An open-label, positron emission tomography study of the striatal D/D receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

Purpose: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D/D receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg.

Methods: Occupancy was measured at 4 and 23.

Comparison of adjunctive use of aripiprazole with bupropion or selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors: analysis of patients beginning adjunctive treatment in a 52-week, open-label study.

Background: This post hoc analysis assessed the safety, tolerability and effectiveness of long-term treatment with aripiprazole adjunctive to either bupropion or selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD).

Methods: Data from de novo patients (did not participate in 2 previous studies) in a 52-week, open-label safety study of adjunctive aripiprazole after documented inadequate response to 1-4 antidepressant treatments (ADTs; SSRI, SNRI, or bupropion) were analyzed post hoc. Assessments included safety and tolerability, sexual functioning (Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI]) and Clinical Global Impressions-Severity (CGI-S).

Stereoselective high-performance liquid chromatography and analytical method characterization of evacetrapib using a brush-type chiral stationary phase: a challenging isomeric separation requiring a unique eluent system.

Using HPLC chiral separation screening, various columns representing the polysaccharide, macrocyclic antibiotic and brush classes were assessed in multiple chromatographic modes for the separation of evacetrapib, a potential cardiovascular drug, from its enantiomer, two diastereomers and several impurities. Screening data consistently pointed to the brush-type Whelk-O 1 chiral column as most promising for this task. A systematic separation optimization process is outlined using the (S,S) Whelk-O 1 chiral column, first for the resolution of the isomers, and later including six potential impurities.

Aripiprazole treatment of irritability associated with autistic disorder and the relationship between prior antipsychotic exposure, adverse events, and weight change.

Objective: The purpose of this study was to evaluate the impact of prior antipsychotic exposure (PAE) on safety and tolerability outcomes in pediatric subjects receiving aripiprazole treatment.

Methods: This study was a post-hoc analysis of pooled data from two 8-week, double-blind, randomized, placebo-controlled studies evaluating aripiprazole for the treatment of irritability in pediatric subjects with autistic disorder, aged 6-17 years. Subjects were stratified by PAE; adverse events (AEs), and changes in weight, and metabolic measures were evaluated.

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.

Early antipsychotic response to aripiprazole in adolescents with schizophrenia: predictive value for clinical outcomes.

Objective: In adults with chronic schizophrenia, most symptom decreases occur in the first few weeks of antipsychotic treatment, and nonresponse at week 2 predicts a later nonresponse. The trajectory of antipsychotic response and the predictive value of early antipsychotic effects were investigated for ultimate outcome in adolescent schizophrenia, where such data are still lacking.

Method: This post hoc analysis of a 6-week, randomized, double-blinded trial of aripiprazole (n = 196) versus placebo (n = 98) evaluated if adolescents 13 to 17 years old with schizophrenia exhibited substantial symptomatic improvement to aripiprazole in the first few treatment weeks and whether early response (ER) versus early nonresponse (ENR) predicted clinically relevant outcomes.

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.

Clinical significance of treatment effects with aripiprazole versus placebo in a study of manic or mixed episodes associated with pediatric bipolar I disorder.

Objective: Published studies in adult and pediatric bipolar disorder have used different definitions of treatment response. This analysis aimed to compare different definitions of response in a large sample of children and adolescents.

Methods: Anexploratory analysis of a 4-week, multicenter, placebo-controlled study assessed patients (n=296; ages, 10-17 years) with an acute manic/mixed episode associated with BIPOLAR I disorder who were randomized to aripiprazole (10 or 30 mg/day) or placebo.

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.

Methods:   A randomized, double-blind, 30-week, placebo-controlled study of aripiprazole (10 or 30 mg/day) in youths (10-17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double-blind treatment (n = 210).

Dosing patterns of aripiprazole and quetiapine for adjunctive treatment of major depressive disorder (2006-2010).

