Farmacologia de Los Medicamentos Antipsicoticos en Am
Farmacologia de Los Medicamentos Antipsicoticos en Am
Farmacologia de Los Medicamentos Antipsicoticos en Am
A Focus on Atypicals
Sanford Finkel, MD
One study focused on EPS in patients treated with an- The NPI scale was developed in 1994 to gather data on the
tipsychotics and investigated whether striatal D2 receptor psychopathological disorders in patients with cerebral
occupancy predicted the occurrence of EPS. They found pathologies. This scale is meant to assess 12 common dis-
that the lowest occupancy was seen with quetiapine and orders, such as delusions, hallucinations, agitation, depres-
clozapine and the highest with haloperidol. Twenty-two of sion, anxiety, euphoria, and eating disorders. The CMAI
71 patients (29%) experienced clinically relevant EPS. was introduced in 1986 and was designed to assess mainly
These patients displayed significantly higher mean striatal agitation and aggressiveness.19 It is important to verify the
D2 receptor occupancy (77%) than those without EPS specific clinical entity for which it was designed when se-
(61%; P 5.002).14 lecting a scale for the elderly. Moreover, appropriate use of
Atypical antipsychotics offer distinct advantages over these scales may facilitate understanding of psychiatric dis-
conventional antipsychotics, including a much lower level eases and response to treatment in elderly patients.20
of movement disorders (e.g., EPS, TD, parkinsonism) and
improved efficacy in treating negative symptoms of psy-
chosis, such as depression and hostility. In addition, atypi- RECEPTOR-BINDING PROFILES OF
cal antipsychotics have better efficacy in addressing the ANTIPSYCHOTICS
positive symptoms of psychosis, such as hallucinations and Underlying the differences in the efficacy and tolerability of
delusions.12 conventional and atypical antipsychotics are the differences
Negative symptoms are a major contributor to low in their respective receptor-binding profiles.
functioning and debilitation in most patients with schizo- The atypical antipsychoticsFclozapine, olanzapine, ris-
phrenia, but their presence, especially in elderly patients, is peridone, quetiapine, ziprasidone, and aripiprazoleFhave
not restricted to this disorder.15 Negative symptoms include different receptor-binding profiles from those of conven-
blunting of affect, poverty of speech and thought, apathy, tional antipsychotics such as haloperidol, chlorpromazine,
anhedonia, reduced social drive, loss of motivation, lack of thioridazine, and promazine. Table 1 compares the recep-
social interest, and inattention to social or cognitive input. tor-binding profiles of the currently used atypical antipsy-
Only modest progress has been made in treating them ef- chotics with that of haloperidol.21 The first four receptors
fectively. Two-thirds of the approximately 35 studies com- (D1–D4) are dopamine receptors, and the next three (5-
paring conventional and atypical antipsychotics in treating HT1A, 2A, 2C) are serotonin receptors. The remaining three
negative symptoms have found atypical antipsychotics to be receptorsFa1-adrenergic, H1-histaminic, and M1-mu-
significantly more effective. In general, atypical antipsy- scarinic receptors (a1, H1, M1, respectively)Fare binding
chotics improve negative symptoms approximately 25%, sites for many conventional antipsychotics, and their asso-
whereas conventional antipsychotics improve such symp- ciation with side effects is well known.22
toms only 10% to 15%.16 The receptor-binding profiles are the following.
