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Zafar A. Sharif, Jeffrey A. Lieberman: Chapter 31. Aripiprazole, in The American Psychiatric Publishing Textbook of

Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric

Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.430665. Printed 5/10/2009 from www.psychiatryonline.com

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Chapter 31. Aripiprazole

HISTORY AND DISCOVERY

Aripiprazole is a dihydroquinolinone antipsychotic agent. Chemically, it is unrelated to phenothiazine,

butyrophenone, thienobenzodiazepine, or other antipsychotic agents. Pharmacologically, it exhibits a

novel mechanism of action, combining partial agonist activity at dopamine2 (D2), dopamine3 (D3), and

serotonin1A (5-HT1A) receptors with antagonist activity at serotonin2A (5-HT2A) and D2 receptors (Burris

et al. 2002; Jordan et al. 2002). The development and approval of aripiprazole represent a significant

event in the history of antipsychotic agents, as it potentially represents another significant innovation

following the introduction of first-generation, or typical, antipsychotic drugs and second-generation, or

atypical, antipsychotic drugs in the pharmacology and mechanism of action of therapeutic agents for

psychotic disorders.

Although effective in alleviating psychotic symptoms and preventing their recurrence, the typical agents

are ineffective in up to 40% of patients with schizophrenia. Even in patients who respond, typical

antipsychotics lack efficacy against the negative symptoms of schizophrenia, such as anhedonia and

apathy. The typical agents are also associated with a considerable burden of extrapyramidal side effects

(EPS) and other side effects, including tardive dyskinesia and hyperprolactinemia. Among patients with

first-episode schizophrenia, parkinsonian side effects have been identified as a predictor of

discontinuation of antipsychotic treatment (Robinson et al. 2002).

The atypical agents are partially effective against negative as well as positive symptoms and are also

associated with fewer EPS. Nevertheless, individual atypical agents are associated with side effects such

as weight gain, hyperprolactinemia, QTc prolongation, and alterations in glucose and lipid levels (Allison et

1. 1999; Glassman and Bigger 2001; Koro et al. 2002a, 2002b; McIntyre et al. 2001). These side effects

may reduce patient adherence to treatment and so increase the long-term risk of acute schizophrenic

relapse (Fleischhacker et al. 1994; Kurzthaler and Fleischhacker 2001). They may also be associated with

harmful medical sequelae.

The development of aripiprazole was guided by prevailing hypotheses of the etiology of schizophrenia. The

dopamine (DA) hypothesis (Seeman and Niznik 1990) proposes that abnormalities in dopaminergic

neurotransmission in the brain cause the symptoms of schizophrenia. In its current form, the DA

hypothesis suggests that schizophrenia involves a biphasic disturbance in dopaminergic pathways, leading

to altered function in different anatomical regions (Davis et al. 1991; Pycock et al. 1980; Weinberger

1987). According to this model, underactivity of the mesocortical dopaminergic pathway leads to

hypodopaminergic activity in the frontal cortex, whereas overactivity in the mesolimbic pathway causes

increased dopaminergic neurotransmission. The latter is presumed to cause positive or psychotic

symptoms, while the former is believed to underlie negative symptoms and cognitive impairment. Another

influential hypothesis suggests that the activity of dopaminergic pathways is modulated by serotonergic

neurons that project from the raphe nuclei to the corpus striatum and the frontal cortex. In the striatum,

serotonin release inhibits DA, while in the frontal cortex it has a modulatory effect on pyramidal neurons

and can affect glutamate release.

These hypotheses help to explain several features of typical and atypical antipsychotic agents. All these

agents behave as full D2 antagonists. Their actions in the mesolimbic pathway would therefore be

expected to benefit patients with schizophrenia by reducing positive symptoms. D2 antagonism in the

other dopaminergic pathways would, however, be expected to cause unwanted side effects, including

exacerbation of negative symptoms (mesocortical pathways), EPS and tardive dyskinesia (nigrostriatal

tract), and hyperprolactinemia (tuberoinfundibular pathway) (Figure 31–1).

FIGURE 31–1. Conventional dopamine (DA) antagonist activity: effect on positive symptoms,

extrapyramidal side effects (EPS), and prolactin levels.Print: Chapter 31. Aripiprazole

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Similarly, the serotonin (5-HT) hypothesis may help to explain why the atypical agents, which have

antagonist activity at 5-HT2A receptors, are associated with fewer EPS and do not exacerbate (and, in fact,

partially alleviate) negative symptoms and cognitive impairment (Leysen et al. 1993; Millan 2000; Rao and

Möller 1994; Richelson 1999).

On the basis of aripiprazole’s unique pharmacodynamic profile—partial agonist activity (rather than full

antagonist activity) at both dopaminergic (D2; Burris et al. 2002) and serotonergic (5-HT1A; Jordan et al.

2002) receptors, and full antagonist activity at 5-HT2A receptors (McQuade et al. 2002)—it was anticipated

that aripiprazole treatment would be associated with a reduced burden of unwanted D2 antagonist activity

in the mesocortical, nigrostriatal, and tuberoinfundibular pathways—the activity associated with some of

the side effects of typical and atypical antipsychotic agents (Figure 31–2).

FIGURE 31–2. Dopamine (DA) partial agonist activity: effect on positive symptoms, extrapyramidal side

effects (EPS), and prolactin levels.

STRUCTURE–ACTIVITY RELATIONS

Aripiprazole is 7-[4-(4-[2,3-dichlorophenyl]-1-piperazinyl)butoxy]-3,4-dihydrocarbostyril (Figure 31–3), aPrint: Chapter 31. Aripiprazole

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dihydroquinolinone.

FIGURE 31–3. Chemical structure of aripiprazole.

PHARMACOLOGICAL PROFILE

Aripiprazole exhibits potent partial agonist activity at D2 (Burris et al. 2002) and 5-HT1A (Jordan et al.

