James M. Eudicone

Aripiprazole monotherapy in patients with rapid‐cycling bipolar I disorder: an analysis from a long‐term, double‐blind, placebo‐controlled study

Aims:  Rapid‐cycling bipolar disorder is difficult to treat and associated with greater morbidity than non‐rapid‐cycling disease. This post hoc analysis evaluated 28 patients with rapid‐cycling bipolar I disorder from a 100‐week, double‐blind, placebo‐controlled study assessing long‐term efficacy, safety and tolerability of aripiprazole in patients with bipolar I disorder (most recently manic/mixed).

Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression☆

OBJECTIVE To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. METHODS Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. RESULTS 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). CONCLUSION Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

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.

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

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

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.

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.

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

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

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.

Multivariate analysis of bipolar mania: Retrospectively assessed structure of bipolar I manic and mixed episodes in randomized clinical trial participants

BACKGROUND Manic episodes are heterogeneous. Mixed states may differ in important clinical characteristics from other manic episodes. However, it has not been established whether mixed states are a distinct type of episodes, or a common basic structure exists across manic episodes. METHODS Using 2179 well-characterized subjects in the pretreatment phase of six randomized, clinical trials, we conducted rotated factor analysis followed by cluster analysis, using all items from the Young Mania Rating Scale and the Montgomery-Åsberg Depression Scale. Analyses were conducted for all subjects (n=2179) and for those in Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) mixed (n=644) and non-mixed (n=1535) episodes separately. RESULTS There were five factors characterized (in order of variance accounted for) as depression, mania, sleep disturbance, judgment/impulsivity and irritability/hostility. Cluster analysis identified five clusters. Three were predominately manic, with depression scores below average for the overall group. Two had high average depression scores; these clusters differed in irritability/hostility. Judgment/impulsivity scores were similar across factors. Essentially identical factors and clusters existed whether analyses were done in all subjects or only in subjects classified by DSM-IV as mixed or non-mixed. LIMITATIONS Exclusion criteria of studies may limit generalizability of findings. DISCUSSION All manic episodes, whether mixed or non-mixed, shared a similar structure according to factor/cluster analysis. Patients with high depression factor scores were heterogeneous with respect to irritability. These data suggest that depressive symptoms should be considered a dimensional property across manic episodes, rather than as defining a specific type of episode.