Effects of adjunctive aripiprazole on sexual functioning in patients with major depressive disorder and an inadequate response to standard antidepressant monotherapy: a post hoc analysis of 3 randomized, double-blind, placebo-controlled studies.

OBJECTIVE: To investigate the specific effect of adjunctive aripiprazole on sexual function in patients with major depressive disorder and a history of an inadequate response to antidepressant medication by controlling for improvement in depressive symptoms as measured by improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total scores. METHOD: For this post hoc analysis, data were pooled from 3 multicenter, randomized, double-blind, placebo-controlled aripiprazole augmentation studies (CN138-139: June 2004-April 2006; CN138-163: September 2004-December 2006; and CN138-165: March 2005-April 2008). Outpatients who met DSM-IV-TR criteria for a major depressive episode that had lasted ≥8 weeks with an inadequate response to prospective antidepressant treatment were randomized to adjunctive aripiprazole or placebo for 6 weeks. Sexual functioning was assessed using the Massachusetts General Hospital Sexual Functioning Inventory (MGH-SFI). To assess whether adjunctive aripiprazole improves sexual functioning directly, rather than as an indirect effect of improvement in depression symptoms, the mean change in MGH-SFI item scores and overall improvement scores was assessed using analysis of covariance, with double-blind baseline and change in MADRS total score as covariates. Correlations between MGH-SFI items and MADRS total score and prolactin levels were also assessed. RESULTS: The analysis included 1,092 subjects (n=737 female and n=355 male). In the total population, adjunctive aripiprazole demonstrated statistically significant greater improvements versus placebo on the MGH-SFI item "interest in sex" (-0.34 vs -0.18, P<.05). In males, no significant treatment differences were observed. In females, improvements in sexual functioning with adjunctive aripiprazole versus placebo were found on the MGH-SFI items "interest in sex" (-0.41 vs -0.21, P<.05) and "sexual satisfaction" (-0.44 vs -0.25, P<.05). CONCLUSIONS: Aripiprazole adjunctive to antidepressant treatment can have some beneficial effects on sexual functioning in patients with major depressive disorder who respond inadequately to standard antidepressant treatment; the benefits in women were specific to sexual interest and satisfaction and were independent of the improvement in depressive symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823, NCT00095758, and NCT00105196.

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

OBJECTIVES: 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. METHODS: Data from three similar 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled for this post hoc analysis. Two age groups were defined: younger patients (aged 18-49 years) and older patients (aged 50-67 years). The older patient group was further divided into three subgroups: 50-55, 56-60, and 61-67 years. The efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from end of the prospective phase (Week 8) to endpoint (Week 14, last observation carried forward (LOCF)). Remission was defined as MADRS total score ≤10 at endpoint. RESULTS: Four hundred and nine older patients (placebo, n = 198; aripiprazole, n = 211) and 679 younger patients (placebo, n = 341; aripiprazole, n = 338) were included in this analysis. Older patients receiving aripiprazole demonstrated significantly greater improvement in MADRS total score versus placebo at Week 14 (-10.0 vs. -6.4; p < 0.001; LOCF), similar to the improvement seen in younger patients. Remission rates were significantly higher with aripiprazole versus placebo in older (32.5% vs. 17.1%; p < 0.001) and younger (26.9% vs. 16.4%; p < 0.001) patients. Akathisia was the most common adverse event in both the older (17.1%) and younger (26.0%) patient groups. CONCLUSIONS: Adjunctive aripiprazole was effective in improving depressive symptoms in older patients, 50-67 years, with MDD who have had an inadequate response to standard antidepressant medication.

Cost-sharing effects on adherence and persistence for second-generation antipsychotics in commercially insured patients.