2002) receptors, together with potent antagonist activity at 5-HT2A receptors. It also has high affinity for

D3 receptors; moderate affinity for dopamine4 (D4), serotonin2C (5-HT2C), serotonin7 (5-HT7),

1-adrenergic, and histamine1 (H1) receptors and the serotonin reuptake site (SERT); and negligible affinity

for cholinergic muscarinic receptors (Table 31–1). The active metabolite of aripiprazole,

dehydroaripiprazole, exhibits a similar affinity at D2 receptors and has not been shown to have a

pharmacological profile that is clinically significantly different from that of the parent compound.

TABLE 31–1. Receptor-binding profile of aripiprazole

Receptor type Ki (nM)

Dopaminergic

D1

265

D2 a

0.34

D3

0.8

D4

44

D5

95

Serotonergic

5-HT1A b

1.7

5-HT2A

3.4

5-HT2C

15

5-HT6

214

5-HT7

39

SERT 98

Histaminic

H1

61

Adrenergic

a1

c

57

IC50 (nM)

Muscarinicc

>1,000

Note. SERT = serotonin reuptake site.

Source. Adapted from McQuade RD, Burris KD, Jordan S, et al.: “Aripiprazole: A Dopamine–Serotonin System

Stabilizer.” International Journal of Neuropsychopharmacology 5 (Suppl 1): S176, 2002, with the following exceptions:

aBurris KD, Molski TF, Xu C, et al.: “Aripiprazole, A Novel Antipsychotic, Is a High Affinity Partial Agonist at Human

Dopamine D2 Receptors.” Journal of Pharmacology and Experimental Therapeutics 302: 381–389, 2002.

b Jordan S, Koprivica V, Chen R, et al.: “The Antipsychotic Aripiprazole Is a Potent, Partial Agonist at the HumanPrint: Chapter 31. Aripiprazole

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5-HT1A Receptor.” European Journal of Pharmacology 441:137–140, 2002.

c “AbilifyTM (Aripiprazole) Tablets.” Full Prescribing Information. Tokyo, Otsuka Pharmaceutical Co., Ltd., November

2006.  

PHARMACOKINETICS AND DISPOSITION

Aripiprazole is available for oral administration as tablets in strengths of 2, 5, 10, 15, 20, and 30 mg. The

effective dose range is 10–30 mg/day for schizophrenia patients and 15–30 mg/day for bipolar I disorder

patients. A rapidly disintegrating oral formulation of aripiprazole is available in 10-mg and 15-mg

strengths. In addition, aripiprazole is available in a 1-mg/mL nonrefrigerated oral solution. Aripiprazole is

taken once daily with or without food and is well absorbed after oral administration, with peak plasma

concentrations occurring within 3–5 hours. Absolute oral bioavailability is 87%. An injectable form of

aripiprazole for intramuscular (IM) use to provide rapid control of agitation in adults with schizophrenia or

bipolar mania was approved by the U.S. Food and Drug Administration (FDA) in September 2006.

Aripiprazole injection is available in single-dose, ready-to-use vials containing 9.75 mg aripiprazole in 1.3

mL of diluent (7.5 mg/mL); the recommended initial dose is 9.75 mg IM. Time to the peak plasma

concentration is 1–3 hours after IM injection, and the absolute bioavailability of a 5-mg injection is 100%.

The mean maximum concentration achieved after an IM dose is on average 19% higher than the maximum

plasma concentration (Cmax) of the oral tablet. While the systemic exposure over 24 hours is generally

similar for aripiprazole administered as an IM injection and as an oral tablet, the aripiprazole area under

the curve (AUC) in the first 2 hours after an IM injection is 90% greater than the AUC after the same dose

in a tablet (Otsuka Pharmaceutical 2006).

In plasma, aripiprazole and its major metabolite, dehydroaripiprazole, are both more than 99% bound to

proteins, primarily albumin. Aripiprazole is extensively distributed outside the vascular system, and

human studies demonstrating dose-dependent occupancy of D2 receptors have confirmed that aripiprazole

penetrates the brain. Elimination half-lives for aripiprazole and dehydroaripiprazole are 75 hours and 94

hours, respectively.

Aripiprazole is metabolized primarily in the liver. Two hepatic cytochrome P450 (CYP) enzymes, 2D6 and

3A4, catalyze dehydrogenation to dehydroaripiprazole. Therefore, coadministration with inducers or

inhibitors of these CYP enzymes may require dosage adjustment of aripiprazole. The active metabolite

accounts for 40% of drug exposure, but the predominant circulating moiety is the parent drug.

Aripiprazole does not undergo direct glucuronidation and is not a substrate for the following CYP enzymes:

1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2E1. Interactions with inhibitors or inducers of these enzymes, or

with chemicals related to cigarette smoke, are therefore unlikely to occur.

Patient demographic characteristics have not been shown to have any clinically significant impact on the

pharmacokinetics of aripiprazole. In general, dosing does not need to be adjusted in respect of a patient’s

age, gender, race, smoking status, or hepatic or renal function.

Following a single oral dose of 14C-labeled aripiprazole, approximately 25% and 55% of the administered

radioactivity were recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole

was excreted in the urine, and approximately 18% of the oral dose was recovered unchanged in the feces.

MECHANISM OF ACTION

Aripiprazole has partial agonist activity at D2 receptors, a feature that distinguishes it from all other

currently available antipsychotics, which are full D2 antagonists. In vitro studies in D2 receptors in rat

striatal membranes (A. Inoue et al. 1997) and rat anterior pituitary slices (T. Inoue et al. 1996) showed

that aripiprazole acts as an antagonist when coadministered in the presence of a DA agonist. In other in

vitro studies using cloned D2 receptors from either rat (Lawler et al. 1999) or human (Burris et al. 2002),

aripiprazole dose-dependently inhibited isoproterenol-stimulated cyclic adenosine monophosphate (cAMP)

synthesis. In these studies, aripiprazole acted as an agonist in the absence of DA, although its maximal

agonist activity was less than that of DA, a full agonist.

