Predictive value of early improvement in bipolar depression trials: a post-hoc pooled analysis of two 8-week aripiprazole studies.

OBJECTIVE: To evaluate the value of early improvement to predict treatment outcome in patients with bipolar depression. METHODS: Data were pooled from two aripiprazole, 8-week, randomized, double-blind, placebo-controlled trials in patients with bipolar depression without psychotic features to determine whether early improvement (≥20% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score at Week 2 or 3) predicts later response (≥50% MADRS Total score reduction at Week 8) or remission (MADRS Total ≤10 at Week 8). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated (LOCF). Univariate and multivariate logistic regression models were used to evaluate early improvement and baseline demographic/clinical characteristics as predictors of response/remission. RESULTS: In total, 311 patients were randomized to placebo and 306 to aripiprazole. Predictive values of early improvement (≥20% MADRS Total score reduction) for remission with aripiprazole at Week 2/3, respectively, were: sensitivity 83%/94%; specificity 41%/33%; PPV 44%/45%; NPV 81%/91%. The corresponding values with placebo were as follows: sensitivity 70%/84%; specificity 60%/51%; PPV 50%/51%; NPV 77%/84%. Univariate linear regression showed that early improvement (≥15%, ≥20%, ≥25%, ≥30% at Week 3) was a significant potential predictor of remission. CONCLUSION: Absence of early improvement after 3 weeks of treatment reliably predicted non-response/non-remission at study endpoint with high sensitivity and NPV. In patients with <20% improvement after 21 days of aripiprazole monotherapy, treatment should be modified, as continued use is unlikely to result in response/remission. Clinical decision-making to optimize treatment course in bipolar I depression may be appropriate after as little as 2 weeks and certainly within the first 3 weeks of treatment.

Effect of aripiprazole versus haloperidol on PANSS Prosocial items in early-episode patients with schizophrenia.

BACKGROUND AND AIM: Improving social functioning is critically important in early-episode schizophrenia, if patients are to achieve functional recovery. This post-hoc, pooled analysis of two studies compared the effect of aripiprazole versus haloperidol on social functioning in early-episode schizophrenia. METHODS: Data were pooled from two 52 week, randomized (2:1), double-blind, multicenter studies involving 1294 patients with chronic schizophrenia who were in an acute psychotic episode and had a history of positive antipsychotic response during previous episodes. The early-episode group was defined as patients who are

Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study.

OBJECTIVES: To evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute bipolar mania. METHODS: Patients with acute bipolar I mania (DSM-IV-TR: YMRS > or =20), manic or mixed (with or without psychotic features) were randomized to double-blind aripiprazole (15-30 mg/day; n=155), placebo (n=165) or lithium (900-1500 mg/day; n=160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks. The primary outcome was the mean change from baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12. RESULTS: Aripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 (-4.3 vs.-2.8; p=0.003), and up to Week 3 (-12.6 vs. -9.0; p<0.001). Significant improvement in YMRS Total score was also seen with lithium versus placebo at Week 3 (-12.0 vs. -9.0; p=0.005). Improvements in YMRS Total score were maintained to Week 12 for aripiprazole (-14.5) and lithium (-12.7). Response rates at Week 3 were significantly higher with aripiprazole (46.8%) and lithium (45.8%) than placebo (34.4%; both p<0.05, LOCF); increasing to Week 12 with aripiprazole (56.5%) and lithium (49.0%). Most common adverse events with aripiprazole were headache, nausea, akathisia, sedation, and constipation; with lithium were nausea, headache, constipation, and tremor. CONCLUSIONS: Aripiprazole provided statistically significant improvement of acute mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of improvement to Week 12 was similar with aripiprazole and lithium.

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). METHODS: Following >or= 6 consecutive weeks' stabilisation with open-label aripiprazole, patients were randomised (1 : 1) to aripiprazole or placebo. Patients completing 26 weeks treatment without relapse could continue for a further 74 weeks. Primary end-point was time to relapse for manic, mixed or depressive symptoms, defined as discontinuation due to lack of efficacy. Safety assessments included adverse event (AE) monitoring and changes in weight and lipid, glucose and prolactin levels. RESULTS: Of the 28 patients (aripiprazole, n = 14; placebo, n = 14) with rapid-cycling bipolar disorder, 12 (aripiprazole, n = 7; placebo, n = 5) completed the initial 26-week treatment period and three (all aripiprazole treated) completed the 100-week, double-blind period. Time to relapse was significantly longer with aripiprazole vs. placebo at week 26 [log-rank p = 0.033; 26-week hazard ratio = 0.21 (95% CI: 0.04, 1.03)] and week 100 [log-rank p = 0.017; 100-week hazard ratio = 0.18 (95% CI: 0.04, 0.88)]. The most commonly reported AEs with aripiprazole during the 100 weeks (>or= 10% incidence and twice placebo) were anxiety (n = 4), sinusitis (n = 4), depression (n = 3) and upper respiratory infection (n = 3). One aripiprazole-treated patient discontinued due to an AE (akathisia). There were no significant between-group differences in mean changes in weight or metabolic parameters. CONCLUSION: In this small, post hoc subanalysis, aripiprazole maintained efficacy and was generally well tolerated in the long-term treatment of rapid-cycling bipolar disorder. Further research with prospectively designed and adequately powered trials is warranted.

