A randomized, double-blind, placebo-controlled study of the kappa opioid receptor antagonist, CERC-501, in a human laboratory model of smoking behavior.

Preclinical data indicate that selective kappa opioid receptor antagonists reduce nicotine self-administration and withdrawal symptoms. The aim of the current study was to determine whether treatment with CERC-501, an orally available, potent, and selective kappa opioid receptor antagonist, could alleviate nicotine withdrawal and craving and mitigate mood alterations associated with nicotine withdrawal in humans. Healthy, adult cigarette smokers were enrolled into this randomized, multisite, double-blind, placebo-controlled, crossover study. Participants completed two 8-day treatment phases during which they received either CERC-501 (15 mg, p.o., once daily) or placebo. On the seventh day of each dosing phase, participants were admitted as inpatients for an 18-hour cigarette abstinence period followed by experimental testing. The primary outcome measures were (a) performance on the McKee Smoking Lapse test (ie, latency to smoke in exchange for money) and (b) number of cigarettes self-administered during a 60-minute ad lib smoking period. Other outcomes included measures of craving, mood, anxiety, nicotine withdrawal, and subjective effects of cigarette smoking. A total of 71 participants who smoked an average of approximately 23 cigarettes per day were enrolled, and 56 subjects completed the study. CERC-501 was well tolerated, but it did not significantly alter the latency to start smoking (CERC-501: 16.5 min vs placebo: 17.7 min) or the number of cigarettes smoked (CERC-501: 3.3 cigarettes vs placebo: 3.1 cigarettes). Compared with placebo, CERC-501 also did not affect cigarette craving, mood, anxiety, nicotine withdrawal, or subjective effects of smoking. These findings do not support a role for CERC-501 in the treatment of nicotine use disorder.

BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial.

BACKGROUND: BMS-927711 is a potent, selective, competitive human calcitonin gene-related peptide (CGRP) receptor antagonist that has shown in vivo efficacy without vasoconstrictor effect. The objective of the current study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine. METHODS: In this randomized, double-blind, placebo controlled, dose-ranging study, 885 patients were randomized using an adaptive design to one of the following dose groups: BMS-927711 (10, 25, 75, 150, 300, or 600 mg); sumatriptan 100 mg (active comparator); and placebo. Patients were treated for a single migraine attack. The primary endpoint was pain freedom at two hours post-dose. RESULTS: Of patients who took the study drug, 799 had one post-randomization efficacy evaluation. Significantly more patients in the BMS-927711 75 mg (31.4%, P = 0.002), 150 mg (32.9%, P < 0.001), and 300 mg (29.7%, P = 0.002) groups and the sumatriptan group (35%, P < 0.001) had pain freedom at two hours post-dose versus placebo (15.3%). For the secondary endpoint of sustained pain freedom from two to 24 hours post-dose, BMS-927711 doses (25-600 mg) were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no patients discontinued because of AEs. CONCLUSIONS: BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Efficacy of adjunctive aripiprazole in patients with major depressive disorder whose symptoms worsened with antidepressant monotherapy.

INTRODUCTION: Efficacy of depression treatments, including adjunctive antipsychotic treatment, has not been explored for patients with worsening symptoms after antidepressant therapy (ADT). METHODS: This post-hoc analysis utilized pooled data from 3 similarly designed, randomized, double-blind, placebo-controlled trials that assessed the efficacy, safety, and tolerability of adjunctive aripiprazole in patients with major depressive disorder with inadequate response to ADT. The studies had 2 phases: an 8-week prospective ADT phase and 6-week adjunctive (aripiprazole or placebo) treatment phase. This analysis focused on patients whose symptoms worsened during the prospective 8-week ADT phase (worsening defined as >0% increase in Montgomery-Åsberg Depressive Rating Scale [MADRS] Total score). During the 6-week, double-blind, adjunctive phase, response was defined as ≥50% reduction in MADRS Total score and remission as ≥50% reduction in MADRS Total score and MADRS score ≤10. RESULTS: Of 1065 patients who failed to achieve a response during the prospective phase, 160 exhibited worsening of symptoms (ADT-Worseners), and 905 exhibited no change/reduction in MADRS scores (ADT-Non-worseners). Response rates for ADT-Worseners at endpoint were 36.6% (adjunctive aripiprazole) and 22.5% (placebo). Similarly, response rates at endpoint for ADT-Non-worseners were 37.5% (adjunctive aripiprazole) and 22.5% (placebo). Remission rates at endpoint for ADT-Worseners were 25.4% (adjunctive aripiprazole) and 12.4% (placebo). For ADT-Non-worseners, remission rates were 29.9% (adjunctive aripiprazole) and 17.4% (placebo). CONCLUSION: These results suggest that adjunctive aripiprazole is an effective intervention for patients whose symptoms worsen during antidepressant monotherapy. The results challenge the view that benefits of adjunctive therapy with aripiprazole are limited to partial responders to ADT.

