baseline. Three of 4 patients who were randomized in ei-
ther a single- or double-blind manner to discontinuation of T4 subse-
quently relapsed.
In the reports to date, supraphysiological T4 has been reported to be
generally well tolerated because the treatment algorithms have called for
slow dose titration, with the upper limit of dosing usually determined by
the appearance of side effects. There is nevertheless a risk of iatrogeni-
cally induced hyperthyroidism, and as such this treatment technique
needs to be used with caution. With respect to other risks of treatment,
there is a theoretical risk of osteoporosis owing to the observation of a
higher prevalence of this condition in untreated hyperthyroidism (Green-
span and Greenspan 1999). To address this concern, Gyulai et al. (1997)
followed up on 10 of the 11 patients previously treated by Bauer and
Whybrow (1990). Serial bone densitometry was performed, and no dif-
ference was observed in bone density in patients treated with high-dosage
Thyroid Hormone Treatment of Psychiatric Disorders 459
Anxiety Disorders
Conclusion
References
Van Den Burg W, Van Praag HM, Bos ERH, et al: TRH by slow, continuous infu-
sion: an antidepressant? Psychol Med 6:393–397, 1976
Vogle HP, Benkert BF, Illig R: Psychoendocrinological and therapeutic effects of
TRH in depression. Acta Psychiatr Scand 56:223–232, 1977
Wehr TA, Sack DA, Rosenthal NE, et al: Rapid-cycling affective disorder: con-
tributing factors and treatment responses in 15 patients. Am J Psychiatry
145:179–184, 1988
Wheatley D: Potentiation of amitriptyline by thyroid hormone. Arch Gen Psychi-
atry 26:229–233, 1972
Whybrow PC, Prange AJ Jr: A hypothesis of thyroid-catecholamine-receptor in-
teraction. Its relevance to affective illness. Arch Gen Psychiatry 38:106–113,
1981
Whybrow PC, Prange AJ Jr, Treadway CR: The mental changes accompanying
thyroid gland dysfunction. Arch Gen Psychiatry 20:48–63, 1969
Wilson IC, Prange AJ Jr, McClane TK, et al: Thyroid hormone enhancement of
imipramine in nonretarded depression. N Engl J Med 282:1063–1067, 1970
Zarate CA, Tohen M, Zarate SB: Thyroid function tests in first-episode bipolar
disorder manic and mixed types. Biol Psychiatry 42:302–304, 1997
Zervas IM, Pehlivanidis AA, Papakostas YG, et al: Effects of TRH administration
on orientation time and recall after ECT. J ECT 14(4):236–240, 1998
This page intentionally left blank
Part VI
Laboratory Testing
This page intentionally left blank
Chapter 17
Laboratory Evaluation of
Neuroendocrine
Systems
O ver the past two decades there has been a rapid increase in
the understanding of neuroendocrine physiology and how it relates to nor-
mal and pathological brain activities. Neuroendocrine function—the ac-
tions of hormones produced and active in the nervous system—has come to
be understood as being critical to the workings of the brain, and particularly
to the integrative processes that characterize much of human behavior.
This information has come from several sources, including extrapolations
from animal models, clinical research in human subjects, and observations
of abnormalities in people with psychiatric and neurological illnesses. An
important part of this work has been the development of a variety of tests
to characterize human neuroendocrine systems. In this chapter we focus on
some of the tests of human neuroendocrine function that are important in
psychiatric illness, on the proper uses and interpretation of these tests, and
on their relevance to clinical practice. This survey is by no means complete,
and it excludes from consideration a number of neuroendocrine hormones.
In particular we focus on the hypothalamic-pituitary-adrenal (HPA) axis
and the hypothalamic-pituitary-thyroid (HPT) axis, with briefer overviews
of the hypothalamic-pituitary-gonadal (HPG) axis and of growth hormone.
The guidelines presented in this chapter can stand alone but can also use-
fully complement the guidelines presented in other chapters of this book
dedicated to the individual endocrine axes.
469
470 PSYCHONEUROENDOCRINOLOGY
Hypothalamic-Pituitary-Adrenal Axis
axis are released into the circulation with a circadian rhythm, with diur-
nal peaks and nadirs. Cortisol and ACTH secretion are highest in the
morning and lowest in the evening. All three of these hormones are se-
creted in a pulsatile fashion, with pulses of CRH leading to ACTH re-
lease, which then leads to cortisol release. CRH has a very short half-life
(several minutes) in the peripheral circulation; ACTH has a slightly
longer half-life (10–20 minutes), and the half-life of cortisol is approxi-
mately 45–60 minutes.
The characteristics described above suggest some of the issues that
arise in testing the HPA axis. First is the problem of hierarchy—the most
accessible and stable product of the axis, cortisol, is also the farthest re-
moved from the brain. Direct measurement of CRH is extremely diffi-
cult because of its short half-life and the relative inaccessibility of the
brain to direct measurement. Basal sampling measures must be taken
with care, because secretory pulses that occur between measurements
spaced too far apart may be undetected. The phenomenon of negative
feedback coupled with circadian variation means that time of day will
usually affect the result of a test.
AVP Infusion
As noted above, AVP is also a stimulus to pituitary ACTH release. Com-
pared with CRH, relatively fewer studies have examined its role in states
of HPA axis dysfunction, perhaps because it is a less potent stimulus than
CRH. However, when it is presented to the pituitary in the presence of
CRH, a synergism between the two peptides leads to greater ACTH re-
lease than either one alone can achieve. In addition, there is evidence in an-
imal models that AVP-induced HPA axis activation is not glucocorticoid
suppressible. These two facts have led some researchers to suggest that
AVP serves as an important modulator of stress responses, and AVP may
also play an important role in chronic HPA axis activation. Studies of AVP
effects on the human HPA axis are much more limited than studies of
CRH, and no single means of administration has become the standard.
Nonetheless, AVP infusion may be helpful in determining the pathophys-
iological mechanisms that maintain hypercortisolism in different states.
We have developed a paradigm in which we administer AVP in a 60-minute
infusion of 1 mIU/kg per minute for 60 minutes. We are currently at-
tempting to determine whether this test can be used to demonstrate hypo-
secretion of CRH in various fatigue states (the response to AVP in the
absence or relative paucity of CRH should be blunted). We have also used
AVP infusion together with oCRH stimulation to provide evidence that
HPA axis hyperactivity in states of immune activation may be physiologi-
cally distinct from that of depression (Michelson et al. 1994). Studies with
AVP are generally well tolerated by subjects. The most important side ef-
fects in our experience, occurring in 5%–10% of subjects, are abdominal or
bladder cramping, and women who undergo the test at the end of the men-
strual cycle may experience painful, exaggerated uterine cramping. These
effects typically resolve within minutes of discontinuing the infusion.
day (in outpatients the test may be performed with a single sample taken
at 4:00 P.M., though some sensitivity may be lost). Although the dexa-
methasone suppression test has been widely studied and provides an inter-
esting research tool, it is of little clinical value because it is neither highly
sensitive (i.e., it produces many false negatives) nor specific (it produces
many false positives). Most studies suggest that its sensitivity is about 50%
and its specificity is 90% or less (Arana and Baldessarini 1987), although
in some subpopulations such as the psychotically depressed it may be more
meaningful (Nelson and Davis 1997). Although there is evidence that
dexamethasone nonsuppression following successful treatment of depres-
sion is a predictor of poorer outcome (i.e., earlier relapse) (Ribeiro et al.
1993; Zobel et al. 1999), these findings are, in our judgment, neither sen-
sitive nor specific enough to usefully guide clinical practice.
