Article

Association of Depression With Viral Load,

CD8 T Lymphocytes, and Natural Killer Cells
in Women With HIV Infection
Dwight L. Evans, M.D.
Thomas R. Ten Have, Ph.D.,
M.P.H.
Steven D. Douglas, M.D.
David R. Gettes, B.S.
Mary Morrison, M.D.
Margaret S. Chiappini, R.N.,
M.N., C.C.R.C.
Priscilla Brinker-Spence, B.S.
Carla Job, M.S.N., C.R.N.P.
Delinda E. Mercer, Ph.D.
Yan Lin Wang, M.S.
Dean Cruess, Ph.D.
Benoit Dube, M.D.
Erik A. Dalen, B.A.
Tiffany Brown, B.A.
Russell Bauer, Ph.D.
John M. Petitto, M.D.

Objective: Clinical and epidemiology

studies have implicated depression as a
risk factor in the morbidity and mortality
of many human diseases. This study
sought to determine if depression was
associated with alterations in cellular immunity variablesspecifically, natural
killer (NK) cells and CD8 T lymphocytes
in women with HIV infection.
Method: Ninety-three women (63 HIVseropositive, 30 HIV-seronegative) were
studied as part of an ongoing longitudinal
study conducted at two sites. Subjects underwent extensive clinical, psychiatric,
and immunological evaluations. CBC
counts and flow cytometry panels were
conducted and NK cell activity assayed for
all subjects; viral load was determined for
HIV-seropositive subjects.
Results: The overall rate of major depression in the HIV-seropositive and HIV-seronegative women was 15.87% (N=10 of
63) and 10.00% (N=3 of 30), respectively.
HIV-seropositive women had higher depressive symptom scores than did the
comparison subjects (Hamilton depression
scale: mean=8.62 [SD=7.26] versus mean=
5.67 [SD=7.33], respectively). Both groups
had similar anxiety scores. Depressive and
anxiety symptoms were significantly asso-

ciated with higher activated CD8 T lymphocyte counts and higher viral load levels. Major depression was associated with
significantly lower natural killer cell activity, and depressive and anxiety symptom
scores showed a similar correlation.
Conclusions: Our findings provide the
first evidence that depression may alter
the function of killer lymphocytes in HIVinfected women and suggest that depression may decrease natural killer cell activity and lead to an increase in activated
CD8 T lymphocytes and viral load. The
rate of current major depression in these
HIV-seropositive women (none of whom
had current substance abuse) is approximately twice that reported for HIV-seropositive men. The rate is also consistent
with studies of women with other medical illnesses and with a recent epidemiology study that associated depression with
mortality in HIV-infected women with
chronic depressive symptoms. Depression
may have a negative impact on innate
immunity. Examination of killer lymphocytes may prove useful in assessing the
potential relationship between depression, immunity, and HIV disease progression in women.
(Am J Psychiatry 2002; 159:17521759)

n increasing number of clinical and epidemiology

studies have implicated depression as a potential risk factor in the morbidity and mortality of a wide range of human diseases. Although neurobiological mechanisms remain unknown, there is a considerable body of basic and
clinical research documenting a relationship between depression and cell-mediated immunity. If this relationship
is clinically relevant, depression could alter key parameters of cellular immunity, thereby accelerating the course
of an immune-based disease. Thus, we and others have investigated the relationship between depression and immune function in individuals with HIV infection.
The increasing spread of HIV to women has become a
significant public health issue, and HIV is among the leading causes of death for U.S. women between the ages of
2544 (1). However, there is a relative paucity of controlled

1752

data regarding the prevalence of depression in HIV-seropositive women. Although estimates of depression vary
widely among the available studies of HIV-seropositive
women, the prevalence of depression appears to be at
least twice as high in women with HIV infection compared
with HIV-seropositive men (1, 2). If depression is associated with greater HIV morbidity and mortality, women
could be particularly vulnerable, given this high prevalence of depression. In fact, a recent, large epidemiology
study found a significant association between depression
and HIV morbidity and mortality in HIV-seropositive
women. The mortality rate was doubled in the women with
chronic depressive symptoms compared with women with
limited or no depressive symptoms (2).
Given the wide variability in the progression of HIV infection, many studies have examined the impact of deAm J Psychiatry 159:10, October 2002