The activity of aripiprazole at D2 receptors has also been studied in animal models of schizophrenia

(Kikuchi et al. 1995). Aripiprazole exhibits DA antagonist activity in an animal model of hyperdopaminergic

activity. In the intact rat with repetitive stereotyped behavior (stereotypy) induced by apomorphine,

aripiprazole inhibits stereotypy and locomotion (Kikuchi et al. 1995). This agent may therefore be

expected to inhibit hyperdopaminergic activity in the mesolimbic pathway of patients with schizophrenia

and so, like other available agents, provide antipsychotic efficacy against the positive symptoms ofPrint: Chapter 31. Aripiprazole

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schizophrenia. On the other hand, in animal models of hypodopaminergic activity, such as the reserpinized

rat, aripiprazole has D2 receptor agonist activity. Because aripiprazole may display either D2 antagonist

activity under hyperdopaminergic conditions or D2 agonist activity under hypodopaminergic conditions,

this agent may be less likely than other antipsychotics to cause excessive D2 antagonism.

Aripiprazole may offer further therapeutic benefits through modulation of central serotonergic pathways.

Preclinical studies showed that aripiprazole has antagonist activity at 5-HT 2A receptors (McQuade et al.

2002), a feature that has been associated with reductions in EPS (Meltzer 1999) and negative symptoms.

In vitro studies also have shown that aripiprazole has partial agonist activity at 5-HT 1A receptors (Jordan

et al. 2002), a feature that has been associated with improvement in negative, cognitive, depressive, and

anxiety symptoms (Millan 2000).

Other receptor activity may explain some of the side effects of aripiprazole; for example, nausea/vomiting

may be explained by its DA agonist effects, whereas orthostatic hypotension and mild sedation/weight

gain are likely related to its antagonist activity at 1-adrenergic and H1 receptors, respectively.

INDICATIONS AND EFFICACY

In the United States, aripiprazole is approved by the FDA for: acute and maintenance treatment of

schizophrenia in adults and in adolescents 13–17 years of age; for acute and maintenance treatment of

manic and mixed episodes associated with bipolar I disorder with or without psychotic features in adults

and pediatric patients 10–17 years of age; as adjunctive therapy to either lithium or valproate for the

acute treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic

features in adults and pediatric patients 10–17 years of age; and as an adjunctive therapy to

antidepressants for the acute treatment of major depressive disorder in adults. Additionally, aripiprazole

injection is indicated for the acute treatment of agitation associated with schizophrenia or bipolar disorder

(manic or mixed) in adults (Abilify [aripiprazole] U.S. Full Prescribing Information).

The efficacy of aripiprazole as a treatment for acute relapse of schizophrenia was demonstrated in four

short-term (4-week) double-blind, placebo-controlled studies. Among these was a pivotal Phase III

parallel-group multicenter study with four treatment arms comparing aripiprazole (15 mg or 30 mg) with

placebo (Kane et al. 2002). Haloperidol (10 mg/day) was used as an active control to confirm the study

population’s responsiveness to antipsychotic therapy. The total group of patients who were randomized to

treatment (N = 414) comprised 282 patients with schizophrenia and 132 with schizoaffective disorder.

Compared with placebo, aripiprazole at either dose produced statistically significant improvements from

baseline in the following psychometric scores: Positive and Negative Syndrome Scale (PANSS)—Total,

PANSS positive subscale, PANSS-derived Brief Psychiatric Rating Scale (BPRS)—Core, Clinical Global

Impression (CGI)–Severity of Illness, and CGI–Improvement. Aripiprazole 15 mg also significantly

improved PANSS negative score compared with placebo. Both doses of aripiprazole produced measurable

improvement rapidly, with improvement from placebo detectable on psychometric scales by week 2. This

trial suggests that at doses of 15 mg and 30 mg, aripiprazole provides effective symptom control in

patients with acute relapse of schizophrenia.

Similar findings emerged from another pivotal short-term multicenter Phase III study involving 404

inpatients with an acute relapse of schizophrenia or schizoaffective disorder (Potkin et al. 2003). Patients

were randomly assigned to aripiprazole 20 mg, aripiprazole 30 mg, risperidone 6 mg, or placebo for 4

weeks. Compared with placebo, aripiprazole at both doses and risperidone treatment produced statistically

significant improvements in scores on standard scales designed to measure antipsychotic efficacy.

Likewise, responder rates (with response defined as a score of 1 or 2 on the CGI–Improvement) for both

doses of aripiprazole and for risperidone were significantly higher than those for placebo. This study

showed that aripiprazole at doses of 20 mg and 30 mg was significantly more effective than placebo.

The antipsychotic efficacy of aripiprazole in acute relapse of schizophrenia was also demonstrated in two

Phase II dose-ranging studies, both of which used haloperidol as an active control. In one study, 307

patients with an acute relapse of schizophrenia were randomized to aripiprazole 2 mg, 10 mg, or 30 mg

daily or haloperidol 10 mg/day (Daniel et al. 2000). All three doses of aripiprazole produced improvements

in efficacy measures from baseline, and the 30-mg dose produced statistically significant improvement

compared with placebo on all illness scores, including CGI–Severity, BPRS–Total, BPRS–Core,

PANSS–Total, and PANSS positive and negative subscales. Similarly, in a Phase II dose-titrating study,

aripiprazole 5–30 mg was superior to placebo in improving BPRS–Total, BPRS–Core, CGI–Severity, and

PANSS–Total scores (Petrie et al. 1997).Print: Chapter 31. Aripiprazole

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Results from the three 4-week fixed-dose studies discussed above were pooled for analysis with those of

an additional 6-week placebo-controlled, fixed-dose study of aripiprazole at doses of 10 mg, 15 mg, and

20 mg (Lieberman et al. 2002). The pooled analysis involving 898 patients randomized to aripiprazole

showed that at all investigated doses greater than 2 mg, aripiprazole exhibited antipsychotic efficacy

superior to placebo. Onset of efficacy was rapid, with improvement on psychometric scores detectable

within 1 week of starting treatment. These pooled efficacy results demonstrate that doses of 10–30 mg

represent an effective therapeutic range for aripiprazole treatment.

