A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 16-Week Study of Adjunctive Aripiprazole for Schizophrenia or Schizoaffective Disorder Inadequately Treated With Quetiapine or Risperidone Monotherapy
Objective: Combining antipsychotics is common practice in the treatment of schizophrenia. This study investigated aripiprazole adjunctive to risperidone or quetiapine for treating schizophrenia and schizoaffective disorder.
Method: In this multicenter, double-blind, 16-week, placebo-controlled study conducted at 43 American sites from July 2006 to October 2007, patients with chronic, stable schizophrenia or schizoaffective disorder diagnosed with DSM-IV-TR were randomly assigned to receive aripiprazole (2–15 mg/d) or placebo in addition to a stable regimen of quetiapine (400–800 mg/d) or risperidone (4–8 mg/d). The primary outcome measure was the mean change from baseline to endpoint (week 16, last observation carried forward) in the Positive and Negative Syndrome Scale (PANSS) total score.
Results: 323 subjects being treated with either risperidone (n = 177) or quetiapine (n = 146) were randomly assigned to receive adjunctive aripiprazole (n = 168) or placebo (n = 155). Baseline characteristics were similar (mean PANSS total score: aripiprazole, 74.5; placebo, 75.9) except for history of suicide attempts (aripiprazole, 27%; placebo, 40%). Nearly 70% of subjects in each arm completed the trial. Adjunctive aripiprazole and placebo groups were similar in the mean change from baseline to endpoint in the PANSS total score (aripiprazole, –8.8; placebo, –8.9; P = .942). The incidence of treatment-emergent adverse events was similar between groups. Mean changes in Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Rating Scale scores were not statistically significantly different. Adjunctive aripiprazole was associated with statistically significantly greater decreases in mean serum prolactin levels from baseline than was adjunctive placebo (–12.6 ng/mL for aripiprazole vs –2.2 ng/mL for placebo; P < .001), an effect that was seen in the risperidone subgroup (–18.7 ng/mL vs –1.9 ng/mL; P < .001) but not in the quetiapine subgroup (–3.01 ng/mL vs +0.15 ng/mL; P = .104).
Conclusions: The addition of aripiprazole to risperidone or quetiapine was not associated with improvement in psychiatric symptoms but was generally safe and well tolerated. Further research is warranted to explore whether antipsychotic combination therapy offers benefits to particular patient populations—for example, in cases of hyperprolactinemia.
Trial Registration: clinicaltrials.gov Identifier: NCT00325689
J Clin Psychiatry 2009;70(10):1348–1357
© Copyright 2009 Physicians Postgraduate Press, Inc.
Submitted: February 20, 2009; accepted May 21, 2009 (doi:10.4088/JCP.09m05154yel).
Corresponding author: John M. Kane, MD, Department of Psychiatry, The Zucker Hillside Hospital, 75–59 263rd Street, Glen Oaks, NY 11004-1150 (firstname.lastname@example.org).
Whereas combination therapy is standard practice in bipolar disorder1 and necessary for difficult-to-treat major depressive disorder,2 monotherapy is still consistently advocated in schizophrenia.3–5 However, antipsychotic polypharmacy is common practice in schizophrenia treatment, with reported incidences from 13% to 90%.6–10 Polypharmacy is often continued after cross-titration when symptom improvement is seen before the initial antipsychotic treatment is discontinued.
Although the benefits of antipsychotic polypharmacy have not been empirically established,11,12 many clinicians resort to combinations to manage chronic, treatment-resistant illness and to alleviate or prevent the dose-dependent side effects.13 With the increasing availability of pharmacologically novel antipsychotics, the likelihood of antipsychotic polypharmacy may also increase.
The rational use of polypharmacy has been hampered by the lack of systematic research due to difficulties in the design and conduct of combination therapy trials.14 Case studies and small trials have reported benefit with the addition of a second atypical antipsychotic to clozapine.15–18 However, larger placebo-controlled or active-controlled studies of clozapine augmentation in nonresponsive or partially responsive patients have produced mixed results, with 1 positive trial of amisulpride augmentation19 and both positive20 and negative21–23 trials with risperidone augmentation reported to date. Thus, further research is needed to establish fully any benefits of antipsychotic polypharmacy, especially for atypical antipsychotics with newer pharmacologic profiles, and for combinations that do not include clozapine, which by far predominate in clinical practice.
