Robert A. Forbes

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.

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 Intramuscular Depot as Maintenance Treatment in Patients With Schizophrenia: A 52-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVE To evaluate the efficacy and tolerability of a once-monthly intramuscular (IM) depot formulation of the dopamine partial agonist aripiprazole as maintenance treatment in adults meeting DSM-IV-TR schizophrenia criteria. METHOD The study was conducted from July 2008 until February 2011. Subjects requiring chronic treatment with an antipsychotic entered a 4- to 12-week oral stabilization phase and received oral aripiprazole (10-30 mg/d). Subjects meeting stability criteria for 4 weeks entered an IM-depot stabilization phase in which they received 400-mg aripiprazole-IM-depot injections every 4 weeks (single decrease to 300 mg permitted) with coadministration of oral aripiprazole tablets in the first 2 weeks. Subjects meeting stability criteria for 12 consecutive weeks were randomly assigned (2:1) to aripiprazole-IM-depot or placebo during a 52-week, double-blind maintenance phase. The primary outcome measure was time to exacerbation of psychotic symptoms/impending relapse (event). Safety and tolerability were also assessed. RESULTS 710 patients entered oral stabilization, 576 progressed to IM-depot stabilization, and 403 were randomly assigned to double-blind treatment. The study was terminated early because efficacy was demonstrated by the preplanned interim analysis (conducted after 64 events). Time to impending relapse was significantly delayed with aripiprazole-IM-depot treatment compared with placebo in both the interim analysis and the final analysis (P < .0001, log-rank test). The hazard ratio (placebo/aripiprazole-IM-depot) at final analysis was 5.03 (95% CI, 3.15-8.02). The rate of impending relapse was significantly lower with aripiprazole-IM-depot than placebo at endpoint (final analysis, 10.0% [n = 27/269] vs 39.6% [n = 53/134]). Improvements in Clinical Global Impressions-Severity of Illness scale and Positive and Negative Syndrome Scale total scores were maintained with aripiprazole-IM-depot treatment but showed significant worsening with placebo (change from double-blind baseline, P < .0001 for aripiprazole-IM-depot vs placebo). The most common treatment-emergent adverse events (occurring in ≥ 5% of aripiprazole-IM-depot subjects and greater than placebo) were insomnia, tremor, and headache. CONCLUSIONS Aripiprazole-IM-depot significantly delayed time to impending relapse compared with placebo and appears to be a well-tolerated maintenance treatment option for schizophrenia. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00705783.

Tolerability and pharmacokinetics of aripiprazole in children and adolescents with psychiatric disorders: an open-label, dose-escalation study.

Abstract This multicenter, open-label, sequential-cohort, dose-escalation study explored the tolerability and pharmacokinetics (PK) of aripiprazole up to the maximum approved adult dose (30 mg/d) in children and adolescents (aged 10-17 years) preferentially with primary psychiatric diagnoses of a bipolar or schizophrenia spectrum disorder. During a dose-escalation phase, patients received aripiprazole for up to 12 days using forced titration to achieve doses of 20, 25, or 30 mg/d. In the subsequent fixed-dose phase, patients received the maximum dose for that cohort for an additional 14 days. Tolerability in each fixed-dose cohort was assessed by measures including evaluation of spontaneously reported adverse events (AEs) and vital signs. If 4 of 6 patients tolerated the maximum dose for the cohort, the dose was considered tolerated, and enrollment in the next dose level began. Of 21 enrolled patients, 17 completed the fixed-dose phase. Aripiprazole treatment was generally well tolerated, with criteria for tolerability met for all doses tested. All patients experienced at least 1 AE, none of which met the regulatory criteria for a serious AE. There were no deaths or clinically relevant changes in vital signs or weight. Aripiprazole PK seemed to be linear across the tested dose range and was comparable with previous PK observations in adults. This study provides information regarding the tolerability and PK of aripiprazole up to the maximum adult dose in children and adolescents. These data provided support for exploration of a 30-mg/d dose in child/adolescent schizophrenia and bipolar disorder.

Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: An open-label, parallel-arm, multiple-dose study☆ , ☆☆

This 24-week, open-label, Phase Ib, parallel-arm, multiple-dose trial assessed the pharmacokinetics, safety and tolerability of a once-monthly injection of aripiprazole (aripiprazole once-monthly) in 41 subjects with schizophrenia. The objective was to determine if aripiprazole plasma concentrations (at doses of 200, 300 and 400mg) were within the therapeutic range observed for the oral tablet (10-30 mg). Completion rates were 36.4% (n=4/11), 50.0% (n=8/16) and 71.4% (n=10/14) for the 200mg, 300 mg and 400mg groups, respectively. Patients were stabilized on oral aripiprazole (10mg/day) before the first injection and received oral aripiprazole (10mg/day) concomitantly with the first dose of aripiprazole once-monthly for 14 days. Administration of aripiprazole once-monthly at doses of 300 and 400mg provided sustained mean aripiprazole plasma concentrations comparable with the concentration range observed following multiple consecutive daily doses of oral aripiprazole. In contrast, plasma concentrations following administration of aripiprazole once-monthly at a dose of 200mg were below the therapeutic range and pharmacokinetic parameters were not proportional to the administered dose compared with the 300 mg and 400mg doses. Treatment with aripiprazole once-monthly, at any dose, did not result in any clinically meaningful changes from baseline in extrapyramidal symptom scales, clinical laboratory tests, vital signs, or electrocardiogram parameters. The most common treatment-emergent adverse events were vomiting (13.3%, 300 mg; 14.3%, 400mg), injection site pain (28.6%, 400mg), upper respiratory tract infection (10%, 200mg; 6.7% 300 mg; 14.3%, 400mg) and tremor (6.7%, 300 mg; 21.4%, 400mg). In conclusion, aripiprazole once-monthly at doses of 300 and 400mg is a viable formulation for treatment of adults with schizophrenia.

Functional potencies of dopamine agonists and antagonists at human dopamine D2 and D3 receptors

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinsons disease, depression and schizophrenia.

Aripiprazole for the treatment of pediatric bipolar I disorder: A 30-week, randomized, placebo-controlled study

Objective:  To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder.

Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older patients: a pooled subpopulation analysis.

To evaluate the efficacy and safety of adjunctive aripiprazole compared with standard antidepressant therapy (ADT) for older patients with major depressive disorder (MDD) who demonstrated an incomplete response to standard antidepressant monotherapy.

In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors.

Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazoles dopamine D(2) and serotonin 5-HT(1A) receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazoles unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D(2S), D(2L), D(3) Ser-9 and D(3) Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D(2)/D(3) receptor partial agonists. Aripiprazoles intrinsic activity at dopamine D(2S) and D(2L) receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazoles intrinsic activity at dopamine D(3) Ser-9 and D(3) Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D(2)/D(3) receptors for clinical efficacy and safety.

Long-term safety and tolerability of aripiprazole once-monthly in maintenance treatment of patients with schizophrenia.

The aim of this study was to evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) for the maintenance treatment of schizophrenia. This long-term, pivotal study had four phases: oral conversion (phase 1, 4–6 weeks); oral stabilization (phase 2, 4–12 weeks); ARI-OM stabilization with coadministration of oral aripiprazole in the first 2 weeks (phase 3, 12–36 weeks); and a 52-week, randomized [phase 4, ARI-OM vs. placebo (2 : 1)], double-blind, maintenance phase. Safety was assessed across study phases by the time of first onset of adverse events, as were objective measures of extrapyramidal symptoms, fasting metabolic parameters, and body weight. Patient enrollment was phase 1=633; phase 2=710, of whom 210 entered phase 2 directly; phase 3=576; and phase 4=403 (ARI-OM, n=269; placebo, n=134). Adverse events (>5%) in any phase were insomnia, headache, anxiety, akathisia, increase in weight, injection-site pain, and tremor. Headache, somnolence, and nausea had a peak first onset within 4 weeks of treatment initiation. The incidence of extrapyramidal symptoms was similar in all phases. There were no unexpected changes in weight or shifts in fasting metabolic parameters across all study phases. ARI-OM had a safety and tolerability profile comparable with oral aripiprazole in maintenance treatment of schizophrenia.