The antipsychotic efficacy of aripiprazole in patients with schizophrenia has been further confirmed in two

long-term double-blind, randomized, controlled multicenter trials. A 26-week placebo-controlled study in

310 patients with chronic stable schizophrenia investigated the efficacy of aripiprazole 15 mg in relapse

prevention (Pigott et al. 2003). Patients who had been symptomatically stable on other antipsychotic

medications for 3 months or longer were taken off these medications and randomly assigned to

aripiprazole 15 mg or placebo for up to 26 weeks and observed for relapse (defined as a score of 5

[minimally worse] on the CGI–Improvement, a score of 5 [moderately severe] on the hostility or

uncooperativeness items of the PANSS, or a 20% increase in the PANSS–Total score). Aripiprazole

treatment significantly increased the time to relapse and resulted in significantly fewer relapses at

endpoint compared with placebo (34% vs. 57%). From week 6 of therapy, PANSS–Total and PANSS

positive subscale scores were significantly more improved with aripiprazole than with placebo.

Another study evaluated the long-term efficacy of aripiprazole when treatment was maintained for up to

52 weeks (Kasper et al. 2003). Patients with acute relapse of schizophrenia (N = 1,294) were randomized

to aripiprazole 30 mg/day (n = 861) or haloperidol 10 mg/day (n = 433). Significantly more

aripiprazole-treated patients were still taking the medication and were responding to treatment at weeks

8, 26, and 52 than were haloperidol-treated patients. Both treatments produced sustained improvements

in the PANSS–Total and PANSS positive subscale scores from baseline. However, aripiprazole produced

significantly greater improvements in negative and depressive symptoms at weeks 26 and 52 and was

associated with significantly lower scores on all EPS assessments compared with haloperidol.

The efficacy of aripiprazole monotherapy in antipsychotic-resistant schizophrenia was evaluated in a

6-week double-blind, randomized trial in 300 patients who had failed to improve in a prospective 4- to

6-week open trial with olanzapine or risperidone (Kane et al. 2007). Subjects were randomly assigned to

aripiprazole (15–30 mg/day) or perphenazine (8–64 mg/day). After 6 weeks, there was no statistical

difference between the two groups on efficacy measures; 27% of aripiprazole-treated patients and 25% of

perphenazine-treated patients were classified as responders (30% improvement from baseline or

CGI–Improvement score of 1 or 2). Compared with aripiprazole, perphenazine was associated with a

higher rate of EPS and elevated serum prolactin.

The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (ages 13–17 years) was

evaluated in a 6-week placebo-controlled trial of outpatients who met DSM-IV (American Psychiatric

Association 1994) criteria for schizophrenia and had a PANSS score ≥70 at baseline (Findling et al. 2008).

In this trial comparing two fixed doses of aripiprazole (10 mg/day or 30 mg/day) with placebo,

aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment

arm and in 11 days in the 30 mg/day treatment arm. Of 302 patients, 85% completed the 6-week study.

Both aripiprazole doses showed statistically significant differences from placebo in reduction in

PANSS–Total score; the 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose.

Adverse events occurring in more than 5% of either aripiprazole group and with a combined incidence at

least twice the rate for placebo were extrapyramidal disorder, somnolence, and tremor. Mean body weight

changes were –0.8, 0.0, and 0.2 kg for placebo, aripiprazole 10 mg, and aripiprazole 30 mg, respectively

The efficacy of aripiprazole in the treatment of acute manic episodes was established in two 3-week

placebo-controlled trials in hospitalized patients who met DSM-IV criteria for bipolar I disorder with manic

or mixed episodes (Keck et al. 2003; Sachs et al. 2006). These trials included patients with and without

psychotic features and with and without a rapid-cycling course. The primary instrument used for assessing

manic symptoms was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally

used to assess the degree of manic symptomatology. A key secondary instrument included the Clinical

Global Impression–Bipolar (CGI-BP) scale. In both trials (n = 268; n = 248), aripiprazole was started at 30

mg/day, but the dosage could be reduced to 15 mg/day on the basis of efficacy and tolerability.

Aripiprazole was superior to placebo in the reduction of YMRS total score and CGI-BP Severity of Illness

score (mania). In a third large randomized, double-blind trial involving 347 patients (Vieta et al. 2005),Print: Chapter 31. Aripiprazole

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aripiprazole was compared with haloperidol in the treatment of acute bipolar mania over a 12-week

period. Significantly more patients remained in treatment and were classified as responders (50%

reduction in YMRS score from baseline) at week 12 for aripiprazole (49.7%) than for haloperidol (28.4%).

EPS adverse events were more frequent with haloperidol than with aripiprazole (62.7% vs. 24.0%).

The efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or

mixed episodes was established in a 6-week placebo-controlled study (N = 384) with a 2-week lead-in

mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This

study included patients with manic or mixed episodes and with or without psychotic features. Patients

were initiated on open-label lithium or valproate at therapeutic serum levels and remained on stable doses

for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response to lithium or valproate

(YMRS total score 16 and 25% improvement on the YMRS total score) were randomized to receive either

aripiprazole (15 mg/day with an increase to 30 mg/day as early as day 7) or placebo as adjunctive

therapy with open-label lithium or valproate. In the 6-week placebo-controlled phase, adjunctive

aripiprazole starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of

0.6–1.0 mEq/L or 50–125 g/mL, respectively) was superior to lithium or valproate with adjunctive

placebo in the reduction of the YMRS total score and CGI-BP Severity of Illness score (mania).

Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered

lithium were on 15 mg/day at the 6-week endpoint.