Intramuscular aripiprazole or haloperidol and transition to oral therapy in patients with agitation associated with schizophrenia: sub-analysis of a double-blind study.

OBJECTIVE: A sub-population analysis of 325 patients with agitation (Positive and Negative Syndrome Scale Excited Component [PEC] score > or = 15 and < or = 32; score of > or = 4 on > or = 2 items) associated with schizophrenia in a randomized, double-blind study investigating the efficacy and tolerability of intramuscular (IM) aripiprazole 9.75 mg, IM haloperidol 6.5 mg, or IM placebo and the transition to oral therapy. RESEARCH DESIGN AND METHODS: Over 24 h, patients could receive up to three IM injections; the second and third administered > or = 2 and > or = 4 h, respectively, after the first, if deemed clinically necessary. Following IM treatment, oral aripiprazole or haloperidol was administered for 4 days. The primary efficacy measure was the mean change in PEC score from baseline at 2 h. RESULTS: At 2 h, mean improvements in PEC scores with IM aripiprazole (-8.0) were significantly greater versus IM placebo (-5.7; p < or = 0.01), and similar versus IM haloperidol (-8.3). Secondary efficacy measures also significantly improved with active IM treatment versus IM placebo. Continuation with oral treatment provided continued efficacy with both active treatments. The safety profiles of IM and oral aripiprazole were similar. The incidence of extrapyramidal symptom-related adverse events was 0% with IM aripiprazole, 1.6% with IM placebo and 16.5% with IM haloperidol. CONCLUSION: Intramuscular aripiprazole is effective in patients with acute agitation associated with schizophrenia, comparable to IM haloperidol, and enables convenient transfer to oral aripiprazole therapy.

Nefazodone pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of nefazodone (NFZ) in depressed children and adolescents. METHOD: Depressed youths aged 7 to 17 years were eligible to participate. Intensive sampling for pharmacokinetic analyses of NFZ and 3 of its active metabolites was performed after single and multiple dose administration. Treatment was continued for 6 more weeks and titrated to maximize clinical response. RESULTS: Twenty-eight patients were enrolled. Systemic exposure to NFZ and 3 metabolites was generally higher in children than adolescents. NFZ and metabolite disposition profiles showed high intra- and interpatient variability. Compared to published data in adults, the half-life of NFZ and 2 of its metabolites appears shorter in children and adolescents. Meta-chlorphenylpiperazine pharmacokinetic parameters were different in 5 patients determined to be poor metabolizers of cytochrome P450 2D6 (CYP2D6). NFZ was well tolerated, and administration was associated with significant reductions (p < .001) in depressive symptoms. CONCLUSIONS: The pharmacokinetics of NFZ in pediatric patients is highly variable. NFZ appears to be safe in this small, short-term study. Pediatric patients who are poor metabolizers of CYP2D6 do not appear to be at increased risk for NFZ-associated adverse events. Open-label treatment of NFZ is associated with reductions in depressive symptoms.

Nefazodone in the treatment of severe, melancholic, and recurrent depression.

The development of a new antidepressant medication is usually accompanied by a concern as to whether or not the compound will be sufficiently effective in clinically important subgroups of patients (e.g., depressed patients with increased severity of symptomatology, patients with melancholic features, and patients whose illness is recurrent). This paper describes results of a pooled analysis of four placebo-controlled studies included in the development program of the antidepressant nefazodone. These studies involved a total of 247 patients receiving nefazodone in a dose of up to 600 mg/day, 251 patients on placebo, and 166 patients receiving imipramine. For purposes of the analysis, patients were defined as being more severely depressed (Clinical Global Impressions scale [CGI] psychopathology score of at least markedly ill), having melancholia using DSM-III-R criteria, or having recurrent major depression (using DSM-III-R criteria). Efficacy was assessed by improvement in the Hamilton Rating Scale for Depression (17 items; HAM-D-17) Total score and CGI scale. Nefazodone (mean dose at endpoint = 379 mg/day) was effective in the management of depressed patients with moderate or severe symptomatology, depressed patients with or without melancholic features, and patients with single or recurrent episodes of depression.