PURPOSE: To assess the relationship between patient cost-sharing (e.g., copayments or coinsurance) and adherence and persistence to second-generation (atypical) antipsychotic (SGA) medications. DESIGN AND METHODOLOGY: A retrospective, observational study of adults aged 18-64 years with schizophrenia or bipolar disorder (n = 7,910) who initiated SGA medications with employer-sponsored insurance in the 2003-2006 MarketScan Commercial Claims and Encounters Database. Adherence was defined as percent of days covered in each calendar quarter. Persistence was defined as days from initiation of SGA to the first 90-day gap in medication on-hand. Generalized Estimating Equations were used to determine the effects of cost-sharing on adherence to SGA medications based on patient-quarter data. A Cox proportional hazards model with patient cost-sharing as a time-varying covariate estimated the effects on persistence with SGA medication. PRINCIPAL FINDINGS: Higher cost-sharing was associated with a lower likelihood of adherence. When compared to plans with cost-sharing below $10, adherence rates were approximately 27% lower for patients in plans with SGA cost-sharing of $50 and above and about 10% lower for patients in plans with cost-sharing between $30 and $50. In both cases, the reduction in adherence was significant. Higher cost-sharing was also associated with a shorter time to discontinuation (HR: 1.028; 95% CI [1.006-1.051]). CONCLUSION: High SGA cost-sharing appears to be a financial barrier to SGA medication compliance, especially when cost-sharing levels exceeded $30. Our findings have implications for health plans, employers, and policymakers who have, or are, contemplating establishing cost-sharing tiers for SCA medications for commercially insured patients with serious mental illnesses.

Effect of inadequate response to treatment in patients with depression.

OBJECTIVES: To assess the effects of inadequate response to antidepressant treatment on healthcare resource utilization and on work productivity in patients diagnosed as having major depressive disorder (MDD). STUDY DESIGN: This study used data from the 2006 US National Health and Wellness Survey, a cross-sectional survey of adults 18 years and older. METHODS: Patients who self-reported a confirmed diagnosis of depression and were currently taking antidepressant medication were included in the analyses. Adequacy of antidepressant treatment response was determined from responses to the mental health domain of the 8-Item Short Form Health Survey (SF-8). Logistic regression analyses adjusted for demographics, comorbidity, and component scores on the SF-8 were used to determine the associations between inadequacy of treatment response and health outcomes. RESULTS: Of 5988 patients who met the inclusion criteria for the study, 30.9% were classified as antidepressant treatment responders, 31.2% were partial responders, and 37.9% were nonresponders. Partial response and nonresponse to treatment were associated with greater likelihood of emergency department utilization (odds ratios [ORs], 1.26 and 1.54, respectively; P <.01 for both) and hospitalization (OR, 1.23; P = .05 and OR, 1.39; P <.01, respectively). Similarly, partial response and nonresponse were associated with lower likelihood of current employment (OR, 0.83; P = .01 and OR, 0.63; P <.01, respectively) and with greater likelihood of work productivity loss among the employed (ORs, 1.42 and 1.99, respectively; P <.01 for both). CONCLUSIONS: Patients with MDD who failed to respond to antidepressant treatment as evidenced by poor self-reported mental health status used more healthcare resources, were less likely to be employed, and had more work productivity loss than those who responded to antidepressant therapy.

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.

Cost burden of treatment resistance in patients with depression.

OBJECTIVE: To develop a claims-based scale for treatment-resistant depression (TRD) and estimate the associated direct cost burden. STUDY DESIGN: Retrospective, observational study of patients receiving antidepressant therapy between January 2000 and June 2007 (N = 78,477). METHODS: The Massachusetts General Hospital (MGH) clinical staging method for treatment resistance (assigning points for adequate trials of antidepressant medication, upward dose titration, extended duration, augmentation, and electroconvulsive therapy) was applied to claims data from the MarketScan Research Databases over a 24-month time period. Direct expenditures were measured over a subsequent 12-month period. Patients identified as having TRD (MGH score >or=3.5) (n = 22,593) were matched to depressed patients without TRD using propensity score methods. Regression models estimated the relationship between TRD and expenditures, controlling for sociodemographics, health plan type, and health status. Similar regression models estimated costs for an antidepressant-only version of the scale (MGH-AD). RESULTS: Treatment resistance among depressed patients was associated with 40% higher medical care costs (P <.001). The MGH-AD score was associated with an increasing gradient in direct costs. Annual costs for patients with mild TRD (MGH-AD 3.5-4) were $1530 higher than those for non-TRD patients, and costs for patients with complex TRD (MGH-AD >or=6.5) were $4425 higher than those for non-TRD patients (all P <.001). A 1-point increase in the MGH-AD score was associated with a $590 increase in annual costs (P <.001). CONCLUSIONS: Early identification of TRD patients, using a claims-based algorithm, may support targeted interventions for these patients.

