The Efficacy and Safety of Lower Doses of Aripiprazole for the Treatment of Patients with Acute Exacerbation of Schizophrenia

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1 The Efficacy and Safety of Lower Doses of for the Treatment of Patients with Acute Exacerbation of Schizophrenia By Andrew J. Cutler, MD, Ronald N. Marcus, MD, Sterling A. Hardy, MS, Amy O Donnell, MD, William H. Carson, MD, and Robert D. McQuade, PhD ABSTRACT Introduction: Efficacy and safety of aripiprazole administered at doses lower than those previously studied systematically were investigated in patients with acute exacerbation of schizophrenia. Methods: In this double-blind, multicenter study, 367 patients requiring inpatient hospitalization for acute relapse of schizophrenia were randomized to one of three fixed doses of aripiprazole (2, 5, or 1 mg/day) or placebo for 6 weeks. Efficacy and safety parameters were assessed weekly. Primary outcome measure was mean change from baseline in Positive and Negative Syndrome Scale (PANSS) Total score at endpoint. Results: 1 mg/day produced statistically significantly greater improvements from baseline compared with placebo for PANSS Total at endpoint ( 11.3 vs 5.3; P=.3) and at weeks mg/day did not produce sig- FOCUS POINTS 1 mg/day is the minimum effective dose for the treatment of patients with schizophrenia experiencing acute relapse. 5 mg/day produced improvements in some outcome measures but not in the primary efficacy measure, suggesting that it may lack efficacy for treating acute psychosis. 2 mg/day did not demonstrate significant differences versus placebo on any efficacy measures and, therefore, seems to be below the clinically effective dose. All doses of aripiprazole were well tolerated; aripiprazole treatment was not associated with significant extrapyramidal symptoms. nificantly greater improvement in PANSS Total compared with placebo at endpoint, although significant differences were seen at weeks 3 5. No statistically significant improvements compared with placebo were achieved with aripiprazole 2 mg/day at any time points. All aripiprazole doses Dr. Cutler is Courtesy Assistant Professor in the department of psychiatry at the University of Florida in Gainesville, and president of CORE Research, Inc., in Maitland, Florida. Dr. Marcus is executive director of Neuroscience Global Clinical Research at Bristol-Myers Squibb Company in Wallingford, Connecticut. Mr. Hardy is associate director of Global Biometric Science at Bristol-Myers Squibb Company. Dr. O Donnell is medical director of Neuroscience Global Clinical Research at Bristol-Myers Squibb Company. Dr. Carson is vice president CNS Abilify of Global Medical Science in Global Development and Commercialization at Otsuka America Pharmaceutical, Inc., in Princeton, New Jersey. Dr. McQuade is vice president of Global Scientific Affairs in Global Development and Commercialization at Otsuka America Pharmaceutical, Inc. Disclosures: Dr. Cutler has received research grants, honoraria, and/or has been consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Forest, GlaxoSmithKline, Johnson and Johnson, Eli Lilly, Merck, Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Sepracor, Shire, Solvay, Sumitomo, Vanda, and Wyeth. Drs. Carson, Marcus, McQuade, O Donnell, and Mr. Hardy do not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Funding/Support: This study was supported by Bristol-Myers Squibb and Otsuka. Submitted for publication: January 25, 26; Accepted for publication: March 27, 26. Please direct all correspondence to: Andrew J. Cutler, MD, CORE Research, Inc., 23 Maitland Center Parkway, Suite 23, Maitland, FL 32751; Tel: , Fax: ; acutler@coreresearch.com. CNS Spectr 11:9 MBL Communications Inc. 691

2 were well tolerated. was not associated with significant extrapyramidal symptoms. Conclusion: While aripiprazole 5 mg/day warrants further study, the 1 mg/day dose provides effective and well-tolerated therapy for management of acute psychosis in patients with schizophrenia. CNS Spectr. 26;11(9): INTRODUCTION is an atypical antipsychotic with a novel mechanism of action. It shows partial agonist activity at dopamine (D) 2 receptors, 1 thus differing from available antipsychotics that are D 2 receptor antagonists. The efficacy of aripiprazole in the treatment of patients with schizophrenia was initially evaluated in a series of short-term trials, three of which showed that aripiprazole was effective in the dose range of 1 3 mg/ day. 2-4 was shown to be superior to placebo at doses of 15 mg/day, 2 mg/day, and 3 mg/day in at least two clinical trials for each dose and at 1 mg/day in another trial. 4 A fourth short-term study, 5 which evaluated the efficacy of aripiprazole 2 3 mg/day in 13 patients with schizophrenia, failed to demonstrate the superiority of aripiprazole versus placebo. treatment was well tolerated across the range of doses studied (2 3 mg/day), with a low potential for extrapyramidal symptoms (EPS), prolactin elevation, QTc interval prolongation, and weight gain. 6 The good efficacy and tolerability of aripiprazole were also demonstrated in longterm clinical trials of up to 52 weeks in patients with schizophrenia. 