The following are guidelines for the dexamethasone suppression test,
which tests the negative feedback response of the HPA axis to glucocor-
ticoids:
• Cushing’s disease
• Severe stress
• Increased metabolism of dexamethasone
• Recent hospitalization
• Pregnancy or increased estrogen
• Recent weight loss
• Medications (e.g., carbamazepine, phenytoin, barbiturates)
• Alcohol withdrawal
• Serious medical illness
• Addison’s disease
• Exogenous glucocorticoid administration
• Medication
Laboratory Evaluation of Neuroendocrine Systems 483
Hypothalamic-Pituitary-Thyroid Axis
Although disorders of the HPT axis are among the most common prob-
lems seen by internists, they are highly relevant for the practicing psychi-
atrist as well. Thyroid dysfunction can manifest itself in psychiatric
symptoms, and psychiatric illness has been associated with abnormalities
of the HPT axis (Jackson 1998; Rosner 1991). A complete description of
the physiology and pathophysiology of the HPT axis is beyond the scope
of this chapter; however, we briefly review the organization and function
of the axis to provide a background against which its laboratory exami-
nation can be considered.
Like glucocorticoid secretion, thyroid hormone secretion involves
hypothalamic, pituitary, and end-organ elements. Thyrotropin-releasing
hormone (TRH), a three–amino acid peptide, is secreted from the paraven-
tricular nucleus of the hypothalamus and is carried in the portal circulation
to the anterior pituitary. There it stimulates the release of thyroid-
stimulating hormone (TSH), a glycoprotein, from thyrotroph cells. TSH is
carried in the peripheral blood to the thyroid gland, where it in turn stim-
ulates secretion of the thyroid hormones tetraiodothyronine (T4) (thyrox-
ine) and triiodothyronine (T3). T4 and some T3 are produced by the
thyroid, but the predominant circulating hormone is T4, and most T3 is
produced from peripheral conversion of T4 at the tissues by deiodination
of the T4 outer ring. T4 can also be metabolized by deiodination of its inner
ring, which results in the production of metabolically inactive reverse T3
(rT3). Regulation of the axis is dynamic, with circulating T4 levels feeding
back at the pituitary to control TSH secretion (increased T4 levels inhibit
TSH secretion, whereas decreased levels stimulate TSH secretion). Also
like the HPA axis, the activity of the HPT axis is pulsatile and has a circa-
dian rhythm. TSH secretion decreases in the afternoon and early evening
and increases late at night and in the early hours of the morning. Thyroid
function can become disordered at either extreme of function (hypoactiv-
ity and hyperactivity), and as with the HPA axis, pathology can occur at the
level of the end-target gland (the thyroid) or the pituitary. Central (i.e., hy-
pothalamic) hypothyroidism, though it does occur, is rare.
Laboratory Evaluation of Neuroendocrine Systems 485
Basal Measurement
The appropriate evaluation of thyroid function in patients depends on
their clinical presentation. With the advent of the sensitive assay for TSH
(see “Assays” below), the following algorithm has been recommended (Klee
and Hay 1987; Surks et al. 1990; Utiger 1995). In apparently euthyroid
people in whom thyroid screening is indicated, the first step and the single
best screening test of thyroid function is measurement of TSH. If TSH lev-
els are within the normal range, no further testing need be done. If TSH
levels are abnormally high (associated with hypothyroidism) or low (asso-
ciated with hyperthyroidism), a further test to evaluate free T4 (FT4) con-
centration is indicated. Because T4 is largely bound to proteins in the plasma,
the total plasma T4 concentration is not always an accurate reflection of
the FT4 that is biologically active at the cellular level. Biologically mean-
ingful measurement of T4 therefore requires either direct measurement
of the FT4 concentration or measurement of total T4 and some measure
of protein binding of T4 to allow calculation of the free thyroxine index
(FTI). Therefore, in patients with illnesses in which thyroid dysfunction
should be ruled out (including many psychiatric patients), a sensitive TSH
test and either direct or estimated determination of FT4 is appropriate. In
patients who present with clinical pictures suggestive of either hypothy-
roidism or hyperthyroidism, both TSH and either direct or estimated FT4
should be evaluated initially. T3 is not a good general measure of thyroid
function because levels fluctuate rapidly and may reflect nonthyroidal fac-
tors. In particular, nonthyroidal illness is often associated with decreases
in concentrations of T3 that result from decreased conversion of T4. Non-
thyroidal illness is associated with a number of other abnormalities of thy-
roid hormones as well, which can include increased rT3, decreases in both
T3 and T4 (the euthyroid sick syndrome), and, paradoxically, increases in
T4 (Gow et al. 1986; Wartofsky and Burman 1982). These changes are
thought to result from several different factors, which include alterations
in protein binding due to changes in protein production as well as meta-
bolic changes associated with the state of illness. Distinguishing true hy-
pothyroidism from the euthyroid sick syndrome can be difficult; the most
useful tools are probably determinations of TSH and FT4, but in severely
ill patients even these may not provide definitive answers (Surks et al.
1990). Normal values for thyroid hormones are listed in Table 17–2.
Thyroid Antibodies
The most common cause of hypothyroidism (outside of areas of endemic
iodine deficiency) is autoimmune thyroiditis (Utiger 1995). Although a
486 PSYCHONEUROENDOCRINOLOGY
variety of antibodies have been described, only two are commonly assayed
in patients suspected of having autoimmune thyroiditis: antimicrosomal
antibodies (also called antithyroid peroxidase antibodies) and antithyro-
globulin antibodies. It is important to be aware that although these tests
can provide confirmation of a presumptive diagnosis of autoimmune thy-
roiditis, they are not highly specific, and many healthy people, patients
with nonthyroidal illnesses, and those with subclinical thyroid disease
will also test positively for these antibodies.
Assays
TSH
Radioimmunoassays of TSH have been available for some years and have
become the most widely available method for determining serum TSH
levels. Early assays were not sensitive enough to distinguish between low
normal TSH levels and those typical of hyperthyroidism. Second-generation
assays extended the lower limits of detection to 0.1–0.2 mU/L, permit-
Laboratory Evaluation of Neuroendocrine Systems 487
T4
As noted above, T4 can be measured as total T4 or as FT4. When total T4
is measured, it is important to assess what portion is not bound to protein
and hence is biologically available. A number of methodologies for mea-
suring total T4 exist, including competitive protein binding assays, immu-
noassays, and enzyme assays. The most commonly used methodology,
however, is probably RIA. Although RIAs vary in sensitivity, typical as-
says have lower limits of detection around 0.4 mg/dL (however, more sen-
sitive assays are available) (Whitley et al. 1994b). As noted above, serum
T4 levels should be measured together with an estimate of how much hor-
mone is bound by proteins to estimate the percentage of FT4. This is com-
monly done using the T3 resin uptake test. In this procedure, radiolabeled
T3 is added to serum, and then a resin that binds T3 is also added to the
serum. Finally, the resin is separated out and the amount of T3 that has
been bound to it is measured (T3 is used because it does not displace T4
already bound to protein and thus measures only open binding sites). This
result is expressed as a percentage of the total T3 added. The difference
between the total added T3 and the amount bound to the resin represents
T3 bound to available protein binding sites in the serum. Often this result
is expressed as a ratio of the percentage uptake in patient serum to the
percentage uptake in a reference serum and is called the thyroid hormone
binding ratio (THBR). The normal value for this ratio is an interval around
1.0; the width of the interval varies somewhat from one laboratory to an-
other. The FTI, an estimate of FT4, is calculated from the T4 and THBR.
As an example, consider the situation of an elevated T3 resin uptake
(and hence an elevated THBR). This implies decreased available protein
binding sites for thyroid hormone (more T3 than expected is binding to the
resin because fewer protein sites are available to bind it). It can occur when
488 PSYCHONEUROENDOCRINOLOGY
apparent and real abnormalities. Drugs that compete for protein binding
sites (e.g., salicylates, phenytoin) or alter protein production (e.g., ste-
roids, including glucocorticoids and estrogens) alter measured T4 levels
(note, however, that changes in binding proteins do not affect the actual
“metabolic state”). Exogenous administration of T4 or T3 suppresses thy-
roid production and release of hormone.
from one measurement to another. In women, both LH and FSH are se-
creted at various levels throughout the menstrual cycle. LH has a marked
rise just before ovulation in midcycle, whereas FSH is highest at the be-
ginning of the follicular phase, declines as the follicular phase progresses,
and has another peak just before ovulation. During the onset of meno-
pause, there is much variation as ovarian function becomes irregular and
the pituitary is exposed to varying levels of negative feedback from ova-
rian sex steroids. In postmenopausal women (and in men and women
with primary gonadal failure) levels of both LH and FSH are persistently
elevated due to the lack of negative feedback from gonadal production of
sex steroids. By contrast, in pituitary or hypothalamic hypogonadism, LH
and FSH are hyposecreted. Thus, under different circumstances, similar
LH and FSH levels in different patients may reflect healthy normal phys-
iology or a pathophysiological process; interpretation requires knowledge
of the clinical context. LH and FSH are stable in serum, and no special
handling is required.