Studies examining the extent to which executive cog-
nitive dysfunction and frontally mediated behavioral dis- D1 receptors play a role in the actions of dopamine in the
turbances are associated with functional impairment in control of motor, cognitive, and cardiovascular function.
patients with mild to moderate AD found that specific cog- Antagonists to this receptor do not show any antipsy-
nitive and behavioral symptoms are associated with func- chotic activity.
tional impairment in patients with AD,17 but another study D2 receptor antagonists play a major role in the treat-
concluded that negative symptoms are a prominent clinical ment of positive symptoms of psychosis. Excessive
feature of AD and that they are related to memory impair- blockade of this receptor may cause EPS and may be
ment but not to mood disturbances.18 involved in the development of TD. All current antipsy-
chotics are D2 antagonists. Positron emission tomo-
graphy studies demonstrate that moderate blockade of
PSYCHIATRIC SCALES FOR THE ELDERLY central D2 receptors is adequate for treatment of psy-
When evaluating effect and severity of psychiatric diseases, chosis, whereas a high degree of D2 occupancy causes
there are many scales that formalize the evaluation of men- EPS. Furthermore, it is known that blockade of D2 re-
tal and physical health of patients. Some of these scales have ceptors in the anterior pituitary gland causes elevation of
been developed specifically for elderly patients, whereas blood prolactin levels.
others have been adapted from scales intended for younger D3 receptor antagonists show no antipsychotic activity.
patients. For instance, the Brief Psychiatric Rating Scale D4 receptor antagonists may play a role in the modula-
(BPRS) was originally developed for use in younger patients tion of gamma-aminobutyric acid (GABA)ergic neuron-
with schizophrenia but has been adapted for use in the al activity by dopamine. The contribution of D4 receptor
evaluation of agitation in elderly patients with dementia. blockade to the therapeutic actions of antipsychotics re-
Scales that have been developed and standardized for older mains to be elucidated.
people are preferable to those developed for the younger 5-HT1A receptor antagonists have a role in relieving
population. Three of the most frequently employed scales anxiety and depression.
for assessing behavioral disorders in the elderly are the 5-HT2A receptor antagonists play a role in treating
Behavioral Scale in AD (BEHAVE-AD), the NPI, and the dysthymias and the negative symptoms of schizophrenia.
Cohen Mansfield Agitation Inventory (CMAI). The BE- This receptor subtype appears to be the most important
HAVE-AD scale was introduced in 1987 and concentrates serotonin receptor, because all the newer antipsychotics
on the specific symptoms of psychosis by measuring cate- (second generation) are relatively potent 5-HT2A antag-
gories such as paranoid ideas, delusions, and hallucinations. onists.
S260 FINKEL DECEMBER 2004–VOL. 52, NO. 12 JAGS
5-HT2C receptor antagonists play a role in treating anx- D2 binding due to fast dissociation should produce few or
iety and panic attacks, as well as increasing food intake. no motor side effects. Again, in vitro evidence suggests that
a1 receptor antagonists are responsible for anti- rapid dissociation from the D2 receptor is predictive of low
adrenergic effects, which can cause orthostatic hypoten- extrapyramidal side-effect potential.25
sion, reflex tachycardia, and the potentiation of
antihypertensives. PHARMACOKINETICS OF ANTIPSYCHOTICS
H1 receptor antagonists are responsible for antihista- Physiological changes secondary to the aging process in-
minergic effects, which can cause sedation, weight gain, clude a decrease in lean body mass and renal and liver
and the potentiation of central nervous system–depres- function changes that must be taken into consideration
sant drugs. when prescribing pharmacotherapy to the elderly. Such pa-
M1 receptor antagonists are responsible for anti- tients often take multiple medications and have concomi-
muscarinic effects, which can cause urinary retention, tant illnesses, such as cardiac and renal diseases, that can
cognition and memory effects, sinus tachycardia, dry alter the pharmacokinetics and pharmacodynamics of these
mouth, blurred vision, and constipation.2 medications.