EVANS, TEN HAVE, DOUGLAS, ET AL.

pression on the course of HIV infection. Recent studies of

HIV-seropositive individuals have demonstrated an association between depression and both early and late HIV
disease progression (35) as well as mortality (2). There is
considerable evidence from meta-analyses (6) as well as
from studies by our group and others (710) that measures
of cellular immunity are altered in depressed subjects
without medical illness. However, in depressed HIV-seropositive individuals, findings have been mixed (1), although several studies have found a significant relationship between depression and immune system measures
(1114). These inconsistent findings may be partially attributed to methodological differences among the available studies, including in their measurement of depression, duration of follow up, differences in the immune
measures examined, and differences in the subject populations studied.
The potential immune mechanisms by which depression may influence HIV disease progression and mortality
remain to be understood. Most studies assessing the effects of depression on immunity in HIV infection have focused primarily on CD4 cell populations and have used
short periods of observation. Because CD4 cells are affected early and profoundly in HIV infection, this cell population may not be the most sensitive or reliable measure
for demonstrating over time the relationship between depression and HIV infection (8, 11).
Clinical studies of depression in subjects without other
medical illness have demonstrated significant alterations
in natural killer (NK) cells as well as CD8 cells, two cellular
immune populations that may play key roles in regulating
HIV infection. Specifically, NK cells may be involved in
natural resistance against viral infection and may have the
capacity to lyse HIV-1 infected cells (1518), while subsets
of CD8 cytolytic cells may inhibit HIV-1 replication in early
stage HIV disease (1923). In our studies of HIV-infected
men, we have found depression-associated alterations of
NK cells and CD8 T lymphocytes (12), which suggests that
killer lymphocytes might mediate the effects of depression
on earlier stages of HIV disease progression. CD8 T lymphocytes may have a beneficial or adverse effect in later
stage infection (2428). Most recently we have found CD8
T lymphocytes are elevated in HIV-infected men with advanced HIV disease (unpublished 2001 study of D. Evans
et al.). A subpopulation of activated CD8 cells (CD8+/
CD38+/DR+ activated CD8 cells) have been correlated
with cytotoxic activity and with HIV disease progression
(20, 29, 30).
The purpose of the present clinical study was to determine if depression was associated with alterations in cellular immunity in women with HIV infection. We specifically focused on killer lymphocytes (NK cells and CD8 T
lymphocytes) on the basis of the extensive immunologic
literature suggesting a potential role for these lymphocytes in the host defense against HIV and also on the large
psychiatric literature suggesting that depression is associAm J Psychiatry 159:10, October 2002

ated with significant alterations in these lymphocyte populations. We used flow cytometry with selected monoclonal antibodies in order to identify subpopulations of
NK and cytotoxic T cells, including activation markers that
have been associated with HIV disease progression (29).
Although NK and CD8 T lymphocyte populations have
been studied in HIV-infected men as possible mechanisms linking depression to HIV disease progression (11,
12), no previous study to our knowledge has examined
these possible cellular-immune mechanisms in HIV-infected women, despite the fact that depression is approximately two times more prevalent in women than in men.

Method
Data were collected in Florida and Pennsylvania as part of an
ongoing longitudinal cohort study investigating neuropsychiatric, psychosocial, neuroendocrine, and immune aspects of HIV
infection in women. Data from the baseline visit were used for
this analysis.

Subjects
HIV-seropositive subjects were recruited from outpatient medical clinics, county health departments, and organizations focusing on HIV illness and care through a combination of community
outreach presentations, clinician referrals, word of mouth, and
newspaper advertisements to identify potential subjects. The seronegative subjects were recruited by word of mouth, advertisements, and by inviting enrolled subjects to recruit a friend or
neighbor. Subjects were included in the study if they were female,
between 18 and 70 years of age, and able to communicate in English. HIV serostatus was determined by enzyme-linked immunoabsorbent assay and confirmed by Western blot analysis. Subjects
were excluded if they 1) had significant chronic, systemic illness;
2) had a significant neurologic disorder, including traumatic
brain injury; 3) had a history of schizophrenia or severe psychotic
disorder; 4) were pregnant or nursing; or 5) met DSM-IV criteria
for current substance/alcohol abuse or dependence.
The protocol was reviewed and approved by the institutional
review boards of both the University of Florida and the University
of Pennsylvania. All subjects provided written informed consent
and were reimbursed for their time, travel expenses, and child
care.