7-9 This double-blind, randomized placebo-controlled study aimed to characterize more fully the efficacy, safety, and tolerability of aripiprazole when administered at lower treatment doses (2 mg/day, 5 mg/day, and 1 mg/day) to patients hospitalized with acute relapse of schizophrenia. In addition, by examining these three doses, the study aimed to provide useful guidance to clinicians regarding the optimal use of aripiprazole in their patients, particularly those who are more sensitive to antipsychotic medications. METHODS The study was conducted in accordance with Good Clinical Practice procedures and the Declaration of Helsinki and its amendments. Approval was gained from the institutional review board or ethics committee at each of the study medical centers, and all patients or their representatives gave informed written consent. Study Design This was a multicenter, randomized, doubleblind, placebo-controlled study, conducted at 36 sites in the United States, comparing the safety and efficacy of three fixed doses of aripiprazole (2 mg/day, 5 mg/day, and 1 mg/day) in patients hospitalized for acute relapse of schizophrenia. After a 3 14-day screening period, which included a washout period of at least 3 days during which patients did not receive antipsychotic medication, patients fulfilling the randomization criteria were randomized to receive one of the three doses of aripiprazole or placebo once daily for 6 weeks. Patients unable to tolerate treatment were discontinued from the study; no dose modification was permitted. Patients were hospitalized for the entire duration of the study. Efficacy and safety evaluations were performed at baseline and at the end of each treatment week. Inclusion and Exclusion Criteria Men and women, >18 years of age, with a diagnosis of schizophrenia, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, in acute relapse, and who had shown a documented worsening of schizophrenia within the previous 3 months and required inpatient hospitalization were eligible for enrollment in the study. In addition, patients were required to have evidence of responsiveness to antipsychotic medication (other than clozapine) in the past 2 years to be eligible for inclusion. Patients (and/or their legal representatives) also had to be able to give informed consent, be able to comprehend and comply with the study protocol, be willing to discontinue all previous psychotropic medication during the study period, and their symptoms had to be reliably rated on the psychiatric scales used in the study. Patients taking a long-acting antipsychotic could be included if a time period of at least one treatment cycle plus 1 week had elapsed since their last treatment. Patients also had to meet the following inclusion criteria at the baseline (randomization) visit to be eligible for randomization to treat- CNS Spectr 11:9 MBL Communications Inc. 692

3 ment: a Positive and Negative Syndrome Scale (PANSS) Total score of >6 and a score of at least 4 on >2 of the PANSS items of delusions, hallucinatory behavior, conceptual disorganization, or suspiciousness. Exclusion criteria included diagnosis of schizoaffective disorder (DSM-IV criteria); clinical history or current presentation consistent with delirium, dementia, amnesic or other cognitive disorder, or bipolar disorder; significant substance abuse disorder within the previous 3 months; history of neuroleptic malignant syndrome; history of epilepsy or seizures (except for a single childhood febrile seizure, posttraumatic, alcohol withdrawal, etc.), or a history of an abnormal electroencephalogram, severe head trauma or stroke, or history or evidence of other unstable medical conditions (eg, unstable angina, recent myocardial infarction, arrhythmia, cancer, or congestive heart failure) that would expose the patient to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the study; hospitalization more than 14 days prior to the study screening visit for the current acute episode; considered to have a significant risk of committing suicide; pregnancy or nursing women or women of childbearing potential not using adequate contraception. Additional exclusion criteria included fluoxetine treatment given within 4 weeks prior to randomization; participation in any clinical study with an investigational drug within 1 month prior to randomization; or electroconvulsive therapy within 2 months prior to randomization. Efficacy Evaluations Treatment efficacy was assessed using the PANSS and Clinical Global Impression (CGI) scales. PANSS consists of 3 items, each of which is assessed on a 7-point severity scale and the scores added together to give the PANSS Total score. Analysis of three PANSS subscales provided additional assessments of efficacy: the Positive subscale (seven items); the Negative subscale (seven items); and the PANSS Excited Component (PEC) (five items: hostility, lack of cooperation, excitement, poor impulse control, and tension). The CGI consists of two 7-point subscales: the Severity of Illness (CGI-S) and the Global Improvement (CGI-I) scales. The primary