Testosterone
Testosterone, the most important male sex steroid, is secreted with a di-
urnal rhythm, peaking early in the morning and declining in the evening.
Like other steroids, the majority of testosterone is bound to proteins in
the plasma. These include a specific binding protein called sex hormone–
binding globulin (SHBG) (sometimes referred to as testosterone/estra-
diol–binding globulin), and albumin, which binds testosterone more
weakly. Bound testosterone equilibrates with a smaller pool of free test-
osterone. As with other protein-bound hormones, the total plasma pool
of testosterone is altered by conditions that affect protein levels and by
substances that compete for protein binding sites. The best measure of
bioavailable testosterone is probably the pool of free testosterone and al-
bumin-bound testosterone, because the latter is relatively weakly bound
(Whitley et al. 1994a). Total testosterone, free testosterone, and bioavail-
able testosterone (i.e., free and albumin-bound testosterone) can all be
measured.
Growth Hormone
Growth hormone is an anterior pituitary hormone that promotes linear
growth as well as other metabolic functions, some immediate and some
delayed (e.g., decrease in blood glucose levels acutely, reduction in body
fat, increase in nitrogen balance). Its secretion is controlled by two hypo-
thalamic factors: growth hormone–releasing hormone, which induces pi-
tuitary growth hormone release, and somatostatin, which inhibits
pituitary growth hormone release. Many of its actions are mediated
through a second hormone, insulin-like growth factor I (IGF-I). Although
psychiatrists will not generally be the primary physicians treating or inves-
tigating disorders of growth hormone, some children with severe psycho-
social stressors experience suppression of growth hormone secretion and
delayed growth and may initially come to psychiatric attention or require
psychiatric care as part of overall treatment. Growth hormone may also be
of importance in depressive disorders, because emerging data suggest that
bone mineral density, the normal regulation of which is linked to growth
hormone, is decreased in depressed patients (Michelson et al. 1996b).
Evaluation of growth hormone usually requires both basal and stim-
ulated measurement. Single samples of growth hormone do not provide
an accurate picture of pituitary growth hormone secretory activity, be-
cause secretion is pulsatile and values can vary widely. Basal function is
therefore best assessed by frequent, multiple samples, overnight if possi-
ble. Plasma IGF-I has not been shown to be well correlated with tissue
activity, and therefore is not a widely used measure (however, in patients
with growth hormone receptor abnormalities resulting in Laron dwarf-
Laboratory Evaluation of Neuroendocrine Systems 493
ism, plasma growth hormone levels are high and IGF-I levels are low, and
in patients with acromegaly IGF-I values are high). Typically patients
with suspected growth hormone abnormalities undergo provocative test-
ing to assess pituitary growth hormone release. Many agents—including
arginine, clonidine, levodopa, and insulin—induce growth hormone re-
lease and are used to assess the functional capacity of the pituitary soma-
totroph. Normal responses are generally defined as pituitary secretion
increasing plasma growth hormone concentrations to some minimum
threshold whose specific value depends on the particular provocative
agent and the growth hormone assay used.
Prolactin
Prolactin is a 199–amino acid peptide hormone secreted by the anterior
pituitary. Its best-characterized physiological action is the stimulation and
maintenance of lactation at the breast. Prolactin secretion is tonically in-
hibited by dopamine from tuberoinfundibular neurons; consequently,
conditions that interfere with dopamine secretion can lead to increases in
prolactin secretion and potentially galactorrhea. This can be particularly
important in psychiatric patients who take drugs that interfere with dopa-
mine secretion. Although many drugs have been associated with galactor-
rhea, antipsychotic agents, many of which have specific effects blocking
dopamine receptors, are particularly relevant to psychiatric practice (for
some newer agents, particularly clozapine and olanzapine, changes in pro-
lactin have been demonstrated to be minimal [Breier et al. 1999; Tollefson
and Kuntz 1999]). One case report showed a strong correlation between
plasma prolactin levels and severity of galactorrhea (Gioia and Asnis 1988),
and the authors suggested obtaining weekly plasma prolactin levels as a
way of adjusting medication dosage. However, serum prolactin levels vary
widely in patients with galactorrhea (Frantz and Wilson 1992), and the
usefulness of plasma prolactin levels in neuroleptic-induced galactorrhea
remains uncertain. Although they were at one time proposed for diagnos-
tic use, prolactin stimulation and suppression tests are not generally fa-
vored by endocrinologists in current practice because the results are too
variable to be generally useful (Frantz and Wilson 1992).
Summary
Over the past several decades, rapid growth in the knowledge of neu-
roendocrinology and the involvement of neuroendocrine factors in
normal brain functioning as well as psychiatric illness has opened many
494 PSYCHONEUROENDOCRINOLOGY
exciting new lines of inquiry. One of these has been the effort to develop
laboratory measures that can inform diagnosis and guide clinical decision
making. As discussed in this chapter, much progress has been made, and
for some illnesses such as depression it seems likely that it will soon be
possible to match different neuroendocrine patterns with specific patho-
physiologies. As yet, however, the primary role of neuroendocrine testing
in the clinical practice of psychiatry remains largely in distinguishing pri-
mary psychiatric illness from other conditions that can cause psychiatric
symptoms. The challenge that lies ahead is to further expand and refine
the knowledge of the neurobiology of psychiatric illnesses and the thera-
peutic armamentarium. In so doing it will be possible to develop tests
that can reliably differentiate the underlying pathology of similar pheno-
types and that can inform clinical interventions.
References
Chrousos GP, Gold PW: The concepts of stress and stress system disorders. JAMA
267:1244–1252, 1992
Dallman MF: Control of adrenocortical growth in vivo. Endocr Res 10:213–242,
1984–1985
DeBold CR, Sheldon WR, DeCherney GS, et al: Arginine vasopressin potentiates
adrenocorticotropin release induced by ovine corticotropin-releasing factor.