Rationale for Adjunctive Treatment Targeting Multiple Mechanisms in Schizophrenia.

Importance: Schizophrenia is a complex syndrome with taxing symptoms and for which treatment challenges remain. Current dopamine D2 receptor-blocking antipsychotics have well-known limitations, including ineffectively treating across all symptom domains and generating common side effects such as motor disturbances, weight gain, and metabolic dysfunction. New approaches are sorely needed to address the continued unmet treatment needs for individuals living with schizophrenia.Observations: Although current antipsychotic drugs indicated for the treatment of schizophrenia interact with various neurotransmitter receptors, they all commonly act as dopamine D2 receptor antagonists or partial agonists. While antipsychotics primarily relieve positive symptoms, residual positive symptoms are still common, and management of negative symptoms and cognitive impairment remains an unmet need. Problematic side effects are common with current agents and can contribute to nonadherence. In addition to alterations in dopaminergic pathways, increasing evidence indicates that the pathophysiology of schizophrenia also includes dysfunction in other neurotransmitter systems including glutamate, acetylcholine, serotonin, and γ-aminobutyric acid. While the pathophysiology of schizophrenia is complex, treatments with novel pharmacologic actions that target these systems are of interest as adjunctive treatment for individuals with schizophrenia.Conclusion and Relevance: An unmet need exists for effective treatment of all the core symptoms of schizophrenia. Novel antipsychotics with a nondopaminergic mechanism of action may be useful candidates for antipsychotic adjunctive treatment in people with schizophrenia who are showing inadequate responses, treatment resistance, or low tolerance to dopamine D2 receptor-blocking antipsychotics.

Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392).

OBJECTIVES: To evaluate the efficacy and safety of aripiprazole (ARI) plus lamotrigine (LTG) compared with placebo (PBO) plus LTG, for long-term treatment in bipolar I disorder patients with a recent manic/mixed episode. METHODS: After a 9-24 week stabilization phase receiving single-blind ARI (10-30 mg/day) plus open-label LTG (100 or 200 mg/day), patients maintaining stability (Young Mania Rating Scale/Montgomery-Åsberg Depression Rating Scale total scores ≤ 12) with ARI+LTG for eight consecutive weeks were randomized to continue on double-blind ARI + LTG or to receive PBO + LTG, after removing ARI from ARI + LTG treatment, and followed up for 52 weeks. The primary outcome measure was time from randomization to relapse into a manic/mixed episode. RESULTS: A total of 787 patients entered the stabilization phase, and 351 were randomized to ARI + LTG (n = 178) or PBO + LTG (n = 173). ARI + LTG yielded a numerically longer time to manic/mixed relapse than PBO + LTG, but it was not statistically significant [hazard ratio (HR) = 0.55; 95% confidence interval (CI): 0.30-1.03; p = 0.058]. The estimated relapse rates at Week 52 were 11% for ARI + LTG and 23% for PBO + LTG, yielding a number needed-to-treat of nine (95% CI: 5-121). The three most common adverse events were akathisia [10.8%, 6.1% for ARI + LTG and PBO + LTG, respectively; number needed-to-harm (NNH) = 22], insomnia (7.4%, 11.5%), and anxiety (7.4%, 3.6%). Mean weight change was 0.43 kg and -1.81 kg, respectively (last observation carried forward, p = 0.001). Rates of ≥ 7% weight gain with ARI + LTG and PBO + LTG were 11.9% and 3.5%, respectively (NNH = 12). CONCLUSIONS: ARI + LTG delayed the time to manic/mixed relapse but did not reach statistical significance. Safety and tolerability results revealed no unexpected adverse events for ARI combination with LTG.