efficacy outcome measure was the mean change from baseline in PANSS Total score at the end of the study. Other secondary efficacy measures included the mean change from baseline at the end of each week of study for PANSS Positive, PANSS Negative, PEC and CGI-S scores, and mean CGI-I scores at each week. The percentage of responders, defined as a reduction of >3% in the PANSS Total score or a CGI-I score of 1 (very much improved) or 2 (much improved), was also assessed weekly. Safety Evaluations Adverse events were recorded as reported to the investigator during study visits. Vital signs (pulse and systolic and diastolic blood pressure) were also measured at each study visit. The occurrence of parkinsonism, akathisia, and dyskinesia was evaluated using standardized EPS rating scales: the Simpson Angus Scale (SAS), the Barnes Akathisia Rating Scale (BAS), and the Abnormal Involuntary Movement Scale (AIMS). The EPS rating scales, together with laboratory tests and electrocardiograms (ECG), were performed at screening (laboratory tests and ECG) or at randomization (EPS ratings) and at the end of the study. Concomitant Medication During the study, the use of psychotropic drugs other than aripiprazole was prohibited, with the exception of lorazepam, which could be prescribed orally for anxiety or insomnia, or intramuscularly for emergent agitation, if deemed necessary by the investigator. Lorazepam was not to be prescribed within 4 hours of safety or efficacy assessments. Doses of up to 4 mg/day could be given during the day for anxiety or emergent agitation. An additional 1 mg or 2 mg dose could be administered at night to aid sleep, if necessary. Non-benzodiazepine treatments for insomnia, such as zolpidem and zaleplon, were also permitted during the study. Anticholinergic treatment of EPS (eg, benztropine) was permitted during the treatment phase of the study (but not during the 24 hours prior to randomization) up to a maximum dose of 6 mg/day, if judged necessary by the investigator. Anticholinergic treatment was not to be administered within 12 hours of efficacy or safety ratings. All uses of concomitant medication were recorded on the appropriate case report forms. Statistical Procedures The primary efficacy outcome measure was the mean change from baseline to endpoint CNS Spectr 11:9 MBL Communications Inc. 693

4 (week 6 last observation carried forward [LOCF]) in the PANSS Total score. Testing of the primary efficacy outcome measure followed a step-down procedure, which assumed monotone increasing dose response. The 1 mg/day treatment group was tested against placebo at the.5 level. If the difference was statistically significant, the 5 mg/ day dose was tested at the.5 level. Similarly, if the 5 mg/day group was significantly different from placebo, the 2 mg/day group was tested at the.5 level. This procedure preserved the overall.5 experiment-wise error rate. The planned sample size of 348 evaluable patients (87 in each treatment group) had sufficient power to detect differences from placebo in the primary efficacy outcome variable of 12 points. The efficacy sample was defined as all patients who received at least one dose of study medication and had at least one post-randomization efficacy evaluation. The safety sample included all patients who received at least one dose of study medication. Efficacy analyses were performed for the efficacy sample and used an LOCF approach. Safety analyses were performed using the safety sample and an LOCF approach was used in the analysis of EPS ratings. Differences between treatment groups for the PANSS Total, PANSS Positive, PANSS Negative, PEC, and CGI-S efficacy measures were evaluated by analysis of covariance, including treatment as a main effect and the baseline measure as a covariate. Baseline data were evaluated by analysis of variance with treatment as a main effect. The row mean score test from the Cochran Mantel Haenszel procedure was used to test for the difference in CGI-I scores between treatment groups. The percentage of responders and the number of patients discontinuing for lack of efficacy were analyzed using the general association test from the Cochran Mantel Haenszel procedure. RESULTS Patient Demographics and Disposition A total of 367 patients were randomized to the four treatment groups: placebo (n=88); aripiprazole 2 mg/day (n=93); aripiprazole 5 mg/day (n=92); aripiprazole 1 mg/day (n=94). All four groups were comparable with respect to demographic characteristics, psychiatric history, and baseline scores, as shown in Table 1. Of the 367 patients, 195 (53.1%) completed the 6 weeks of double-blind treatment. The rate of discontinuation was similar across the treatment groups, ranging from 43.6% in the 1 mg/ day group to 5.