J Clin Invest 73:533–538, 1984
Demitrack MA, Dale JK, Gold PW, et al: Evidence for impaired activation of the
hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syn-
drome. J Clin Endocrinol Metab 73:1224–1230, 1991
Deuster PA, Petrides JS, Singh A, et al: Endocrine response to high-intensity ex-
ercise: dose-dependent effects of dexamethasone. J Clin Endocrinol Metab
85:1066–1073, 2000
Evans P, Peters J, Dyas J, et al: Salivary cortisol levels in true and apparent hyper-
cortisolism. Clin Endocrinol (Oxf) 20:709–715, 1984
Fish HR, Chernow B, O’Brian JT: Endocrine and neurophysiologic responses of
the pituitary to insulin-induced hypoglycemia. Metabolism 35:763–780,
1986
Frantz A, Wilson G: Endocrine disorders of the breast, in Williams Textbook of
Endocrinology, 8th Edition. Edited by Wilson J, Foster D. Philadelphia, PA,
WB Saunders, 1992, pp 953–976
Gispen-de Wied CC, Jansen LM, Wynne HJ, et al: Differential effects of hydro-
cortisone and dexamethasone on cortisol suppression in a child psychiatric
population. Psychoneuroendocrinology 23:295–306, 1998
Glinoer D, De Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during
pregnancy. J Clin Endocrinol Metab 71:276–287, 1990
Gioia P, Asnis G: Serial plasma levels in neuroleptic-induced galactorrhea: a case
report. J Clin Psychiatry 49:29–31, 1988
Gold PW, Loriaux DL, Roy A, et al: Responses to corticotropin-releasing hor-
mone in the hypercortisolism of depression and Cushing’s disease. Patho-
physiologic and diagnostic implications. N Engl J Med 314:1329–1335,
1986
Gold PW, Goodwin FK, Chrousos GP: Clinical and biochemical manifestations
of depression, I: relation to the neurobiology of stress. N Engl J Med 319:
348–353, 1988
Gow SM, Elder A, Caldwell G, et al: An improved approach to thyroid function
testing in patients with non-thyroidal illness. Clin Chim Acta 158:49–58,
1986
Halbreich U, Zumoff B, Kream J, et al: The mean 1300–1600 h plasma cortisol
concentration as a diagnostic test for hypercortisolism. J Clin Endocrinol
Metab 54:1262–1264, 1982
Jackson IM: The thyroid axis and depression. Thyroid 8:951–956, 1998
Joffe RT, Levitt AJ: The thyroid and depression, in The Thyroid Axis and Psychi-
atric Illness. Edited by Joffe RT, Levitt AJ. Washington, DC, American Psy-
chiatric Press, 1993, pp 195–253
496 PSYCHONEUROENDOCRINOLOGY
Klee GG, Hay ID: Assessment of sensitive thyrotropin assays for an expanded
role in thyroid function testing: proposed criteria for analytic performance
and clinical utility. J Clin Endocrinol Metab 64:461–471, 1987
Luger A, Deuster P, Kyle SB, et al: Acute hypothalamic-pituitary-adrenal re-
sponses to the stress of treadmill exercise. Physiologic adaptations to physical
training. N Engl J Med 316:1309–1315, 1987
Martinelli CE, Sader SL, Oliveira EB, et al: Salivary cortisol for screening of Cush-
ing’s syndrome in children. Clin Endocrinol (Oxf) 51:67–71, 1999
Michelson D, Stone L, Galliven E, et al: Multiple sclerosis is associated with al-
terations in hypothalamic pituitary adrenal axis function. J Clin Endocrinol
Metab 79:848–853, 1994
Michelson D, Altemus M, Galliven E, et al: Naloxone-induced pituitary-adrenal
activation does not differ in patients with depression, obsessive compulsive
disorder and healthy controls. Neuropsychopharmacology 15:207–212,
1996a
Michelson D, Stratakis C, Hill L, et al: Bone mineral density in women with de-
pression. N Engl J Med 335:1176–1181, 1996b
Munck A, Guyre PM, Holbrook NJ: Physiological functions of glucocorticoids in
stress and their relation to pharmacological actions. Endocr Rev 5:25–44,
1984
Naitoh Y, Fukata J, Toiminaga T, et al: Interleukin-6 stimulates the secretion of
adrenocorticotrophic hormone in conscious, free-moving rats. Biochem Bio-
phys Res Commun 155:1459–1463, 1988
Nelson JC, Davis JM: DST studies in psychotic depression: a meta-analysis. Am
J Psychiatry 154:1497–1503, 1997
Nieman LK, Loriaux DL: Corticotropin-releasing hormone: clinical applications.
Annu Rev Med 40:331–339, 1989
Orth DJ: Medical progress: Cushing’s syndrome. N Engl J Med 332:791–803,
1995
Orth D, Kovacs W, DeBold C: The adrenal cortex, in Williams Textbook of Endo-
crinology, 8th Edition. Edited by Wilson J, Foster D. Philadelphia, PA, WB
Saunders, 1992, pp 489–620
Payet N, Leboux JG, Isler H: Effect of ACTH on the proliferative and secretory
activities of the adrenal glomerulosa. Acta Endocrinol (Copenh) 93:365–
374, 1980
Ribeiro SC, Tandon R, Grunhaus L, et al: The DST as predictor of outcome in
depression: a meta-analysis. Am J Psychiatry 150:1618–1629, 1993
Rosner W: Plasma steroid-binding proteins. Endocrinol Metab Clin North Am 20:
697–720, 1991
Salata RA, Jarrett DB, Verbalis JG, et al: Vasopressin stimulation of adrenocorti-
cotropin hormone (ACTH) in humans. J Clin Invest 81:766–774, 1988
Sapolsky R, Rivier C, Yamamoto G, et al: Interleukin-1 stimulates the secretion
of hypothalamic corticotropin-releasing factor. Science 238:522–524, 1987
Schmidt PJ, Roca CA, Bloch M, et al: The perimenopause and affective disorders.
Semin Reprod Endocrinol 15:91–100, 1997
Laboratory Evaluation of Neuroendocrine Systems 497
Schmidt PJ, Nieman LK, Danaceau MA, et al: Differential behavioral effects of
gonadal steroids in women with and in those without premenstrual syn-
drome. N Engl J Med 338:209–216, 1998
Singh A, Petrides JS, Gold PW, et al: Differential hypothalamic-pituitary-adrenal
axis reactivity to psychological and physical stress. J Clin Endocrinol Metab
84:1944–1948, 1999
Surks MI, Chopra IJ, Mariash CN: American Thyroid Association guidelines for
use of laboratory tests in thyroid disorders. JAMA 263:1529–1532, 1990
Tollefson GD, Kuntz AJ: Review of recent clinical studies with olanzapine. Br J
Psychiatry Suppl 37:30–35, 1999
Tyrrel J, Brooks R, Fitzgerald P, et al: Cushing’s disease: selective transsphenoidal
resection of pituitary microadenomas. N Engl J Med 298:753–757, 1978
Utiger RD: The thyroid: physiology, thyrotoxicosis, hypothyroidism and the
painful thyroid, in Endocrinology and Metabolism, 3rd Edition. Edited by
Felig F, Baxter JD, Frohman LA. New York, McGraw-Hill, 1995, pp 435–
520
Wartofsky L, Burman K: Alterations in thyroid function in patients with systemic
illness: the “euthyroid sick syndrome.” Endocr Rev 3:164–217, 1982
Whitley RJ, Meikle AW, Watts NB: Endocrinology: gonadal steroids, in Tietz
Textbook of Clinical Chemistry, 2nd Edition. Edited by Burtis CA, Ashwood
ER. Philadelphia, PA, WB Saunders, 1994a, pp 1843–1886
Whitley RJ, Meikle AW, Watts NB: Endocrinology: the thyroid, in Tietz Text-
book of Clinical Chemistry, 2nd Edition. Edited by Burtis CA, Ashwood ER.
Philadelphia, PA, WB Saunders, 1994b, pp 1698–1739
Winters SJ: Endocrine evaluation of testicular function. Endocrinol Metab Clin
North Am 23:709–723, 1994
Yanovski JA, Cutler GB Jr, Chrousos GP, et al: Corticotropin-releasing hormone
stimulation following low-dose dexamethasone administration: a new test to
distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA 269:
2232–2238, 1993
Zobel AW, Yassouridis A, Frieboes RM, et al: Prediction of medium-term out-
come by cortisol response to the combined dexamethasone-CRH test in pa-
tients with remitted depression. Am J Psychiatry 156:949–951, 1999
This page intentionally left blank
Chapter 18
Hypothalamic-Pituitary-Adrenal Axis
499
500 PSYCHONEUROENDOCRINOLOGY
Each adrenal gland lies bilaterally in the perirenal space. The weight of
the normal adrenal, from autopsy reports, varies considerably (Quinian
and Berger 1933). On the computed tomographic scan, the adrenal
glands show an inverted Y configuration. Computed tomography is an
excellent technique—and is probably the single best and most cost-effective
technique—for imaging the adrenals (Dunnick 1988). Routine radio-
graphic examinations use 1-cm sections through the whole gland, and
slices of 5 mm thickness provide even better detail of pathology when
smaller-size pathology is suspected to be present.