Conventional and atypical antipsychotic drugs block The pharmacokinetics of some commonly prescribed
the D2 (dopamine) receptors in the nigrostriatal dopamine antipsychotics are discussed in Table 2.21 From a practical
pathway. Atypical antipsychotics differ from conventional point of view, both long and short elimination half-lives
antipsychotics by blocking the 5-HT2A (serotonin) recep- have their advantages. Antipsychotics with short elimina-
tors, as well as the D2 receptors. This effect keeps prolactin tion half-lives are appropriate for elderly patients because
levels normal, spares cognition, and obviates EPS. Theo- they carry a lower risk of side effects. Long elimination half-
retically, the dopamine blockade with atypical antipsycho- life antipsychotics allow less-frequent dosing and may en-
tics lasts only long enough to cause an antipsychotic action courage patient compliance.
but not long enough to cause the side effects associated with
conventional antipsychotics.22 The rationale behind the ATYPICAL ANTIPSYCHOTICS AND DRUG-DRUG
antipsychotics’ blockade of the D2 receptors and the 5- INTERACTIONS
HT2A receptors is based on the theory that serotonin reg- Drug-drug interactions are more likely to occur in elderly
ulates dopamine release. The presence of serotonin in the patients because, for many of these patients, polypathology
nigrostriatal pathway, a part of the extrapyramidal nervous and polypharmacy are a way of life.26 In addition, age-
system, which is known for its association with movement, related physiological changes in the elderly affect the phar-
inhibits the release of dopamine, the neurotransmitter that macokinetics and pharmacodynamics of many drugs.
helps to transmit messages to the striatum, where move- Oxidative metabolism by cytochrome P450 enzymes is
ment is initiated and controlled. This is not the case in other a primary method of drug metabolism. There are multiple
dopamine pathways, such as the mesolimbic pathway, different enzyme isoforms within the cytochrome P450 sys-
where serotonin has little or no effect on inhibiting the re- tem, and the individual enzymes are responsible for specific
lease of dopamine.23 It is apparent, then, that the D2 re- drug-drug interactions and assist in determining how pa-
ceptor blockade plays an important role in the efficacy of tients react to various drug regimens. Drug interactions in-
antipsychotics, as well as in the parkinsonian side effects volving the cytochrome P450 system are common and
that accompany some of these agents. result from enzyme inhibition or induction. Enzyme inhi-
A synopsis of the receptor-binding patterns of antipsy- bition involves competition with another drug for enzyme
chotics is presented in Table 1. Theoretically, it takes a brief binding sites. Enzyme induction occurs when one drug
blockade of the D2 receptor to cause antipsychotic action, stimulates increased metabolic capacity. Age-related chang-
whereas longer-lasting action at the receptor site causes ex- es in metabolism, distribution, and excretion influence drug
trapyramidal side effects.24 Following this hypothesis, low distribution. Between ages 20 and 75, the percentage of fat
Clozapine Induces CYP 1A2, 2D6, 3A4 Decrease Phenytoin, nicotine, rifampin
Inhibits CYP 1A2, 2D6, 3A4 Increase Cimetidine, caffeine, erythromycin
Olanzapine Induces CYP 1A2 Decrease Carbamazepine
Inhibits CYP 1A2 Increase Fluvoxamine
Risperidone Inhibits CYP 2D6 Increase Quinidine
Quetiapine Induces CYP 3A4 Decrease Phenytoin
Inhibits CYP 3A4 Increase Ketoconazole, itraconazole,
fluconazole, erythromycin
Ziprasidone Induces CYP 3A4 Decrease Carbamazepine
Inhibits CYP 3A4 Increase Ketoconazole
Aripiprazole44 Induces CYP 3A4 Decrease Carbamazepine
Inhibits CYP 3A4 Increase Ketoconazole
Inhibits CYP 2D6 Increase Fluoxetine
The aripiprazole data were unavailable in27 and have been added from the prescribing information for aripiprazole.
Risperidone may interfere with metabolism of drugs metabolized by cytochrome P450 (CYP) 2D6.