Aripiprazole in bipolar depression: a pooled, post-hoc analysis by severity of core depressive symptoms.

OBJECTIVE: This post-hoc analysis of pooled data from two similarly designed trials assessed the impact of aripiprazole monotherapy vs. placebo on treatment outcomes based on baseline severity of core depressive symptoms in patients with bipolar I disorder. METHODS: Patients were classified as severely depressed (Bech-6 Total score > 15) or less severely depressed (Bech-6 Total score < 15). Efficacy was assessed by mean changes in Montgomery-Åsberg Depression Rating Scale (MADRS) Total and MADRS-6 subscale scores from baseline to endpoint using a mixed model repeated measures analysis. RESULTS: A total of 133 patients (n = 62 on active aripiprazole) were classified as severely depressed and 612 patients (n = 309 aripiprazole) as less severely depressed. At endpoint, the mean MADRS Total score reduction for severely depressed patients receiving aripiprazole compared with placebo was -19.4 vs. -15.4 (P = 0.14), whereas MADRS-6 subscale score reduction for patients receiving aripiprazole compared with placebo was -13.8 vs. -10.3 (P = 0.07). Adverse event profiles were similar between the two severity groups. CONCLUSIONS: Symptomatic improvements assessed here suggest that aripiprazole monotherapy at the doses studied may provide some improvements in core symptoms of depression in patients with bipolar I disorder who were more severely depressed.

Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study.

OBJECTIVES: To evaluate the efficacy and safety of aripiprazole (ARI) adjunctive to lithium (Li) or valproate (Val) (ARI+Li / Val) compared with placebo (PLB) adjunctive to Li or Val (PLB+Li / Val) as maintenance therapy for patients with bipolar I disorder who had an inadequate response to Li or Val monotherapy. METHODS: Patients with a current manic/mixed episode received Li or Val for at least 2 weeks. Those with an inadequate response [Young Mania Rating Scale (YMRS) total score ≥ 16 and ≤ 35% decrease from baseline at 2 weeks] received adjunctive single-blind ARI plus mood stabilizer. Patients who achieved stability [YMRS and Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤ 12] for 12 consecutive weeks were randomized to double-blind ARI (10-30 mg/day) or PLB+Li / Val. Relapse was monitored for 52 weeks. Adverse events (AEs) were also evaluated. RESULTS: A total of 337 patients were randomized to ARI+ Li / Val (n=168) or PLB+Li / Val (n=169). The Kaplan-Meier relapse rate at 52 weeks was 17% with ARI+Li / Val and 29% with PLB+Li / Val. ARI+Li / Val significantly delayed time to any relapse compared with PLB+Li / Val; hazard ratio=0.54 (95% confidence interval: 0.33-0.89; log-rank p=0.014). The most common AEs ≥ 5%(ARI+Li / Val versus PLB+Li / Val) were headache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%), tremor (6.0% versus 2.4%), and insomnia (5.4% versus 9.6%). CONCLUSIONS: Continuation of ARI+Li / Val treatment increased the time to relapse to any mood episode compared with Li or Val monotherapy, and was relatively well tolerated during the one-year study. These findings suggest that there is a long-term benefit in continuing ARI adjunctive to a mood stabilizer after sustained remission is achieved.

A pooled MADRS/IDS cross-correlation analysis: clinician and patient self-report assessment of improvement in core depressive symptoms with adjunctive aripiprazole.