Aripiprazole monotherapy was also evaluated in the treatment of nonpsychotic depressive episodes

associated with bipolar I disorder. The results of two identically designed 8-week randomized,

double-blind, placebo-controlled multicenter studies were reported by Thase et al. (2008). Patients were

randomly assigned to placebo or aripiprazole (initiated at 10 mg/day, then flexibly dosed at 5–30 mg/day

based on clinical effect and tolerability). The primary endpoint was mean change from baseline to week 8

(last observation carried forward [LOCF]) in the Montgomery-Åsberg Depression Rating Scale (MADRS)

total score. Although statistically significant differences were observed during weeks 1–6, aripiprazole did

not achieve statistical significance versus placebo at week 8 in either study in the change in MADRS total

score (primary endpoint). In addition, despite early statistical separation on the Clinical Global

Impressions Bipolar Version Severity of Illness–Depression score (key secondary endpoint), aripiprazole

was not superior to placebo at endpoint. Aripiprazole was associated with a higher incidence of akathisia,

insomnia, nausea, fatigue, restlessness, and dry mouth versus placebo. More patients discontinued with

aripiprazole versus placebo in both studies. Thus, aripiprazole monotherapy as dosed in this study design

was not significantly more effective than placebo in the treatment of bipolar depression at endpoint

(Thase et al. 2008).

To evaluate the long-term effectiveness of aripiprazole in delaying relapse in bipolar I disorder patients, a

trial was conducted in patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed

episode who had been stabilized on open-label aripiprazole and who had maintained a clinical response for

at least 6 weeks (Keck et al. 2006). The first phase of this trial was an open-label stabilization period in

which inpatients and outpatients were clinically stabilized (YMRS score 10 and MADRS score 13) and

then maintained on open-label aripiprazole (15 or 30 mg/day, with a starting dose of 30 mg/day) for at

least 6 consecutive weeks. One hundred sixty-one outpatients were then randomized in a double-blind

fashion to either the same dose of aripiprazole they were on at the end of the stabilization and

maintenance period or a switch to placebo and were then monitored for manic or depressive relapse.

During the randomization phase, aripiprazole was superior to placebo on time to the number of combined

affective relapses (manic plus depressive), the primary outcome measure for this study. The majority of

these relapses were due to manic rather than depressive symptoms. Aripiprazole-treated patients had

significantly fewer relapses than placebo-treated patients (25% vs. 43%). Aripiprazole was superior to

placebo in delaying the time to manic relapse but did not differ from placebo in delaying time to depressive

relapse. Significant weight gain (7% increase from baseline) was seen in 13% of the aripiprazole patients

and none of the placebo patients. An examination of population subgroups did not reveal any clear

evidence of differential responsiveness on the basis of age and gender; however, there were insufficient

numbers of patients in each of the ethnic groups to adequately assess intergroup differences.

The efficacy of aripiprazole in the treatment of bipolar I disorder in pediatric patients (ages 10–17 years)

was evaluated in a 4-week placebo-controlled trial of outpatients (N = 296) who met DSM-IV criteria for

bipolar I disorder manic or mixed episodes with or without psychotic features and had a YMRS score 20 at

baseline. This double-blind, placebo-controlled trial compared two fixed doses of aripiprazole (10 mg/dayPrint: Chapter 31. Aripiprazole

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or 30 mg/day) against placebo. The aripiprazole dose was started at 2 mg/day, which was increased to 5

mg/day after 2 days and to the target dose in 5 days in the 10 mg/day treatment arm and in 13 days in

the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in change from

baseline to week 4 on the YMRS total score. Although maintenance efficacy in pediatric patients has not

been systematically evaluated, maintenance efficacy can be extrapolated from adult data, along with

comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients (Abilify

[aripiprazole] U.S. Full Prescribing Information).

Aripiprazole is also available in an injectable formulation for IM administration. The efficacy of aripiprazole

injection in controlling acute agitation was evaluated in three short-term (24-hour) randomized,

double-blind, placebo-controlled studies in patients with schizophrenia (Andrezina et al. 2006;

Tran-Johnson et al. 2007) and patients with bipolar disorder (manic or mixed) (Zimbroff et al. 2007),

involving a total of 1,086 patients. The effectiveness of aripiprazole injection in controlling agitation was

measured in these studies using several instruments, including the PANSS Excited Component (PANSS EC)

and CGI–I scale. The primary efficacy measure used for assessing signs and symptoms of agitation was

the change from baseline in the PANSS EC at 2 hours’ postinjection. PANSS EC includes five items: poor

impulse control, tension, hostility, uncooperativeness, and excitement. Aripiprazole injection was

statistically superior to placebo (P 0.05) in all three studies, as measured with the PANSS EC. In the two

studies in agitated patients with schizophrenia, injectable aripiprazole and IM haloperidol were compared

with placebo. The injectable formulations of aripiprazole and haloperidol were both superior to placebo. In

the study in agitated bipolar I disorder (manic or mixed) patients, aripiprazole injection and lorazepam

injection were compared with placebo. Both active agents were superior to placebo. FDA-approved dosage

preparations are as follows: 5.25 mg/0.7 mL, 9.75 mg/1.3 mL, and 15 mg/2.0 mL. The recommended

initial dose of aripiprazole injection is 9.75 mg.

De Deyn et al. (2005) compared the efficacy, safety, and tolerability of aripiprazole against placebo in

patients with psychosis associated with Alzheimer’s disease (AD). This 10-week double-blind multicenter

study randomized 208 outpatients (mean age = 81.5 years) with AD-associated psychosis to aripiprazole

(n = 106) or placebo (n = 102). The initial aripiprazole dose of 2 mg/day was titrated upward (5, 10, or 15

mg/day) according to efficacy and tolerability. Evaluations included the Neuropsychiatric Inventory (NPI)

Psychosis subscale and the BPRS, adverse event (AE) reports, EPS rating scales, and body weight

measurement. Overall, 172 patients (83%) completed the study. The mean aripiprazole dose at study

endpoint was 10.0 mg/day. The NPI Psychosis subscale score showed improvements in both groups

(aripiprazole, –6.55; placebo, –5.52; P = 0.17 at endpoint). Aripiprazole-treated patients showed

significantly greater improvements from baseline in BPRS Psychosis and BPRS–Core subscale scores at

endpoint compared with placebo-treated patients. Somnolence was mild and was not associated with falls

or accidental injury. There were no significant differences from placebo in EPS scores or in clinically

significant electrocardiogram abnormalities, vital signs, or weight.