Procedures
Each subject received a thorough outpatient assessment that
included a physical examination and a structured psychiatric interview. Subjects also completed a comprehensive set of questionnaires that assessed mood, psychosocial factors, and health
habits. Current and lifetime DSM-IV axis I diagnoses were assessed by a research psychiatric clinician with a modified Structured Clinical Interview for DSM-III-R (31, 32). Consensus diagnoses were determined at diagnostic conferences. Symptoms of
depression and anxiety were evaluated with the 17-item Hamilton Depression Rating Scale (33) and the Hamilton Anxiety Rating
Scale (34). We also used a modified version of the Hamilton depression scale that eliminated six of the 17 symptom items (e.g.,
somatic symptoms, weight loss, retardation) that could overlap
with the physical symptoms of HIV disease (12) to help avoid confounding depression with HIV disease.
All of the HIV-seropositive women were aware of their HIV-1
status at baseline. HIV serostatus for all subjects was confirmed by
using enzyme-linked immunosorbent assay with Western blot
analysis for confirmation of the presence of anti-HIV-1 antibodies.

1753

DEPRESSION IN WOMEN WITH HIV

TABLE 1. Demographic Characteristics of 93 Women With
or Without HIV Infection
HIV-Seropositive
Women (N=63)
Characteristic
Education
Less than high school
High school diploma
Some college
College degree
Graduate school
Race
White
Black
Other race/ethnicity

HIV-Seronegative
Women (N=30)

20
35
5
1
2

32.26
56.45
8.06
1.59
3.23

11
15
4
0
0

36.67
50.00
13.33
0.00
0.00

11
47
5

17.46
74.60
7.94

7
22
1

23.33
73.33
3.33

To control for potential circadian effects on immunity, all subjects were studied at the same time of day, as in our previous studies (10). Specifically, subjects were placed in a recumbent position, an intravenous line was started at approximately 9:00 a.m.,
and intravenous line patency was maintained with a slow, normal
saline drip. Blood was drawn approximately 1 hour later (35).

Immune System Measures

Complete blood cell counts and flow cytometry panels were
performed on peripheral blood samples from all subjects. For the
flow cytometry panel, the specimens were collected in EDTA
tubes with a minimum of 2 l of blood and the specimens were
processed within 30 hours from the time of collection. Leukocyte
viability was greater than 97%, and temperature variability during
shipment was less than 2 C. Monoclonal antibodies (Becton
Dickinson Immunocytometry System, San Jose, Calif.) were used
to measure the predominant reactivity to the following lymphocyte subsets: CD3+/CD4+; CD3+/CD8+; CD3/CD56+/CD16+
(NK cells); and CD8+/CD38+/DR+ (activated CD8+) (36). All studies were performed by a dual- or tri-labeling (double- or triplestaining) technique, with the combination of fluorescein isothiocyanate and phycoerythrin-conjugated antibodies. Absolute lymphocyte subset counts were derived from lymphocyte subset percentages total lymphocyte counts 100.
NK cell activity was assessed by using a modification of standard techniques that we have established (37). Aliquots of 100 microliters of various CD4+, NK cells, and function concentrations of
peripheral blood mononuclear cells (effector cells) were incubated in triplicate with 100 microliters of labeled target cells for 4
hours at 37C with 5% CO2 (effector/target ratios of 50:1, 25:1, 12.5:
1, and 6.25:1 were studied). Maximum release of 51Cr was determined by addition of 100 microliters of 1% Triton X solution to
triplicate wells of K562 cells. At the end of the incubation period,
100 l of the supernatants were harvested and counted in a
gamma counter (Beckman Instruments, Inc., Fullerton, Calif.). NK
activity was calculated as ([mean sample activity mean spontaneous release]/[mean maximum release mean spontaneous release]) 100. The results were expressed as percent cytotoxicity.
Lytic units/107 peripheral blood mononuclear cells and lytic
units/107 NK cells were calculated after the method of Bryant et al.
(38) and Friberg et al. (39) in order to transform cell lysis data into
a single number. Further, by measuring the percentage of CD16+/
CD56+ cells in the peripheral blood mononuclear cell preparation,
we determined the lytic units of NK activity per NK cell (40). Expressing the NK data as lytic units per NK cell adjusts for the differences in the percentage of NK cells (CD16+/CD56+) in the effector
cell population (peripheral blood mononuclear cells).