BACKGROUND: These analyses aimed to examine the pattern of improvement in depression symptoms with adjunctive aripiprazole. METHODS: Data were pooled (724 subjects: n = 356 placebo, n = 368 aripiprazole) from 2 double-blind, 6-week aripiprazole studies. Pearson correlation coefficients (r) were calculated between changes on the Montgomery-Asberg Depression Rating Scale (MADRS) line items and selected Inventory of Depressive Symptomatology (IDS) line items using last observation carried forward. The magnitude of change was expressed as a between-group effect size (ES). RESULTS: At end point, adjunctive aripiprazole demonstrated significant improvement versus antidepressant therapy alone in 8 of the 10 MADRS items (MADRS total score Cohen effect size = 0.37) and 12 of the 30 IDS items (IDS total score Cohen ES = 0.18). Analysis of correlation data identified 5 MADRS items assessing mood, lassitude, inability to feel, self-worth, and suicidal thoughts that correlated with similar IDS items; these showed a similar pattern of rapid, sustained response to adjunctive aripiprazole and a similar ES. Other symptoms associated with depression (tension associated with feeling anxious, irritability, and lack of concentration) did not show statistically significant changes on either scale at end point. The IDS identified an additional 3 important depression-related symptoms (diminished libido, view of self, and interpersonal sensitivity) that showed significant rapid and sustained improvement with adjunctive aripiprazole. CONCLUSIONS: This cross-correlation analysis confirmed that improvement in core depressive symptoms with adjunctive aripiprazole was identified by both clinicians and patients. Clinically, these changes were maintained during the study. Theoretically, these findings lead to important questions regarding neurochemical changes produced by aripiprazole when used in combination with antidepressants.

Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study.

BACKGROUND: Well-tolerated and effective therapies for bipolar mania are required. AIMS: To evaluate the efficacy and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with bipolar I disorder experiencing manic or mixed episodes. METHOD: Patients were randomised to double-blind aripiprazole (15 or 30 mg/day; n=167), placebo (n=153) or haloperidol (5-15 mg/day, n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated patients remained on masked treatment for 9 additional weeks. RESULTS: Mean change in Young Mania Rating Scale Total score (primary end-point) at week 3 was significantly greater with aripiprazole (-12.0; P<0.05) and haloperidol (-12.8; P<0.01) than with placebo (-9.7). Improvements were maintained to week 12 for aripiprazole (-17.2) and haloperidol (-17.8). Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (53.3% v. 23.5%). CONCLUSIONS: Clinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.

Effects of aripiprazole on prolactin levels in subjects with schizophrenia during cross-titration with risperidone or olanzapine: analysis of a randomized, open-label study.

Hyperprolactinemia, an adverse effect associated with the use of typical antipsychotics and the atypical antipsychotic risperidone, has both acute and chronic clinical consequences. One option for clinical management is switching to an agent with a lower liability for inducing hyperprolactinemia. This post-hoc sub-analysis of an 8-week, open-label study in outpatients with schizophrenia (CN138-215) examined short-term effects on prolactin levels during a switch from risperidone or olanzapine to aripiprazole 30 mg/day. Three switch strategies were used: (I) immediate aripiprazole initiation with simultaneous immediate discontinuation of olanzapine/risperidone; (II) immediate aripiprazole initiation while tapering off olanzapine/risperidone over 14 days; (III) titrating aripiprazole upwards while tapering off olanzapine/risperidone over 14 days. Changes in prolactin levels from baseline to each last observation carried forward time point were compared with t-tests using Bonferroni correction for multiple comparisons. This sub-analysis included 269 subjects: 105 previously treated with risperidone; 164 previously treated with olanzapine. Mean baseline prolactin levels (ng/mL) were within normal range for the three olanzapine groups (Group-I, 11.7; Group-II, 13.2; Group-III, 11.2), but above normal for the risperidone groups (Group-I, 39.7; Group-II, 48.5; Group-III, 33.5). Following aripiprazole initiation, mean prolactin levels decreased significantly (p<0.001) at week-1 and were maintained to week-8 in all groups irrespective of prior treatment. Previously elevated prolactin levels in the risperidone groups were reduced to within normal range within 1 week, irrespective of switching strategy. Tolerability was good regardless of prior medication or switching strategy. Overall, rapid decreases of prolactin levels were achieved safely with all three aripiprazole switching strategies. Reversal of hyperprolactinemia during the crossover period indicates the safety and potential utility of aripiprazole addition in patients with elevated prolactin.