The aim of this study was to investigate the dosing patterns of adjunctive quetiapine or adjunctive aripiprazole in the treatment of major depressive disorder from 2006 to 2010, and to evaluate the impact of Food and Drug Administration (FDA) approval on these dosing patterns. Patients included in the study were adults diagnosed with major depressive disorder, and treated with adjunctive aripiprazole or quetiapine between the years 2006 and 2010. The average daily dose and dose distribution were calculated and assessed statistically over the same time period.

Efficacy of adjunctive aripiprazole in major depressive disorder: a pooled response quartile analysis and the predictive value of week 2 early response.

Objective: To assess varying levels of response to aripiprazole adjunctive to standard antidepressant therapy (ADT) and the predictive value of an early response for a sustained response.

Method: This post hoc analysis of 3 similarly designed randomized, double-blind, placebo-controlled phase 3 studies investigated the efficacy and safety of adjunctive aripiprazole to standard ADT in patients with major depressive disorder (DSM-IV-TR criteria) who had a prior inadequate response to 1-3 ADTs (CN138-139 [September 2004-December 2006], CN138-163 [June 2004-April 2006], and CN138-165 [March 2005-April 2008]). Response levels were defined as percent decreases from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment, with a ≤ 25% decrease for minimal, > 25 to < 50% decrease for partial, ≥ 50% to < 75% decrease for moderate, and ≥ 75% decrease for a robust response to treatment.

Medical care costs and hospitalization in patients with bipolar disorder treated with atypical antipsychotics.

Background: A large proportion of costs associated with the treatment of bipolar disorder are attributable to patient hospitalization.

Objective: To investigate medical care costs and hospitalization rates among patients with bipolar disorder who were managed with aripiprazole compared with olanzapine, quetiapine, risperidone, or ziprasidone.

Methods: This retrospective cohort study assessed patients who were aged 18 to 64 years, diagnosed with bipolar disorder, and who were receiving therapy with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone.

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).

Trends in combination antipsychotic use among persons with commercial insurance: a data snapshot.

In this data snapshot, the IMS PharMetrics Database was examined to assess the prevalence of combination antipsychotic therapy for the years 2003 through 2009 among 122,349 commercially insured adult individuals with bipolar disorder, depression, or schizophrenia. Although all three diagnostic groups were associated with varying amounts of combination antipsychotic use that included aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone, persons with schizophrenia exhibited the highest rates. These findings indicate that from the perspective of "practice-based evidence," providers see value in combination therapy.

Cost-effectiveness of adjunctive therapy with atypical antipsychotics for acute treatment of major depressive disorder.

Background: While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown.

Objective: To examine the cost-effectiveness of aripiprazole, quetiapine, and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy.

Methods: Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone.

Impact of cost-sharing on treatment augmentation in patients with depression.

Objectives: Many patients with depression do not respond to first-line antidepressant therapy and may require augmentation with another concurrent treatment such as a second antidepressant, a stimulant, a mood stabilizer, or a second-generation antipsychotic (SGA). The objective of this study was to examine the relationship between patient cost-sharing and the use of augmentation among a sample of commercially insured patients.

Study Design: Retrospective observational study of adult patients diagnosed with depression and receiving antidepressant therapy (n = 48,807).

Adjunctive aripiprazole for depression: predictive value of early assessment.

Objectives: To determine whether early symptom improvement with adjunctive aripiprazole in major depressive disorder (MDD) predicts overall symptom remission.

Study Design: Post hoc pooled analysis of 3 randomized, double-blind studies evaluating efficacy, safety, and tolerability of adjunctive aripiprazole or placebo with standard antidepressant therapy (ADT) in inadequate responders to a prospective 8-week ADT and at least 1 historical ADT.

Methods: A multivariate logistic regression model was developed to determine factors predicting remission most strongly at the end point.

Improvement in functional outcomes with adjunctive aripiprazole versus placebo in major depressive disorder: a pooled post hoc analysis of 3 short-term studies.

