W. Landsberg

Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial

Clozapine is associated with significant weight gain and metabolic disturbances. This multicentre, randomized study comprised a double-blind, placebo-controlled treatment phase of 16 wk, and an open-label extension phase of 12 wk. Outpatients who met DSM-IV-TR criteria for schizophrenia, who were not optimally controlled while on stable dosage of clozapine for > or =3 months and had experienced weight gain of > or =2.5 kg while taking clozapine, were randomized (n=207) to aripiprazole at 5-15 mg/d or placebo, in addition to a stable dose of clozapine. The primary endpoint was mean change from baseline in body weight at week 16 (last observation carried forward). Secondary endpoints included clinical efficacy, body mass index (BMI) and waist circumference. A statistically significant difference in weight loss was reported for aripiprazole vs. placebo (-2.53 kg vs. -0.38 kg, respectively, difference=-2.15 kg, p<0.001). Aripiprazole-treated patients also showed BMI (median reduction 0.8 kg/m(2)) and waist circumference reduction (median reduction 2.0 cm) vs. placebo (no change in either parameter, p<0.001 and p=0.001, respectively). Aripiprazole-treated patients had significantly greater reductions in total and low-density lipoprotein (LDL) cholesterol. There were no significant differences in Positive and Negative Syndrome Scale total score changes between groups but Clinical Global Impression Improvement and Investigators Assessment Questionnaire scores favoured aripiprazole over placebo. Safety and tolerability were generally comparable between groups. Combining aripiprazole and clozapine resulted in significant weight, BMI and fasting cholesterol benefits to patients suboptimally treated with clozapine. Improvements may reduce metabolic risk factors associated with clozapine treatment.

Defining the minimal clinically important difference (MCID) of the Heinrichs–carpenter quality of life scale (QLS)

To determine the Minimal Clinically Important Difference (MCID) of the Heinrichs–Carpenter Quality of Life Scale (QLS). Data from the “Schizophrenia Trial of Aripiprazole” (STAR) study were used in this analysis. The MCID value of the QLS total score was estimated using the anchor‐based method. These findings were substantiated/validated by comparing the MCID estimate to other measurements collected in the study. Half of the patients (49%) showed improvement in Clinical Global Impressions of Severity (CGI‐S) during the trial. The estimated MCID of the QLS total score was 5.30 (standard error: 2.60; 95% confidence interval: [0.16; 10.43]; p < 0.05). Patients were divided into two groups: “QLS improvers” (QLS total score increased ≥ six points) and “non‐improvers”. The QLS improvers had significantly better effectiveness and reported significantly higher levels of preference for their current medications. There was a statistically significant difference between the two groups in the change in two of the four domains of QLS; “Interpersonal relations” and “Intrapsychic foundations” domains during the study. These findings support the value of the estimated MCID for the QLS and may be a useful tool in evaluating antipsychotic treatment effects and improving long‐term patient outcomes in schizophrenia. Copyright