Metabolic syndrome in patients enrolled in a clinical trial of aripiprazole in the maintenance treatment of bipolar I disorder: a post hoc analysis of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the effects of maintenance treatment with aripiprazole or placebo on the incidence of metabolic syndrome in bipolar disorder. METHOD: Patients with DSM-IV bipolar I disorder were stabilized on aripiprazole therapy for 6-18 weeks prior to double-blind random assignment to aripiprazole or placebo for 26 weeks. The rate of metabolic syndrome in each group was calculated at maintenance phase baseline (randomization) and endpoint for evaluable patients using a last-observation-carried-forward (LOCF) approach. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. The study was conducted from March 2000 to June 2003 at 76 centers in Argentina, Mexico, and the United States. RESULTS: At entry into the maintenance phase, 45/125 patients (36.0%) overall met criteria for metabolic syndrome. Mean changes in the 5 components of metabolic syndrome (waist circumference, triglyceride levels, high-density lipoprotein cholesterol level, blood pressure, and glucose level) from baseline to week 26 were small except for a meaningful reduction in triglycerides (placebo -18.9 mg/dL; aripiprazole -11.5 mg/dL). By the end of the maintenance phase (endpoint, LOCF), 5/18 placebo-treated patients (27.8%) and 4/14 aripiprazole-treated patients (28.6%) no longer met metabolic syndrome criteria. The proportion of patients with metabolic syndrome was similar in the placebo and aripiprazole groups at both baseline and week 26. There were no significant changes in any of the individual components of metabolic syndrome between aripiprazole- and placebo-treated patients during maintenance phase treatment. CONCLUSIONS: The prevalence of metabolic syndrome in patients with bipolar disorder is higher than that commonly reported in the general population. The effect of 26 weeks of treatment with aripiprazole on the incidence of metabolic syndrome and its components was similar to placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00036348.

Effects of aripiprazole adjunctive to standard antidepressant treatment on the core symptoms of depression: a post-hoc, pooled analysis of two large, placebo-controlled studies.

BACKGROUND: Although antipsychotic agents have a long history of use in depression, their effectiveness in treating core symptoms of depression such as loss of interest has been questioned. Adjunctive aripiprazole is beneficial for the treatment of patients with major depressive disorder but its effects on specific symptoms have not been reported. The objective of this study was to examine the effects of aripiprazole on core symptoms of depression. METHODS: This is a post-hoc, pooled analysis of two trials of aripiprazole augmentation of standard antidepressants (ADT) in patients with major depression. Patients with an inadequate response to ADT received adjunctive aripiprazole (n=373) or placebo (n=368) for 6 weeks. Change on four subscales of the 17-item Hamilton Depression Rating Scale (HAM-D17) that capture core depression symptoms was determined and change on individual HAM-D items also was assessed. The magnitude of within-group change for the subscales and individual items was expressed as effect size (ES) and between-group significance tested with ANCOVA. The magnitude of change was also examined comparing the response rates for aripiprazole and placebo on HAM-D17 and the four subscales. Change on three composite subscales - anxiety, insomnia and drive was also examined. RESULTS: Within-group change on the four core subscales was substantial (ES=1.1-1.2) and similar to that for the 17-item HAM-D total score. Between-group comparisons indicated mean change and response rates were significantly greater with adjunctive aripiprazole than placebo for each core subscale (all p<0.01). Individual HAM-D17 items showing the greatest change from baseline with adjunctive aripiprazole: depressed mood (within-group ES=1.03) work and activities (ES=0.86), guilt (ES=0.77) and psychic anxiety (ES=0.67) are the same symptoms identified by each of the core subscales and each of these items differed significantly from change on that item with placebo (p<0.01). On three composite scales, adjunctive aripiprazole was significantly more effective than placebo with respect to mean change for anxiety, insomnia and drive (all p<0.001). CONCLUSIONS: Aripiprazole augmentation of standard ADT results in significant, clinically meaningful changes in the core symptoms of depression. It is also associated with significant change in anxiety, insomnia, and drive components of the 17-item HAM-D.

Evaluation of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder: a post hoc analysis of pooled data from short- and long-term aripiprazole trials.