Aripiprazole is a second-generation antipsychotic that has been shown to be efficacious in patients with schizophrenia.24–26 The rationale for using aripiprazole as an adjunctive agent relates to its distinct pharmacologic profile; aripiprazole has potent partial-agonist activity at the dopamine D2 and D3 receptors27–29 and serotonin-1A (5-HT1A)30,31 receptors, as well as antagonism of 5-HT2 receptors.32 Combining clozapine and aripiprazole was effective and tolerable in numerous case reports and open-label studies (see the Englisch and Zink review33). Furthermore, controlled trials have shown favorable improvement in negative symptoms34 and significant benefits in weight and metabolic parameters.35 Although other combinations are also justifiable, a rationale exists for adjunctive use of aripiprazole with risperidone or quetiapine. Aripiprazole has much higher affinity for D2, 5-HT1A, and 5-HT2A receptors than does quetiapine,27,28 potentially increasing mesolimbic D2 occupancy, thus increasing control of positive symptoms without the risk of histamine receptor H1–related and muscarinic receptor M1–related side effects that may limit higher quetiapine dosing, and improving depressive, cognitive, and negative symptoms. Adjunctive aripiprazole with risperidone may optimize D2 receptor activity and hence diminish risk for extrapyramidal symptoms associated with risperidone36 and decrease prolactin elevation resulting from high D2 receptor occupancy by the full antagonist.37 Thus, adjunctive aripiprazole may have potential benefits for efficacy and for amelioration of side effects that occur with monotherapy. To test this hypothesis, we undertook a controlled, prospective study to investigate the efficacy, safety, and tolerability of aripiprazole versus placebo as adjunctive therapy to a stable regimen of either risperidone or quetiapine monotherapy in patients with schizophrenia or schizoaffective disorder who did not fully respond to risperidone or quetiapine.
This was a randomized, double-blind, placebo-controlled, 16-week adjunctive therapy study consisting of a screening/washout phase (4–7 days), followed by a 16-week, double-blind treatment phase in which patients received either adjunctive aripiprazole or placebo with quetiapine or risperidone. Outpatients with chronic, stable schizophrenia or schizoaffective disorder, defined by the DSM-IV-TR,38 who had an inadequate response to a stable dose of either quetiapine or risperidone, per investigator judgment, were enrolled. The trial was undertaken at 43 American sites from July 2006 to October 2007, and in accordance with the Declaration of Helsinki, the International Conference on Good Clinical Practice, and local regulatory requirements. Written informed consent was obtained from all patients.
Outpatients of either gender, aged ≥ 18 years with chronic, stable schizophrenia or schizoaffective disorder and currently receiving a stable dose of quetiapine (400–800 mg/d) or risperidone (4–8 mg/d) for ≥ 4 weeks but with an inadequate response, were entered. To be considered stable, the patient must not have shown significant improvement or worsening of symptoms within 1 month of screening. Inadequate response was primarily defined by investigators’ judgment as a Clinical Global Impressions-Severity of Illness scale (CGI-S)39 score of 4 to 6, and patients had to have shown previous antipsychotic responsiveness (except with clozapine) in the past 12 months. Women of childbearing potential (not pregnant or breastfeeding) were permitted if they had a negative pregnancy test within 72 hours prestudy and were using contraception. Exclusion criteria included (1) a history of clozapine failure, (2) hospitalization due to their psychiatric illness in the past 3 months, (3) first episode of schizophrenia or schizoaffective disorder within the past year, (4) acute depression during the past month, (5) previous participation in a trial within the past month or any aripiprazole clinical trial, (6) suicidal ideation, (7) substance abuse/dependence, or (8) a history of seizure disorder. Patients were also ineligible if they had any medically significant abnormal laboratory test or vital sign or any medical condition that could interfere with assessments or expose them to unnecessary risk.
Eligible patients must have received a stable dose of either quetiapine (400–800 mg/d) or risperidone (4–8 mg/d) for ≥ 4 weeks. Upon entry into the double-blind, dual-therapy phase, patients were stratified by current medication and randomly assigned to either adjunctive aripiprazole or placebo in a 1:1 ratio. Adjunctive aripiprazole was initiated at 5 mg/d with an option to decrease to a minimum of 2 mg/d (before week 2) if required for tolerability. By the end of week 2, an increase in dosage up to 10 mg/d was permitted, with a maximum of 15 mg/d allowed by the end of week 6. A 1-step reduction was allowed for tolerability between the end of weeks 2 and 8, and patients were subsequently discontinued if the lower dose was not tolerated. After the end of week 8, no dose changes were allowed. The target dose of aripiprazole was 10 mg/d (maximum, 15 mg/d). Concomitant medications, including the majority of antidepressants (only fluoxetine and paroxetine were not allowed); anticholinergics; mood stabilizers, including anticonvulsants (carbamazepine was not allowed); and benzodiazepines were permitted if patients had been receiving a regular dose for ≥ 4 weeks prior to study entry. New benzodiazepine use up to the maximum daily dose per package insert was permitted to manage treatment-emergent agitation or anxiety. Efficacy or safety rating-scale assessments were not conducted if benzodiazepines had been taken within 8 hours.