In another double-blind, multicenter study (Mintzer et al. 2007), 487 institutionalized patients with

psychosis associated with AD were randomized to placebo or aripiprazole, 2, 5 or 10 mg/day. Primary

efficacy assessment was the mean change from baseline to week 10 on the Neuropsychiatric

Inventory–Nursing Home (NPI-NH) version Psychosis Subscale score. Aripiprazole 10 mg/day showed

significantly greater improvements than placebo on the NPI-NH Psychosis Subscale (–6.87 vs. –5.13; P =

0.013) by analysis of covariance; CGI-S (–0.72 vs. –0.46; P = 0.031); BPRS Total (–7.12 vs. –4.17; P =

0.030); and NPI-NH Psychosis response rate (65% vs. 50%; P = 0.019). Aripiprazole 5 mg/day showed

significant improvements versus placebo on BPRS and Cohen-Mansfield Agitation Inventory (CMAI) scores.

Aripiprazole 2 mg/day was not efficacious. Four cases of cerebrovascular adverse events were reported in

the aripiprazole 10 mg/day group, two in the 5-mg group, and one in the 2-mg group. No cerebrovascular

adverse events were reported in the placebo group.

In 2005, the FDA issued a black box warning for second-generation antipsychotics based on increased

mortality rates (4.5% vs. 2.6%) observed in patients with dementia-related psychosis treated with

second-generation antipsychotics as compared with placebo over a modal duration treatment period of 10

weeks. This warning was extended in June 2008 to include all older conventional antipsychotic agents. No

antipsychotic is currently approved in the United States for treating the behavioral and psychotic

symptoms that frequently accompany dementia.

Nickel et al. (2006) conducted a double-blind, placebo-controlled study in 52 subjects (43 women and 9

men) meeting criteria for borderline personality disorder who were randomly assigned in a 1:1 ratio to 15Print: Chapter 31. Aripiprazole

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mg/day of aripiprazole (n = 26) or placebo (n = 26) for 8 weeks. Significant changes in scores on most

scales of the Symptom Checklist (SCL-90-R), on the Hamilton Rating Scale for Depression (Ham-D), on the

Hamilton Anxiety Scale (Ham-A), and on all scales of the State-Trait Anger Expression Inventory were

observed in subjects treated with aripiprazole after 8 weeks. The improvements noted at 8 weeks of

therapy were maintained at 18-month follow-up (Nickel et al. 2007).

Because of aripiprazole’s partial DA agonist activity, there has been substantial interest in evaluating the

utility of aripiprazole in reducing cravings and drug use in cocaine-, alcohol-, and amphetamine-abusing

patients and as an augmentation strategy in patients with treatment-resistant depression. Tiihonen et al.

(2007) conducted a study in individuals meeting DSM-IV criteria for intravenous amphetamine

dependence (N = 53) who were randomly assigned to receive aripiprazole (15 mg/day), slow-release

methylphenidate (54 mg/day), or placebo for 20 weeks. The study was terminated prematurely because of

unexpected results of interim analysis. Contrary to the hypothesized result, patients who received

aripiprazole treatment had significantly more amphetamine-positive urine samples than did patients in the

placebo group, whereas patients who received methylphenidate had significantly fewer

amphetamine-positive urine samples than patients who had received placebo. Studies in cocaine-abusing

subjects are ongoing.

In a study in alcoholic patients (Anton et al. 2008) the efficacy and safety of aripiprazole was compared

with placebo in a 12-week double-blind multicenter trial in 295 patients with alcohol dependence

according to DSM-IV criteria. Patients were randomly assigned to treatment with aripiprazole (initiated at

2 mg/day and titrated to a maximum dose of 30 mg/day at day 28) or placebo after minimum 3 day

abstinence during the screening period. The primary efficacy measure was percentage of days abstinent

over 12 weeks. Discontinuations (40.3% vs. 26.7%) and treatment-related adverse events (82.8% vs.

63.6%) were higher with aripiprazole than with placebo. Mean percentage of days abstinent was similar

between aripiprazole and placebo (58.7% vs. 63.3%; P = 0.227). Percentage of subjects without a heavy

drinking day and the time to first drinking day were also comparable between groups, although the

aripiprazole group had fewer drinks per drinking day (4.4 vs. 5.5 drinks; P<0.001). The aripiprazole group

showed a larger decrease in percentage carbohydrate-deficient transferrin, a biomarker of heavy alcohol

consumption at weeks 4 (–14.91% vs. –2.23%; P = 0.02) and 8 (–16.92% vs. –5.33%; P = 0.021),

although not at week 12 (–9.06% vs. –4.12%; P = 0.298). At study endpoint, aripiprazole-treated subjects

reported more positive subjective treatment effects and less overall severity of alcohol dependence than

placebo-treated subjects. Although there was no difference between aripiprazole and placebo on the

primary endpoint, effects on the secondary outcomes suggest that further study of aripiprazole for

treatment of alcohol dependence may be warranted at lower doses (Anton et al. 2008).

The efficacy of aripiprazole in the adjunctive treatment of major depressive disorder was demonstrated in

two identical short-term (6-week) placebo-controlled trials of adult patients meeting DSM-IV criteria for

major depressive disorder who had had an inadequate response to prior antidepressant therapy (1 to 3

courses) in the current episode. In both studies, a 7- to 28-day screening phase was followed by an

8-week prospective antidepressant treatment phase and a 6 week double-blind adjunctive treatment

phase. During prospective antidepressant treatment, patients received one of several antidepressants

(escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release), each

with single-blind adjunctive placebo. Patients with incomplete response (defined as 50% improvement on

the 17-item version of the Hamilton Rating Scale for Depression [Ham-D-17], a final Ham-D-17 score 14,

and a Clinical Global Impressions Improvement rating of no better than minimal improvement) continued

on the antidepressant and were randomly assigned to double-blind adjunctive placebo or adjunctive

aripiprazole (2–15 mg/day with potent CYP2D6 inhibitors fluoxetine or paroxetine; 2–20 mg/day with all

other antidepressants). The primary efficacy measure was mean change from end of prospective

treatment to end of double-blind treatment (LOCF) in MADRS total score (analysis of covariance). A key

secondary outcome was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess

the impact of depression on three domains of functioning (work/school, social life, and family life), with

each item scored from 0 (not at all) to 10 (extreme).