The safety profile of nefazodone.

Comprehensive review of safety data from approximately 3500 patients who received nefazodone in premarketing clinical trials demonstrates the drug to be very well tolerated, with a favorable side effect profile compared with other antidepressant drugs. Nefazodone treatment was associated with fewer side effects than were the control drugs. The incidence of side effects was generally low, and treatment discontinuations for adverse effects were less frequent with nefazodone than with imipramine and comparable with fluoxetine. No late-appearing side effects or toxicity emerged during the long-term treatment (1 year or longer) of several hundred patients. There were no drug-related fatalities and no evidence that nefazodone caused specific organ toxicity, although some cardiovascular side effects were noted (e.g., asymptomatic reduced systolic blood pressure, asymptomatic sinus bradycardia). Experience in 488 elderly patients treated with nefazodone yielded no evidence of increased susceptibility of older patients to nefazodone-associated adverse experiences, including those pertaining to the cardiovascular system. However, treatment should be initiated at a reduced dose in elderly patients because of reduced hepatic clearance of nefazodone in this age group. Final dose range may be similar in healthy younger and older patients. Although nefazodone may interact with some other medications (e.g., increases at steady state in AUC: alprazolam, twofold; triazolam, fourfold), drug-drug interactions involving patients have been clinically minor. On the basis of the inhibition of cytochrome P450 3A4 isoenzyme by nefazodone in vitro, coadministration of terfenadine or astemizole with nefazodone is contraindicated because nefazodone can increase the plasma levels of these two drugs. Extensive clinical experience provides substantial evidence that nefazodone is an extremely safe and effective treatment for depression, with important advantages over existing therapies. Therapeutic benefits include a low incidence of clinically troublesome side effects and lack of unwanted psychic activation, sexual dysfunction, weight change, and the cardiotoxicity of other antidepressants.

Therapeutic dose range of nefazodone in the treatment of major depression.

The therapeutic dose range of nefazodone for treatment of major depression was examined in a series of placebo-controlled efficacy studies carried out during phase 2 and 3 premarketing clinical evaluation. Nefazodone is a new antidepressant drug with pharmacologic effects on both serotonin and norepinephrine neurotransmitters. The usual starting dose of nefazodone for depressed patients, unless they are being switched from a serotonin selective reuptake inhibitor (SSRI), is 100 mg. b.i.d. A lower starting dose is recommended for elderly patients or patients being treated with an SSRI. Following assessment of the patient's clinical response after the first week of therapy, the daily dose should be adjusted upward for most patients. In the efficacy studies, the majority of patients were being maintained on a dose of 300 to 500 mg daily at the end of the acute treatment period. The side effects of nefazodone most often related to dosage were sedation, nausea, and visual symptoms. Imipramine-treated patients, on the other hand, had a high incidence of dry mouth, constipation, and asthenia. In these studies, nefazodone was found to be effective and well tolerated by patients, the majority of whom were being maintained at a 300- to 500-mg/day dose, following an initial starting dose of 100 mg b.i.d.

A double-blind, placebo-controlled trial of two dose ranges of nefazodone in the treatment of depressed outpatients.

BACKGROUND: Nefazodone hydrochloride, a 5-HT2 receptor antagonist that selectively inhibits serotonin reuptake, was evaluated in a double-blind, dose-finding study of novel design, involving 240 patients with major depression. METHOD: Patients were randomly assigned to three treatment groups and received either placebo (2-6 capsules per day), a lower-dose range of nefazodone (50-300 mg/day), or a higher-dose range of nefazodone (100-600 mg/day) for 6 weeks. RESULTS: At the end of treatment, the Hamilton Rating Scale for Depression and the clinician- and patient-rated Inventory for Depressive Symptomatology scores showed significant improvement (p < or = .05) for patients receiving higher-dose range nefazodone (mean = 392 mg/day) compared with placebo treatment. The percentage of responders (at least "much improved" on the Clinical Global Impressions-Improvement scale) in the higher-dose range nefazodone group (58%) was significantly greater (p < or = .05) than in the placebo group (39%). The treatment group receiving nefazodone in the lower-dose range was not differentiated in clinical response from placebo controls. The rate of discontinuation for adverse experience (14%) was similar for patients treated with higher-dose range nefazodone and placebo. CONCLUSION: The findings of this study indicate that nefazodone is an effective and well-tolerated antidepressant drug, with a recommended therapeutic dose range of 100 to 600 mg/day and a starting dose of 100 mg b.i.d.

