William H. Carson

Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder

OBJECTIVE: The objective of this study was to evaluate short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder who were manifesting behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these. METHODS: This 8-week, double-blind, randomized, placebo-controlled, parallel-group study was conducted of children and adolescents (aged 6–17 years) with autistic disorder. Patients were randomly assigned (1:1) to flexibly dosed aripiprazole (target dosage: 5, 10, or 15 mg/day) or placebo. Efficacy outcome measures included the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression–Improvement score (CGI-I). Safety and tolerability were also assessed. RESULTS: Ninety-eight patients were randomly assigned to receive placebo (n = 51) or aripiprazole (n = 47). Mean improvement in Aberrant Behavior Checklist irritability subscale score was significantly greater with aripiprazole than with placebo from week 1 through week 8. Aripiprazole demonstrated significantly greater global improvements than placebo, as assessed by the mean CGI-I score from week 1 through week 8; however, clinically significant residual symptoms may still persist for some patients. Discontinuation rates as a result of adverse events (AEs) were 10.6% for aripiprazole and 5.9% for placebo. Extrapyramidal symptom-related AE rates were 14.9% for aripiprazole and 8.0% for placebo. No serious AEs were reported. Mean weight gain was 2.0 kg on aripiprazole and 0.8 kg on placebo at week 8. CONCLUSIONS: Aripiprazole was efficacious in children and adolescents with irritability associated with autistic disorder and was generally safe and well tolerated.

A Placebo-Controlled, Fixed-Dose Study of Aripiprazole in Children and Adolescents With Irritability Associated With Autistic Disorder

OBJECTIVE To evaluate the short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. METHOD Two hundred eighteen children and adolescents (aged 6-17 years) with a diagnosis of autistic disorder, and with behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these symptoms, were randomized 1:1:1:1 to aripiprazole (5, 10, or 15 mg/day) or placebo in this 8-week double-blind, randomized, placebo-controlled, parallel-group study. Efficacy was evaluated using the caregiver-rated Aberrant Behavior Checklist Irritability subscale (primary efficacy measure) and the clinician-rated Clinical Global Impressions-Improvement score. Safety and tolerability were also assessed. RESULTS At week 8, all aripiprazole doses produced significantly greater improvement than placebo in mean Aberrant Behavior Checklist Irritability subscale scores (5 mg/day, -12.4; 10 mg/day, -13.2; 15 mg/day, -14.4; versus placebo, -8.4; all p < .05). All aripiprazole doses demonstrated significantly greater improvements in mean Clinical Global Impressions-Improvement score than placebo at week 8. Discontinuation rates due to adverse events were as follows: placebo 7.7%, aripiprazole 5 mg/day 9.4%, 10 mg/day 13.6%, and 15 mg/day 7.4%. The most common adverse event leading to discontinuation was sedation. There were two serious adverse events: presyncope (5 mg/day) and aggression (10 mg/day). At week 8, mean weight change (last observation carried forward) was as follows: placebo +0.3 kg, aripiprazole 5 mg/day +1.3 kg, 10 mg/day +1.3 kg, and 15 mg/day +1.5 kg; all p < .05 versus placebo. CONCLUSIONS Aripiprazole was efficacious and generally safe and well tolerated in the treatment of children and adolescents with irritability associated with autistic disorder.

Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia

Aripiprazole is a novel atypical antipsychotic for the treatment of schizophrenia. It is a D2 receptor partial agonist with partial agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2A receptors. The long-term efficacy and safety of aripiprazole (30 mg/d) relative to haloperidol (10 mg/d) were investigated in two 52-wk, randomized, double-blind, multicentre studies (using similar protocols which were prospectively identified to be pooled for analysis) in 1294 patients in acute relapse with a diagnosis of chronic schizophrenia and who had previously responded to antipsychotic medications. Aripiprazole demonstrated long-term efficacy that was comparable or superior to haloperidol across all symptoms measures, including significantly greater improvements for PANSS negative subscale scores and MADRS total score (p<0.05). The time to discontinuation for any reason was significantly greater with aripiprazole than with haloperidol (p=0.0001). Time to discontinuation due to adverse events or lack of efficacy was significantly greater with aripiprazole than with haloperidol (p=0.0001). Aripiprazole was associated with significantly lower scores on all extrapyramidal symptoms assessments than haloperidol (p<0.001). In summary, aripiprazole demonstrated efficacy equivalent or superior to haloperidol with associated benefits for safety and tolerability. Aripiprazole represents a promising new option for the long-term treatment of schizophrenia.

Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study.