The objective of this article is to assess the clinical characteristics of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder receiving aripiprazole, haloperidol, olanzapine, or placebo. We conducted post hoc analyses of pooled safety data from trials in patients with schizophrenia, schizoaffective disorder, and bipolar I disorder. Outcome measures included the incidence of akathisia, time to onset, duration, severity, and discontinuation due to akathisia, concomitant use of benzodiazepines and/or anticholinergics, Barnes Akathisia Rating Scale (BARS) scores, and the correlation between antipsychotic efficacy and akathisia. The results for schizophrenia and schizoaffective disorder were as follows: akathisia in 9% of aripiprazole- and 6% of placebo-treated patients; 12.5% of aripiprazole- versus 24% of haloperidol-treated patients; 11% of aripiprazole- versus 6% of olanzapine-treated patients. Bipolar I disorder: akathisia in 18% of aripiprazole- and 5% of placebo-treated patients. The clinical characteristics of akathisia were similar between each data set, regardless of disease. Akathisia was generally mild-to-moderate in severity. Discontinuation due to akathisia was low in both the schizophrenia trials (aripiprazole 0.3%; placebo 0%; aripiprazole 0.9%; haloperidol 2.3%; aripiprazole 1.2%; olanzapine 0.2%) and the bipolar trials (aripiprazole 2.3%; placebo 0%). Treatment-emergent akathisia was not associated with a poorer clinical response. In conclusion, akathisia with aripiprazole occurred early in treatment, was mild-to-moderate in severity, led to few study discontinuations, and did not compromise therapeutic efficacy.

A systematic review of augmentation strategies for patients with major depressive disorder.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Clinicians need to determine the most appropriate and effective interventions for patients who do not benefit from first-line treatment. A systematic review of the literature on augmentation strategies for major depression was conducted. A total of 32 eligible studies were included in the final review. Identified augmentation strategies included lithium, thyroid hormone, buspirone, stimulant drugs (methylphenidate and modafinil), and atypical antipsychotics (olanzapine, quetiapine, aripiprazole, and risperidone). Additional studies used other augmentation strategies (yohimbine, atomoxetine, inositol, testosterone, and lamotrigine), or combinations with a second antidepressant (mianserin, mirtazapine, and desipramine). There was no evidence of clinical efficacy as measured by response in augmentation with buspirone, testosterone, methylphenidate, yohimbine, inositol, and atomoxetine. Although some studies of combined antidepressant therapy and lithium augmentation did show statistically significant clinical effects, results were inconsistent across studies. The only eligible study of thyroid augmentation was positive, though this study evaluated patients treated with tricyclic antidepressants. It is possible due to small sample sizes, that some of the trials failed to detect significant differences versus placebo because of inadequate statistical power. Adjunctive therapy with atypical antipsychotics showed higher response rates compared with antidepressant monotherapy and placebo but also had more withdrawals due to adverse events. Given ongoing concerns with the longer term tolerability and safety of the atypical antipsychotics, future research will need to investigate optimal duration of augmentation therapy in patients with major depressive disorder who do not respond to first line therapy.

Global benefit-risk analysis of adjunctive aripiprazole in the treatment of patients with major depressive disorder.

OBJECTIVE: This study quantified the overall merit of adjunctive aripiprazole in major depressive disorder (MDD). METHODS: Global benefit-risk (GBR) analysis quantified the benefit and risk differences between adjunctive aripiprazole and antidepressant (ADT) monotherapy. Three hundred and fifty six patients receiving ADT monotherapy and 366 patients receiving ADT and adjunctive aripiprazole (2-20 mg/day) were included. Efficacy measures included the Montgomery-Asberg depression rating scale (MADRS) Total score response (> or =50% reduction) and remission (response plus Total score < or = 10). Treatment-emergent adverse events were classified by severity. GBR ratio measures evaluated the relative benefit of adjunctive aripiprazole. Logistic regression models tested the effect of adjunctive aripiprazole on GBR and were used to identify predictors of net benefit and potential factors affecting the adjunctive aripiprazole treatment effect. RESULTS: For MADRS-defined response and remission, the relative gain of adjunctive aripiprazole versus ADT monotherapy was 1.46 (p = 0.044) and 1.43 (p = 0.085), respectively. Gender, current escitalopram, duration of current episode, and baseline body mass index are potential factors affecting the adjunctive aripiprazole treatment effect. CONCLUSIONS: Compared with ADT monotherapy, adjunctive aripiprazole was associated with an improved benefit-risk profile in MDD.

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.

Healthcare costs associated with treatment of bipolar disorder using a mood stabilizer plus adjunctive aripiprazole, quetiapine, risperidone, olanzapine or ziprasidone.