% in the placebo group (Table 2). The most frequently reported reason for discontinuation was withdrawal of consent (n=8; 21.8%), followed by lack of efficacy (n=69; 18.8%). The percentage of patients discontinuing for lack of efficacy was higher for the placebo and aripiprazole 2 mg/day groups (22.7% and 23.7%, respectively) compared with the 5 mg/day and 1 mg/day groups (14.1% and 14.9%, respectively), although no statistically significant differences in discontinuation rates were observed between any of the active treatments and placebo. Overall, 3.5% (n=13) of patients withdrew early due to adverse events. The overall use of concomitant psychopharmacologic medications during the study was similar across the four treatment groups (Table 3). The most commonly used psychopharmacologic medications were lorazepam (85.8% of patients overall), and the hypnotics, zolpidem and zaleplon (together, 69.3% of patients). Sedative use was slightly more common in the 1 mg/day group (75.5%) than in the other groups (65.9% to 68.8%); lorazepam use showed minor differences across the groups (82.4% to 89.4%). Efficacy 1 mg/day produced a statistically significantly greater improvement in the primary efficacy parameter, PANSS Total score, from baseline compared with placebo at the end of the study ( 11.3 vs 5.3; P=.3). Statistically significantly greater mean improvements in PANSS Total scores relative to placebo were evident from week 2 (Figure 1). PANSS Positive subscale scores also showed significant improvements over placebo with the 1 mg/day dose at endpoint ( 4.2 vs 2.3; P=.3), and at weeks 2, 4, and 5 (Figure 2), while PANSS Negative subscale scores showed significant improvements over placebo at weeks 2 and 4 (Figure 3). 1 mg/day produced a significant improvement in PEC score from baseline at endpoint compared with placebo (.8 vs.5; P=.34) (Figure 4). Analysis of CGI-S scores showed significantly greater mean improvements at endpoint for aripiprazole 1 mg/day (.6) compared with placebo (.3; P=.28), and at most other time points during the study (weeks 2, 3, and 4). Mean CGI-I scores were numerically better at endpoint for 1 mg/day (3.2) compared with placebo (3.6), CNS Spectr 11:9 MBL Communications Inc. 694

5 but only showed statistically significant improvements at weeks 2, 3, and 4. The overall response rate (ie, percentage of patients achieving a CGI-I score of 1 or 2, or reduction in PANSS Total score of >3%) at the end of the study was numerically greater for the 1 mg/day group (43%) than for the placebo group (33%). Differences in response rate were not significant at the end of the study, but statistically significant differences from placebo were observed at weeks 3 and 4. TABLE 1. Demographic Characteristics and Baseline Scores for Randomized Patients 2 mg/day 5 mg/day 1 mg/day Randomized, n Gender, n (%) Male Female 72 (81.8) 16 (18.2) 74 (79.6) 19 (2.4) 7 (76.1) 22 (23.9) 72 (76.6) 22 (23.4) Mean Age (years) Race, n (%) White Black/African American Other Schizophrenia Type, n (%) Disorganized Paranoid Undifferentiated Mean age at time of first hospitalization for schizophrenia (years) Mean number of days since start of current relapse Mean PANSS Score, Baseline Total Positive Negative 39 (44.3) 43 (48.9) 6 (6.8) 3 (3.4) 76 (86.4) 8 (9.1) 47 (5.5) 41 (44.1) 5 (5.4) 3 (3.2) 77 (82.8) 13 (14.) 39 (42.4) 48 (52.2) 5 (5.4) 3 (3.3) 8 (87.) 8 (8.7) 52 (55.3) 4 (42.6) 2 (2.1) 3 (3.2) 82 (87.2) 9 (9.6) Mean CGI-S score, baseline PANSS=Positive and Negative Syndrome Scale; CGI-S=Clinical Global Impression-Severity of Illness. Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No TABLE 2. Discontinuation Rates (Randomized Sample) 2 mg/day 5 mg/day 1 mg/day Randomized, n Completed Treatment, n (%) 44 (5.) 51 (54.8) 47 (51.1) 53 (56.4) Discontinued Early, n (%) 44 (5.) 42 (45.2) 45 (48.9) 41 (43.6) Reasons for Discontinuation, n (%) Patient withdrew consent Lack of efficacy Adverse event Other 16 (18.2) 2 (22.7) 6 (6.8) 2 (2.3) 17 (18.3) 22 (23.7) 2 (2.2) 1 (1.1) Includes lost to follow-up, no longer met study criteria, poor or noncompliance, and other known cause. Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No (28.3) 13 (14.1) 1 (1.1) 5 (5.4) 21 (22.3) 14 (14.9) 4 (4.3) 2 (2.1) CNS Spectr 11:9 MBL Communications Inc. 695

6 5 mg/day did not show a statistically significantly greater improvement from baseline in PANSS Total score compared with placebo at endpoint ( 1.6 vs 5.3; P=.58). However, significantly greater reductions in PANSS Total scores compared with placebo were observed at weeks 3 5 (P<.5) (Figure 1). Among the secondary efficacy measures, statistically significant improvements over placebo were observed for 5 mg/day for PANSS Negative subscale scores at week 2 to endpoint (Figure 3) and for the CGI-S score at weeks 1, 3, 4, and endpoint (endpoint: 5 mg/day,.6; placebo:.3; P=.45). Mean CGI-I scores were significantly better for the 5 mg/day group compared with placebo at weeks 1, 3, and 4, but the difference between groups did not reach statistical significance at endpoint. Similarly, the percentage of responders was numerically greater at each assessment point (endpoint: 5 mg/day, 37%; placebo, 33%), but differences only reached statistical significance at week 3. Other secondary efficacy measures (PANSS Positive; PEC) did not separate from placebo at any time point. Patients in the 2 mg/day group showed numerically greater mean improvements in PANSS Total score from baseline compared with placebo at all time points, but the difference