Metabolic assessment of aripiprazole as adjunctive therapy in major depressive disorder: a pooled analysis of 2 studies.

In 2 identical multicenter, double-blind, placebo-controlled trials, an 8-week prospective treatment phase to ensure inadequate response to standard antidepressants was followed with 6 weeks of aripiprazole (2-20 mg/d) or placebo, plus a standard antidepressant. This pooled analysis involving 737 patients across the 2 studies evaluated the metabolic effects of adjunctive aripiprazole in patients with major depressive disorder. Outcomes included mean change from end of prospective treatment phase to endpoint in body weight, waist circumference, fasting levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides (TG), fasting plasma glucose, and glycosylated hemoglobin (hemoglobin A1C). Logistic regression determined whether baseline variables were associated with weight gain or whether weight change was associated with clinical outcome. Statistically significant increases occurred in mean body weight (adjunctive aripiprazole, +1.73 kg, vs adjunctive placebo, +0.38 kg; P < 0.001). Significantly more subjects receiving adjunctive aripiprazole had clinically relevant (> or = 7%) weight gain versus placebo (5.2% vs 0.6%; P < 0.001). More patients treated with adjunctive aripiprazole shifted body mass index category group from normal to overweight and from overweight to obese than those treated with adjunctive placebo. Body mass index, sex, age, Montgomery-Asberg Depression Rating Scale score, fasting TG, fasting glucose, and standard antidepressants were not clinically meaningful predictors of weight gain with adjunctive aripiprazole, and change in weight had no correlation with clinical outcome. Adjunctive aripiprazole produced no significant changes versus placebo in mean waist circumference, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TG, fasting plasma glucose, or hemoglobin A1C. Also, there was no apparent change in the incidence of National Cholesterol Education Program-defined abnormal metabolic measures after treatment with aripiprazole.

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).

A proposed anti-maladaptive aggression agent classification: improving our approach to treating impulsive aggression.

Proper drug categorization enables clinicians to readily identify the agents most appropriate for patients in need. Currently, patients with maladaptive aggression do not all always fall into a single existing diagnostic or treatment category. Such is the case for those with impulsive aggression (IA). IA is an associated feature of numerous neuropsychiatric disorders, and can be described as eruptive, aggressive behavior or a 'short fuse'. Although agents from a broad spectrum of drug classes have been used to treat maladaptive aggression, few have been tested distinctly in patients with IA, and there is no drug specifically indicated by the US Food and Drug Administration (US FDA) for IA. Further, current treatments often fail to sufficiently treat IA symptomatology. These issues create an unclear and inadequate treatment path for patients. Here we will propose the establishment of a class of anti-maladaptive aggression agents to begin addressing this clinical issue. The development of such a class would unify the various drugs currently used to treat maladaptive aggression and streamline the treatment approach towards IA. As an important case example of the range of candidate drugs that could fit into a new anti-maladaptive aggression agent category, we will review an investigational IA pharmacotherapy. SPN-810 (extended-release molindone) is currently being investigated as a novel treatment for children with IA and ADHD. Based on these studies we will review how SPN-810 may be well suited for a new, anti-maladaptive aggression drug class and more precisely, a proposed subgroup of IA modulators. The goal of this review is to begin improving the identification of and therapeutic approach for maladaptive aggression as well as IA through more precise anti-maladaptive aggression agent categorization.

Changes in non-high-density lipoprotein cholesterol levels and triglyceride/high-density lipoprotein cholesterol ratios among patients randomized to aripiprazole versus olanzapine.