S262 FINKEL DECEMBER 2004–VOL. 52, NO. 12 JAGS
inhibit the activity of cytochrome P450 isozymes may in- placebo (4.4%).33 A 2003 study examined risperidone in
crease clozapine levels. the treatment of aggression, agitation, and psychosis of de-
Clinical studies of clozapine have not included suffi- mentia. In this randomized, double-blind, placebo-control-
cient numbers of subjects aged 65 and older to determine led trial, 345 elderly nursing home patients with dementia
whether they respond differently than younger patients. It is were studied. Seventy-three percent of the patients in the
important to remember that elderly patients, particularly risperidone group completed the trial. The primary end-
those with underlying cardiac conditions, may be more point of the study, the difference from baseline to endpoint
susceptible to orthostatic hypotension, tachycardia, and in CMAI total aggression score, indicated a significantly
anticholinergic effects. Caution is advised in selecting a (Po.001) greater reduction in aggressive behavior for ris-
dose for these patients because there is a greater frequency peridone than for placebo. Overall, 94% and 92% of the
of decreased hepatic, renal, and cardiac function; concom- risperidone and placebo groups, respectively, reported at
itant medical conditions; and medications. The prevalence least one adverse event. In the risperidone treatment group,
of TD appears to be highest in the elderly, especially elderly somnolence and urinary tract infections were more com-
women.30 mon adverse events, whereas agitation was more common
Other serious side effects experienced by elderly pa- in the placebo group.34
tients include urinary retention and sedation. The possibil- Risperidone has a high affinity for binding to serotonin
ity of life-threatening agranulocytosis and the compulsory 5-HT, dopamine D2, histamine H1, and a1 and a2 ad-
monitoring schedule that accompanies it ranks clozapine renergic receptors. It has low to moderate affinity for the
among the most problematic of the atypical antipsycho- serotonin 5-HT1D and 5-HT1A receptors, weak affinity for
tics.31 Therefore, it is important for healthcare providers to dopamine D1 and haloperidol-sensitive sigma site, and no
keep in mind that the dosage of clozapine needs to be much affinity for cholinergic muscarinic or b1 and b2 adrenergic
lower in elderly patients than in younger patients. receptors.
Risperidone is well absorbed, and plasma protein bind-
ing is 90%. After oral administration, the mean peak con-
Risperidone centration of risperidone occurs at 1 hour. The active
In 1994, risperidone was the second of the atypical anti- moiety has an overall mean elimination half-life of about
psychotics to come to the U.S. market. In 2003, it received 20 hours.
an FDA indication for bipolar mania. Like clozapine, ris- In healthy elderly subjects, renal clearance of risperi-
peridone is FDA indicated for treatment of schizophrenia done and 9-hydroxyrisperidone (main metabolite) was
and has also been studied in treatment of dementia. Ris- shorter, and elimination half-lives were longer than in
peridone has been the most extensively studied atypical younger healthy subjects. The recommended initial dose is
antipsychotic in elderly patients with dementia. Three stud- 0.5 mg bid followed by slow titration in elderly patients,
ies, all 12 weeks in length, compared the efficacy of ris- debilitated patients with severe renal or hepatic impair-
peridone with placebo in more than 1,300 elderly patients. ment, and patients predisposed to hypotension. Consider-
In all the studies, it was found that treatment with low-dose ation should be given to monitoring for orthostatic
risperidone (1 mg/d) was well tolerated and resulted in sig- hypotension. Furthermore, risperidone has not been shown
nificant reduction in aggression, agitation, and psychosis to be safe and effective in the treatment of patients with
associated with dementia.32–34 Seventy percent of the pa- dementia-related psychosis.35
tients completed the first large (625 patients) double-blind, An Australian study demonstrated that risperidone
placebo-controlled study conducted to evaluate risperidone carried a higher risk of cerebrovascular events than placebo.
in the treatment of psychotic and behavioral symptoms in The cause-and-effect relationship between risperidone and
institutionalized elderly patients with dementia. At 12 cerebrovascular adverse events has not been established.
weeks, significantly greater reductions in BEHAVE-AD to- The manufacturers of risperidone and olanzapine have is-
tal scores and psychosis and aggressiveness subscale scores sued warnings through ‘Dear Doctor’ letters regarding the
were seen in patients receiving 1 mg/d or 2 mg/d of risperi- risk of cerebrovascular adverse events in elderly patients
done than in those receiving placebo (P 5.005 and Po.001, with dementia.34
respectively). Patients receiving 2 mg/d of risperidone re-
ported more adverse events than those receiving 1 mg/d.