Initiation of aripiprazole once-monthly in patients with schizophrenia

Abstract Objective: This article provides rationale for recommendations on how to initiate aripiprazole once-monthly 400 mg (AOM 400), an injectable suspension, in patients with schizophrenia, supported by pharmacokinetic (PK) data and based on clinical studies. Methods: An overview of data from a PK study, PK simulations, controlled clinical trials, and a naturalistic study is presented. Results: Pharmacokinetic data support 400 mg as the starting and maintenance dose of AOM; the plasma concentration profile of aripiprazole after initiating AOM 400 was consistent with therapeutic concentrations observed with oral aripiprazole 10 to 30 mg/d. PK simulations and observed data from a single-dose clinical trial indicate that median aripiprazole plasma concentrations reach therapeutic levels within 7 days of initiating AOM 400. Because of interpatient variability, a 14-day overlap with oral aripiprazole or another antipsychotic medication is considered sufficient to ensure therapeutic concentrations. In clinical studies, when patients initiated AOM 400 with concomitant oral aripiprazole (10–15 mg/d based on stabilized dose) or continued their previous antipsychotic for ≤14 days, mean aripiprazole plasma concentration after 4 weeks (93 to 112 ng/mL) was in range of the therapeutic window established for aripiprazole (94.0–534.0 ng/mL). In clinical studies, the 400-mg starting dose of AOM was efficacious and well tolerated. Across studies of variable duration and design, 1296/1439 (90.1%) patients initiated AOM 400 and required no dose change. Overall rates of discontinuation due to lack of efficacy across clinical studies were low in patients treated with AOM 400 (range, 2.3%–10.0%). In a post hoc analysis from a naturalistic study, cross-titration from other oral antipsychotic therapies to oral aripiprazole before initiating AOM 400 was better tolerated with a >1- to 4-week cross-titration period versus a ≤1-week period, as evidenced by lower rates of discontinuation due to adverse events during cross-titration (2.7% [7/239] vs 10.4% [5/48]). The efficacy and safety of AOM 400 in the month after initiation in the pivotal maintenance studies were comparable between subpopulations of patients previously stabilized on 10- or 30-mg doses of oral aripiprazole. Conclusions: Findings from PK data, PK simulations, and clinical studies all support that 400 mg is the appropriate initiation dose of AOM for patients with schizophrenia. When switching to oral aripiprazole before initiating AOM 400, tapering the prior oral antipsychotic while titrating up the oral aripiprazole dose (target dose 10–30 mg/d) over >1 to 4 weeks may be an effective strategy. The efficacy, safety, and tolerability of AOM 400 were comparable regardless of whether patients were previously stabilized on oral aripiprazole 10 or 30 mg/d or other antipsychotic therapy and continued to receive the same oral antipsychotic for the first 14 days after initiating AOM 400.

Efficacy and safety of aripiprazole once-monthly in obese and nonobese patients with schizophrenia: a post hoc analysis

Purpose To assess the efficacy and safety of aripiprazole once-monthly 400 mg (AOM 400), an extended-release injectable suspension of aripiprazole, in obese and nonobese patients. Patients and methods This post hoc analysis of a 38-week randomized, double-blind, active-controlled, noninferiority study (NCT00706654) compared the clinical profile of AOM 400 in obese (body mass index [BMI] ≥30 kg/m2) and nonobese (BMI <30 kg/m2) patients with schizophrenia for ≥3 years. Patients were randomized 2:2:1 to AOM 400, oral aripiprazole 10–30 mg/d, or aripiprazole once-monthly 50 mg (AOM 50 mg) (subtherapeutic dose). Within obese and nonobese patient subgroups, treatment-group differences in Kaplan–Meier estimated relapse rates at week 26 (z-test) and in observed rates of impending relapse through week 38 (chi-square test) were analyzed. Treatment-emergent adverse events (TEAEs) (>10% in any treatment group) were summarized. Results At baseline of the randomized phase, obesity rates were similar among patients randomized to AOM 400 (n=95/265, 36%), oral aripiprazole (n=95/266, 36%), and AOM 50 mg (n=43/131, 33%). In both obese and nonobese patients, relapse rates through week 38 for patients randomized to AOM 400 (obese, 7.4%; nonobese, 8.8%) were similar to those in patients on oral aripiprazole (obese, 8.4%; nonobese, 7.6%), whereas relapse rates were significantly lower with AOM 400 versus AOM 50 mg (obese, 27.9% [P=0.0012]; nonobese, 19.3% [P=0.0153]). The most common TEAEs with AOM 400 in obese and nonobese patients were insomnia (12.6% and 11.2%), headache (12.6% and 8.2%), injection site pain (11.6% and 5.3%), akathisia (10.5% and 10.6%), upper respiratory tract infection (10.5% and 4.7%), weight increase (10.5% and 8.2%), and weight decrease (6.3% and 11.8%). Within the AOM 400 group, 7.6% of patients who were nonobese at baseline became obese, and 17.9% of obese patients became nonobese during randomized treatment. Conclusion The clinical profile of AOM 400 was similar in obese and nonobese patients.