The primary efficacy endpoint was the mean change from baseline to endpoint (week 16, last observation carried forward [LOCF]) in the Positive and Negative Syndrome Scale (PANSS)40 total score. The key secondary endpoint was the mean change in the CGI-S score. Further secondary measurements were the mean change from baseline to endpoint in the scores of the following scales: the PANSS positive and negative subscales, the Calgary Depression Scale for Schizophrenia (CDSS),41 the Arizona Sexual Experience Scale (ASEX),42 the Fatigue Symptom Inventory (FSI),43 the Brief Assessment of Cognition in Schizophrenia (BACS),44 and the Subjective Well-Being under Neuroleptics (SWN)45 scale. The mean scores at endpoint for the Clinical Global Impressions-Improvement scale (CGI-I)39 and the Investigator’s Assessment Questionnaire (IAQ)46 total score were also assessed. The percentage of responders in each treatment group (defined as a decrease from baseline in PANSS total score ≥ 20% or a CGI-I score of 1 or 2) was also calculated. Assessments with the PANSS and CDSS were carried out on day 1 and weeks 2, 4, 8, 12, and 16 (or early termination point). The CGI-I assessment was conducted at weeks 2, 4, 6, 8, 12, and 16, while the CGI-S was also done at screening and day 1. The ASEX assessments were carried out on day 1 and week 16 or early termination point. The FSI was performed at day 1 and weeks 2, 6, 12, and 16. The SWN measurements were taken at day 1 and weeks 2, 8, and 16. The IAQ assessment was conducted at weeks 2, 4, 8, and 16.
Safety assessments included recording of adverse events (at day 1 and weeks 2, 4, 6, 8, 12, and 16 or early termination), physical examination (at screening and week 16 or early termination), measurements of vital signs (at screening, day 1, and weeks 2, 4, 6, 8, 12, and 16 or early termination), and laboratory tests (at screening and week 16 or early termination). Changes from baseline to week 16 in body weight, fasting glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, fasting triglycerides, and prolactin were monitored. Abnormal metabolic laboratory parameters were defined as follows: fasting glucose ≥ 100 mg/dL, total cholesterol ≥ 240 mg/dL, HDL cholesterol < 40 mg/dL, LDL cholesterol ≥ 160 mg/dL, and fasting triglycerides ≥ 150 mg/dL. The percentage of patients gaining ≥ 7% of baseline body weight was also assessed. The mean changes from baseline to week 16 for the Simpson-Angus Scale,47 Abnormal Involuntary Movement Scale (AIMS),48 and Barnes Akathisia Rating Scale (BARS)49 scores were also measured. The Simpson-Angus Scale was measured at day 1 and weeks 4, 8, and 16; the AIMS was evaluated at day 1 and week 16; and the BARS was assessed at day 1 and weeks 2, 4, 8, and 16.
Analyses for efficacy and safety were also conducted for the quetiapine and risperidone subgroups, as well as for patients with schizophrenia only and schizoaffective disorder only.
The sample size calculation was from nQuery Advisor, version 6.0 (STATCON, Witzenhausen, Germany), using the 2 means comparison method. It was anticipated that 338 patients would be randomly assigned and that 90% would be evaluable, 152 per arm, giving 90% power to differentiate between aripiprazole and placebo (plus atypical antipsychotic) when the true difference on the primary endpoint is 6, which assumes a standard deviation of 16 with a 2-sided t test at the level of .05 significance.
Safety summaries included all randomly assigned patients who took at least 1 treatment dose. The aripiprazole safety sample, however, included 1 patient randomly assigned to placebo who received aripiprazole. Efficacy analyses included all safety-sample patients who had at least 1 postrandomization efficacy evaluation. The LOCF data set was used for all analyses unless stated otherwise.
The primary endpoint—mean change from baseline to endpoint (week 16, LOCF) in the PANSS total score—was analyzed by analysis of covariance, with treatment as main effect, controlling for baseline PANSS total score, study center, and open-label medication status for the pooled data set (both quetiapine and risperidone open-label medication groups).
The mean changes in PANSS total score, CGI-S score, SWN score, total IAQ score, and safety endpoints that are continuous variables were analyzed using analysis of covariance or analysis of variance. Unless otherwise specified, categorical variables were analyzed by the Cochran-Mantel-Haenszel test. The time-to-event endpoints were analyzed using the log rank test to test the null hypothesis of identical survival function between 2 treatments. The P values for comparisons of aripiprazole and placebo were 2-tailed, using the 5% significance level.
Patient Disposition and Demographics
In total, 323 patients were randomly assigned to adjunctive aripiprazole (n = 168) or placebo (n = 155), and the distribution of patients currently receiving either quetiapine (n = 78 for aripiprazole vs n = 68 for placebo) or risperidone (n = 90 for aripiprazole vs n = 87 for placebo) was similar (Figure 1). Completion rates were similar, with 68.5% of aripiprazole-treated patients (n = 115) and 69.0% of placebo-treated patients (n = 107) remaining at week 16. There was no difference in the time to discontinuation between adjunctive aripiprazole and placebo (hazard ratio [HR] = 1.01; P = .948), irrespective of whether the initial antipsychotic was quetiapine or risperidone. The reasons for study discontinuation were the following (adjunctive aripiprazole vs placebo): adverse event (5.4% vs 10.3%); subject withdrew consent (8.9% vs 5.8%); subject was lost to follow-up (7.1% vs 7.7%); poor/noncompliance (7.1% vs 3.2%); other reasons (2.4% vs 3.9%); and lack of efficacy (0.6% vs 0%) (Figure 1).