between the two groups did not reach statistical significant at endpoint (2 mg/day: 8.2; placebo: 5.3, P=.289) or any other assessments (Figure 1). Furthermore, aripiprazole 2 mg/day did not separate from placebo for any of the secondary efficacy measures at any assessment point. Safety Adverse Events All three aripiprazole doses were well tolerated, with most adverse events being mild to moderate in intensity. A total of 13 (3.5%) patients discontinued the study due to adverse events: six patients (6.8%) in the placebo group; two (2.2%) in the 2 mg/day group; one (1.1%) in the 5 mg/day group; and four (4.3%) in the 1 mg/day group. The most frequent adverse event leading to discontinuation was agitation, which was reported in five patients (placebo: n=2; 2 mg/day: n=2; 5 mg/day: n=1). The only other adverse event that occurred in more than one patient receiving aripiprazole and led to discontinuation was paranoia (one patient in the 2 mg/day group and one patient in the 5 mg/day group). Treatment-emergent adverse events were reported by 68.5% of patients. The incidence was comparable for the aripiprazole and placebo groups (placebo: 68%; 2 mg/day: 71%; 5 mg/ day: 65%; 1 mg/day: 7%). The most frequently reported treatment-emergent adverse events (ie, occurring in at least 5% of patients in any group) are shown in Table 4. Headache was the most frequently reported treatment-emergent adverse event and occurred at a similar incidence in all TABLE 3. Use of Psychopharmacologic Medications During the Study (Safety Sample) n=87 2 mg/day n=93 5 mg/day n=91 1 mg/day n=94 Any medication, n (%) 83 (95.4) 92 (98.9) 88 (96.7) 92 (97.9) Anesthetic, local, n (%) 2 (2.2) 1 (1.1) Anticholinergic, n (%) 6 (6.9) 4 (4.3) 4 (4.4) 8 (8.5) Antidepressant, n (%) 2 (2.2) Antiepileptic, n (%) 2 (2.3) Antimigraine preparation, n (%) 1 (1.1) Antipsychotic, n (%) 5 (5.7) 7 (7.5) 3 (3.3) 1 (1.1) Anxiolytic 75 (86.2) 79 (84.9) 75 (82.4) 84 (89.4) Hypnotic and sedative, n (%) 58 (66.7) 64 (68.8) 6 (65.9) 71 (75.5) Opioid, n (%) 3 (3.4) 1 (1.1) 2 (2.2) 3 (3.2) Other analgesic and antipyretic, n (%) 53 (6.9) 63 (67.7) 56 (61.5) 69 (73.4) Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No CNS Spectr 11:9 MBL Communications Inc. 696

7 four treatment groups (16.% to 2.7%). Nausea showed a dose-related trend with aripiprazole, increasing in incidence from 5.4% with 2 mg/ day to 6.6% with 5 mg/day and to 1.6% with 1 mg/day; the incidence with placebo was 3.4%. However, vomiting showed no such trend and the incidence in all three aripiprazole groups (4.3% to 5.4%) was lower than with placebo (8.%). Constipation and abdominal pain (upper) also had higher incidence rates at the 1 mg/ day dose than with placebo or other aripiprazole doses, while the incidence of back pain was greater in the 5 mg/day and 1 mg/day groups than the other two groups (Table 4). No doserelated trend was observed for sedation. Thirty patients experienced serious adverse events; the incidence was similar across the treatment groups (placebo: 8.%; 2 mg/day: 9.7%; 5 mg/day: 4.4%; 1 mg/day: 1.6%). Most events were related to the underlying disease, with psychotic disorder being reported in 14 patients and schizophrenia in nine patients. There was one death during the study. This patient, in the 1 mg/day group, discontinued treatment as a result of moderate acute abdominal pain, which was judged not to be related to study medication and which resolved after discontinuation. Other adverse events (constipation, nausea, and vomiting) that were ongoing at the time and not considered to be related to medication also resolved following discontinuation; however, 15 days after the last dose of study medication, the patient had a very severe myocardial infarction and died. The investigator judged the event as not being related to study medication. Extrapyramidal Symptoms EPS-related adverse events were reported by 3.4% of the placebo group compared with 4.3% of all patients receiving aripiprazole (2 mg/day: 1.1%; 5 mg/day: 3.3%; 1 mg/day: 8.5%). None of the individual EPS-related events occurred in more than two patients in any treatment group, and none of the patients discontinued treatment due to EPS-related adverse events. Only small changes in SAS, AIMS, and BAS scores occurred over the course of the study in all four treatment groups (Table 5). There were no statistically significant differences in changes in scores over the course of the study for any of the aripiprazole groups compared with placebo. Akathisia occurred infrequently during the study, as indicated by the small number of adverse event reports (placebo: n=1 [1.1%]; aripiprazole 1 mg/day: n=2 [2.1%]) and the mean improvements in BAS scores across all treatment groups. Use of anticholinergic medication for potential treatment of EPS (benztropine) was slightly higher for patients in the 1 mg/day group (8.5%) than FIGURE 1. Mean change from baseline in PANSS Total score (LOCF analysis) Mean Change in PANSS Total Score from Baseline Weeks mg/day 5 mg/day 1 mg/day FIGURE 2. Mean change from baseline in PANSS Positive score (LOCF analysis) Mean Change in PANSS Positive Score from Baseline Weeks mg/day 5 mg/day 1 mg/day P<.5 vs placebo PANSS=Positive and Negative Syndrome Scale; LOCF=last observation carried forward. Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No P<.5 vs placebo PANSS=Positive and Negative Syndrome Scale; LOCF=last observation carried forward. Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No CNS Spectr 11:9 MBL Communications Inc. 697