EPA-0809 - Aripiprazole once-monthly for the treatment of schizophrenia in obese and non-obese patients; a post-hoc analysis

Objective To evaluate efficacy and safety of aripiprazole once-monthly 400mg (AOM-400mg), an extended release injectable suspension of aripiprazole, in obese (BMI =30kg/m 2 ) and non-obese (BMI 2 ) patients with schizophrenia. Methods Data from a 38-week, double-blind, active-controlled, non-inferiority study (NCT00706654); randomisation (2:2:1) to AOM-400mg, oral aripiprazole (10-30mg/day) (ARI), or aripiprazole once-monthly 50mg (AOM-50mg) assessing the efficacy and safety of AOM in patients requiring chronic antipsychotic treatment were used for this post-hoc analysis. We report the overall relapse rates in the 38-week randomized phase. Comparisons of overall relapse rates were analyzed using the Chi-squared test. Results 662 patients were randomized to: AOM-400mg (n=265); ARI (n=266); or AOM-50mg (n=131). Of these, the following were obese: AOM- 400mg: n=95; ARI: n=95; AOM-50mg: n=43. In the obese patients, the overall relapse rate was significantly (p=0.0012) lower with AOM-400mg (7.4%) than with AOM-50mg (27.9%). The difference between AOM-400mg and ARI (8.4%) was not significantly different. In the non-obese patients, the overall relapse was significantly (p=0.0153) lower with AOM-400mg (8.8%) than with AOM-50mg (19.3%). The difference between AOM-400mg and ARI (7.6%) was not significantly different. For patients treated with AOM-400mg, the most common TEAEs (>10% in any group) are presented in Table 1. Table 1 . TEAE: AOM-400mg Obese Non-obese Insomnia 12.6% 11.2% Headache 12.6% 8.2% Injection site pain 11.6% 5.3% Akathesia 10.5% 10.6% Upper respiriatory tract infection 10.5% Weight increase 10.5% 8.2% Weight decrease 6.3% 11.8% Conclusions The efficacy and tolerability of aripiprazole once-monthly 400mg were similar in both the obese and non-obese subgroups. Disclosure Supported by Otsuka Pharmaceutical Development & Commercialization, Inc. , and H. Lundbeck A/S

PW01-60 - Similar short- and long-term efficacy results of aripiprazole in post-pubertal adolescents (ages 15-17) and adults with schizophrenia

Introduction Available data suggest that sex hormone levels during puberty may affect symptom onset and expression, treatment responsiveness and outcomes in schizophrenia, whereas post-pubertal adolescents may have a similar clinical presentation and treatment response compared to adults with schizophrenia. Objectives Post-hoc analyses were conducted to assess the similarity of short- and long-term efficacy between post-pubertal adolescents and adults with schizophrenia treated with aripiprazole. Methods Based on available European epidemiologic data, a cut-off age of 15 years was used to isolate a subgroup of mostly post-pubertal adolescents with schizophrenia in aripiprazole clinical studies. Outcome measures from this subgroup (ages 15-17; n=147) were then compared to outcomes from one adult study (n=853) on short and long-term measures of efficacy, including PANSS scores, response rates, and remission rates. Results Comparable short and long-term treatment effects were observed on the PANSS total and subscale scores, demonstrated by overlapping 95% confidence intervals (mean change from baseline in PANSS total score (OC dataset): at week 6 in adults: -27,7; in adolescents 15-17 yr: -29,6; at week 30 in adults: -39,2; in adolescents 15-17 yr: -36). Percent of adolescents achieving response (defined as ≥ 30% decrease in PANSS total score from baseline) at 32 weeks (80,2%) on open label treatment was similar to that in adult studies at week 34 (80%) on double blind treatment (OC dataset). Conclusions Adolescents with schizophrenia (ages 15-17, mostly post-pubertal) demonstrate a positive treatment response in short-term and long-term studies which is similar to that observed in the adult patient population.