This study compares the efficacy, safety, and tolerability of a partial dopamine agonist, aripiprazole, with placebo in the treatment of patients with bipolar I disorder experiencing an acute manic or mixed episode. In total, 272 hospitalized patients were randomized to aripiprazole 30mg/day or placebo in this 3-week, double-blind, placebo-controlled trial. Dosing could be reduced to 15mg/day for tolerability and, subsequently, increased to 30mg/day based on clinical response. Primary efficacy measure was mean change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score; response was defined as 50% decrease from baseline YMRS score. Aripiprazole-treated patients demonstrated significantly greater improvement from baseline to endpoint in mean YMRS total scores compared with placebo-treated patients as early as Day 4 and sustained through Week 3. A significantly higher response rate was observed in aripiprazole-treated patients (53% vs. 32% at endpoint). Aripiprazole produced significantly greater improvements from baseline on other efficacy assessments compared with placebo, including Clinical Global Impression – Bipolar Version Severity and Improvement scores. The 30mg/day dose was maintained by 85% of aripiprazole-treated patients. Incidence of discontinuations due to adverse events was similar for aripiprazole (8.8%) and placebo (7.5%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight and was not associated with elevated serum prolactin or QTc prolongation. In conclusion, aripiprazole demonstrated superior efficacy to placebo in the treatment of patients with bipolar I disorder presenting with acute manic or mixed episodes, and exhibited a favourable safety and tolerability profile.

A Multiple-Center, Randomized, Double-Blind, Placebo- Controlled Study of Oral Aripiprazole for Treatment of Adolescents With Schizophrenia

OBJECTIVE Aripiprazole is a dopamine partial agonist approved for use in adults for short- and long-term treatment of schizophrenia and bipolar disorder. This study was designed to examine the acute efficacy, safety, and tolerability of aripiprazole for adolescents with schizophrenia. METHOD This was a 6-week multicenter, double-blind, randomized, placebo-controlled trial. Subjects 13 to 17 years old with a DSM-IV diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score of 70 or more were randomly assigned (1:1:1 ratio) to placebo or 10 or 30 mg/day of aripiprazole. The primary endpoint was mean change from baseline to endpoint (last observation carried forward) in PANSS total score. Assessments of safety and tolerability included spontaneously reported adverse events, extrapyramidal symptom scores, serum prolactin concentration, body weight, and metabolic measures. RESULTS Of 302 patients, 85% completed the 6-week study. The mean baseline PANSS score was 94.1. At the end of the study, both aripiprazole doses showed statistically significant differences from placebo in reduction in PANSS total score. Adverse events occurring in more than 5% of either aripiprazole group and with a combined incidence at least twice the rate for placebo were extrapyramidal disorder, somnolence, and tremor. Mean changes in prolactin were -8.45, -11.93, and -15.14 ng/ml for placebo and 10 mg and 30 mg of aripirazole, respectively. Mean body weight changes were -0.8, 0.0, and 0.2 kg for placebo and 10 mg and 30 mg of aripiprazole, respectively. CONCLUSION Both 10- and 30-mg/day doses of aripiprazole were superior to placebo in the acute treatment of adolescents with schizophrenia. Aripiprazole was generally well tolerated.

Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies.

Although most treatment research on bipolar disorder has focused on mania, depressive episodes occur more frequently among patients with bipolar disorder. Here, we report the results of 2 identically designed, 8-week, multicenter, randomized, double-blind, placebo-controlled studies (CN138-096 and CN138-146) to evaluate the efficacy and safety of aripiprazole monotherapy in outpatients with bipolar I disorder experiencing a major depressive episode without psychotic features. Patients were randomized to placebo or aripiprazole (initiated at 10 mg/d, then flexibly dosed at 5-30 mg/d based on clinical effect and tolerability). The primary end point was mean change from baseline to Week 8 (last observation carried forward) in the Montgomery-Åsberg Depression Rating Scale total score. In Studies 1 and 2, respectively, 186 and 187 patients were randomized to aripiprazole, and 188 and 188 to placebo. Although statistically significant differences were observed during Weeks 1 to 6, aripiprazole did not achieve statistical significance versus placebo at Week 8 in either study in the change in Montgomery-Åsberg Depression Rating Scale total (primary end point). In addition, despite early statistical separation on the Clinical Global Impressions Bipolar Version Severity of Illness-Depression score (key secondary end point), aripiprazole was not superior to placebo at end point. Aripiprazole was associated with a higher incidence of akathisia, insomnia, nausea, fatigue, restlessness, and dry mouth versus placebo. More patients discontinued with aripiprazole versus placebo in Study 1 (46.8% vs 35.1%) and Study 2 (41.2% vs 29.8%). Aripiprazole monotherapy-as dosed in this study design-was not significantly more effective than placebo in the treatment of bipolar depression at end point (Week 8).