8 for the other aripiprazole groups (5 mg/day: 4.4%; 2 mg/day: 4.3%) and those receiving placebo (6.9%). Electrocardiograms The incidence of potentially clinically significant ECG abnormalities during the study was low. No patients were found to have clinically significant QTc prolongation (ie, QTc interval >45 milliseconds and a 1% increase from baseline) calculated using the Food and Drug Administration Neuropharmacological Division correction factor (ie, QT c N=QT/RR.37 ). Vital Signs and Laboratory Evaluations The incidence of potentially clinically significant vital sign or laboratory abnormalities during the study was low. The most frequently reported potentially clinically significant vital sign abnormalities were increases in standing heart rate (placebo: n=2; aripiprazole 2 mg/day: n=2; aripiprazole 5 mg/day:, n=1; aripiprazole 1 mg/day: n=4) and standing diastolic blood pressure (placebo: n=2; aripiprazole 2 mg/day: n=3; aripiprazole 5 mg/day: n=1; aripiprazole 1 mg/day: n=2). Many of these increases were attributed by the investigators to patient anxiety. The most frequently reported potentially clinically significant laboratory finding was an abnormal total creatinine phosphokinase (CPK) value. Patients with abnormal CPK values did not exhibit any muscle or cardiac symptoms and, in most cases, the investigators attributed increased CPK to increased muscle activity due to agitation or exercise. No patients discontinued due to abnormal vital sign or laboratory results. DISCUSSION The results of this short-term, fixed-dose, multicenter study show that 1 mg/day is the minimum effective dose of aripiprazole for the treatment of patients hospitalized with acute relapse of schizophrenia. This study replicates the findings from a previous clinical trial that demonstrated the efficacy of the aripiprazole 1 mg/day in this patient population. 4 In the current study, the 1 mg/day dose produced a statistically significant improvement in PANSS Total score over placebo at endpoint, with a significant reduction in score apparent at all assessments from week 2 onward. Secondary efficacy measures showed that the 1 mg/day produced significant improvements across the range of schizophrenia symptoms: compared with placebo, aripiprazole 1 mg/day showed significant improvements from baseline for all assessments at various intermediate time points during the study, and at endpoint for PANSS Positive, PEC, and CGI-S scores. While the improvements in PANSS Total scores were broadly similar with aripiprazole 1 mg/day and 5 mg/day, the 5 mg/day dose failed to achieve a statistically significant improvement in PANSS Total score compared with placebo at endpoint. As apparent in Figure 1, a placebo response was observed at endpoint, which may have contributed to the failure of the change in PANSS Total score to reach statistical significance with aripiprazole 5 mg/day. 5 mg/day did not produce significant improvements in PANSS Positive or PEC scores over placebo at any assessment during the study, indicating a lack FIGURE 3. Mean change from baseline in PANSS Negative score (LOCF analysis) Mean Change in PANSS Negative Score From Baseline Weeks mg/day 5 mg/day 1 mg/day P<.5 vs placebo PANSS=Positive and Negative Syndrome Scale; LOCF=last observation carried forward. Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No FIGURE 4. Mean change from baseline in PEC score (LOCF analysis) Mean Change in PEC Score From Baseline mg/day 5 mg/day 1. 1 mg/day Weeks P<.5 vs placebo PEC=Positive and Negative Syndrome Scale Excited Component; LOCF=last observation carried forward. Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No CNS Spectr 11:9 MBL Communications Inc. 698

9 of efficacy against key symptoms of acute psychosis. However, patients treated with aripiprazole 5 mg/day did show significant improvements in PANSS Negative score from week 2 to endpoint compared with placebo, and significant improvements in CGI-S scores at endpoint and both CGI-S and CGI-I scores at intermediate time points during the study. These findings suggest that further examination of this dose is warranted, particularly for the management of the negative symptoms of schizophrenia. 2 mg/day did not demonstrate significant differences compared with placebo on any of the efficacy measures, and therefore seems to be below the clinically effective dose. This is in agreement with results previously reported for the 2 mg/day dose. 1 This study is the second randomized, placebocontrolled clinical trial to demonstrate the efficacy of aripiprazole 1 mg/day for the treatment of hospitalized patients with acute exacerbation of schizophrenia. To date, the efficacy of aripiprazole has been replicated in at least two clinical TABLE 4. Incidence of Treatment-Emergent Adverse Events Occurring in 5% of Patients in any Treatment Group (Safety Sample) System Organ Class/ MedDRA Preferred Term Gastrointestinal disorders, n (%) n=87 2 mg/day n=93 5 mg/day n=91 1 mg/day n=94 Abdominal pain upper 1 (1.1) 5 (5.3) Constipation 4 (4.6) 8 (8.6) 4 (4.4) 1 (1.6) Diarrhea 6 (6.9) 5 (5.4) 3 (3.3) 1 (1.1) Dyspepsia 8 (9.2) 5 (5.4) 7 (7.7) 5 (5.3) Nausea 3 (3.4) 5 (5.4) 6 (6.6) 1 (1.6) Toothache 3 (3.4) 6 (6.5) 5 (5.5) 3 (3.2) Vomiting 7 (8.) 