The most common dose-related adverse events were EPS, Olanzapine
somnolence, and mild peripheral edema.32 The study of 344 Olanzapine was introduced in the U.S. market in 1996. It is
patients with dementia in a double-blind study in which FDA approved for the treatment of schizophrenia, the short-
patients were randomly assigned to receive placebo or flex- term treatment of acute mixed or manic episodes associated
ible doses (0.5–4 mg/d) of risperidone or haloperidol found with bipolar I disorder, and maintenance therapy for bipolar
that the mean dose of risperidone at the end of this study I disorder. The intramuscular formulation is indicated for
was 1.1 mg/d. Although not significant (P 5.25), a higher the treatment of agitation associated with schizophrenia
percentage of patients receiving risperidone than receiving and bipolar I mania. Olanzapine has high affinity binding to
placebo showed a 30% or greater reduction from baseline serotonin 5-HT, dopamine D1-4, muscarinic M1-5, histamine
to endpoint in BEHAVE-AD total score, although reduc- H1, and a1 adrenergic receptors. It binds weakly to GABAA,
tions in BEHAVE-AD total score were significantly greater benzodiazepine, and b-adrenergic receptors.
(P 5.05) with risperidone than with placebo at Week 12. Olanzapine is well absorbed and reaches peak concen-
The incidence of somnolence was higher with active treat- trations in approximately 6 hours. It is 93% bound to plas-
ments (12.2% risperidone, 18.3% haloperidol) than with ma proteins, and its half-life ranges from 21 to 54 hours. In
JAGS DECEMBER 2004–VOL. 52, NO. 12 ANTIPSYCHOTICS IN THE ELDERLY S263
a study involving 24 healthy subjects, the mean elimination Of the approximately 2,400 patients in clinical studies
half-life was approximately 1.5 times greater in elderly with quetiapine, 190 (8%) were aged 65 and older. In gen-
(465) than in younger subjects. Dosing should be done eral, there was no indication of any differences in tolera-
cautiously in the elderly, especially if other factors are bility in the elderly than in younger adults. The presence of
present that might influence drug metabolism or pharma- factors that might decrease pharmacokinetic clearance, in-
cological sensitivity. crease the pharmacodynamic response to quetiapine, or
Of 2,500 patients in premarketing clinical studies with cause poorer intolerance or orthostasis should lead to con-
olanzapine, 263 (11%) were aged 65 and older. In those sideration of a lower dose, slower titration, and careful
with schizophrenia, there was no indication of any differ- monitoring during the initial dosing period in the elderly.39
ence in tolerability of olanzapine between elderly and There have been two trials investigating quetiapine’s
young subjects, but caution should be used in treating eld- efficacy in the treatment of psychoses related to AD. In a
erly patients with olanzapine. The presence of factors that subanalysis of 78 patients with AD who were part of a
might decrease drug clearance or increase the pharmaco- larger 1-year open-label trial of quetiapine in elderly pa-
dynamic response to olanzapine should lead to considera- tients with psychosis, a significant improvement was shown
tion of a lower starting dose for elderly patients.36 in the BPRS positive symptoms cluster at 12 and 24 weeks.