OBJECTIVE: Bipolar disorder has an associated economic burden due to its treatment, including medication and hospitalization costs as well as costs associated with treatment of comorbid conditions. This study compared healthcare costs in patients treated with a mood stabilizer and adjunctive aripiprazole versus adjunctive olanzapine, quetiapine, risperidone or ziprasidone. RESEARCH DESIGN AND METHODS: A retrospective propensity score-matched cohort study was conducted in the LabRx integrated claims database from January 2003 to December 2006. Patients (18-65 years) with bipolar disorder and 180 days of pre-index enrolment without atypical treatment and 90 days post-index enrolment were eligible. Mood stabilizer therapy was initiated prior to index atypical prescription. Generalized gamma regressions were used to compare the total healthcare costs of adjunctive aripiprazole treatment and treatment with adjunctive olanzapine, quetiapine, risperidone or ziprasidone. RESULTS: After controlling for differences in baseline characteristics and pre-index cost, psychiatric costs and subtotal psychiatric and general medical costs were higher for all adjunctive atypicals than adjunctive aripiprazole (p<0.001). Based on gamma regressions cost ratios, there was no significant difference in general medical costs between aripiprazole and ziprasidone, olanzapine, or quetiapine; risperidone general medical costs were 18% higher versus aripiprazole (p=0.041). Aripiprazole pharmacy costs were higher than quetiapine and risperidone (p<0.001) but not olanzapine or ziprasidone. Total healthcare costs were higher for ziprasidone, olanzapine, or risperidone (p<0.001) but not quetiapine. LIMITATIONS: Methodological restriction of patients to those newly initiated on an atypical antipsychotic and incomplete medication history limit the generalizability of the findings. CONCLUSION: Adjunctive aripiprazole may have economic benefits over other atypicals in terms of lower psychiatric treatment costs than adjunctive olanzapine, quetiapine, risperidone or ziprasidone, and lower total healthcare costs than adjunctive olanzapine, risperidone or ziprasidone.

Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event database: a systematic Bayesian signal detection analysis.

BACKGROUND: Prior literature suggests that the risk of diabetes-related adverse events (DRAEs) differs between atypical antipsychotics. The present study evaluated the potential association between atypical antipsychotics or haloperidol and diabetes using data from the FDA AERS database. METHODS: Analysis of AERS data was conducted for clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole or haloperidol with 24 DRAEs from the Medical Dictionary for Regulatory Activities using a Multi-item Gamma Poisson Shrinker (MGPS) data-mining algorithm. Using MGPS, adjusted reporting ratios (Empiric Bayes Geometric Mean or EBGM) and 90% confidence intervals (CIs; EB05-EB95) were calculated to estimate the degree of drug-event association relative to all drugs and events. Logistic regression odds ratios and 90% CIs (LR05-LR95) were calculated for diabetes mellitus events. RESULTS: All six atypicals had an EB05 >/= 2 for at least one DRAE. The most common event was diabetes mellitus (2,784 cases). Adjusted reporting ratios (CIs) for diabetes mellitus were: olanzapine 9.6 (9.2-10.0; 1306 cases); risperidone 3.8 (3.5-4.1; 447 cases); quetiapine 3.5 (3.2-3.9; 283 cases); clozapine 3.1 (2.9-3.3; 464 cases); ziprasidone 2.4 (2.0-2.9; 74 cases); aripiprazole 2.4 (1.9-2.9; 71 cases); haloperidol 2.0 (1.7-2.3; 139 cases). Logistic regression odds ratios agreed with adjusted reporting ratios. CONCLUSIONS: In the AERS database, lower associations with DRAEs were seen for haloperidol, aripiprazole and ziprasidone, and higher associations were seen for olanzapine, risperidone, clozapine and quetiapine. Our findings support differential risk of diabetes across atypical antipsychotics, reinforcing the need for metabolic monitoring of patients taking antipsychotics.

The efficacy, safety, and tolerability of aripiprazole for the treatment of schizoaffective disorder: results from a pooled analysis of a sub-population of subjects from two randomized, double-blind, placebo-controlled, pivotal trials.