Statistical Analyses
Two sets of statistical analyses were performed: 1) baseline
comparisons between HIV-seropositive and HIV-seronegative

1754

participants with respect to immune and depression/anxiety outcomes and 2) separate analyses of correlations between immune
and depression/anxiety outcomes separately for HIV-seropositive and HIV-seronegative participants. For the baseline comparisons of the HIV-seropositive and seronegative participants, we
used nonparametric tests of group differences (i.e., Kruskal-Wallis test). We relied on nonparametric statistics instead of transforming outcomes in an attempt to achieve normality. The results
are similar between analyses of transformed data and nonparametric analyses. We also used the nonparametric Kruskal-Wallis
test to compare the HIV-seropositive and HIV-seronegative
women with respect to the 11-item and 17-item Hamilton depression scale scores and anxiety variables and used Fishers exact test
to compare the rate of major depression in the two groups. For
the correlational analyses, Spearman correlations were computed after we adjusted for antiretroviral medication use, and viral load was dichotomized by the measurement threshold level in
the HIV-seropositive group. Since approximately one-half of the
HIV-seropositive subjects had a viral load at 400 RNA copies/l,
we dichotomized the viral load variable at 400 (i.e., <400 RNA copies/l and 400 RNA copies/l) for analysis because there is no
transformation that would resolve the skewed distribution problem at 400. We used the nonparametric Spearman approach because transformations, such as the log or square root transformation, did not successfully transform distributions to normality
such that the assumptions underlying the Pearson correlation approach could be satisfied (41).
To adjust for disease status, we controlled for viral load and antiretroviral medication use. Serum HIV RNA viral load was determined from archived samples with the Amplicor Monitor assay
(Roche Diagnostics, Branchburg, N.J.). The lower limit of quantification for this assay is 400 copies/ l blood. Because approximately half the sample was at this lower limit, we analyzed viral
load as a binary variable: equal to 400 and greater than 400.

Results
A total of 93 women were studied at two sites, 49 (52.6%)
from Pennsylvania (35 HIV-seropositive and 14 HIV-seronegative) and 44 (47.3%) from Florida (28 HIV-seropositive and 16 HIV-seronegative). The demographic and behavioral characteristics of the two sites were similar. The
racial composition was predominantly African American
at both sites (Pennsylvania: 73.4%, N=36; Florida: 75.0%,
N=33). Although Pennsylvania seropositive subjects had
somewhat more education than did the Florida seropositive subjects (high school diploma: 62.9% [N=22] versus
46.4% [N=13], respectively), the difference in education did
not reach statistical significance (2=1.34, df=1, p=0.06).
Depressive and anxiety symptom scores (from the 11- and
17-item Hamilton depression scale and the Hamilton anxiety scale) also were similar across the sites. Comparable
17-item Hamilton depression scale scores between Pennsylvania and Florida subjects were seen for the HIV-seropositive subjects (mean=8.60, SD=5.37 [N=35] and mean=
8.64, SD=9.21 [N=28], respectively) and the HIV-seronegative women (mean=5.36, SD=5.37 [N=14] and mean=5.94,
SD=8.87 [N=16]). Overall, the median age of the HIV-seropositive subjects was 38 years (range=19 to 60), and the
median age of the seronegative subjects was 40 years
(range=18 to 69). Table 1 displays demographic characteristics of the study group.
Am J Psychiatry 159:10, October 2002

EVANS, TEN HAVE, DOUGLAS, ET AL.

TABLE 2. Severity of Depressive and Anxiety Symptoms Among 93 Women With or Without HIV Infection
Symptom Score
HIV-Seropositive Women (N=63)
Measure
Depressive symptoms
17-item Hamilton scale
11-item Hamilton scalea
Anxiety symptoms (Hamilton scale)
a

HIV-Seronegative Women (N=30)

Analysis

Median

Mean

SD

Median

Mean

SD

Kruskal-Wallis 2 (df=1)

8.00
4.00
7.00

8.62
5.16
8.17

7.26
4.96
7.57

3.00
2.00
4.50

5.67
4.03
6.00

7.33
5.39
5.81

5.01
2.47
2.04

0.03
0.12
0.16

Modified from the 17-item Hamilton depression scale through elimination of six items that could overlap with physical symptoms of HIV
disease to avoid confounding.

