Efficacy of adjunctive aripiprazole in patients with major depressive disorder who showed minimal response to initial antidepressant therapy.

To evaluate the efficacy of adjunctive aripiprazole in patients with minimal response to prior antidepressant therapy (ADT). Pooled data from three randomized, double-blind, placebo-controlled studies assessing the efficacy of adjunctive aripiprazole to ADT in patients with major depressive disorder who had a minimal response [< 25% reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS)] to an 8-week prospective ADT. During the 6-week, double-blind adjunctive phase, response was defined as at least 50% reduction in the MADRS score and remission as at least 50% reduction in MADRS score and a MADRS score ≤ 10. Rates were examined using analysis of covariance and Cochran-Mantel-Haenszel tests. Kaplan-Meier curves were used to calculate time to response and remission. Of 1038 patients, 72% (n=746) exhibited a minimal response to ADT (ADT minimal responder). Time to response and remission were significantly shorter for ADT minimal responders receiving aripiprazole+ADT versus adjunctive placebo+ADT. ADT minimal responders on aripiprazole+ADT showed significantly greater improvements in MADRS score at endpoint compared with minimal responders on placebo+ADT (-10.3 vs. -6.5, P<0.0001). In addition, ADT minimal responders exhibited significantly higher response rates with aripiprazole+ADT than placebo+ADT (36 vs. 19%, respectively, P<0.0001) and higher remission rates (24 vs. 12%, respectively, P<0.0001). The numbers needed to treat with aripiprazole+ADT were six for response and eight for remission. Aripiprazole augmentation had a rapid and clinically meaningful effect in ADT minimal responders.

Safety and tolerability of aripiprazole in the treatment of irritability associated with autistic disorder in pediatric subjects (6-17 years old):results from a pooled analysis of 2 studies.

BACKGROUND: With increasing use of atypical antipsychotics among pediatric patients, detailed information about safety and tolerability is crucial. METHOD: Data were pooled from two 8-week, randomized, double-blind, multicenter, parallel-group trials comparing aripiprazole versus placebo in subjects aged 6 to 17 years with irritability associated with DSM-IV-TR-diagnosed autistic disorder: one flexibly dosed (aripiprazole 2-15 mg/d; target of 5, 10, or 15 mg/d), the other fixed-dose (aripiprazole 5, 10, or 15 mg/d). The first was conducted from June 2006-April 2008, and the second, from June 2006-June 2008. Adverse events were characterized with respect to incidence, duration, severity, timing of peak incidence of onset, and dose-response relationship. Extrapyramidal symptoms, drooling, and metabolic parameters were evaluated. RESULTS: Three hundred thirteen subjects comprised the safety sample (aripiprazole 212, placebo 101). Discontinuations due to adverse events with aripiprazole versus placebo were, overall, 10.4% versus 6.9%; subjects 6-12 years: 10.8% versus 5.1%; and subjects 13-17 years: 8.9% versus 13.6%. Common adverse events with aripiprazole versus placebo included sedation (20.8% vs 4.0%), fatigue (16.5% vs 2.0%), vomiting (13.7% vs 6.9%), increased appetite (12.7% vs 6.9%), somnolence (10.4% vs 4.0%), and tremor (9.9% vs 0.0%). Most adverse events were mild or moderate and occurred early. Only fatigue showed a dose-response relationship (P < .05). Mean body weight change (last observation carried forward, 1.6 vs 0.4 kg) was higher with aripiprazole than placebo (P < .001). There were no between-treatment differences in metabolic changes. The extrapyramidal symptom-related adverse event incidence with aripiprazole versus placebo was, overall, 20.8% vs 9.9%; the incidence of akathisia-related events was 3.3% vs 8.9%. CONCLUSIONS: Aripiprazole was generally safe and well tolerated in subjects (6-17 years) with irritability associated with autistic disorder in these 8-week studies; clinicians should be aware of this clinical profile and strategies to manage adverse events if they occur. TRIAL REGISTRATION: clinicaltrials.gov Identifiers NCT00332241 and NCT00337571.

Functional G-protein heterotrimers are associated with vesicles of putative glutamatergic terminals: implications for regulation of transmitter uptake.

Changes in the vesicular transmitter content modulate synaptic strength and may contribute to synaptic plasticity. Several transporters mediating transmitter uptake into small synaptic vesicles (SSVs) have been identified but their regulation is largely unknown. Here we show by quantitative immunoelectron microscopy that the heterotrimeric G-protein subunits Galphao(2), Galpha(q/11), Gbeta(2), and Ggamma(7) are associated with vesicle-containing areas in terminals of cerebellar parallel fibers. These terminals also contain the vesicular glutamate transporter 1 (VGLUT1). In contrast, SSVs of climbing fiber terminals that contain VGLUT2 express one of the Gbeta-subunits Gbeta(1), Gbeta(3), or Gbeta(4), Ggamma(7), and one Galpha-subunit, probably Galphao(2). Glutamate uptake into cerebellar SSVs was inhibited by more than 50% by GMppNp, an activator of G proteins. Thus, vesicle populations with different subtypes of vesicular glutamate transporters contain functional G proteins with distinct subunit profiles. Heterotrimeric G proteins may play an important role in the control of vesicular filling.