OBJECTIVE: Non-high-density lipoprotein cholesterol (non-HDL-C) and the triglyceride to high-density lipoprotein cholesterol ratio (TG:HDL-C) are predictors of cardiovascular risk. This post-hoc analysis assessed changes in these parameters during treatment with the atypical antipsychotics olanzapine or aripiprazole using pooled data from three randomized, long-term clinical studies in patients with schizophrenia. METHODS: Data were pooled from one open-label and two double-blind (26- or 52-week) studies in patients randomized to olanzapine (5-20 mg/day) or aripiprazole (15-30 mg/day). Change from baseline in non-HDL-C levels between groups was analyzed in the Observed Case (OC) dataset at each time point and Last Observation Carried Forward (LOCF) dataset at endpoint using analysis of covariance, with treatment as main effect and baseline non-HDL-C as covariate. Differences between groups in median changes from baseline in TG:HDL-C were assessed with Kruskal-Wallis tests. RESULTS: This analysis included 546 patients (olanzapine, n=274; aripiprazole, n=272). Mean changes from baseline in non-HDL-C levels were significantly different (p<0.0001) with olanzapine versus aripiprazole at Weeks 26 (+13.0 versus -7.5 mg/dL) and 52 (+12.2 versus -8.1 mg/dL). Baseline TG:HDL-C was high in the olanzapine (3.73) and aripiprazole (3.79) groups. Differences in median changes from baseline in TG:HDL-C were significant with olanzapine versus aripiprazole at Weeks 26 (+0.22 versus -0.54; p<0.0001) and 52 (+0.24 versus -0.62; p=0.004). CONCLUSIONS: Long-term aripiprazole treatment is associated with improvements in lipid profiles of schizophrenia patients versus no improvement or worsening during olanzapine treatment. Consideration of cardiovascular risk is needed when prescribing antipsychotics, as is close monitoring for metabolic changes during treatment.

A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease.

OBJECTIVE: To evaluate the efficacy and safety of aripiprazole treatment for psychotic symptoms associated with Alzheimer disease (AD). METHODS: In this parallel group, randomized, double-blind, placebo-controlled, flexible-dose trial, institutionalized subjects with AD and psychotic symptoms were randomized to aripiprazole (n = 131) or placebo (n = 125) for 10 weeks. The aripiprazole starting dose was 2 mg/day, and could be titrated to higher doses (5, 10, and 15 mg/day) based on efficacy and tolerability. RESULTS: No significant differences in mean change [2 x SD] from baseline between aripiprazole (mean dose approximately 9 mg/day at endpoint; range = 0.7-15.0 mg) and placebo were detected in the coprimary efficacy endpoints of Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) Psychosis score (aripiprazole, -4.53 [9.23]; placebo, -4.62 [9.56]; F = 0.02, df = 1, 222, p = 0.883 [ANCOVA]) and Clinical Global Impression (CGI)-Severity score (aripiprazole, -0.57 [1.63]; placebo, -0.43 [1.65]; F = 1.67, df = 1, 220, p = 0.198 [ANCOVA]) at endpoint. However, improvements in several secondary efficacy measures (NPI-NH Total, Brief Psychiatric Rating Scale Total, CGI - improvement, Cohen-Mansfield Agitation Inventory and Cornell Depression Scale scores) indicated that aripiprazole may confer clinical benefits beyond the primary outcome measures. Treatment-emergent adverse events (AEs) were similar in both groups, except for somnolence (aripiprazole, 14%; placebo, 4%). Somnolence with aripiprazole was of mild or moderate intensity, and not associated with accidental injury. Incidence of AEs related to extrapyramidal symptoms was low with aripiprazole (5%) and placebo (4%). CONCLUSIONS: In nursing home residents with AD and psychosis, aripiprazole did not confer specific benefits for the treatment of psychotic symptoms; but psychological and behavioral symptoms, including agitation, anxiety, and depression, were improved with aripiprazole, with a low risk of AEs.

The effect of antipsychotic medication on sexual function and serum prolactin levels in community-treated schizophrenic patients: results from the Schizophrenia Trial of Aripiprazole (STAR) study (NCT00237913).