Neuroendocrine challenge studies have noted that a high dose of ACTH
results in a greater-than-normal cortisol response in depressed patients
(Kalin et al. 1987); however, this was not the case when a low dose of
ACTH was administered (Krishnan et al. 1990b), suggesting that sensi-
tivity of the adrenal cortex to the pituitary hormone is not altered in de-
pression. In animals, hypertrophy of all layers of the adrenal cortex, but
not the adrenal medulla, occurs after long-term stimulation with ACTH
(Malendowicz 1986). These observations, when taken together with the
Endocrine Imaging in Depression 501
The pituitary is a small gland that lies in the sella turcica at the base of the
brain, connected to the hypothalamus by the pituitary stalk. The gland is
about 1 cm in diameter and weighs 0.5–1 g. The volume of the pituitary
gland in a living individual can be estimated with MRI technology using
sagittal and coronal sections through the gland.
Numerous neuroendocrine investigators have reported that ACTH
secretion is increased in depressed patients, and this appears to be in re-
sponse to hypersecretion of CRH (Gold et al. 1984). Metyrapone, a drug
that inhibits 11b-hydroxylase and leads to decreased serum cortisol level,
has been given orally or intravenously in clinical neuroendocrine experi-
ments to assess the ability of the pituitary to enhance its secretion of
ACTH when cortisol synthesis is inhibited. In depressed patients, after
metyrapone administration, ACTH response to CRH was found to be
greater than in nondepressed control subjects (Lisansky et al. 1989). Sim-
ilarly, exaggerated ACTH response to CRH was observed in depressed
patients after administration of dexamethasone (Holsboer et al. 1987). In
animal experiments, it has been demonstrated that with short-term ad-
ministration of CRH (Westlund et al. 1985), there is enlargement of pi-
tuitary corticotrophs, whereas long-term administration of this peptide
results in an increase in numbers of these adenohypophyseal cells that se-
crete ACTH (Gertz et al. 1987).
When taken together, the findings described above raised a strong sus-
picion that an enlargement of the pituitary might be found in depressed
patients. This prompted Krishnan et al. (1991) to conduct an imaging
study of pituitary size in depression. This study included 19 patients and
19 control subjects. Sixteen patients had unipolar depression and 3 had
bipolar depression, and 14 of the 19 patients had recurrent depression.
In this MRI study, the midsagittal T1 image centered around the pituitary
stalk was used to measure the central height, maximum length, and cross-
sectional area of the pituitary, a method previously applied by Lemort et
504 PSYCHONEUROENDOCRINOLOGY
al. (1988). The coronal T1 image through the pituitary stalk was used to
measure the maximum width of the gland. Estimates of the volume of
the pituitary were made by applying the same method used by Gonza-
lvez et al. (1988). Depressed patients had significantly greater pituitary
cross-sectional area (43±10 mm2) than did control subjects (32±9 mm2;
P<0.0009). Depressed patients also had a significantly larger pituitary
volume (577.5±167 mm3) compared with nondepressed control sub-
jects (408.4±172 mm3; P<0.0007) in this study (Krishnan et al. 1991).
The increased volume most likely reflected increase in the size of the an-
terior pituitary, because the posterior pituitary is a neural tissue com-
posed mainly of glial-like cells called pituicytes, and the only conditions
that are expected to enlarge the size of this tissue would be extremely
rare neuroendocrine tumors. A difference in pituitary length was also ob-
served, with depressed patients having a greater length of the pituitary
(P<0.04).
The next step was to study whether there was a relationship between
the observed pituitary anatomical changes and DST findings. Hence, an-
other experiment was conducted in our laboratory in which 24 patients
(17 females and 7 males) with depression underwent the standard DST;
their pituitary volumes were estimated using 3-mm sagittal slices (Axelson
et al. 1992). In this study, pituitary volume was measured directly from
high-quality hard copies of magnetic resonance images instead of estimat-
ing it using linear parameters. After determination of point counts for each
sagittal image of the pituitary, the volume was calculated using Cavalieri’s
(1966) systematic sampling theorem, with the following formula:
amygdala. The uncus, cornu ammonis, dentate gyrus, fimbria, and subic-
ulum were included in the measurement. The two investigators who
rated AHC volumes were blind to the diagnoses and to endocrine data.
No differences were found in hippocampal volume between depressed
patients and nondepressed control subjects. In this study, the patients
were also given the standard DST. There was no difference between DST
suppressors and DST nonsuppressors in their left or right hippocampal
volumes. Also, there were no relationships between the peak postdexa-
methasone cortisol level at 3:00 P.M. or 11:00 P.M. and either left or right
hippocampal volume. Age was negatively correlated with both left and
right AHC volumes. A relationship was observed between left hippo-
campal volume and postdexamethasone cortisol concentration at 11:00
P.M., after covarying for age and sex. In general, the results of this study
provided limited support for the hypothesis of Sapolsky and McEwen
(1988) regarding a key role for the hippocampus in the hypersecretory
state of glucocorticoids in major depression.
The finding of reduced hippocampal volumes was noted even after
resolution of a depressive episode. Sheline et al. (1999) studied 24 women
with a history of depression and found a significant inverse correlation
between hippocampal volume and total lifetime duration of depression.
There was no significant correlation between age and hippocampal vol-
ume in either the patients or the matched control subjects in this study.
Interestingly, decreased hippocampal volume and increased pituitary
volume have been noted in patients with alcohol dependence also (Beres-
ford et al. 1999).
In light of the knowledge that elevated cortisol levels are associated
with depressive symptoms as well as cognitive impairments (Sapolsky
and McEwen 1988), O’Brien et al. (1996) examined this issue further
and found an inverse relationship between hippocampal volume and
postdexamethasone cortisol levels in patients with Alzheimer’s disease
and suggested that hippocampal damage might explain high rates of ab-
normal DST results in Alzheimer’s disease.
Summary
References
Amsterdam JD, Marinelli DL, Arger P, et al: Assessment of adrenal gland volume
by computed tomography in depressed patients and healthy volunteers: a pi-
lot study. Psychiatry Res 21:384–387, 1987
Axelson DA, Doraiswamy PM, Boyko OB, et al: In vivo assessment of pituitary
volume with magnetic resonance imaging and systematic stereology: rela-
tionship to dexamethasone suppression test results in patients. Psychiatry
Res 46:63–70, 1992
Axelson DA, Doraiswamy PM, McDonald WM, et al: Hypercortisolemia and
hippocampal changes in depression. Psychiatry Res 47:163–173, 1993
Beresford T, Arciniegas D, Rojas D, et al: Hippocampal to pituitary volume ratio:
a specific measure of reciprocal neuroendocrine alterations in alcohol depen-
dence. J Stud Alcohol 60:586–588, 1999
Carroll BJ, Curtis GC, Mendels J: Neuroendocrine regulation in depression, II:
discrimination of depressed from nondepressed patients. Arch Gen Psychia-
try 33:1051–1058, 1976
Carroll BJ, Feinberg M, Greden JF, et al: A specific laboratory test for the diagno-
sis of melancholia: standardization, validation, and clinical utility. Arch Gen
Psychiatry 38:15–22, 1981
Cavalieri B: Deometra delqi Indivisibili. Turin, Italy, Unione tipografo Editrice, 1966
De Kloet ER, Reul JMHM: Feedback action and tonic influence of corticosteroids
on brain function: a concept arising from the heterogeneity of brain receptor
systems. Psychoneuroendocrinology 12:83–105, 1987
508 PSYCHONEUROENDOCRINOLOGY
Doraiswamy PM, Krishnan KRR, Hussain MM, et al: A brain magnetic resonance
imaging study of pituitary gland morphology in anorexia nervosa and bu-
limia. Biol Psychiatry 28:110–116, 1990
Doraiswamy PM, Krishnan KRR, Boyko OB, et al: Pituitary abnormalities in eat-
ing disorders: further evidence from MRI studies. Prog Neuropsychopharma-
col Biol Psychiatry 15:351–356, 1991
Dunnick NR: The adrenal gland, in Radiology: Diagnosis-Imaging-Intervention.