TABLE 3. Immune System Variables in 93 Women With or Without HIV Infection

HIV Seropositive Women (N=63) HIV Seronegative Women (N=30)
Variable
Cell counts (cells/mm3)
Helper T cells: CD4+
Cytotoxic/suppresor T cells: CD8+
Activated CD8 T lymphocytes: CD8+/
CD38+/DR+
NK activity (lytic units/peripheral
blood mononuclear cell)

Analysis
Kruskal-Wallis 2 (df=1)

Median

Mean

SD

Median

Mean

SD

404.00
773.00

448.44
902.67

272.36
573.52

972.00
455.00

1069.73
501.03

423.01
241.32

43.99
16.85

<0.0001
<0.0001

26.50

73.00

132.10

7.00

10.68

14.45

16.77

<0.0001

502.00

2346.22

8514.52

581.00

1494.10

2882.82

0.00

0.98

Table 2 presents the depression and anxiety characteristics of the HIV-seropositive and seronegative subjects.
The rate of current major depression in the HIV-seropositive subjects was 15.87% (N=10 of 63), which was not significantly higher than the rate seen in the seronegative
women (10.00%, N=3 of 30) (p<0.54, Fishers exact test).
The HIV-seropositive subjects had a higher level of depressive symptoms than did the HIV-seronegative subjects, as measured by the 17-item Hamilton depression
scale. Both serostatus groups had similar levels of anxiety
symptoms as measured by the Hamilton anxiety scale.
Differences in immune system variables between the
HIV-seropositive and HIV-seronegative subjects are
shown in Table 3. Consistent with HIV infection, the HIVseropositive women had significantly lower CD4+ cell
counts and significantly higher CD8+ and activated CD8+
cell counts. There were no significant differences in natural killer cell activity (expressed as lytic units/peripheral
blood mononuclear cells) between HIV-seropositive and
seronegative groups.
The relationship of a major depression diagnosis as well
as depressive and anxiety symptoms to the immune system variables in HIV-seropositive women are presented in
Table 4. These correlations were adjusted for antiretroviral
medication and viral load.
Depressive symptoms, as measured by the 17-item
Hamilton depression scale, were significantly associated
with higher activated CD8 T lymphocyte (CD8+/CD38+/
DR+) counts and viral load levels. The 11-item Hamilton
depression scale, which removes possible confounding
physical symptoms, had essentially the same associations
as the 17-item scale. Anxiety symptoms were significantly
related to higher activated CD8 T lymphocyte counts and
viral load.
Major depression, which occurred in 15.87% of the HIVseropositive women (N=10 of 63), was associated with sigAm J Psychiatry 159:10, October 2002

nificantly lower natural killer cell activity. Depressive and

anxiety symptoms showed similar correlations with lower
natural killer cell activity. We found no relationship for
CD4 cell count, CD8 cell count, or CD56+ cell count with
depressive symptoms, anxiety symptoms, or diagnosis of
major depression. Among the HIV-seronegative women,
neither depression nor anxiety was related to any of the
immune system variables (p>0.10). However, the 11-item
Hamilton depression scale and 17-item Hamilton depression scale correlations with natural killer cell activity
ranged between 0.20 and 0.30, values which are of similar magnitude and in the same direction as the analogous
correlations in the HIV-seropositive subjects. The lack of
significance may be due to the relatively small size of the
HIV-seronegative group or greater immune system sensitivity to depression in individuals with HIV infection.

Discussion
This study is the first systematic report to show that depression is related to alterations in killer lymphocytes and
viral load in women with HIV infection. These data demonstrate that depression and anxiety are associated with
alterations in these measures of immunity in HIV-seropositive women. Specifically, we found that women with
major depression exhibited significantly lower NK cell
activity. In addition, depressive symptoms and anxiety
symptoms were associated with lower NK cell activity and
higher activated CD8 T lymphocyte levels and viral load.
Since each of these measures has been associated with
disease progression in HIV, together these findings suggest
that depression may be associated with a higher likelihood
of disease progression.
The findings from the present study of HIV-infected
women extend our previous investigations in HIV-infected men by showing significant killer lymphocyte alter-