Aripiprazole Augmentation in Major Depressive Disorder: A Double-Blind, Placebo-Controlled Study in Patients with Inadequate Response to Antidepressants

INTRODUCTION Effective management of major depressive disorder (MDD) continues to be a challenging task for psychiatrists and primary care physicians. This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials. METHODS Patients (N=1,147) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled (week 0); 827 received single-blind adjunctive placebo plus open-label antidepressant (escitalopram, fluoxetine, paroxetine controlled release, sertraline, or venlafaxine extended release) for 8 weeks to confirm inadequate response to antidepressants; 349 patients with inadequate response were randomized (1:1) to double-blind, adjunctive placebo (n=172) or adjunctive aripiprazole (n=177; 2-20 mg/day). Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) Total score from baseline (week 8) to endpoint (week 14). RESULTS Clinically significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole (-10.1) than placebo (-6.4; P<.001). Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo (week 14, 36.8% vs 18.9%; P<.001). Completion rates with adjunctive aripiprazole and placebo were high (83% vs. 87%) and discontinuations due to adverse events were low (6.2% vs 1.7%). CONCLUSION For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy, adjunctive therapies can significantly improve depressive symptoms. As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo. This, and previous studies, have shown that discontinuations due to adverse events were low and completion rates were high, and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe. This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to standard antidepressant monotherapy (ClinicalTrials.gov study NCT00105196).

Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study.

OBJECTIVES To determine the efficacy and safety of aripiprazole for the treatment of pediatric bipolar I disorder, manic or mixed episode, with or without psychotic features. METHOD Subjects were enrolled between March 2005 and February 2007 in a randomized, multicenter, double-blind 4-week study of aripiprazole 10 mg/d, aripiprazole 30 mg/d, and placebo. Subjects (n = 296) were 10 to 17 years old with a DSM-IV diagnosis of bipolar I disorder with current manic or mixed episodes, with or without psychotic features, and a Young Mania Rating Scale (YMRS) score > or = 20. The primary efficacy variable was change from baseline in the YMRS total score. RESULTS Both doses of aripiprazole were superior to placebo on the YMRS total score beginning at week 1 and continuing through week 4. Aripiprazole 10 mg and 30 mg were more effective than placebo on global improvement, mania, and overall bipolar illness outcome measures. Response ( > or = 50% reduction in YMRS total score) at week 4 was achieved by 44.8%, 63.6%, and 26.1% of subjects in the aripiprazole 10 mg, aripiprazole 30 mg, and placebo groups, respectively (P < .01 both doses vs placebo). Both doses were generally well tolerated. The most common adverse events were extrapyramidal disorder and somnolence; rates were higher for aripiprazole 30 mg compared with aripiprazole 10 mg. Average weight gain was not significantly different between the aripiprazole 10 mg (+0.82 kg) or 30 mg (+1.08 kg) groups compared with the placebo group (+0.56 kg) (P = .35 and P = .13, respectively). CONCLUSIONS Aripiprazole in daily doses of 10 mg or 30 mg is an effective and generally well-tolerated acute treatment for pediatric subjects with bipolar I mania or mixed episodes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00110461.

Aripiprazole monotherapy in the treatment of acute bipolar I mania: A randomized, double-blind, placebo- and lithium-controlled study

OBJECTIVES To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute bipolar mania. METHODS Patients with acute bipolar I mania (DSM-IV-TR: YMRS > or =20), manic or mixed (with or without psychotic features) were randomized to double-blind aripiprazole (15-30 mg/day; n=155), placebo (n=165) or lithium (900-1500 mg/day; n=160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks. The primary outcome was the mean change from baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12. RESULTS Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 (-4.3 vs.-2.8; p=0.003), and up to Week 3 (-12.6 vs. -9.0; p<0.001). Significant improvement in YMRS Total score was also seen with lithium versus placebo at Week 3 (-12.0 vs. -9.0; p=0.005). Improvements in YMRS Total score were maintained to Week 12 for aripiprazole (-14.5) and lithium (-12.7). Response rates at Week 3 were significantly higher with aripiprazole (46.8%) and lithium (45.8%) than placebo (34.4%; both p<0.05, LOCF); increasing to Week 12 with aripiprazole (56.5%) and lithium (49.0%). Most common adverse events with aripiprazole were headache, nausea, akathisia, sedation, and constipation; with lithium were nausea, headache, constipation, and tremor. CONCLUSIONS Aripiprazole provided statistically significant improvement of acute mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of improvement to Week 12 was similar with aripiprazole and lithium.

Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease

Psychosis affects at least 5% to 8% of medication‐treated patients with idiopathic Parkinsons disease (PD). Treatment options include reducing medications used for the treatment of PD‐related motor symptoms or introducing an atypical antipsychotic drug. Only clozapine has been demonstrated to be efficacious and tolerated in double‐blind controlled trials. This study evaluated the effect of aripiprazole, an atypical antipsychotic, on psychosis in PD in an open‐label pilot study. Fourteen patients meeting entry criteria were started on aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg as needed. Subjects were evaluated on the Unified Parkinsons Disease Rating Scale (UPDRS) part III for motor function, the Neuropsychiatric Inventory (NPI), and the Brief Psychiatric Rating Scale (BPRS) for psychiatric response. Statistically significant improvement in mean BPRS and positive BPRS subscales occurred with open‐label aripiprazole, but eight subjects discontinued the study due to worsened Parkinsonism (three), worsened psychosis (two), worsening of both (two), and lack of efficacy (one). While some patients had a favorable response, aripiprazole was associated with an exacerbation of motor symptoms. In this small study on psychosis in PD, aripiprazole did not appear promising.