In the first trial (Berman et al. 2007), a total of 178 patients were randomly assigned to adjunctive

placebo and 184 to adjunctive aripiprazole in the double-blind adjunctive treatment phase. The mean

change in MADRS total score was significantly greater with adjunctive aripiprazole (–8.8) than with

adjunctive placebo (–5.8; P0.001). Adverse events that occurred in 10% or more of patients with

adjunctive placebo or adjunctive aripiprazole were akathisia (4.5% vs. 23.1%), headache (10.8% vs.Print: Chapter 31. Aripiprazole

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6.0%), and restlessness (3.4% vs. 14.3%). Discontinuations due to adverse events were low with

adjunctive placebo (1.7%) and adjunctive aripiprazole (2.2%); only one adjunctive aripiprazole–treated

patient discontinued because of akathisia. About 1% of placebo recipients and 7.1% of aripiprazole

recipients experienced weight gain of 7% or greater from baseline.

In the second trial (Marcus et al. 2008), 190 patients were randomly assigned to adjunctive placebo and

191 to adjunctive aripiprazole. The mean change in MADRS total score was significantly greater with

adjunctive aripiprazole than with placebo (–8.5 vs. –5.7; P = 0.001). Remission rates were significantly

greater with adjunctive aripiprazole than placebo (25.4% vs. 15.2%; P = 0.016) as were response rates

(32.4% vs. 17.4%; P<0.001). The mean SDS total score—the key secondary outcome measure—improved

significantly more with adjunctive aripiprazole than with adjunctive placebo at endpoint (–1.3 vs. –0.7; P

= 0.012). Adverse events occurring in 10% or more of patients with adjunctive placebo or aripiprazole

were akathisia (4.2% vs. 25.9%), headache (10.5% vs. 9.0%), and fatigue (3.7% vs. 10.1%). Incidence

of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs. adjunctive

aripiprazole [3.7%]). By the last study visit, continuing akathisia was reported in 25 (51%) of the 49

patients who had ever reported this symptom. Furthermore, the majority of akathisia (n = 38/49; 78%)

was first reported during the first 3 weeks of treatment. Akathisia, at its maximum, was generally mild ( n

= 12/49; 25%) or moderate (n = 33/49; 67%) in severity, with few patients reporting akathisia as severe

(n = 4/49; 8%). For those subjects whose akathisia resolved during the study (n = 24), 58% (n = 14/24)

received dosage reduction and 42% (n = 10/24) received no intervention. Mean (SE) weight gain in the

adjunctive aripiprazole group (1.47 ± 0.16 kg) was significantly greater than the placebo group (0.42 ±

0.17 kg; P<0.001; LOCF). Weight gain of 7% or greater from baseline occurred in 0% of adjunctive

placebo–treated patients and 3.4% of adjunctive aripiprazole–treated patients (P = 0.031).

These scientifically rigorous studies confirmed initial observations from case reports, retrospective chart

reviews, and small open-label trials of the utility of aripiprazole in augmenting antidepressants in patients

with major depressive disorder and led to the FDA approval for this indication in late 2007.

SIDE EFFECTS AND TOXICOLOGY

The safety and tolerability of antipsychotic therapy are important aspects of schizophrenia management,

as they have an impact on treatment adherence and so on patients’ risk of relapse and quality of life.

Specific side effects seen with some antipsychotics, such as weight gain and hyperprolactinemia, may also

have long-term implications for patient health.

A pooled analysis of safety and tolerability data from the five short-term studies (Marder et al. 2003; Stock

et al. 2002) showed that aripiprazole treatment was well tolerated. The most commonly reported adverse

events with aripiprazole were headache, insomnia, agitation, and anxiety; these were also the most

frequently reported events in the placebo, haloperidol, and risperidone groups. The incidence of adverse

events was similar in the aripiprazole and placebo groups. Akathisia, somnolence, and EPS were more

common among patients receiving haloperidol than those receiving aripiprazole, while akathisia,

somnolence, and tachycardia were more frequent in the risperidone group than in the aripiprazole group.

The adverse-event profile of aripiprazole did not vary according to patient characteristics of age, gender,

and race, and no deaths were reported during the short-term studies. Data from the four fixed-dose

studies showed that somnolence was the only adverse event seen with aripiprazole that was possibly

dose-related. The overall incidence of somnolence with aripiprazole, however, was similar to that seen

with placebo and lower than that seen with other active treatments. Objective rating scale assessments

were used to assess changes in parkinsonian symptoms (Simpson-Angus Scale [SAS]), dyskinesias

(Abnormal Involuntary Movement Scale [AIMS]), and akathisia (Barnes Akathisia Rating Scale [BAS]). SAS

scores with aripiprazole did not differ significantly from those with placebo, whereas AIMS scores

improved significantly from baseline with aripiprazole compared with placebo. Aripiprazole did not

produce consistent dose-dependent changes in BAS scores. Haloperidol produced significant increases in

SAS and BAS scores over placebo. Rates of discontinuation due to adverse events were similar among the

groups: 9.4% with placebo, 8.0% with haloperidol, and 7.3% with aripiprazole (Otsuka Pharmaceutical

2006). According to the product labeling for aripiprazole in the United States, treatment-emergent adverse

events reported with aripiprazole in short-term trials of patients with schizophrenia (up to 6 weeks) or

bipolar disorder (up to 3 weeks) that occurred at an incidence greater than or equal to 10% and greater

than placebo, respectively, included headache (30% vs. 25%), anxiety (20% vs. 17%), insomnia (19% vs.

14%), nausea (16% vs. 12%), vomiting (12% vs. 6%), dizziness (11% vs. 8%), constipation (11% vs.

7%), dyspepsia (10% vs. 8%), and akathisia (10% vs. 4%). A similar adverse-event profile was observedPrint: Chapter 31. Aripiprazole

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in a 26-week trial in schizophrenia except for a higher incidence of tremor (aripiprazole 8% vs. placebo

2%).