Objective: To evaluate the effect of adjunctive aripiprazole to antidepressant therapy (ADT) on functional outcomes, as assessed by the Sheehan Disability Scale (SDS).

Method: A post hoc analysis of pooled data from 3 similarly designed randomized, placebo-controlled trials was conducted (CN138-139 [September 2004-December 2006], CN138-163 [June 2004-April 2006], and CN138-165 [March 2005-April 2008]). Patients with DSM-IV major depressive disorder who had a prior inadequate response to ADT received adjunctive aripiprazole or placebo to standard ADT.

Beneficial effects of adjunctive aripiprazole in major depressive disorder are not dependent on antidepressant therapy history: a post hoc analysis of 3 randomized, double-blind, placebo-controlled trials.

Objective: To determine whether switching within or between antidepressant therapy (ADT) classes prior to the use of adjunctive antipsychotic treatment is associated with different outcomes in major depressive disorder (MDD).

Method: This was a post hoc analysis of pooled data from 3 similar, multicenter, randomized, double-blind, placebo-controlled registrational studies of aripiprazole adjunctive to ADT conducted between September 2004 and April 2008. The trials comprised the following 3 phases: a 7- to 28-day screening phase, an 8-week single-blind prospective treatment phase, and a 6-week double-blind, randomized phase.

Association between second-generation antipsychotic medication half-life and hospitalization in the community treatment of adult schizophrenia.

Objective: To examine the effect of antipsychotic medication half-life on the risk of psychiatric hospital admission and emergency department (ED) visits among adults with schizophrenia.

Methods: Retrospective claims-based cohort study of adult Medicaid patients with schizophrenia who were prescribed second-generation antipsychotic monotherapy following hospital discharge between 1/1/04 and 12/31/06. Cox proportional hazards models were applied to compare adjusted hazards of mental disorder admission among patients treated with oral antipsychotics that have either a long [risperidone (t(1/2) = 20 h), olanzapine (t(1/2) = 30 h), aripiprazole (t(1/2) = 75 h)] (n = 1479) or short [quetiapine (t(1/2) = 6 h), ziprasidone (t(1/2) = 7 h)] (n = 837) half-life.

Comparison of second-generation antipsychotic treatment on psychiatric hospitalization in Medicaid beneficiaries with bipolar disorder.

Objective: To compare second-generation antipsychotics on time to and cost of psychiatric hospitalization in Medicaid beneficiaries with bipolar disorder.

Methods: Retrospective study using healthcare claims from 10 US state Medicaid programs. Included beneficiaries were aged 18-64, initiated a single second-generation antipsychotic (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone) between 1/1/2003-6/30/2008 (initiation date=index), and had a medical claim with an ICD-9-CM diagnosis code for bipolar disorder.

Intent-to-treat analysis of health care expenditures of patients treated with atypical antipsychotics as adjunctive therapy in depression.

Objective: To compare health care utilization and expenditures in patients with depression whose initial antidepressant (AD) treatment was augmented with a second-generation antipsychotic.

Methods: Claims data from January 1, 2001, through June 30, 2009, were used to select patients aged 18 to 64 years with depression treated with ADs augmented with aripiprazole, olanzapine, or quetiapine. Patients were required to have 6 months of continuous eligibility before the first AD prescription and 6 months after the second-generation antipsychotic augmentation (index) date.

Young mania rating scale line item analysis in pediatric subjects with bipolar I disorder treated with aripiprazole in a short-term, double-blind, randomized study.

Objective: The aim of this study was to evaluate the effects of aripiprazole treatment on individual Young Mania Rating Scale (YMRS) line items in pediatric subjects with manic or mixed episodes associated with bipolar I disorder to better understand the discrete symptom improvements.

Methods: This was a post hoc analysis of the YMRS line item data from a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Two hundred ninety-six eligible subjects were randomized to aripiprazole 10 mg/day (n = 98), aripiprazole 30 mg/day (n = 99), or placebo (n = 99).

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. Aripiprazole's 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 aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics.