ARIPIPRAZOLE IS A novel antipsychotic with a

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1 Psychiatry and Clinical Neurosciences 2009; 63: doi: /j x Regular Article Long-term efficacy and safety of aripiprazole in patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder: 26-week prospective study Jun Soo Kwon, MD, PhD, 1,2 * Joon Hwan Jang, MD, 1 Do-Hyung Kang, MD, 1 So Young Yoo, MD, 3 Yong Ku Kim, MD, PhD, 4 Seong-Jin Cho, MD, PhD 3 and the APLUS study group 1 Department of Psychiatry, Seoul National University College of Medicine, 2 BK 21 Human Life Science, Seoul National University College of Medicine, Seoul, 3 Department of Psychiatry, Gil Medical Center, Gachon Medical School, Incheon and 4 Department of Psychiatry, Korea University Ansan Hospital, College of Medicine, Ansan, Korea Aims: To date there have been no reports of longterm efficacy of aripiprazole in Asian populations. The aim of the present study was therefore to investigate the long-term efficacy, safety and tolerability of aripiprazole in a large number of patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder in Korea. Methods: This study was a prospective, multicenter, single-group, 26-week open study of patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. A total of 300 Korean patients participated in the study. The primary efficacy measure was the Positive and Negative Syndrome Scale (PANSS) total score, and secondary efficacy measures included the PANSS positive and negative subscales, Clinical Global Impression Severity of Illness (CGI-S). Tolerability and safety were assessed by monitoring the frequency and severity of treatmentemergent adverse events, extrapyramidal symptoms (EPS), vital signs, weight, and laboratory tests. Results: Aripiprazole produced rapid and significant improvements on all efficacy measures. As evidenced by PANSS total score, PANSS positive subscales and the CGI-S scores, first-episode drug-naïve patients demonstrated significantly greater efficacy relative to patients who had previously experienced one or more episodes of relapse. Aripiprazole was associated with significant decrease of serum prolactin level. The subjects showed mild weight gain. Conclusion: Aripiprazole is an effective antipsychotic in the long-term treatment of both positive and negative symptoms. This study extends the findings of previous long-term studies, and has found that there is no significant difference with regard to ethnicity in response to aripiprazole. Key words: aripiprazole, efficacy, long-term treatment, safety, schizophrenia. ARIPIPRAZOLE IS A novel antipsychotic with a unique mechanism of action that differs from previous antipsychotics. 1,2 Most antipsychotic agents *Correspondence: Jun Soo Kwon, MD, PhD, Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-no, Chongno-gu, Seoul, Korea kwonjs@plaza.snu.ac.kr Received 18 February 2008; revised 9 September 2008; accepted 22 September that are currently used are dopamine D 2 receptor antagonists. Blockade of dopamine receptors in the mesolimbic pathway is thought to mediate antipsychotic efficacy, especially the ability to decrease positive symptoms. Conventional antipsychotics, however, which are thought to function primarily through D 2 antagonism, are thought to be comparatively less effective for the treatment of negative and cognitive symptoms. In addition, conventional antipsychotics are also associated with higher adverse 73

2 74 J. S. Kwon et al. Psychiatry and Clinical Neurosciences 2009; 63: event burden, particularly extrapyramidal symptoms (EPS) and risk of tardive dyskinesia. Development and approval of atypical (or second-generation) antipsychotics have markedly improved the standard of pharmacotherapy options for the treatment of patients with schizophrenia. 3 Atypical agents have demonstrated efficacy against both positive and negative symptoms and have lower risk of adverse events such as EPS, which are associated with decreased patient adherence, and subsequent risk of relapse. 4 6 Aripiprazole is a dopamine D 2 receptor partial agonist with partial agonistic activity at serotonin 5-HT 1A receptors and antagonistic activity at 5-HT 2A receptors. 1,2 The dopamine hypothesis of schizophrenia postulates that a subcortical excess of dopamine is associated with positive symptoms, while a deficit of dopamine in the cortex is thought to give rise to negative or cognitive symptoms. The D 2 partial agonist can act as a functional antagonist in dopamine-rich environments, such as the mesolimbic pathway, whereas relative agonist activity is more prominent in dopamine-depleted environments, 7 as in the proposed hypoactive mesocortical input to areas of the cortex that integrate processes of higher functioning. This dopamine stabilization effect of aripiprazole may alleviate side-effects caused by the excessive blockade of dopamine receptors. There have been a few clinical studies demonstrating the efficacy of aripiprazole in the acute treatment 8,9 and long-term maintenance of patients with schizophrenia. 10,11 In a 4-week randomized study comparing aripiprazole and risperidone in patients with schizophrenia and schizoaffective disorder, 9 aripiprazole (20 mg/day, 30 mg/day) and risperidone (6 mg/day) both produced antipsychotic effects, and aripiprazole demonstrated more rapid onset of efficacy for negative symptoms, evident from week 1. Kasper et al. reported that aripiprazole (30 mg/day) demonstrated long-term efficacy that was comparable or superior to that of haloperidol (10 mg/day) across all symptoms measures, including significantly greater improvements for Positive and Negative Symptom Scale (PANSS) negative subscale scores and Montgomery Asberg Depression Rating Scale (MADRS) total scores. 10 Aripiprazole was also associated with significantly fewer EPS and dropouts than haloperidol. In a study with stabilized patients with chronic schizophrenia the patients treated with aripiprazole for 26 weeks experienced a significantly longer time to relapse and lower relapse rate than those receiving placebo. 11 These results suggest that aripiprazole may be a new option for the treatment of schizophrenia and other psychotic disorders without aggravation of psychotic symptoms or drug-related adverse events. Most of the studies mentioned here, however, were conducted in North America or Europe. With these limited results, it is unclear whether aripiprazole would be effective equally in other ethnic groups such as Asian patients. Recently, in a 4-week study conducted in 83 Chinese patients, aripiprazole was found to have favorable efficacy and safety profiles. 12 To date, however, there have been no reports of long-term efficacy of aripiprazole in Asian samples. The purpose of the present prospective study was therefore to demonstrate the efficacy, safety, and tolerability of aripiprazole for the treatment of Korean patients with schizophrenia, schizophreniform disorder, and schizoaffective disorder, and to determine whether response to aripiprazole varied with ethnicity. METHODS Subjects This study was conducted at 30 medical centers in Korea between 8 July 2004 and 4 August Men and non-pregnant, non-lactating women aged years who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder were eligible for enrollment in the study. For inclusion, patients had to have a total score of 60 on the PANSS with a score of 4 on any two of the four PANSS items that constitute the PANSS positive subscale (hallucinatory behavior, delusion, conceptual disorganization, and suspiciousness/ persecution) at the time of the baseline (week 0) study visit. Exclusion criteria were a history of violence; significant suicide risk as determined by the investigator; presence of neurological disorder or other psychiatric disorder; considered likely to require prohibited concomitant medications such as carbamazepine, valproic acid, or lithium; history of substance abuse or dependence; history of surgical operation on the gastrointestinal system; or any unstable medical conditions. A total of 300 patients (132 male, 168 female) participated. Of the total population, 273 patients (91.0%) were diagnosed with schizophrenia, 11 (3.7%) were diagnosed with schizoaffective disorder, and 16 (5.3%) were diagnosed with schizophreni-

3 Psychiatry and Clinical Neurosciences 2009; 63: Efficacy and safety of aripiprazole 75 Table 1. Baseline patient characteristics Characteristic Gender, n (%) Male 132 (44) Female 168 (56) Age (years; mean SD) Bodyweight (kg) (mean SD) Diagnosis, n (%) Schizophrenia 273 (91.0) Schizophreniform disorder 16 (5.3) Schizoaffective disorder 11 (3.7) Drug-naïve, in first episode, n (%) Yes 106 (35.3) No 194 (64.7) PANSS score (mean SD) Total Positive Negative CGI-S score (mean SD) CGI-S, Clinical Global Impression Severity of Illness scale; PANSS, Positive and Negative Syndrome Scale. form disorder according to DSM-IV criteria. 13 All patients were Korean. The baseline demographic characteristics of the subjects are presented in Table 1. Remarkably, 106 patients were drug-naïve patients in their first episode ( first-episode patients ). The patients who experienced at least one episode of recurrence ( recurrence patients ) had been diagnosed for a mean of years prior to commencing the present study. The study was approved by the local institutional review board, and written informed consent was obtained from all subjects after the procedures had been fully explained. Study design Subjects receiving antipsychotic medication were to complete at least a 5-day placebo washout period prior to the baseline study visit. The initial dose of aripiprazole was 15 mg/day and was maintained until week 2. After that time the treating clinicians were permitted to adjust the dose within a range of mg/day. The use of carbamazepine, valproic acid, or lithium was prohibited during the acute phase (until week 8). During the maintenance phase (weeks 8 26), concomitant medication including carbamazepine, valproic acid, and lithium was permitted if judged to be necessary by the investigator. All concomitant medication used during the study were recorded on the appropriate case report forms. Assessments The primary efficacy measure was mean change from baseline on the PANSS total score. 