Edited by Taveras JM, Ferrucci JT. Philadelphia, PA, JB Lippincott, 1988,
pp 16–22
Gadde KM, Krishnan KRR: Endocrine factors in depression. Psychiatr Ann 24:
521–524, 1994
Gertz BJ, Contreras LN, McComb DJ, et al: Chronic administration of CRF in-
creases pituitary corticotroph numbers. Endocrinology 120:381–388, 1987
Gold PW, Chrousos G, Kellner C, et al: Psychiatric implication of basic and clinical
studies of corticotrophic releasing factor. Am J Psychiatry 141:619–624, 1984
Gonzalvez JG, Elizando G, Salvidor D: Pituitary gland growth during normal
pregnancy: an in vivo study using magnetic resonance imaging. Am J Med
85:217–220, 1988
Gundersen HJ, Jensen EB: The efficiency of systematic sampling in stereology
and its prediction. J Microsc 147:229–263, 1987
Holsboer F, Van Bardeleben U, Widemann, et al: Serial assessment of corticotro-
phin-releasing hormone response after dexamethasone in depression. Biol
Psychiatry 22:228–234, 1987
Jacobson L, Sapolsky RM: The role of the hippocampus in feedback regulation of
the hypothalamic-pituitary-adrenal axis. Endocr Rev 12:118–134, 1991
Kalin NH, Dawson G, Tariot P, et al: Function of the adrenal cortex in patients
with major depression. Arch Gen Psychiatry 44:233–240, 1987
Kathol RG, Gehris T: Persistent elevation of urinary free cortisol and loss of cir-
cannual periodicity in recovered depressed patients: a trait finding. J Affect
Disord 8:137–145, 1985
Krishnan KRR, Hussain MM, McDonald WM, et al: In vivo stereological assess-
ment of caudate volume in men: effect of normal aging. Life Sci 47:1325–
1329, 1990a
Krishnan KRR, Ritchie JC, Saunders WB, et al: Adrenocortical sensitivity to low
dose ACTH administration in depressed patients. Biol Psychiatry 27:930–
933, 1990b
Krishnan KRR, Doraiswamy PM, Lurie SN, et al: Pituitary size in depression.
J Clin Endocrinol Metab 72:256–259, 1991
Landfield PW, Eldridge JC: The glucocorticoid hypothesis of brain aging and neu-
rodegeneration: recent modifications. Acta Endocrinol (Copenh) 125:54–
64, 1991
Lemort M, Haesendonck P, Louryan S, et al: MRI of the sellar region and supra-
sellar cisterns: normal morphology on sagittal sections, in Brain Anatomy and
Magnetic Resonance Imaging. Edited by Gouaze A, Salamon G. New York,
Springer-Verlag, 1988, pp 158–163
Endocrine Imaging in Depression 509
513
514 PSYCHONEUROENDOCRINOLOGY
The work of Selye (1956) revealed the delicate balance between the pro-
tective effects of adrenal steroids secreted in response to stressful experi-
Stress and Neuroendocrine Function 515
ences and the negative consequences that these same hormones may have
for many processes. Indeed, the body depends on adequate levels of ad-
renal steroids to prevent extremes of responses to challenge, and yet too
much adrenal steroid is also deleterious.
On the positive side, acute elevations of adrenal steroids promote
adaptive processes, such as increased appetite (McEwen et al. 1993), mem-
ory for emotionally charged events (deQuervain et al. 1998; Roozendaal
et al. 1996), and enhanced immunological function (Dhabhar and McEwen
1999) On the negative side, chronic elevations of adrenal steroid levels
promote abdominal obesity and insulin resistance (Bjorntorp 1990; Brind-
ley and Rolland 1989; Jayo et al. 1993), suppress immune function (Dhab-
har and McEwen 1997; McEwen et al. 1997), and impair memory (see
“Importance of the Brain as Controller of and Target for Stress” below as
well as Newcomer et al. 1999; Wolkowitz et al. 1990).
However, whereas chronic exposure to adrenal steroids suppresses
immune defense mechanisms and causes negative consequences such as
neural damage, muscular atrophy, and calcium loss from bone (Sapolsky
1992; Sapolsky et al. 1986), an insufficiency of adrenal steroids makes
the organism much more vulnerable to inflammatory disturbances and
autoimmune responses, fever, and damage from catecholamine metabo-
lites and alcohol (Leonard et al. 1991; Morrow et al. 1993; Ramey and
Goldstein 1957; Spencer and McEwen 1990; Sternberg et al. 1989), and
it also increases fear response and anxiety (Weiss et al. 1970). Therefore,
the adrenocortical system is vital for survival, and there is a generalized
inverted U–shaped dose-time response curve to describe its actions that
range from protection in the low to intermediate range to exacerbation
of pathology at the extreme end of dose and duration of exposure.
Fear and anxiety are neural events, and the brain governs the endocrine
and autonomic nervous systems and their numerous effects on the im-
mune system and metabolic processes. Moreover, circulating stress hor-
mones feed back on the brain and regulate its structure and function.
Therefore, it is imperative to consider the impact of stress on the nervous
system.
The brain is involved directly in the response to stressors and to diur-
nal changes in the secretion of adrenal steroids; this was shown after it
516 PSYCHONEUROENDOCRINOLOGY
Containment by Glucocorticoids
Glucocorticoid secretion is one of the most frequent responses to stress-
ful events. Adrenal steroid secretion as a result of stress has multiple ac-
tions on the brain and body that have been characterized as containing or
counterregulating other responses to stress and trauma such as inflamma-
tions, fever, edema, and immune responses (Munck et al. 1984). The
term containment implies that glucocorticoids prevent responses from be-
ing excessive (Figure 19–2). In the brain, glucocorticoids contain the syn-
thesis of corticotropin-releasing hormone (CRH) and vasopressin, two
neuropeptide-releasing hormones that stimulate production of adreno-
corticotropic hormone (ACTH); in doing this they prevent hypothalamic
CRH—which has anxiogenic, arousing, immunosuppressive, and anorex-
igenic effects—from becoming hyperactive (McEwen et al. 1992). Other
examples of containment are discussed below in conjunction with the
noradrenergic and serotonergic systems.
formation, in both the locus coeruleus and the adrenal medulla (see Nisen-
baum et al. 1991). Stress-induced activation of catecholamine biosynthe-
sis also increases the catalytic efficiency of tyrosine hydroxylase and leads
to increased catecholamine formation (see Nisenbaum et al. 1991).
Thus, in the face of increased amount and activity of tyrosine hydroxyl-
ase, there is a need for various forms of containment (see Figure 19–2).
Glucocorticoids fill this role in several ways, reducing the formation of
cyclic adenosine monophosphate in the cerebral cortex in response to
noradrenaline (see McEwen et al. 1992), and decreasing catecholamine
biosynthesis and release (Pacak et al. 1992, 1993).
In view of the importance of noradrenaline in promoting excitability
and disinhibition of hippocampal neurons (Doze et al. 1991; Dunwiddie
Stress and Neuroendocrine Function 521
nal steroid receptors, and its effect in depressed subjects indicates that
there is an increased drive to release ACTH that is held partially in check
by glucocorticoid feedback acting via type II receptors (Bailey 1991).
portive group therapy to double the survival time for breast cancer pa-
tients after the end of intervention (Spiegel et al. 1989). On the negative
side are reports that psychological stress increases the susceptibility to
the common cold (Cohen et al. 1991) and increases the incidence of
mononucleosis in medical students with examination stress (Kiecolt-Glaser
and Glaser 1991).
More prolonged effects of stress on diseases related to the immune
system are not so easy to document. Nevertheless, a recent study of type
1 diabetes in children found that stressful life events stemming from ac-
tual or threatened losses within the family and occurring during ages 5–9
years increased the relative risk for the disease, even after normalization
for confounding factors such as age, gender, and family socioeconomic
status (Hagglof et al. 1991). An increased frequency of negative life
events is also associated with newly diagnosed Graves’ disease in adults,
which suggests a possible interaction between hereditary factors and
stress (Winsa et al. 1991). Moreover, psychosocial influences on another
autoimmune disease, rheumatoid arthritis, are strongly suggestive but are
confounded by the heterogeneity of the disease (Weiner 1992), as is also
the case for asthma (Mrazek and Klinnert 1991). Personality features,
such as the ability to express anger and irritation, as well as stressful life
events, were implicated as risk factors in women with rheumatoid arthritis
in whom there was not a family history of this disease (Yehuda et al. 1991).