BACKGROUND: The aim of this paper is to evaluate the effect of antipsychotics for the treatment of schizophrenia in a community based study on sexual function and prolactin levels comparing the use of aripiprazole and standard of care (SOC), which was a limited choice of three widely used and available antipsychotics (olanzapine, quetiapine or risperidone) (The Schizophrenia Trial of Aripiprazole [STAR] study [NCT00237913]). METHOD: This open-label, 26-week, multi-centre, randomised study compared aripiprazole to SOC (olanzapine, quetiapine or risperidone) in patients with schizophrenia (DSM-IV-TR criteria). The primary effectiveness variable was the mean total score of the Investigator Assessment Questionnaire (IAQ) at Week 26. The outcome research variables included the Arizona Sexual Experience scale (ASEX). This along with the data collected on serum prolactin levels at week 4, 8, 12, 18 and 26 will be the focus of this paper. RESULTS: A total of 555 patients were randomised to receive aripiprazole (n = 284) or SOC (n = 271). Both treatment groups experienced improvements in sexual function from baseline ASEX assessments. However at 8 weeks the aripiprazole treatment group reported significantly greater improvement compared with the SOC group (p = 0.007; OC). Although baseline mean serum prolactin levels were similar in the two treatment groups (43.4 mg/dL in the aripiprazole group and 42.3 mg/dL in the SOC group, p = NS) at Week 26 OC, mean decreases in serum prolactin were 34.2 mg/dL in the aripiprazole group, compared with 13.3 mg/dL in the SOC group (p < 0.001). CONCLUSION: The study findings suggest that aripiprazole has the potential to reduce sexual dysfunction, which in turn might improve patient compliance.

Examining the efficacy of adjunctive aripiprazole in major depressive disorder: a pooled analysis of 2 studies.

BACKGROUND: Patients with major depressive disorder (MDD) who fail to achieve complete remission with antidepressant therapy may benefit from augmentation therapy with an atypical antipsychotic. METHOD: A pooled analysis was performed on 2 identical 14-week studies (8-week prospective antidepressant therapy treatment phase followed by 6-week randomized double-blind phase) evaluating the efficacy of adjunctive aripiprazole (2-20 mg/day) in DSM-IV-TR-defined MDD patients with an inadequate response to antidepressant therapy. Primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (week 8) to end of randomized phase (week 14, last observation carried forward). Subgroup analyses were performed. The key secondary endpoint was mean change in Sheehan Disability Scale (SDS) mean score. RESULTS: At endpoint, mean change in MADRS total score was significantly greater with adjunctive aripiprazole (-8.7) than with adjunctive placebo (-5.7; p < .001). Except for a differential treatment-by-sex interaction, change in MADRS total scores were consistently greater with adjunctive aripiprazole than with adjunctive placebo, regardless of race, age, episode duration, prior antidepressant therapy response, number of historical treatment failures, severity of depressive symptoms, and antidepressant. At endpoint, MADRS remission rates were significantly greater with adjunctive aripiprazole than with placebo (25.7% vs. 15.4%; p < .001). Adjunctive aripiprazole also demonstrated significantly greater improvements in mean change from baseline in SDS total score than adjunctive placebo (-1.2 vs. -0.6; p = .001). CONCLUSION: Augmentation of antidepressant therapy with the atypical antipsychotic aripiprazole resulted in significant efficacy benefits across a range of subgroups of patients with MDD. Further study of a treatment-by-sex interaction is needed. TRIAL REGISTRATION: www.clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.

Preference of medicine and patient-reported quality of life in community-treated schizophrenic patients receiving aripiprazole vs standard of care: results from the STAR study.

OBJECTIVE: To evaluate quality of life and patient preference for schizophrenia treatment in a community based study comparing the use of aripiprazole to the standard of care (SOC). METHOD: This open-label, 26-week, multi-centre, randomised study compared aripiprazole with SOC (olanzapine, quetiapine or risperidone) in patients with schizophrenia (DSM-IV-TR criteria). The primary effectiveness variable was the mean total score of the Investigator Assessment Questionnaire (IAQ) at Week 26. The outcome research variables included the Preference of Medicine (POM) questionnaire, the Quality of Life Scale (QLS), and the EuroQoL-5D (EQ-5D). The results from these outcome research variables are the focus of this paper addressing quality of life and patient preference. RESULTS: A total of 555 patients were randomised to receive aripiprazole (n=284) or SOC (n=271). The OC data at Week 26, reported that more respondents rated the study medication as 'much better' compared with their previous medication in the aripiprazole group versus SOC for patients (59% vs 35%, P<0.001) and caregivers (58% vs 30%, P=0.014). The improvement in QLS total score was also significantly greater in the aripiprazole group compared with SOC--mean change from baseline in QLS total score of 16.21 vs 10.01 (P<0.001) at Week 26 (OC data set). A greater proportion of patients (93% vs 85%; P=0.005) in the aripiprazole group had a satisfactory response on the EQ-5D Self Care Scale; all other EQ-5D scores were similar. CONCLUSION: The study findings suggest that quality of life and patient medication preference measures were better for aripiprazole than for SOC.