Click figure to enlarge
Click figure to enlarge
Patient demographics are displayed in Table 1. Overall, the mean age was 44 years, and the majority of the population were male (61.3%), black/African American (53.3%), and diagnosed with schizophrenia (78.0%). The mean PANSS total score at baseline was 75.
At baseline, the percentage of patients with abnormal metabolic laboratory parameters was high—and similar between aripiprazole and placebo (fasting total cholesterol, 7.7% vs 7.8%; HDL cholesterol, 32.5% vs 22.2%; fasting triglycerides, 26.6% vs 28.1%; fasting glucose, 25.4% vs 26.8%; LDL cholesterol, 7.7% vs 6.5%; safety sample). Baseline mean body mass index (BMI [kg/m2]) values were similar between groups (aripiprazole, 31.8 vs placebo, 31.1), and a similar proportion of patients in each group had BMI values in the overweight (BMI 25–30: aripiprazole, 31.7% vs placebo, 25.2%) or obese (BMI ≥ 30: aripiprazole, 48.8% vs placebo, 50.3%) categories at baseline (efficacy sample). Similar baseline values were seen in the atypical antipsychotic subgroups.
Treatment and Dosing
The mean dose of aripiprazole at endpoint was 10.3 mg/d and was similar between those receiving adjunctive quetiapine (10.2 mg/d) and risperidone (10.4 mg/d). The mean dose of quetiapine at endpoint was 516 mg/d and 513 mg/d for the placebo and aripiprazole arms, respectively. The mean dose of risperidone at endpoint was 4.8 mg/d and 4.6 mg/d for the placebo and aripiprazole arms, respectively. Mean doses of both quetiapine and risperidone are consistent with the current recommendations in the product labels.
Click figure to enlarge
There was no difference in the mean change from baseline to week 16 in PANSS total score between the adjunctive aripiprazole and placebo groups (–8.8 vs –8.9; F1,269 = 0.01, P = .942; LOCF) (Figure 2). When we compared the data by antipsychotic subgroup (quetiapine or risperidone), no significant differences were seen in the change of PANSS total score at week 16 between aripiprazole and placebo.
Click figure to enlarge
Table 2 summarizes the secondary efficacy results. There were no significant between-group differences in mean change from baseline in CGI-S scores, PANSS positive or negative scores, SWN scores, or mean CGI-I score. Both groups showed improvements in CDSS scores, although the difference between groups was not significant. Response rates were also similar between treatments (aripiprazole, 41.3% vs placebo, 40.7%; χ21 = 0.053, P = .818), as were mean IAQ scores at study endpoint (aripiprazole, 27.2 vs placebo, 27.5; F1,170 = 0.36, P = .55).
There was no difference in the mean change from baseline to week 16 in ASEX total scores between adjunctive aripiprazole and placebo groups (0.2 vs –0.4; F1,212 = 1.20, P = .275; observed cases). Both groups experienced similar mean improvement from baseline in FSI items using the “most fatigued days” scales (aripiprazole, –0.6 vs placebo, –0.6; F1,269 = 0.05, P = .819; LOCF) and FSI interference total score (aripiprazole, –1.4 vs placebo, –2.2; F1,269 = 0.21, P = .650; LOCF). Mean changes from baseline to week 16 in the BACS Z-score (calculated from BACS standardized composite score) and individual subtests are shown in Table 3 for the total population and by antipsychotic subgroup (quetiapine or risperidone). There were no significant differences between the adjunctive aripiprazole and placebo groups in either Z-scores or individual test scores for either the total population or individual atypical subgroups.
Click figure to enlarge
Subgroup analysis revealed that improvement in mean PANSS total scores with aripiprazole versus placebo was greater in patients with schizoaffective disorder (–13.6 vs –8.1; treatment difference, –5.5; P = .145) than in those with schizophrenia (–7.3 vs –8.5; treatment difference, 1.2; P = .505), although not statistically significant.
Click figure to enlarge
Safety and Metabolic Parameters
Adverse events occurring in ≥ 5% of either the adjunctive aripiprazole or placebo group are displayed in Table 4. The 3 most common adverse events with adjunctive aripiprazole were fatigue (8.3%), headache (7.1%), and insomnia (6.5%), and the 3 most common with adjunctive placebo were headache (8.5%), insomnia (8.5%), and akathisia (7.2%). Fewer patients had serious treatment-emergent adverse events with adjunctive aripiprazole than with placebo (4.7% vs 12.4%). The most frequently reported serious adverse events were psychiatric disorders (aripiprazole, n = 2 [1.2%]; placebo, n = 15 [9.8%]): in the aripiprazole group, these were 1 case of agitation and 1 of psychotic disorder; in the placebo group, there were 7 reports of psychotic disorder, 5 reports of suicidal ideation, and 1 report each for depression, hallucinations, homicidal ideation, paranoia, self-injurious behavior, and suicide attempt. No deaths were reported.
Click figure to enlarge
Extrapyramidal symptom–related events were reported by 8.3% of adjunctive aripiprazole–treated and 12.4% of adjunctive placebo–treated patients. Akathisia was reported in 5.9% of adjunctive aripiprazole–treated and 7.2% of adjunctive placebo–treated patients. Minimal, nonsignificant changes from baseline to endpoint in the AIMS total score and the BARS akathisia global clinical assessment were seen with adjunctive aripiprazole and placebo (Figure 3). There was also no difference in the mean decreases in the Simpson-Angus total scores between adjunctive aripiprazole and placebo (Figure 3).
Click figure to enlarge
There were no significant differences in median changes from baseline to week 16 in fasting glucose, total cholesterol, fasting triglycerides, LDL cholesterol, or HDL cholesterol between treatment groups (Table 5). Most patients in both treatment groups experienced no change in metabolic parameters during 16 weeks of treatment (aripiprazole vs placebo: fasting total cholesterol, 91.3% vs 91.7%; HDL cholesterol, 85.2% vs 80.3%; LDL cholesterol, 92.0% vs 89.4%; fasting triglycerides, 75.2% vs 77.3%; fasting glucose, 77.2% vs 66.7%). The percentage of patients experiencing improvement (abnormal at baseline and normal at week 16) or worsening (normal at baseline and abnormal at week 16) of metabolic parameters during treatment is shown in Figure 4A and 4B, respectively.
Click figure to enlarge
Click figure to enlarge
Mean weight change was similar between subjects receiving adjunctive aripiprazole and adjunctive placebo (1.3 kg vs 1.1 kg, respectively; P = .728); clinically relevant weight gain (≥ 7% gain from baseline) was observed at any time in 13.4% of patients in the adjunctive aripiprazole group and in 9.9% of patients in the adjunctive placebo group (P = .445).
Analysis of mean serum prolactin levels showed that adjunctive aripiprazole was associated with a statistically significant decrease from baseline in serum prolactin levels in comparison with adjunctive placebo (–12.6 ng/mL vs –2.2 ng/mL; P < .001; LOCF) (Figure 5). Subgroup analysis showed that mean serum prolactin levels were also significantly decreased with adjunctive aripiprazole compared to adjunctive placebo in the risperidone subgroup (–18.7 ng/mL vs –1.9 ng/mL; P < .001) but not in the quetiapine subgroup (–3.01 ng/mL vs + 0.15 ng/mL; P = .104) at endpoint. More adjunctive aripiprazole patients than adjunctive placebo patients with abnormal prolactin levels at baseline had normal prolactin levels at week 16 (19.5% vs 9.1%).
In this multicenter, randomized, double-blind, placebo-controlled trial, the addition of aripiprazole to either quetiapine or risperidone was not associated with a greater improvement in schizophrenia symptoms, as measured by PANSS total score, versus placebo. Patients in both groups had a similar decrease in PANSS scores; the majority of improvement occurred during the first 4 weeks, with a subsequent plateau from weeks 8 to 16. Decreases in the PANSS were moderate but should be considered in the context of the relatively low mean baseline score of 75. The changes in secondary outcome measures were also comparable between groups. Aripiprazole added to quetiapine or risperidone was not associated with worsening of schizophrenia symptoms; in fact, there were 7 cases of psychosis exacerbation with antipsychotic monotherapy versus only 1 case with aripiprazole adjunctive to risperidone or quetiapine.
In general, aripiprazole added to quetiapine or risperidone was not associated with increases in side effects (including akathisia). There was a greater decrease in prolactin levels with aripiprazole than with placebo, driven by the decreases in the risperidone subgroup. Similar reductions in prolactin levels were seen following adjunctive use of aripiprazole in haloperidol-treated patients with hyperprolactinemia.37 Importantly, there was no worsening of metabolic parameters following the addition of aripiprazole, and potential improvements are possible and warrant further investigation. Physical health issues are of high clinical relevance due to their associated cardiovascular morbidity and mortality, which improve following reduction of lipid levels.50 Previous studies have shown some beneficial effects on lipid levels in aripiprazole augmentation of clozapine.34,35,51
This study is the largest double-blind, placebo-controlled, randomized study to date evaluating the effects of combining 2 atypical antipsychotics. It has addressed a key research question in schizophrenia—namely, the value of antipsychotic polypharmacy as a therapeutic strategy. Although this strategy is common in clinical practice, few studies with rigorous design have evaluated the outcomes of antipsychotic polypharmacy; the majority of studies undertaken used very small patient populations and produced conflicting data.12,15–18,20–22
Despite a prospective, randomized design, some methodological issues may have impacted the results; specifically, there was no requirement for a minimum baseline PANSS total score. Thus, the potential existed to enroll patients who were mildly symptomatic and not reflective of the patients who would most need combination therapy in real-life practice. Additionally, the lack of a prospective treatment phase to assess response to either quetiapine or risperidone means that we cannot be certain of the stability of patients’ symptoms, treatment compliance, or adequate duration of treatment before entering the study.
Patients entering randomized treatment may not have been truly nonresponsive to previous medication. This possibility is supported by the large improvement in the adjunctive placebo group, which suggests that patients entering the study may not have been on a stable dose of their current antipsychotic long enough to have exhausted the benefits of the initial antipsychotic. It is also possible that some degree of expectancy bias influenced the ratings. Finally, the aripiprazole doses used may have been too low. If so, this may have had a major impact on efficacy; however, it is unclear whether increased doses of aripiprazole would have resulted in a switching effect.
This study failed to demonstrate that augmentation with aripiprazole 2–15 mg/d offers statistically significant improvement in psychiatric symptoms compared with placebo in patients with schizophrenia showing suboptimal response to quetiapine or risperidone monotherapy. However, aripiprazole augmentation was generally well tolerated. Adjunctive aripiprazole therapy may be beneficial for some patients by decreasing prolactin or triglycerides, although these findings need to be corroborated. Further studies to help elucidate the potential benefits and risks of various antipsychotic and nonantipsychotic augmentation strategies are needed. Subsequent studies should carefully establish the parameters of prior monotherapy treatment and response to maximize power to detect effects of the augmenting agent.
Drug names: aripiprazole (Abilify), carbamazepine (Carbatrol, Equetro, and others), clozapine (FazaClo, Clozaril, and others), fluoxetine (Prozac and others), paroxetine (Paxil, Pexeva, and others), quetiapine (Seroquel), risperidone (Risperdal and others).
Author affiliations: Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, New York (Drs Kane and Correll); Department of Psychiatry, Massachusetts General Hospital, and Harvard Medical School, Boston (Dr Goff); Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta (Dr Kirkpatrick); Semel Institute of Neuroscience, University of California, Los Angeles (Dr Marder); Bristol-Myers Squibb, Paris, France (Dr Vester-Blokland); Bristol-Myers Squibb, Plainsboro, New Jersey (Drs Sun and Assunção-Talbott); Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, New Jersey (Dr Carson); and Otsuka America Pharmaceutical, Inc, Rockville, Maryland (Dr Pikalov). Dr Assunção-Talbott is a former employee of Bristol-Myers Squibb, Plainsboro, New Jersey, and was employed there during this study.
Financial disclosure: Dr Kane has provided consultancy services and has participated in advisory boards for Abbott, Bristol-Myers Squibb, Otsuka, Eli Lilly, Janssen, Johnson & Johnson Pharmaceutical Research & Development, Pfizer, Wyeth, Lundbeck, Vanda, AstraZeneca, and PGxHealth and has received honoraria from or been a member of the speakers bureaus of Bristol-Myers Squibb, Janssen, Otsuka, and AstraZeneca. Dr Correll has been a consultant or data and safety monitoring board member for or has received honoraria from AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Ortho-McNeil-Janssen/Johnson & Johnson, Otsuka, Pfizer, Supernus, and Vanda and has served on the speakers/advisory boards of AstraZeneca, Bristol-Myers Squibb/Otsuka, Pfizer, and Vanda. Dr Goff has been a consultant for Eli Lilly and Indevus; has received grant/research support from Bristol-Myers Squibb, Cephalon, GlaxoSmithKline, Janssen, Novartis, and Pfizer; has received honoraria from Bristol-Myers Squibb, Eli Lilly, Forest, Indevus, Janssen, and Pfizer; has served on the speakers/advisory boards of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Merck, Organon, Pfizer, Proteus, Vanda, and Xytis; and has served on data and safety monitoring boards for Wyeth and Pfizer. Dr Kirkpatrick has received consulting and advisory board fees from Cephalon, Pfizer, Bristol-Myers Squibb, Organon, Wyeth, AstraZeneca, and Solvay. Dr Marder has been a consultant for Bristol-Myers Squibb, Otsuka, Wyeth, Roche, GlaxoSmithKline, and Pfizer; has received honoraria from Bristol-Myers Squibb, Otsuka, and Solvay; has served on the advisory boards of Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Wyeth, Abbott, and Cephalon; and has served on data and safety monitoring boards for Wyeth and Acadia. Dr Vester-Blokland is an employee and stock shareholder of Bristol-Myers Squibb. Dr Assunção-Talbott is a former employee and stock shareholder of Bristol-Myers Squibb and was employed by Bristol-Myers Squibb at the time of the study. Drs Sun, Carson, and Pikalov report no additional financial or other relationships relevant to the subject of this article.