Adrenal steroids have multiple effects on the immune system, acting
along with autonomic nervous system innervation (and virtually every
hormone in the body) to biphasically modulate immune function (Mad-
den and Felten 1995; McEwen and Sapolsky 1995). These modulatory
actions can best be appreciated in states of disease. Although many of the
actions of adrenal steroids on the immune system are adaptive and pro-
mote the body’s ability to fight an infection, tumor, or inflammatory or
autoimmune disorder, continuing high levels of HPA activity and sympa-
thetic neural activity (allostatic load) are deleterious to immune function.
with life events (Seligman 1975). It has been reported that adrenal ste-
roid insufficiency exacerbates learned helplessness in an animal model
(Edwards et al. 1990). As noted above (see “Stress and Serotonin”), ad-
renal steroids potentiate serotonergic activity, and the risk for anger and
hostility is linked in some cases to suicidal depression in individuals with
low levels of serotonergic activity (Williams and Chesney 1993; Williams
and Williams 1993).
Recurrent depression is a model of brain and systemic allostatic load.
Not only is there an increased incidence of cardiovascular disease in de-
pressive illness (Musselman et al. 1998), there is also exaggerated platelet
reactivity and hence increased risk for stroke and myocardial infarction
(Musselman et al. 1996), as well as increased abdominal fat deposition
(Thakore et al. 1997) and decreased heart rate variability (Krittayaphong
et al. 1997). Recurrent depression is also associated with decreased bone
mineral density in association with elevated glucocorticoid levels (Mich-
elson et al. 1996). In the brain, recurrent depression has been linked to
atrophy of the hippocampus and amygdala (Sheline et al. 1996, 1999) as
well as the prefrontal cortex (Drevets et al. 1997). The cellular basis for
these changes is not known; reduced glial cell volume is a possibility,
along with reduced branching of dendrites, reduced numbers of dentate
gyrus granule neurons, and outright loss of pyramidal neurons. This is dis-
cussed further under “Neurobiology of Stress and Glucocorticoid Effects
on Dendritic Branching” below.
It is noteworthy that hippocampal atrophy is also reported in post-
traumatic stress disorder, which occurs along with depressive illness in
many subjects (Bremner et al. 1995, 1997; Gurvits et al. 1996). It is not
clear when the reduced hippocampal volume develops in relation to the
traumatic event, although existing evidence suggests that it may be a
gradual and delayed event over years, as also appears to be the case for
depressive illness.
around them to hide and locate food, and voles and deer mice that
traverse large distances to find mates, have larger hippocampal volumes
than closely related species that do not have these behaviors; moreover,
there are indications that hippocampal volume may change during the
breeding season (Galea et al. 1994; Sherry et al. 1992). Indeed, the rate
of neurogenesis in the male and female prairie vole varies according to
the breeding season (Galea and McEwen 1999). In contrast, an enriched
environment has been found to increase dentate gyrus volume in mice by
increasing neuronal survival without altering the rate of neurogenesis
(Kempermann et al. 1997). Thus there are several ways to maintain the
balance between neuronal apoptosis and neurogenesis.
Learning that involves the hippocampus also appears to affect the
survival of newly formed dentate granule neurons. When rats were
trained in a task involving the hippocampus, the survival of previously la-
beled granule neurons was prolonged (Gould et al. 1999b).
Another important effect is that of acute and chronic stress. Acute
stress involving the odor of a natural predator, the fox, inhibits neurogen-
esis in the adult rat (Galea et al. 1996). Acute psychosocial stress in the
adult tree shrew, involving largely visual cues, inhibits neurogenesis
(Gould et al. 1997a). Inhibition of neurogenesis is also seen in the den-
tate gyrus of the marmoset after acute psychosocial stress (Gould et al.
1997a). Chronic psychosocial stress in the tree shrew results in a more
substantial inhibition of neurogenesis than after a single acute stressful
encounter (Gould et al. 1997a). This finding suggests that there may be
other changes such as atrophy of dendritic branching to account for the
decrease in dentate gyrus volume.
Changes in dentate gyrus volume appear to have consequences for cog-
nitive functions subserved by the hippocampus. In enriched-environment
studies (Kempermann et al. 1997), increased dentate gyrus volume was
accompanied by better performance on spatial learning tasks. In contrast,
decreased dentate gyrus volume in chronically stressed tree shrews is par-
alleled by impaired spatial learning and memory (Czeh et al. 2001), al-
though this might be as much due to atrophy of dendrites of CA3
pyramidal neurons and dentate granule neurons (see “Neurobiology of
Stress and Glucocorticoid Effects on Dendritic Branching” above) as to
reduced dentate gyrus neurogenesis.
Conclusion
stress disorder (Green et al. 1992), and possibly also for schizophrenia
(Norman and Malla 1993). It is interesting to note that both posttrau-
matic stress disorder and schizophrenia appear to involve neuroanatom-
ical disturbances in hippocampal volume and structure (Arnold et al.
1991; Barbeau et al. 1995; Bogerts et al. 1993; Bremner et al. 1995; Luchins
1990; Shenton et al. 1992), whereas there are some suggestions that ma-
jor depressive illness may be linked through glucocorticoid excess to re-
duced hippocampal volume and cognitive impairment (Axelson et al.
1993; McEwen and Sapolsky 1995; Sheline et al. 1996, 1999). However,
we are at a very early stage of understanding the etiology of these disor-
ders and the role of neurological disturbances, and much remains to be
learned about the pathways from perceived stress to the neurochemical
and neuroanatomical features of these disorders. Therefore, the discus-
sion of the roles of the hippocampus, glucocorticoids, CRH, the HPA
axis, serotonin, and noradrenaline will have to be broadened to include
other brain structures and neurochemical mediators. Nevertheless, the
principles outlined in this chapter concerning anticipation and anxiety
leading to allostatic load and the normal role of adrenal steroids in con-
taining various aspects of the primary stress response should be useful in
understanding the roles of other mediators and brain regions in coping
with potentially stressful events.