14 Secondary efficacy measures included mean change in scores from baseline for the PANSS positive and negative subscales, and Clinical Global Impression Severity of Illness (CGI-S), 15 and the number and percentage of responders (patients with a 30% decrease from baseline in PANSS total score or a score of 1 or 2 on CGI Improvement [CGI-I] scale). Symptoms and safety assessments were serially obtained at every study visit (baseline, week 1, week 2, week 3, week 4, week 6, and week 8 [acute phase], also week 12, week 16, and week 26 [maintenance phase]). Adverse events were monitored at the end of the placebo washout period (baseline) and throughout the study as scheduled. EPS were evaluated at every study visit using Simpson Angus Scale (SAS), 16 Abnormal Involuntary Movement Scale (AIMS), 15 and Barnes Akathisia Rating Scale (BAS). 17 Vital signs and bodyweight were also measured at every study visit. Physical examinations, 12-lead electrocardiogram recordings, blood samples, and urinalyses were performed at baseline, week 8, and week 26. Statistical analyses The analyses of primary and secondary variables data and safety measures were based on the data obtained at initiation of the study drug through to the patient s last visit, regardless of whether they had completed the study or not. Efficacy analysis was performed on the basis of the intention-to-treat principle. Missing data were accounted for the using last observation carried forward method. Changes from baseline in PANSS (total score, positive and negative subscales) and CGI-S scores were evaluated on Wilcoxon signed rank sum test. Comparisons between the first-episode patients and the recurrence patients with regard to efficacy measures and bodyweight were done on Wilcoxon rank sum test. Paired t-test was used to evaluate changes from baseline in vital sign or laboratory measures (includ-

4 76 J. S. Kwon et al. Psychiatry and Clinical Neurosciences 2009; 63: ing serum prolactin level) and safety measures such as those measured on EPS scales (SAS, AIMS, and BAS). All statistical procedures were performed with SAS software (version 9.1, SAS Institute, Cary, NC, USA), and statistical tests were performed at a two-sided level of 5%. RESULTS Patients A total of 300 Korean patients completed the washout period and were included in the present study. Of the 300 patients, 191 (63.7%) completed the 8-week acute phase, and 109 discontinued treatment. The mean aripiprazole daily dose received during the acute phase was mg. Of the 191 patients who completed the 8-week trial, 148 patients (77.5%) completed the maintenance phase (from week 8 until week 26). The mean aripiprazole daily dose received during the maintenance phase was mg. Overall, 49.3% of patients (n = 148) completed the entire 26-week study. Participant flow through the 26 weeks of treatment is summarized in Fig. 1. Relatively few patients, nine (3%), discontinued due to adverse events. Seventy-five (25.0%) discontinued due to withdrawal of consent or loss to follow up, and 32 (10.7%) discontinued due to insufficient clinical response. Two hundred and eighty-four patients used concomitant medications at any given time after baseline. Most frequently prescribed concomitant medications were anxiolytics (254 patients), anticholinergics (156 patients), mood stabilizers (107 patients), and antidepressants (48 patients). Efficacy data Aripiprazole produced significant improvement in symptoms as measured by change from baseline on the following: PANSS total score: baseline, ; week 8, ; week 26, ; PANSS positive symptoms subscale: baseline, ; week 8, ; week 26, ; PANSS negative symptoms subscale: baseline, ; week 8, ; week 26, CGI-S scores were as follows: baseline, ; week 8, ; week 26, (Figs 2,3). Aripiprazole demonstrated rapid onset of efficacy. For all four parameters, the statistically significant differences from baseline were evident from week 1 and sustained throughout the 26 weeks of treatment (for both first-episode patients and recurrence patients). With regard to PANSS total score, PANSS positive symptoms subscale and the CGI-S scores, first-episode patients had significant improvements compared to recurrence patients (asterisks in Figs 2,3). Responder rate, based on the criteria of 30% improvement from baseline in PANSS total score or a score of 1 or 2 on the CGI-I scale, was 59.20% at week 8 and 64.40% at week 26. In the acute phase there was no significant difference in responder rate between first-episode patients and recurrence patients. As compared with recurrence patients, however, the first-episode patients had a superior response rate during maintenance phase (at week 26; 72.7% vs 60.0%, P = ). Figure 1. Flowchart of the 26-weeks treatment procedure. Safety Adverse events The number of subjects who experienced at least one treatment-emergent adverse event was 206 at the