Funding/support: This work was supported by Bristol-Myers Squibb, Princeton, New Jersey, and Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan. Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld and funded by Bristol-Myers Squibb.
Previous presentation: Presented at the 1st Schizophrenia International Research Society Conference, June 21–25, 2008, Venice, Italy.
1. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Bipolar Disorder [Revision]. Am J Psychiatry. 2002;159(suppl 4):1–50. doi:10.1176/appi.ajp.159.1.1
2. Ng F, Dodd S, Berk M. Combination pharmacotherapy in unipolar depression. Expert Rev Neurother. 2006;6(7):1049–1060. doi:10.1586/1473722.214.171.1249 PubMed
3. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia, Second Edition. Am J Psychiatry. 2004;161(suppl 2):1–56. PubMed
4. Miller AL, Chiles JA, Chiles JK, et al. The Texas Medication Algorithm Project (TMAP) schizophrenia algorithms. J Clin Psychiatry. 1999;60(10):649–657. PubMed
5. National Institute for Health and Clinical Excellence. The clinical effectiveness and cost effectiveness of newer atypical antipsychotic drugs for schizophrenia [NICE guidance]. http://www.nice.org.uk/cat.asp?c=32878; 2002.
6. Faries D, Ascher-Svanum H, Zhu B, et al. Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics. BMC Psychiatry. 2005;5:26. doi:10.1186/1471-244X-5-26 PubMed
7. Keks NA, Altson K, Hope J, et al. Use of antipsychosis and adjunctive medications by an inner urban community psychiatric service. Aust N Z J Psychiatry. 1999;33(6):896–901. doi:10.1046/j.1440-1614.1999.00639.x PubMed
8. Broekema WJ, de Groot IW, van Harten PN. Simultaneous prescribing of atypical antipsychotics, conventional antipsychotics and anticholinergics—a European study. Pharm World Sci. 2007;29(3):126–130. doi:10.1007/s11096-006-9063-1 PubMed
9. Ito C, Kubota Y, Sato M. A prospective survey on drug choice for prescriptions for admitted patients with schizophrenia. Psychiatry Clin Neurosci. 1999;53(suppl):S35–S40. PubMed
10. Rupnow MF, Greenspan A, Gharabawi GM, et al. Incidence and costs of polypharmacy: data from a randomized, double-blind, placebo-controlled study of risperidone and quetiapine in patients with schizophrenia or schizoaffective disorder. Curr Med Res Opin. 2007;23(11):2815–2822. doi:10.1185/030079907X233359 PubMed
11. Miller AL, Craig CS. Combination antipsychotics: pros, cons, and questions. Schizophr Bull. 2002;28(1):105–109. PubMed
12. Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009;35(2):443–457. doi:10.1093/schbul/sbn018 PubMed
13. Miller AL. Polypharmacy in schizophrenia: science, art, and fiction. Curr Psychosis & Ther Rep. 2005;3(2):61–67. doi:10.1007/BF02629423
14. Correll CU. Antipsychotic polypharmacy, part 2: why use 2 antipsychotics when 1 is not good enough? J Clin Psychiatry. 2008;69(5):860–861. PubMed
15. Gupta S, Sonnenberg SJ, Frank B. Olanzapine augmentation of clozapine. Ann Clin Psychiatry. 1998;10(3):113–115. PubMed
16. Henderson DC, Goff DC. Risperidone as an adjunct to clozapine therapy in chronic schizophrenics. J Clin Psychiatry. 1996;57(9):395–397. PubMed
17. Morera AL, Barreiro P, Cano-Munoz JL. Risperidone and clozapine combination for the treatment of refractory schizophrenia. Acta Psychiatr Scand. 1999;99(4):305–306 [discussion 306–307]. doi:10.1111/j.1600-0447.1999.tb07230.x PubMed
18. Raskin S, Katz G, Zislin Z, et al. Clozapine and risperidone: combination/augmentation treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatr Scand. 2000;101(4):334–336. PubMed
19. Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled study. Br J Psychiatry. 1997;171:569–573. doi:10.1192/bjp.171.6.569 PubMed
20. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005;162(1):130–136. doi:10.1176/appi.ajp.162.1.130 PubMed
21. Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006;354(5):472–482. doi:10.1056/NEJMoa053222 PubMed
22. Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry. 2005;66(1):63–72. PubMed
23. Freudenreich O, Henderson DC, Walsh JP, et al. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial. Schizophr Res. 2007;92(1–3):90–94. doi:10.1016/j.schres.2006.12.030 PubMed
24. Tandon R, Marcus RN, Stock EG, et al. A prospective, multicenter, randomized, parallel-group, open-label study of aripiprazole in the management of patients with schizophrenia or schizoaffective disorder in general psychiatric practice: Broad Effectiveness Trial With Aripiprazole (BETA). Schizophr Res. 2006;84(1):77–89. doi:10.1016/j.schres.2005.12.857 PubMed