Olanzapine has also been shown to be an effective Patients in this trial received a median dose of 100 mg/d.40
treatment for psychotic and behavioral symptoms in patients In a second, larger trial,41 AD patients with psychosis
with AD.12 In an attempt to determine an effective dosing (N 5 284) were studied by comparing the efficacy of quetia-
strategy for olanzapine in the elderly, four groups of elderly pine, haloperidol, and placebo. Subjects were divided into
nursing home residents with AD were tested.37 The groups three groups, and flexible dosing was used according to
received 5 mg/d, 10 mg/d, or 15 mg/d olanzapine or placebo. their response and tolerability. The objective of this 10-
Findings revealed that the 5 mg/d and 10 mg/d doses were week study was to compare quetiapine’s safety, tolerability,
significantly superior to placebo. A smaller dose of 2.5 mg/d and efficacy for improving psychotic symptoms in patients
tested in an earlier study was no more effective than placebo, with AD with those of haloperidol and placebo.
whereas the 15 mg/d study dose produced an increase in side Findings revealed that both treatment groups experi-
effects, including peripheral anticholinergic effects (signifi- enced diminished psychotic symptoms, with no significant
cant) and central anticholinergic effects (not significant). In difference among the groups. More specifically, quetiapine
this study, the safety profile of low-dose olanzapine revealed and haloperidol improved agitation more than placebo,
that it was generally tolerated as well as placebo.37 quetiapine produced greater improvements in daily func-
In addition, the Expert Consensus Guidelines for Using tion than placebo or haloperidol, quetiapine demonstrated
Antipsychotic Agents in Older Patients do not recommend better tolerability than haloperidol, and quetiapine demon-
olanzapine (or clozapine or conventional antipsychotics) for strated similar EPS and anticholinergic effects to placebo.
patients with diabetes mellitus, dyslipidemia, or obesity.38
Ziprasidone
Quetiapine The FDA approved the fifth atypical antipsychotic, ziprasi-
Quetiapine joined the atypical antipsychotic market in done, in 2001 for treatment of positive and negative symp-
1997 for the treatment of schizophrenia and recently re- toms of schizophrenia. It exhibits binding affinity for
ceived FDA approval for the treatment of acute manic ep- serotonin 5-HT2A, 5-HT2C, 5-HT1D, and 5-HT1A; dopa-
isodes associated with bipolar I disorder as monotherapy mine D2 and D3; and a1 adrenergic receptors and moderate
for duration of 12 weeks or as adjunct therapy with lithium affinity for the histamine H1. The drug functions as an an-
or divalproex for duration of 3 weeks. tagonist at the D2, 5-HT2A, and 5-HT1D receptors and as an
Quetiapine is an antagonist at multiple neurotransmit- agonist at the 5-HT1A receptor.
ters in the brain: serotonin 5-HT1A and 5-HT2, dopamine Ziprasidone has a mean terminal half-life of about 7
D1 and D2, histamine H1, and a1 and a2 adrenergic recep- hours and a steady-state concentration achieved within 1 to
tors. It has no appreciable affinity at cholinergic, mu- 3 days of dosing and is unlikely to interfere with the phar-
scarinic, or benzodiazepine receptors. macokinetics of drugs metabolized by cytochrome P450.
Quetiapine is rapidly absorbed, reaches peak plasma It is rapidly absorbed orally and reaches peak plasma
concentration in 1.5 hours, and is 83% bound to plasma concentration in 6 to 8 hours. It is more than 99% bound to
proteins. It is eliminated mainly via hepatic metabolism, plasma proteins. The absolute bioavailability of a 20-mg
with a mean terminal half-life of approximately 6 hours; it dose under fasting conditions is 60%. The absorption of
is expected that steady state will be achieved within 2 days this drug can double in the presence of food. It is extensively
of dosing. It is unlikely to interfere with the pharmacoki- metabolized after oral administration, with only a small
netics of drugs metabolized by the cytochrome P450 en- amount excreted in the urine (o1%) or feces (o4%) as
zymes. Mean elimination half-life was approximately 1.5 unchanged drug. The bioavailability of ziprasidone admin-
times greater in the elderly (465) than in younger subjects. istered intramuscularly is 100%. Peak serum concentra-
Consideration should be given to a slower dose titration tions typically occur at approximately 60 minutes postdose
and a lower targeted dose in elderly debilitated patients or or earlier, and the mean half-life ranges from 2 to 5 hours.