5 Psychiatry and Clinical Neurosciences 2009; 63: Efficacy and safety of aripiprazole 77 Figure 3. Mean change in Clinical Global Impression Severity of Illness (CGI-S) score from baseline over 26 weeks of aripiprazole treatment (last observation carried forward). *Significant difference between ( ) first-episode patients and ( ) recurrence patients (P < 0.05). ( ) All patients. acute phase, and 73 at the maintenance phase. Most common adverse events were insomnia, constipation, headache, dyspepsia, and upper respiratory tract infection. The majority of adverse events were deemed to be mild or moderate in severity and unrelated to study medication and occurred mainly during the acute phase. Adverse events occurring at an incidence of 3% are shown in Table 2. The incidence of discontinuation due to adverse events during the course of 26 weeks of treatment was 3%. Overall, 14 patients had a serious adverse event during the study (10 patients in the acute phase; four patients in the maintenance phase). Among them, only five serious adverse events during the acute phase were considered related to study medication (increased blood creatine phosphokinase, n = 1; aggravation of psychotic symptoms, n = 2; akathisia, n = 2). There were three patients who showed aggravation of psychotic symptoms and one report of a suicide attempt. No death occurred during the present study. Figure 2. Mean change in (a) Positive and Negative Syndrome Scale (PANSS) total, (b) positive and (c) negative scores from baseline over 26 weeks of aripiprazole treatment (last observation carried forward). *Significant difference between ( ) first-episode patients and ( ) recurrence patients (P < 0.05). ( ) All patients. Extrapyramidal symptoms As illustrated in Table 3, the BAS indicated that there was a statistically significant worsening of symptoms of akathisia during the acute phase. Although insignificant, aripiprazole was associated with improving trends of EPS during the maintenance phase as measured by mean changes from baseline to last study visit on the EPS scales (SAS, BAS, and AIMS).

6 78 J. S. Kwon et al. Psychiatry and Clinical Neurosciences 2009; 63: Table 2. Treatment-emergent adverse events (>3% incidence during acute phase or maintenance phase) Acute phase (n = 300) n (%) Maintenance phase (n = 191) n (%) Gastrointestinal system Constipation 61 (20.3) 11 (5.8) Dyspepsia 33 (11.0) 6 (3.1) Vomiting 19 (6.3) 2 (1.0) Abdominal pain 17 (5.6) 4 (2.1) Nausea 14 (4.7) 1 (0.5) Diarrhea 13 (4.3) 7 (3.7) Nervous system Insomnia 73 (24.3) 9 (4.7) Headache 48 (16.0) 9 (4.7) Dizziness 9 (3.0) 4 (2.1) Respiratory system Upper respiratory tract infection 30 (10.0) 10 (5.2) Musculoskeletal system Arthralgia 11 (3.7) 1 (0.5) Eye Blurred vision 12 (4.0) 4 (2.1) Urogenital system Dysuria 13 (4.3) 1 (0.5) (P = 0.344) from baseline to last visit between firstepisode patients and recurrence patients. Bodyweight The mean change in bodyweight from baseline to last study visit was significant (+2.06 kg overall; kg for first-episode patients; kg for recurrence patients). There was no significant difference with regard to bodyweight change between first-episode patients and recurrence patients (P = 0.094). The incidence of clinically significant weight gain ( 7% increase from baseline) at week 26 was 26.4% (n = 71). There also were increases of total cholesterol in patients who had clinically significant weight gain (week 8, mg/dl, P = 0.031; week 26, mg/ dl, P = 0.064). When stratified by mean body mass index (BMI) at baseline study visit, first-episode patients with the lowest baseline BMI (<23 kg/m 2 ) experienced a significantly greater weight gain than recurrence patients with the lowest baseline BMI (P = 0.010). In contrast, first-episode patients with a relatively high baseline BMI (>25kg/m 2 ) lost weight after the 26-week trial (-0.18kg; Fig. 4). First-episode patients had significant worsening of SAS score compared to recurrence patients (week 8, vs -0.24, P = 0.044; week 26, vs -0.38, P = 0.048). There was no significant difference with regard to BAS (P = 0.490) and AIMS score change Vital signs and laboratory analyses Serum prolactin levels significantly decreased from baseline levels (week 8, ng/ml, P < 0.001; week 26, ng/ml, P < 0.001). There was no significant change in serum prolactin level between first-episode patients and recurrence patients. A total Table 3. Extrapyramidal symptom scores SAS score BAS score AIMS score P P P Mean baseline Mean change Week < Week < Week < Week Week Week Week Mean change from baseline (last observation carried forward). AIMS, Abnormal Involuntary Movement Scale; BAS, Barnes Akathisia Rating Scale; SAS, Simpson Angus Scale.