The most frequently reported adverse events with aripiprazole injection were headache (aripiprazole 12%

1. placebo 7%), nausea (aripiprazole 9% vs. placebo 3%), dizziness (aripiprazole 8% vs. placebo 5%),

and somnolence (aripiprazole 7% vs. placebo 4%). In the three aripiprazole injection trials, the safety

profile was comparable to that of placebo regarding the incidence of EPS, akathisia, or dystonia. The

incidence of akathisia-related adverse events with aripiprazole injection was 2% (vs. 0% for placebo),

while the incidence of dystonia with aripiprazole injection was less than 1% (vs. 0% for placebo). In

addition, the incidence of QTc prolongation was also comparable between aripiprazole injection and

placebo.

Weight gain is another adverse event of concern seen with some antipsychotic treatments, as it is

associated with noncompliance (Allison et al. 1999), and excessive weight gain and obesity are linked to

an increased risk of morbidity and mortality from heart disease, hypertension, and diabetes (Aronne

2001). Minimal changes in mean body weight were observed with aripiprazole treatment in short-term

studies (pooled data, +0.71 kg) (Marder et al. 2003) and long-term studies (26-week: –1.26 kg; 52-week:

+1.05 kg) (Kasper et al. 2003; Pigott et al. 2003).

Olanzapine and aripiprazole were compared on their propensity to cause weight gain and other metabolic

disturbances in a 26-week randomized, double-blind multicenter trial in patients with DSM-IV

schizophrenia who were in acute relapse and required hospitalization (McQuade et al. 2004). Significant

weight gain was defined as more than 7% increase in body weight from baseline. Three hundred

seventeen patients were randomly assigned to aripiprazole (n = 156) or olanzapine (n = 161). By week

26, 37% of olanzapine-treated patients had experienced significant weight gain, compared with 14% of

aripiprazole-treated patients (P<.001). Statistically significant differences in mean weight change were

observed between treatments beginning at week 1 and sustained throughout the study. At week 26, there

was a mean weight loss of 1.37 kg (3.04 lb) with aripiprazole compared with a mean increase of 4.23 kg

(9.40 lb) with olanzapine among patients who remained on therapy (P0.001). Changes in fasting plasma

levels of total cholesterol, high-density lipoprotein cholesterol, and triglycerides were significantly

different in the two treatment groups, with worsening of the lipid profile among patients treated with

olanzapine.

Aripiprazole treatment was not associated with increases in prolactin levels during short- or long-term

studies (in fact, prolactin levels were shown to be slightly decreased by aripiprazole). Patients receiving

aripiprazole treatment also showed decreases in mean QTc interval that were similar to those seen in

patients who were receiving placebo in short-term studies (4.4 msec vs. 3.5 msec), as well as a low

incidence of QTc increase ≥30 msec (aripiprazole: 4.3%; placebo: 5.5%). Aripiprazole was not associated

with significant increases in QTc interval in long-term studies. Aripiprazole treatment was not associated

with adverse changes in glucose or lipid levels during short- or long-term studies.

Overall, aripiprazole treatment is associated with a low incidence of EPS-related symptoms and with

minimal or no effects on weight gain, QTc interval, or circulating levels of cholesterol, glucose, and

prolactin. Treatment with aripiprazole may reduce the burden of antipsychotic-associated side effects,

which is expected to improve patient adherence and reduce the risk of acute relapse.

DRUG–DRUG INTERACTIONS

Aripiprazole is metabolized primarily by the hepatic cytochrome P450 enzymes 2D6 and 3A4, so it has the

potential to interact with other substrates for these enzymes. Inducers of these enzymes may increase

clearance and so lower blood levels of aripiprazole, whereas inhibitors of 3A4 or 2D6 may inhibit

elimination and so increase blood levels of aripiprazole. In vivo studies showed decreased levels of

aripiprazole and dehydroaripiprazole in the plasma when aripiprazole was coadministered with

carbamazepine, a cytochrome P450 3A4 inducer. The aripiprazole dose should therefore be increased

when the drug is administered concomitantly with carbamazepine. In vivo studies coadministering

aripiprazole and ketoconazole (a 3A4 inhibitor) or quinidine (a 2D6 inhibitor) suggest that the aripiprazole

dose should be reduced when aripiprazole is administered with strong 3A4 or 2D6 inhibitors.

Aripiprazole is not a substrate for the cytochrome P450 enzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or

2E1 and so is unlikely to interact with inhibitors or inducers of these enzymes. Specific studies have

demonstrated no clinically important interactions of aripiprazole with famotidine, valproate, lithium,

dextromethorphan, warfarin, or omeprazole. Aripiprazole exhibits 1-adrenergic receptor antagonistPrint: Chapter 31. Aripiprazole

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activity and so may enhance the effects of certain antihypertensive agents.

CONCLUSION

Aripiprazole is a novel antipsychotic agent that combines partial agonist activity at D2 receptors with

partial agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2A receptors. This makes

aripiprazole the first agent that is not a full D2 antagonist to show rapid and sustained antipsychotic

activity, and it may be considered the first partial DA agonist combined with 5-HT-stabilizing properties.

Short-term and long-term clinical trials in adult and pediatric patients with schizophrenia and bipolar I

disorder have demonstrated that aripiprazole combines sustained antipsychotic and mood-stabilizing

efficacy with an excellent safety and tolerability profile. Additional augmentation trials have confirmed the

utility of aripiprazole in alleviating depressive symptomatology in patients with major depressive disorder

who have not achieved adequate symptom relief with antidepressants alone. In general, aripiprazole

treatment is associated with a low liability for EPS, QTc interval prolongation, prolactin elevation, weight

gain, or disturbances of glucose or lipid metabolism. This combination of efficacy, safety, and tolerability

suggests that aripiprazole has the potential to improve treatment adherence and decrease relapse rates

and so represents an important new option for both acute and long-term treatment of schizophrenia and

bipolar I disorder and as an adjunct to antidepressants in major depressive disorder.

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