References
Akana SF, Dallman MF: Feedback and facilitation in the adrenocortical system:
unmasking facilitation by partial inhibition of the glucocorticoid response to
prior stress. Endocrinology 131:57–68, 1992
Al-Damluji S, White A: Central noradrenergic lesion impairs the adrenocorti-
cotrophin response to release of endogenous catecholamines. J Neuroendo-
crinol 4:318–323, 1992
Anda R, Williamson D, Jones D, et al: Depressed affect, hopelessness and the risk
of ischemic heart disease in a cohort of U.S. adults. Epidemiology 4:285–294,
1993
Anisman H, Merali Z: Chronic stressors and depression: distinguishing character-
istics and individual profiles. Psychopharmacology (Berl) 134:330–332,
1997
Archer T: Serotonin and fear retention in the rat. J Comp Physiol Psychol 96:
491–516, 1982
Arnold SE, Lee VM-Y, Gur RE, et al: Abnormal expression of two microtubule-
associated proteins (MAP2 and MAP5) in specific subfields of the hippo-
campal formation in schizophrenia. Proc Natl Acad Sci U S A 88:10850–
10854, 1991
Stress and Neuroendocrine Function 537
Graeff F: Role of 5-HT in defensive behavior and anxiety. Rev Neurosci 4:181–
211, 1993
Gray J: Precis of the neuropsychology of anxiety: an enquiry into the functions of
the septo-hippocampal system. Behav Brain Sci 5:469–534, 1982
Green BL, Lindy JD, Grace MC, et al: Chronic posttraumatic stress disorder and
diagnostic comorbidity in a disaster sample. J Nerv Ment Dis 180:760–766,
1992
Gurvits TV, Shenton ME, Hokama H, et al: Magnetic resonance imaging study of
hippocampal volume in chronic, combat-related posttraumatic stress disor-
der. Biol Psychiatry 40:1091–1099, 1996
Hagglof B, Bloom L, Dahlquist G, et al: The Swedish childhood diabetes study:
indications of severe psychological stress as a risk factor for type I (insulin-
dependent) diabetes mellitus in childhood. Diabetologia 34:579–583,
1991
Jacobs BL, Tanapat P, Reeves AJ, et al: Serotonin stimulates the production of
new hippocampal granule neurons via the 5HT1A receptor in the adult rat
(abstract 796.6). Abstr Soc Neurosci 24:1992, 1998
Jayo JM, Shively CA, Kaplan JR, et al: Effects of exercise and stress on body fat
distribution in male cynomolgus monkeys. Int J Obes Relat Metab Disord
17:597–604, 1993
Kaplan JR, Adams MR, Clarkson TB, et al: Social behavior and gender in biomed-
ical investigations using monkeys: studies in atherogenesis. Lab Anim Sci 41:
334–343, 1991a
Kaplan JR, Pettersson K, Manuck SB, et al: Role of sympathoadrenal medullary
activation in the initiation and progression of atherosclerosis. Circulation 84
(suppl 6):VI23–VI32, 1991b
Kaplan MS, Bell DH: Mitotic neuroblasts in the 9-day-old and 11-month-old ro-
dent hippocampus. J Neurosci 4:1429–1441, 1984
Kaplan MS, Hinds JW: Neurogenesis in the adult rat: electron microscopic anal-
ysis of light radioautographs. Science 197:1092–1094, 1977
Kempermann G, Kuhn HG, Gage FH: More hippocampal neurons in adult mice
living in an enriched environment. Nature 586:493–495, 1997
Kempermann G, Kuhn HG, Gage FH: Experience-induced neurogenesis in the
senescent dentate gyrus. J Neurosci 18:3206–3212, 1998
Kennet GA, Dickinson SL, Curzon G: Central serotonergic responses and behav-
ioural adaptation to repeated immobilization: the effect of the corticoster-
one synthesis inhibitor metyrapone. Eur J Pharmacol 119:143–152, 1985
Kiecolt-Glaser JK, Glaser R: Stress and immune function in humans, in Psycho-
neuroimmunology. Edited by Ader R, Felton D, Cohen N. San Diego, CA,
Academic Press, 1991, pp 849–865
Kirschbaum C, Wolf OT, May M, et al: Stress- and treatment-induced elevations
of cortisol levels associated with impaired verbal and spatial declarative
memory in healthy adults. Life Sci 58:1475–1483, 1996
Krishnan KRR, Reed D, Wilson WH, et al: RU486 in depression. Prog Neuropsy-
chopharmacol Biol Psychiatry 16:913–920, 1992
Stress and Neuroendocrine Function 541
Krittayaphong R, Cascio WE, Light KC, et al: Heart rate variability in patients
with coronary artery disease: differences in patients with higher and lower
depression scores. Psychosom Med 59:231–235, 1997
Kuroda Y, Mikuni M, Ogawa T, et al: Effect of ACTH, adrenalectomy and the
combination treatment on the density of 5-HT2 receptor binding sites in
neocortex of rat forebrain and 5-HT2 receptor-mediated wet-dog shake be-
haviors. Psychopharmacology 108:27–32, 1992
Kuroda Y, Mikuni M, Nomura N, et al: Differential effect of subchronic dexa-
methasone treatment on serotonin-2 and beta-adrenergic receptors in the rat
cerebral cortex and hippocampus. Neurosci Lett 155:195–198, 1993
Landfield P: Modulation of brain aging correlates by long-term alterations of ad-
renal steroids and neurally active peptides. Prog Brain Res 72:279–300, 1987
Landfield PW, Eldridge JC: Evolving aspects of the glucocorticoid hypothesis of
brain aging: hormonal modulation of neuronal calcium homeostasis. Neuro-
biol Aging 15:579–588, 1994
Leonard JP, MacKenzie FJ, Patel HA, et al: Hypothalamic noradrenergic path-
ways exert an influence on neuroendocrine and clinical status in experimen-
tal autoimmune encephalomyelitis. Brain Behav Immun 5:328–338, 1991
Luchins DJ: A possible role of hippocampal dysfunction in schizophrenic symp-
tomatology. Biol Psychiatry 28:87–91, 1990
Luine V, Villegas M, Martinez C, et al: Repeated stress causes reversible impair-
ments of spatial memory performance. Brain Res 639:167–170, 1994
Lupien SJ, McEwen BS: The acute effects of corticosteroids on cognition: inte-
gration of animal and human model studies. Brain Res Brain Res Rev 24:1–
27, 1997
Lupien S, Lecours AR, Lussier I, et al: Basal cortisol levels and cognitive deficits
in human aging. J Neurosci 14:2893–2903, 1994
Lupien SJ, Gaudreau S, Sharma S, et al: Stress-induced declarative memory im-
pairment in healthy elderly subjects: relationship to cortisol reactivity. J Clin
Endocrinol Metab 82:2070–2075, 1997
Lupien SJ, DeLeon MJ, De Santi S, et al: Cortisol levels during human aging pre-
dict hippocampal atrophy and memory deficits. Nat Neurosci 1:69–73, 1998
Madden KS, Felten DL: Experimental basis for neural-immune interactions.
Physiol Rev 75:77–106, 1995
Magarinos AM, McEwen BS: Stress-induced atrophy of apical dendrites of hippo-
campal CA3c neurons: comparison of stressors. Neuroscience 69:83–88, 1995
Magarinos AM, McEwen BS, Flugge G, et al: Chronic psychosocial stress causes
apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordi-
nate tree shrews. J Neurosci 16:3534–3540, 1996
Magarinos AM, Deslandes A, McEwen BS: Effects of antidepressants and benzo-
diazepine treatments on the dendritic structure of CA3 pyramidal neurons
after chronic stress. Eur J Pharmacol 371:113–122, 1999
Martire M, Pistritto G, Preziosi P: Different regulation of serotonin receptors fol-
lowing adrenal hormone imbalance in the rat hippocampus and hypothala-
mus. J Neural Transm 78:109–120, 1989
542 PSYCHONEUROENDOCRINOLOGY
Welch JE, Farrar GE, Dunn AJ, et al: Central 5-HT1A receptors inhibit adreno-
cortical secretion. Neuroendocrinology 57:272–281, 1993
Williams RB, Chesney MA: Psychosocial factors and prognosis in established cor-
onary artery disease. The need for research on interventions. JAMA 270:
1860–1861, 1993
Williams RB, Williams VP: Anger Kills: Seventeen Strategies for Controlling the
Hostility That Can Harm Your Health. New York, Harper Perennial, 1993
Winokur A, Maislin G, Phillips JL, et al: Insulin resistance after oral glucose tol-
erance testing in patients with major depression. Am J Psychiatry 145:325–
330, 1988
Winsa B, Adami HO, Bergstrom R, et al: Stressful life events and Graves’ disease.
Lancet 338:1475–1479, 1991
Wolkowitz O, Reus V, Weingartner H: Cognitive effects of corticosteroids. Am
J Psychiatry 147:1297–1303, 1990
Woolley C, Gould E, McEwen BS: Exposure to excess glucocorticoids alters den-
dritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:
225–231, 1990
Woolley C, Gould E, Sakai R, et al: Effects of aldosterone or RU28362 treatment
on adrenalectomy-induced cell death in the dentate gyrus of the adult rat.
Brain Res 554:312–315, 1991
Yehuda R, Giller E, Southwick S, et al: Hypothalamic-pituitary-adrenal dysfunc-
tion in posttraumatic stress disorder. Biol Psychiatry 30:1031–1048, 1991
Index
547
548 PSYCHONEUROENDOCRINOLOGY