7 Psychiatry and Clinical Neurosciences 2009; 63: Efficacy and safety of aripiprazole 79 Figure 4. Mean change in bodyweight from baseline to last visit when stratified by mean body mass index (BMI; last observation carried forward). *Significant difference between ( ) first-episode patients and ( ) recurrence patients (P < 0.05). ( ) All patients. of three patients (week 8), and 12 patients (week 26) had prolactin elevations greater than the upper limit of normal (23 ng/ml), respectively. Other than serum prolactin levels, there were no significant vital sign or laboratory abnormalities. DISCUSSION To the best of our knowledge the present study is the first to evaluate long-term efficacy and safety of aripiprazole in an Asian sample. The authors also clarified the distinction of the efficacy measures or adverse events between first-episode patients and recurrence patients, and acute phase and maintenance phase, respectively. The present results indicate that aripiprazole demonstrated long-term efficacy, with favorable safety and tolerability for the treatment of patients with schizophrenia, schizophreniform disorder, and schizoaffective disorder. Statistically significant improvements were demonstrated in efficacy measures (PANSS total score, PANSS positive and negative scores, CGI-S) as early as week 1 and were sustained through the course of the 26-week study. Especially, as compared to drugnaïve patients, aripiprazole has an equivalent effect on negative symptoms in patients who had previously been treated with antipsychotics. In a previous report aripiprazole showed not only comparable long-term efficacy in improving PANSS total and positive scores, but also in treating negative and depressive symptoms as indicated by improvements in PANSS negative and MADRS total score, respectively. 10 Aripiprazole s differential effects on treating both negative and depressive symptoms may be related to its potent partial agonist activity at D 2 dopamine and 5-HT 1A serotonin receptors associated with 5-HT 2A antagonist activity. Improvements in these symptoms can have some influences on patients overall quality of life, including social and family interaction, and a decreased risk of psychotic relapse and suicide. 18 Recently, a series of three case studies also showed an improvement in refractory negative symptoms following augmentation of clozapine with aripiprazole. 19 In the present study there were numerically greater improvements in efficacy measures compared with the previous 26-week study. 11 This might be due to the difference of subjects and study design. In the previous study the enrolled chronic patients (mean age, 41.7 years) continued antipsychotic treatment at least 2 years prior to entry and must have shown a response to this treatment. In contrast to that report, the mean age of patients in the present study was 33.8 years, and 106 patients were drug naïve. The treating clinicians were permitted to adjust the dose of aripiprazole and use concomitant medications if judged to be necessary in the present study. The present results and those from a 4-week trial in Chinese subjects 12 provide evidence that aripiprazole produces clinically meaningful improvements in Asian samples, as has been shown in European and Western/American subjects. In that study by Chan et al., which used the same responder criteria, the percentage of responders was 51%, 12 which was similar to the present results (51.4% at week 4). Aripiprazole has been associated with fewer EPS In the present study, however, there were no significant improvements on EPS scales (SAS, BAS, and AIMS). We suggest that this is due to the fact that many patients in the present study had no experience of antipsychotics. First-episode patients had significantly worsening of SAS score compared to recurrence patients in the present study. EPS have the potential to limit antipsychotic effectiveness and adherence to medications. 20 In a previous study, patients treated with aripiprazole had significantly lower discontinuation rates due to adverse events than those treated with haloperidol. 10 The dopamine