BACKGROUND: Schizoaffective disorder shares clinical characteristics with schizophrenia and affective disorders, with patients experiencing concurrent manic, mixed, or depressive episodes during psychosis. Because efficacy may be better in schizoaffective disorder than schizophrenia, this post-hoc analysis examines the efficacy, safety, and tolerability of aripiprazole in patients with schizoaffective disorder. METHOD: Data were obtained from a sub-sample of subjects with schizoaffective disorder (randomized: aripiprazole n=123, placebo n=56) who participated in two 4-week, multicenter, double-blind trials of subjects with schizophrenia or schizoaffective disorder. Aripiprazole was administered at fixed doses of 15 mg/day, 20 mg/day, or 30 mg/day. Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS) Total score, and the Positive, Negative, and General Psychopathology subscale scores. Safety and tolerability evaluations included incidence of treatment-emergent adverse events and extrapyramidal symptom assessments (SAS, BARS, and AIMS), and metabolic profile changes including weight and BMI. RESULTS: A significantly greater improvement from baseline to endpoint was observed with aripiprazole compared with placebo on the PANSS Total (-15.9 vs. -3.4; p=0.038) and PANSS Positive subscale (-4.6 vs. -1.0; p=0.027). Differences between treatments were not significant for the PANSS Negative subscale score (-3.7 vs. -1.2; p=0.15) or PANSS General Psychopathology subscale score (-8.3 vs. -3.1; p=0.06). There were no statistically significant differences at endpoint between groups in the mean change from baseline to endpoint in weight, glucose, or total cholesterol, or on SAS, BARS, or AIMS scores. There was a statistically significant decrease in prolactin in subjects treated with aripiprazole compared with placebo (-5.6 vs. -1.3, p<0.001). CONCLUSION: Aripiprazole was efficacious and well tolerated in patients with schizoaffective disorder.

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.

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.

Adjunctive aripiprazole in major depressive disorder: analysis of efficacy and safety in patients with anxious and atypical features.

OBJECTIVE: To evaluate the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with anxious/atypical features at baseline. METHOD: Data from 2 identical 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled to evaluate efficacy and safety in the 2 subgroups. The primary efficacy endpoint was mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of ADT treatment to end of randomized treatment (last observation carried forward). Anxious depression was defined by a Hamilton Rating Scale for Depression anxiety/somatization factor score ≥ 7, and atypical depression was defined by previously described criteria on the Inventory of Depressive Symptomatology-Self-Report. Both anxious and atypical subtypes were defined based on symptoms at entry into prospective ADT (week 0). Patients were enrolled between June 2004 and April 2006 in one study and from September 2004 to December 2006 in the other (total randomized population, N = 742; anxious/nonanxious population, N = 740; atypical/nonatypical population, N = 737). RESULTS: Completion rates were between 84% and 90% and comparable across all subgroups, with low discontinuations due to adverse events. Patients receiving adjunctive aripiprazole demonstrated significantly greater improvement in MADRS total score versus patients receiving adjunctive placebo, starting at week 1 or week 2 and continuing through to endpoint (anxious: -8.72 vs. -6.17, p ≤ .001; nonanxious: -8.61 vs. -4.97, p ≤ .001; atypical: -9.31 vs. -5.15, p ≤ .001; nonatypical: -8.08 vs. -6.22, p < .05). At endpoint, remission rates were also significantly higher with adjunctive aripiprazole versus adjunctive placebo (p < .05) in all subgroups. Treatment emergent adverse event profile was similar in all subgroups and comparable to the total population. Reporting of akathisia and weight gain on aripiprazole treatment did not differ between subgroups. CONCLUSION: Adjunctive aripiprazole is an effective treatment for patients with major depression presenting with either anxious or atypical features. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.

Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia spectrum or bipolar spectrum disorders: recent developments and current perspectives.

Hyperprolactinemia is increasingly studied as a frequent and potentially important consequence of antipsychotic medication treatment. Some individuals presenting with hyperprolactinemia remain asymptomatic, but others may exhibit a wide range of clinical symptoms resulting from either the direct effects of prolactin on body tissues (galactorrhea, gynecomastia) or endocrine-related secondary effects (sexual and reproductive dysfunction in the short term, and possibly the risk of tumorigenesis and osteoporosis in the longer term). Short-term side effects may negatively impact medication compliance, and long-term effects have the potential for serious health consequences. Antipsychotic medications have differing propensities to cause prolactin elevation. The first-generation antipsychotics, as well as the second-generation antipsychotic risperidone and its active metabolite paliperidone, have been shown to cause marked and sustained elevations in prolactin levels, whereas others of the second-generation antipsychotics appear to have little or no effect on prolactin levels or may decrease prolactin. A comprehensive overview of antipsychotics and hyperprolactinemia is presented together with a review of emerging evidence about the short- and long-term health risks of hyperprolactinemia.