5 (5.4) 4 (4.4) 4 (4.3) Infections and infestations, n (%) Upper respiratory tract infection 4 (4.6) 3 (3.3) 5 (5.3) Vaginitis 1 (6.3) 1 (4.8) Musculoskeletal and connective tissue disorders, n (%) Back pain 2 (2.3) 1 (1.1) 4 (4.4) 6 (6.4) Nervous system disorders, n (%) Dizziness 6 (6.9) 4 (4.3) 5 (5.5) 4 (4.3) Headache 18 (2.7) 16 (17.2) 17 (18.7) 15 (16.) Sedation 4 (4.3) 6 (6.6) 3 (3.2) Psychiatric disorders, n (%) Psychotic disorder 2 (2.3) 5 (5.4) 2 (2.2) 5 (5.3) Respiratory, n (%) Cough 2 (2.3) 5 (5.4) 4 (4.4) 3 (3.2) Pharyngolaryngeal pain 5 (5.4) 4 (4.4) 4 (4.3) Skin, n (%) Rash 1 (1.1) 5 (5.4) 1 (1.1) 5 (5.3) Incidence adjusted for gender (women): placebo: n=16; aripiprazole 5 mg/day: n=21 MedDRA=Medical Dictionary for Regulatory Activities. Cutler AJ, Marcus RN, Hardy SA. O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No CNS Spectr 11:9 MBL Communications Inc. 699

10 trials for doses of 1 mg/day, 15 mg/day, 2 mg/ day, and 3 mg/day. 4 The current study demonstrated the efficacy of aripiprazole 1 mg/day in reducing positive symptoms and the symptoms of hostility and excitement, as assessed by the PEC score. These symptoms are important targets in the early treatment of patients experiencing acute relapse, suggesting that the 1 mg/day dose provides an effective dose suitable for starting patients on aripiprazole therapy. Although it is not possible to directly compare independent studies with differing designs and patient populations, the improvements in symptoms of schizophrenia observed with aripiprazole 1 mg/day in this study are consistent with findings from other short-term aripiprazole studies. 2,3 For example, changes from baseline in PANSS Total scores after 4 weeks of treatment with aripiprazole 15 3 mg/day have been reported in 11.4 to ,3 These previously reported improvements are broadly in line with the change of 11.3 from baseline to endpoint with aripiprazole 1 mg/day in this study. The efficacy of aripiprazole at doses of >1 mg/ day is consistent with findings from positron emission tomography studies with aripiprazole. 12 These studies showed receptor occupancy of ~85% to 9% for dopamine D 2 and D 3 receptors with clinically effective aripiprazole 1 mg/day and 3 mg/ day. Furthermore, these high receptor occupancy levels occurred at aripiprazole doses that are not associated with significant EPS, in contrast to positron emission tomography studies with typical antipsychotics, which reported acute EPS at occupancy levels of ~8% and above. 13 In contrast to the higher aripiprazole doses, aripiprazole 2 mg/ day, which lacks efficacy in clinical trials, showed lower occupancy rates (7% to 75%), suggesting that these levels are insufficient to produce an adequate clinical response. The clinical efficacy of aripiprazole at doses as low as 1 mg/day for the treatment of acute psychosis in schizophrenia now appears to be well established. However, individual variation between patients in terms of receptor density and/or sensitivity, and with regard to pharmacokinetic factors, can impact on their treatment response, so that some patients may require higher aripiprazole doses (ie, >1 mg/day) in order to achieve a satisfactory response to medication. All of the aripiprazole doses were well tolerated. The most frequently reported adverse events with aripiprazole treatment were headache and gastrointestinal events, which is consistent with findings from other aripiprazole clinical trials. 6 In the current study, the incidence of headache was similar in the aripiprazole-treated patients and those receiving placebo. Nausea showed an increased incidence in the three aripiprazole groups compared with placebo, although vomiting and diarrhea were less frequently reported in each of the three aripiprazole groups than with placebo. Constipation, abdominal pain, and back pain were also reported more frequently with aripiprazole 1 mg/day than with placebo and the lower aripiprazole doses. There were few discontinuations due to adverse events during the study. Only seven patients receiving aripiprazole (2.5%) discontinued early due to adverse events TABLE 5. Mean changes from baseline in SAS, AIMS, and BAS Scores Over The Course of The Study (LOCF) (Safety Sample) SAS Mean baseline Mean change at (LOCF) AIMS Mean baseline Mean change at (LOCF) BAS Mean baseline Mean change at (LOCF) (n=84) mg/day (n=87) mg/day (n=84) mg/day (n=85) SAS=Simpson-Angus Scale; AIMS=Abnormal Involuntary Movement Scale; BAS=Barnes Akathisia Rating Scale; LOCF=last observation carried forward..5.1 Cutler AJ, Marcus RN, Hardy SA, O Donnell A, Carson WH, McQuade RD. CNS Spectr. Vol 11, No CNS Spectr 11:9 MBL Communications Inc. 7