8 80 J. S. Kwon et al. Psychiatry and Clinical Neurosciences 2009; 63: partial agonist effect of aripiprazole may account for this result. Weight gain is also a common side-effect of antipsychotics, particularly atypical antipsychotics. 21 Increases in bodyweight can have serious implications for general health including metabolic syndrome, and are associated with decreased treatment adherence. 22 Mean weight changes were relatively tolerable (+2.06 kg) in the present study. Furthermore, the weight gain observed in patients was predominantly associated with those with relatively low baseline BMI (especially in first-episode patients). In contrast, in first-episode patients with BMI > 25 kg/m 2, aripiprazole was associated with weight loss. Interventions for antipsychotic medication-induced weight gain are necessary to reduce the risk of obesity-associated morbidity and mortality. Choosing the treatment for a patient with schizophrenia should take prevention of weight gain into consideration. Long-term hyperprolactinemia can lead to galactorrhea, amenorrhea, gynecomastia, impotence, and sexual dysfunction. It may also limit patient drug adherence. 23 In the present study there was a significant decrease in prolactin levels from baseline. Only 10.7% of patients had an abnormal prolactin level (>23 ng/ml) throughout the entire study. Because dopamine inhibits prolactin release, the decrease in serum prolactin level with aripiprazole administration is probably due to partial agonism at D 2 receptors in the tubero-infundibular pathway. There were limitations in the present study. First, the present study was an open study and not designed to have a placebo or active comparators. This may limit the universality of this data. Second, we did not limit use of concomitant medications (especially during the maintenance phase). Thus, we cannot exclude the possibility that the present results were affected by the concomitant medications. In summary, the present results have demonstrated that aripiprazole has sustained efficacy with a good safety and tolerability profile. This may be due to the unique mechanism of aripiprazole. The present study extends the findings of previous studies in the USA and other countries, 9,10 and showed there may be no significant ethnic difference in response to aripiprazole. The marked response rate and percentage of patients remaining on treatment with aripiprazole may translate into potential for decreased utilization of health-care resources. ACKNOWLEDGMENTS This study was supported by Korea Otsuka Pharmaceutical (Seoul, Korea). Members of the APLUS study group: Bo Hyun Yoon. MD; Bum Seok Jeong, MD, PhD; Byung Ook Lee, MD; Chan Hyung Kim, MD, PhD; Chang Yoon Kim, MD, PhD; Chi-Un Pae, MD; Chul Eung Kim, MD; Do Hoon Kim, MD, PhD; Dong Seok Yang, MD; Duk-In Jon, MD, PhD; Jae-Jin Kim, MD, PhD; Jae Gong Cyn, MD; Jeong-Ho Seok, MD; Jeong Gee Kim, MD, PhD; Jong-Il Lee, MD; Jun Soo Kwon, MD, PhD; Jung-Seo Yi, MD; Jung Goo Lee, MD, PhD; Kyung Sue Hong, MD, PhD; Min-Soo Lee, MD, PhD; Sang Ick Lee, MD; Sang Yeol Lee, MD, PhD; Seong-Jin Cho, MD, PhD; Sun Woo Lee, MD, PhD; Tak Youn, MD, PhD; Won-Myong Bahk, MD, PhD; Yanghyun Lee, MD; Yong Ku Kim, MD, PhD; Young Chul Chung, MD, PhD; Young Chul Shin, MD, PhD; Young Hoon Kim, MD, PhD REFERENCES 1 Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-ht1a receptor. Eur. J. Pharmacol. 2002; 441: 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: Tandon R, Jibson MD. Efficacy of newer generation antipsychotics in the treatment of schizophrenia. Psychoneuroendocrinology 2003; 28 (Suppl. 1): Kurzthaler I, Fleischhacker WW. The clinical implications of weight gain in schizophrenia. J. Clin. Psychiatry 2001; 62 (Suppl. 7): Casey DE. Dyslipidemia and atypical antipsychotic drugs. J. Clin. Psychiatry 2004; 65 (Suppl. 18): Newcomer JW. Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J. Clin. Psychiatry 2004; 65 (Suppl. 18): Kikuchi T, Tottori K, Uwahodo Y et al. 7-(4-[4-(2,3- Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H) -qui nolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J. Pharmacol. Exp. Ther. 1995; 274: Kane JM, Carson WH, Saha AR et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J. Clin. Psychiatry 2002; 63: Potkin SG, Saha AR, Kujawa MJ et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone

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