those who are predisposed to hypotension. When indicated, A multiple-dose study involving 32 subjects showed no
dose escalation should be done with caution. Quetiapine difference in the pharmacokinetics of ziprasidone between
dose adjustment is needed when coadministered with men and women or between elderly (465) and young
phenytoin or ketoconazole. (18–45) subjects. In addition, population pharmacokinetic
S264 FINKEL DECEMBER 2004–VOL. 52, NO. 12 JAGS
evaluation of patients in controlled trials revealed no evi- enrolled 192 outpatients (mean age 81.5) who received
dence of clinically significant age- or sex-related differences aripiprazole or placebo. Under the flexible-dose study de-
in its pharmacokinetics. The intramuscular formulation has sign, patients received 2 to 10 mg/d, with a mean dose at
not been evaluated systematically in the elderly. endpoint of 10 mg/d. In terms of efficacy, findings revealed a
Because of the drug’s dose-related prolongation of the significant reduction in the BPRS46 score and psychosis
QT interval on electrocardiogram and the known associa- scores but not in the NPI47 score at endpoint. In terms of
tion between fatal arrhythmias and QT-interval prolonga- safety and tolerability, aripiprazole was similar to placebo
tion by some other drugs, ziprasidone is contraindicated in in discontinuation due to adverse events, EPS-related or
patients with a known history of QT-interval prolongation, orthostatic events, and somnolence.45
with recent myocardial infarction, or with uncompensated
heart failure. Ziprasidone use should be avoided in com- SUMMARY
bination with other drugs that are known to prolong the
Not all atypical antipsychotics are created equal. There are
QTc interval.
differences between them, specifically in efficacy and side
Of the approximately 4,500 patients in clinical studies
effects, as well as the quantity of data available for the
treated with ziprasidone, 109 (2.4%) were aged 65 and
elderly and for patients with AD and dementia. Atypical
older. In general, there was no indication of any different
antipsychotics are safer than conventional antipsychotics
tolerability of ziprasidone or reduced clearance of ziprasi-
when considering adverse events, but they do have limita-
done in elderly than in younger adults. The presence of
tions and risks. The elderly patient population is especially
factors that might decrease pharmacokinetic clearance, in-
vulnerable to side effects, and great care and much consid-
crease the pharmacodynamic response to ziprasidone, or
eration should go into individualizing the best treatments
cause worse intolerance or orthostasis should lead to con-
for each of these patients. In general, beginning elderly
sideration of a lower dose, slower titration, and careful
patients with low dosages of antipsychotics and titrat-
monitoring during the initial dosing period in the elderly.42
ing slowly constitutes the safest approach to treating these
Comments and recommendations for the use of zip-
patients.
rasidone in the treatment of elderly patients are scarce to
nonexistent. Efficacy studies, most of which have focused
on schizophrenia, have revealed some advantages: low risk ACKNOWLEDGMENTS
of EPS, low risk of sedation, and low risk of weight gain in The author is on the speaker’s bureau of AstraZeneca,
nonelderly patient groups. Antipsychotic-induced weight Janssen, and Pfizer. He is also a consultant for AstraZeneca
gain is thought by many to predispose patients to cardio- and Janssen. Author has received research grants from Eli
vascular disease and type 2 diabetes mellitus and to have Lilly, Janssen, Novartis and Pfizer.
a negative effect on patient compliance with this medica- The author is solely responsible for the study concept,
tion.43 design, acquisition of subjects and/or data, analysis and in-
terpretation of data, and preparation of this manuscript.
The sponsor of this paper was not involved in the de-
Aripiprazole sign, methods, subject recruitment, data collection, analy-
Approved by the FDA in 2002 for the treatment of schiz- sis, or preparation of this paper.
ophrenia, aripiprazole is the newest of the atypical anti-
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