11 (2 mg/day: n=2; 5 mg/day: n=1; 1 mg/day: n=4), compared with six patients in the placebo group (6.8%). Patients in the aripiprazole and placebo groups also reported a low incidence of both agitation and insomnia in this study (both <5%), in contrast to the findings from previous short-term trials, in which these adverse events were generally more widely reported. 6 The widespread use of non-benzodiazepine sedative medications in the current study (~7% of patients), a possible consequence of explicitly permitting the use of these sedative agents in the study protocol, may account for the lower incidence of these adverse events compared with earlier studies. This illustrates how concomitant medications can be used to manage patients effectively when using antipsychotics with a low incidence of sedation. Overall, the incidence of EPS-related adverse events with aripiprazole was low (4.3%) and similar to that with placebo (3.4%). Individual EPS-related events occurred infrequently, with none reported by more than two patients in any treatment group. Only three patients experienced akathisia as an adverse event during the study (placebo: n=1 [1.1%]; aripiprazole 1 mg/day: n=2 [2.1%]). The incidence of EPS-related adverse events and the use of anticholinergic medication to treat EPS were both slightly higher in the 1 mg/day group than with placebo, while values for the 2 mg/day and 5 mg/day groups were lower than or comparable to placebo. However, changes in ratings on the three EPS assessment measures (ie, SAS, AIMS, and BAS) over the course of the study were similar for all four treatment groups, and did not differ significantly between active treatment and placebo. The low potential for EPS seen with aripiprazole is consistent with findings from other aripiprazole studies involving doses up to 3 mg/day. 6,9 Pooled data from short-term studies 6 showed minimal mean changes in EPS rating scale scores from baseline with aripiprazole, and a similar incidence of EPSrelated adverse events with aripiprazole and placebo, while a longer-term study showed similar EPS-related adverse event rates with aripiprazole and olanzapine. 9 The low incidence of akathisia observed with aripiprazole 1 mg/day in the current study compares favorably with rates reported for higher aripiprazole doses (15 3 mg/day) in other short-term studies. 2,3 had a low potential for prolongation of the QTc interval, as has been consistently demonstrated for aripiprazole at doses of up to 3 mg/day during short-term 2,3,6 and long-term studies. 7-9 The incidence of potentially clinically significant vital sign or laboratory abnormalities during the study was low across the treatment groups, and there were no discontinuations due abnormal vital sign or laboratory results. Dosing can have a large impact on the overall clinical effectiveness of some antipsychotic therapies, as higher doses can increase the risk of unwanted side effects. For typical antipsychotics, such as haloperidol, higher doses are associated with high rates of adverse events and treatment discontinuations but show similar efficacy to lower doses. 14 Among the atypicals, doserelated increases in rates of prolactin elevation and EPS-related adverse events have been observed with risperidone, 15 while olanzapine treatment is associated with dose-related increases in weight gain, 16 transient serum prolactin elevation, 15,17 and EPS. 15 Dose-related increases in extrapyramidal syndrome and increased use of anticholinergic medication have been reported with ziprasidone treatment, 18 while increased incidences of postural hypotension and dizziness have been seen with higher doses of quetiapine. 19 With aripiprazole, somnolence seems to be the only adverse event with a possible dose-response relationship. This effect was only evident at the 3 mg/day dose, but has only been assessed in short-term studies. 5 Dosing and its effect on treatment tolerability is a particularly important consideration, given that adverse events, and particularly EPS, weight gain, and sexual dysfunction, are a major reason for non-adherence to medication. 2,21 Thus, the choice of antipsychotic can have a major impact on treatment adherence and, hence, patient outcome. An antipsychotic that offers consistent efficacy and good tolerability across a range of treatment doses therefore offers a valuable treatment option across the full spectrum of schizophrenia patients. CONCLUSION The results of this study confirm that aripiprazole 1 mg/day is the minimum effective dose for the treatment of patients with schizophrenia experiencing acute relapse, replicating findings from a previous study involving the 1 mg/day dose. Although aripiprazole 5 mg/day produced improvements in some outcome measures, notably negative symptoms, it failed to achieve significant improvements over placebo in this study for the PANSS Total scores at endpoint, or for PANSS Positive or PEC scores, which are key symptom domains in acute psychosis. All aripiprazole doses were well tolerated. CNS CNS Spectr 11:9 MBL Communications Inc. 71

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