Response of anxiety and agitation symptoms during nefazodone treatment of major depression.

A meta-analysis of six randomized, placebo-controlled, double-blind trials was carried out to evaluate the effectiveness of the new antidepressant nefazodone in relieving symptoms of anxiety and agitation associated with major depression. Nefazodone blocks serotonin2 (5-HT2) receptors and selectively inhibits serotonin (5-HT) reuptake. This pharmacologic profile may confer clinical benefits that differ from those of other antidepressants, such as tricyclics (TCAs) and serotonin selective reuptake inhibitors (SSRIs). The data base included 817 patients with major depression and baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores > or = 18; 345 received placebo, 288 imipramine, and 184 nefazodone. Both nefazodone and imipramine exhibited antidepressant efficacy compared with that of placebo, irrespective of baseline anxiety levels. Statistically significant improvement in Hamilton Rating Scale for Anxiety (HAM-A), HAM-D anxiety factor, HAM-D psychic anxiety item, and HAM-D agitation item scores was observed with both active treatments. Nefazodone-treated patients showed significantly greater improvement in somatic anxiety (HAM-D item 11) ratings than placebo-treated patients from Week 4 through end of treatment (p < or = .01), while imipramine-treated patients did not differ from placebo patients on this item. Nefazodone-treated patients improved more rapidly (as early as Week 1) than imipramine- and placebo-treated patients on agitation (HAM-D item 9) (p < or = .01). Nefazodone was found to have an excellent safety profile and was well tolerated, with 5% of nefazodone patients prematurely discontinuing treatment for adverse experiences compared with 17% for imipramine and 5% for placebo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Nefazodone: aspects of efficacy.

BACKGROUND: Nefazodone hydrochloride, a 5-HT2 receptor antagonist and serotonin (5-HT) uptake inhibitor, was evaluated in four Phase 3 double-blind, imipramine- and placebo-controlled studies involving outpatients with major depression. METHOD: Patients who qualified for well-controlled efficacy trials in major depression were enrolled in a series of active- and placebo-controlled trials to establish the comparative efficacy of nefazodone and a standard tricyclic antidepressant drug. The primary efficacy measures employed were the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Improvement (CGI) scale. Safety profiles were also compared as well as survival analyses of double-blind acute and continuation treatment of patients in efficacy trials. RESULTS: Three of four Phase 3 active- and placebo-controlled studies showed nefazodone to be an effective antidepressant drug with overall efficacy generally similar to that of imipramine. The remaining study did not differentiate either active drug from placebo controls. Superiority of nefazodone and imipramine over placebo was evidenced by greater improvement on core depression symptoms in addition to the primary outcome measures (HAM-D-17 and CGI). The incidence of side effects and premature treatment discontinuations for imipramine-treated patients was higher than for nefazodone therapy. Both drugs showed evidence of continuing efficacy during long-term treatment with significantly fewer dropouts (p < .05) than for placebo controls. CONCLUSION: Nefazodone, an antidepressant that modulates serotonin receptors and enhances serotonin-mediated neurotransmission, has been shown to be an effective and well-tolerated new antidepressant drug with greater patient acceptability and safety than imipramine.

Inpatient care of the substance-abusing patient with a concomitant eating disorder.

Substance abuse rehabilitation programs have been increasingly faced with the difficult task of treating patients with both an eating disorder and a chemical dependency disorder. The authors discuss screening patients with substance abuse for eating disorder and describe a strategy for care that integrates an eating disorder treatment protocol with a standard chemical abuse rehabilitation program. Elements of the treatment protocol include a thorough medical evaluation, nutritional stabilization, strategies to stop the patient's aberrant eating behavior, psychotherapy, medication, and discharge planning that actively addresses both the substance abuse and the eating disorder.

DSM-III-R personality disorders in patients with eating disorders.

The authors conducted a systematic examination of DSM-III-R personality disorders among 35 patients with eating disorders. Fifty-seven percent of the patients met the criteria for at least one axis II diagnosis; borderline, self-defeating, and avoidant were the most frequently assigned personality disorders. Forty percent of the patients were given two or more diagnoses, and 17% of the patients met criteria for five to seven diagnoses. No differences were found between patients with anorexia nervosa, anorexia and bulimia nervosa, and bulimia nervosa in the distribution of diagnoses or the frequency with which individual criteria (traits) were assigned.