Symptomatic remission in schizophrenia patients treated with aripiprazole or haloperidol for up to 52 weeks.

BACKGROUND: The Remission in Schizophrenia Working Group (RSWG) has defined criteria for symptomatic remission based on achieving and maintaining a consistently low symptom threshold for at least six consecutive months. This analysis examined symptomatic remission in acutely ill patients with schizophrenia receiving either aripiprazole or haloperidol for one year. METHODS: Pooled data from two 52-week, randomized, double-blind, multicenter, comparative trials of aripiprazole and haloperidol in acutely ill patients with schizophrenia were analyzed. Measures of symptomatic remission were calculated according to RSWG criteria. RESULTS: Remission rates were significantly higher for patients treated with aripiprazole compared with haloperidol (32% vs 22%, respectively; p<0.001, LOCF). Among remitters, aripiprazole-treated patients achieved symptom criteria in a significantly shorter time than haloperidol-treated patients (log rank p=0.0024). For trial completers, remission rates were similarly high in both groups (aripiprazole, 77%; haloperidol, 74%). Regardless of treatment type, remitters received significantly higher global clinical ratings than nonremitters (p<0.0001). Aripiprazole was associated with a significantly lower rate of discontinuations due to adverse events (AEs) than haloperidol (8.0% vs 18.4%, respectively; p<0.001) as well as lower concomitant medication use for extrapyramidal symptoms (EPS) (23% vs 57%, respectively; p<0.001). CONCLUSION: Acutely ill schizophrenia patients treated with aripiprazole demonstrated a significantly higher rate of symptomatic remission across 52 weeks compared with haloperidol-treated patients. The similar remission rates among trial completers in both treatment groups, combined with fewer AE-related discontinuations and lower EPS medication use in the aripiprazole group, suggest that better tolerability with aripiprazole may have contributed to superior overall remission rates.

Effects of teamwork training on adverse outcomes and process of care in labor and delivery: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of teamwork training on the occurrence of adverse outcomes and process of care in labor and delivery. METHODS: A cluster-randomized controlled trial was conducted at seven intervention and eight control hospitals. The intervention was a standardized teamwork training curriculum based on crew resource management that emphasized communication and team structure. The primary outcome was the proportion of deliveries at 20 weeks or more of gestation in which one or more adverse maternal or neonatal outcomes or both occurred (Adverse Outcome Index). Additional outcomes included 11 clinical process measures. RESULTS: A total of 1,307 personnel were trained and 28,536 deliveries analyzed. At baseline, there were no differences in demographic or delivery characteristics between the groups. The mean Adverse Outcome Index prevalence was similar in the control and intervention groups, both at baseline and after implementation of teamwork training (9.4% versus 9.0% and 7.2% versus 8.3%, respectively). The intracluster correlation coefficient was 0.015, with a resultant wide confidence interval for the difference in mean Adverse Outcome Index between groups (-5.6% to 3.2%). One process measure, the time from the decision to perform an immediate cesarean delivery to the incision, differed significantly after team training (33.3 minutes versus 21.2 minutes, P=.03). CONCLUSION: Training, as was conducted and implemented, did not transfer to a detectable impact in this study. The Adverse Outcome Index could be an important tool for comparing obstetric outcomes within and between institutions to help guide quality improvement. CLINICAL TRIAL REGISTRATION: (www.ClinicalTrials.gov), NCT00381056 LEVEL OF EVIDENCE: I.