1755

DEPRESSION IN WOMEN WITH HIV

TABLE 4. Correlation of Immune System Variables and Viral Load With Depression and Anxiety Symptom Scores and
Depression Diagnosis in HIV-Seropositive Women (N=63)
Correlation With Symptom Scorea

Variable
Helper T cells: CD4+
Cytotoxic/suppresor T cells: CD8+
Activated CD8 T lymphocytes: CD8+/CD38+/DR+
NK activity
Viral load

17-Item Hamilton
Depression Scale

11-Item Hamilton
Depression Scaleb

Hamilton Anxiety
Scale

Correlation With
Diagnosis of
Major Depressiona

rs
0.16
0.21
0.30
0.27
0.28

rs
0.19
0.19
0.28
0.28
0.29

rs
0.14
0.16
0.42
0.30
0.31

rs
0.04
0.16
0.18
0.36
0.10

p
0.23
0.11
0.03
0.04
0.03

p
0.15
0.14
0.05
0.03
0.03

p
0.27
0.23
0.002
0.02
0.02

p
0.76
0.22
0.22
0.004
0.46

Spearman correlations were adjusted for antiretroviral medication use and viral load for all immune system variable analyses and for antiretroviral medication use for the viral load analyses.
b Modified from the 17-item Hamilton depression scale through elimination of six items that could overlap with physical symptoms of HIV disease to avoid confounding.

ations. In this study of women, we have expanded our assessment of the cellular-immune system by including a
functional measure (lytic units per NK cell), which measures natural killer cell activity adjusted for the number of
NK cells in the assay performed. Our finding of lower natural killer cell activity in association with depression could
be clinically relevant, since NK cells have the capacity to
lyse HIV-infected cells and may be involved in the host defense against viral infection (1518, 42).
Our finding in HIV-seropositive women that depression
is associated with significant increases in subsets of CD8
cells that represent activated CD8 T lymphocytes is a new
finding. Previously, we reported significant decreases in
CD8 cells in association with depression and stress in HIVseropositive men (12). These findings appear consistent
with recent evidence suggesting that the CD8 T lymphocytes may play a beneficial role in early HIV disease infection and may, in fact, be detrimental to the host in the defense against HIV later in the course of disease (24). In
early HIV disease, there is evidence that populations of
CD8 T lymphocytes expand in what is believed to be a
compensatory immune response to control HIV infection
by inhibiting viral replication and by lysing HIV-infected
cells (4345). However, recent evidence suggests that in
HIV-infected individuals with progressive disease, CD8 T
lymphocyte responses could have a deleterious effect on
the immune system and thereby have a negative effect on
HIV disease progression (24). In fact, studies assessing
CD8 cells with activation markers (CD38+, HLA-DR) as
used in the present study have found strong associations
with greater viral load, lower CD4 count, progression to
AIDS, and mortality (29, 30). Thus, depression-associated
increases in the subsets of activated CD8 T lymphocytes as
found in the present study also may be a mechanism by
which depression may have a negative effect on HIV disease survival (2).
In the present study, we found no relationship between
depression and CD4 cells, which is consistent with several
previous studies (4648). These previous studies did not
assess NK cells or CD8 T cell subsets. Further, NK cells are
among the major cells of the innate immune system. NK
cells are capable of eliminating HIV-infected cells both by

1756

direct cytotoxicity and by antibody-directed cytotoxicity.

NK cells produce cytokines and chemokines (28) that also
are important in HIV responses.
There is increasing evidence that depression may be predictive of human morbidity and mortality in a wide range
of diseases (4953). Studies of depressed but otherwise
medically healthy individuals suggest that depression may
alter cellular immunity and may therefore contribute to
disease progression in certain immune diseases such as
HIV infection (1). Thus, the present study suggests that depression-related alterations in NK and CD8 cells in HIV-seropositive women could be one of the mechanisms underlying the association between depression and mortality in
the recent epidemiology study of HIV-seropositive women
(2). Since viral loads were also higher, another consideration includes the role of adherence to antiretroviral medication treatment. Poor adherence has been reported in depressed individuals (54) and in depressed HIV-seropositive
individuals (5558). In the present study, we controlled for
the potential confounding effects of lack of adherence by
controlling for two surrogate markers of adherence (reported medication use and viral load) in all depression-immune analyses. In future studies, we plan to use electronic
monitoring systems as an additional surrogate marker of
adherence in order to assess the direct effects of depression
on HIV medication adherence (56, 59, 60).
Several strengths of the present study should be noted.
Subjects underwent comprehensive structured interviews
to assess psychiatric diagnoses as well as mood and anxiety symptoms. In order to address carefully the effects of
depression on cellular immune function, we excluded
subjects with current alcohol or substance abuse or dependence to avoid the potential confounding effects on
immune function. We focused on specific lymphocyte
subsets that are believed to play an important role in host
resistance against HIV infection, and we standardized our
biological assessments by performing phlebotomy at the
same time of day and following 1 hour of rest in a recumbent position to avoid potential circadian effects on immunity and potential nonspecific methodological factors
(11, 12, 35). In all depression-immune analyses, we controlled for stage of disease by controlling for viral load as
Am J Psychiatry 159:10, October 2002