25. Wolf J, Janssen F, Lublin H, et al. A prospective, multicentre, open-label study of aripiprazole in the management of patients with schizophrenia in psychiatric practice in Europe: Broad Effectiveness Trial With Aripiprazole in Europe (EU-BETA). Curr Med Res Opin. 2007;23(10):2313–2323. doi:10.1185/030079907X225448 PubMed
26. Kerwin R, Millet B, Herman E, et al. A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic patients: Schizophrenia Trial of Aripiprazole (STAR) Study. Eur Psychiatry. 2007;22(7):433–443. doi:10.1016/j.eurpsy.2007.03.002 PubMed
27. Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302(1):381–389. doi:10.1124/jpet.102.033175 PubMed
28. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400–1411. doi:10.1038/sj.npp.1300203 PubMed
29. Tadori Y, Forbes RA, McQuade RD, et al. Characterization of aripiprazole partial agonist activity at human dopamine D(3) receptors. Eur J Pharmacol. 2008;597(1–3):27–33. doi:10.1016/j.ejphar.2008.09.008 PubMed
30. Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT(1A) receptor. Eur J Pharmacol. 2002;441(3):137–140. doi:10.1016/S0014-2999(02)01532-7 PubMed
31. Hirose T, Uwahodo Y, Yamada S, et al. Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile. J Psychopharmacol. 2004;18(3):375–383. doi:10.1177/026988110401800308 PubMed
32. Jordan S, Koprivica V, Dunn R, et al. In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function. Eur J Pharmacol. 2004;483(1):45–53. doi:10.1016/j.ejphar.2003.10.025 PubMed
33. Englisch S, Zink M. Combined antipsychotic treatment involving clozapine and aripiprazole. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(6):1386–1392. doi:10.1016/j.pnpbp.2008.02.010 PubMed
34. Chang JS, Ahn YM, Park HJ, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69(5):720–731. PubMed
35. Fleischhacker WW, Heikkinen ME, Olié JP, et al. Weight change on aripiprazole-clozapine combination in schizophrenic patients with weight gain and suboptimal response on clozapine: 16-week double-blind study. Eur Psychiatry. 2008;23(suppl 2):S114–S115. doi:10.1016/j.eurpsy.2008.01.784
36. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825–835. PubMed
37. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007;164(9):1404–1410. doi:10.1176/appi.ajp.2007.06071075 PubMed
38. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000:345–428.
39. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Dept Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health; 1976:218–222.
40. Kay SR, Opler LA, Fizbein A. The Positive and Negative Syndrome Scale (PANSS) Manual. North Tonawanda, NY: Multi-Health System; 1986.
41. Addington D, Addington J, Maticka-Tyndale E, et al. Reliability and validity of a depression rating scale for schizophrenics. Schizophr Res. 1992;6(3):201–208. PubMed doi:10.1016/0920-9964(92)90003-N
42. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther. 2000;26(1):25–40. PubMed doi:10.1080/009262300278623
43. Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: further validation of the Fatigue Symptom Inventory. Qual Life Res. 2000;9(7):847–854. PubMed doi:10.1023/A:1008900413113
44. Keefe RS, Goldberg TE, Harvey PD, et al. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68(2–3):283–297. PubMed doi:10.1016/j.schres.2003.09.011
45. Naber D. A self-rating to measure subjective effects of neuroleptic drugs, relationships to objective psychopathology, quality of life, compliance and other clinical variables. Int Clin Psychopharmacol. 1995;10(suppl 3):133–138. PubMed doi:10.1097/00004850-199509000-00017
46. Tandon R, Devellis RF, Han J, et al. IAQ Validation Study Group. Validation of the Investigator’s Assessment Questionnaire, a new clinical tool for relative assessment of response to antipsychotics in patients with schizophrenia and schizoaffective disorder. Psychiatry Res. 2005;136(2–3):211–221. PubMed doi:10.1016/j.psychres.2005.05.006
47. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;45(suppl 212):11–19. doi:10.1111/j.1600-0447.1970.tb02066.x
48. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Dept Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health; 1976:534–537.
49. Barnes TR. The Barnes Akathisia Rating Scale–revisited. J Psychopharmacol. 2003;17(4):365–370. PubMed doi:10.1177/0269881103174013
50. Kane JM, Barrett EJ, Casey DE, et al. Metabolic effects of treatment with atypical antipsychotics. J Clin Psychiatry. 2004;65(11):1447–1455. PubMed
51. Henderson DC, Kunkel L, Nguyen DD, et al. An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand. 2006;113(2):142–147. doi:10.1111/j.1600-0447.2005.00612.x PubMed