EVANS, TEN HAVE, DOUGLAS, ET AL.

well as antiretroviral medication use. We also performed

depression analyses with the traditional 17-item Hamilton
depression scale, as well as an 11-item instrument that
eliminated those physical symptoms that might possibly
overlap with symptoms of HIV disease progression.
Some possible limitations of this study should be noted.
This was not a population-based study, and thus the results may be biased by the methods of recruitment and
enrollment. For example, recruiting comparison subjects
through friendship with participants could bias toward better mental health, since individuals with someone to refer
may have a larger or more active social support network
from which to recruit. Although recruitment was open to
subjects of any race and ethnic background, African American and Caucasian subjects comprised the majority of the
subjects. A small number of subjects of other ethnicity
were enrolled; however, the findings may not be generalizable to Hispanic or Asian populations. The study eligibility
criteria excluded women who were currently abusing alcohol or other substances. This exclusion avoided confounding our results with the known association of substance/
alcohol abuse and depression, but it limits the generalizability of our findings. Subjects were recruited from two
sites, one in Florida and one in Pennsylvania. Before the
data were analyzed, comparisons of the site-specific demographic characteristics and behavioral characteristics of
subjects did not reveal any substantive differences between
the sites in demographic or behavioral characteristics. All
psychiatric diagnoses were confirmed at consensus conferences, and interviewers as well as consensus reviewers were
not blinded regarding the serostatus of study participants.
In our previous studies, we have not found a satisfactory
way to maintain such a blind and achieve validation of the
consensus diagnosis. Therefore, there is a small but potential bias in psychiatric diagnoses.
The finding that 16% of HIV-seropositive women without current substance abuse have current major depression represents a prevalence rate that is approximately
twice that reported for HIV-seropositive men (32, 6163).
Of note, this rate of current major depression is similar to
that found in studies of women with other medical illnesses, such as cancer (64) and heart disease (65). It is also
consistent with a recent epidemiology study associating
depression to mortality in HIV-infected women in which
42% of seropositive women experienced chronic depressive symptoms when depressive symptoms were measured
by the CES-D Scale, a self-report screening instrument (2).
In conclusion, our findings provide the first evidence
that depression may alter the function of killer lymphocytes in HIV-seropositive women. These findings suggest
that depression may decrease natural killer cell activity
and may lead to an increase in activated CD8 T lymphocytes and viral load. Increasing evidence suggests that depression may have a negative impact on innate immunity,
and the present study suggests that the examination of
killer lymphocytes may prove useful in assessing the poAm J Psychiatry 159:10, October 2002

tential relationship between depression, immunity, and

HIV disease progression in women.
Received Dec. 26, 2001; revision received May 14, 2002; accepted
May 23, 2002. From the University of Pennsylvania School of Medicine and the McKnight Brain Institute, University of Florida College of
Medicine, Gainesville. Address reprint requests to Dr. Evans, Department of Psychiatry, University of Pennsylvania School of Medicine,
305 Blockley Hall, Philadelphia, PA 19104-6021; [email protected].
upenn.edu (e-mail).
Supported by NIMH grant MH-55454 (Dr. Evans).
The authors thank the Childrens Hospital of Philadelphia Clinical
Virology Laboratory (Dr. Richard Hodinka, Director) for viral load determinations and Clinical Immunology Laboratory (Dr. Donald E.
Campbell, Director) for the flow cytometry studies.

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