Olanzapine versus placebo in acute mania: treatment responses in subgroups

Two double-blind, placebo-controlled trials of olanzapine in acute mania showed significant overall antimanic efficacy, based on reductions in mania ratings. Their subject-level data were pooled to increase statistical power to test for differences in treatment responses among 10 subgroup pairs of interest using generalized estimating equations methods. Similar drug/placebo superiority and responsiveness to olanzapine was found in men versus women, psychotic versus nonpsychotic subjects, and those presenting in mania versus mixed states, and responses were independent of onset age, current age, or prior illness based on episodes, hospitalizations, recent rapid cycling, lifetime substance use, or previous antipsychotic treatment. Olanzapine and placebo responses paralleled closely (r(s) = 0.73). Patients were relatively more responsive to olanzapine who were younger at illness onset, lacked prior substance abuse, and had not previously received antipsychotic treatment (efficacy ratios 1.5-1.7, all P < 0.01). These well-powered comparisons of subgroups of interest indicate broad efficacy of olanzapine in the treatment of acute mania.     

Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania

Quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) for the treatment of mania was evaluated in 2 double-blind, placebo-controlled studies. Patients were randomized to 3 or 6 weeks of treatment with QTP plus Li/DVP or placebo (PBO) plus Li/DVP. Quetiapine was dosed up to 800 mg/d; Li was dosed to achieve serum concentrations of 0.7-1.0 mEq/L and DVP to 50-100 microg/mL. A total of 402 patients were randomized: 197 to QTP + Li/DVP and 205 to PBO + Li/DVP. The mean quetiapine dose in responders was 492 (+/-204) mg/d. Improvement in the Young Mania Rating Scale (YMRS) at day 21 in the QTP + Li/DVP group (-15.29) was statistically superior to the PBO + Li/DVP group (-12.19) (P < 0.05). A statistically significant difference in favor of quetiapine was observed within the first week (P < 0.05). Significantly more QTP + Li/DVP patients achieved a response (> or =50% decrease in the YMRS) at day 21 (QTP + Li/DVP, 55.7%; PBO + Li/DVP, 41.6%;P < 0.01). Improvements in Clinical Global Impression-Bipolar Severity of Illness scores by day 21 were also significantly greater in QTP + Li/DVP-treated patients (-1.59) versus PBO + Li/DVP (-1.19) (P < 0.01). Common adverse events (> or =5% and twice that in the PBO + Li/DVP group) in the QTP + Li/DVP group were somnolence, dry mouth, and asthenia. Quetiapine combined with Li/DVP was not associated with extrapyramidal symptoms (including akathisia) or emergent depression. More QTP + Li/DVP-treated patients completed the trial, and there was no difference in discontinuation rates due to adverse events between the two groups. Quetiapine, in combination with lithium or divalproex, is well tolerated and has superior efficacy to lithium or divalproex alone in the treatment of bipolar mania.     

Quetiapine for acute mania in bipolar disorder.

PURPOSE: The efficacy and tolerability of quetiapine in the treatment of acute mania were reviewed. SUMMARY: Five randomized, placebo-controlled trials involving quetiapine as monotherapy or adjunct therapy in combination with either divalproex or lithium in the treatment of bipolar mania in either adolescents or adults were identified and reviewed. The primary outcome measure used in the trials was a change in Young Mania Rating Scale total scores. Monotherapy trials evaluated quetiapine, lithium, haloperidol, and placebo. Quetiapine was superior to placebo in both trials. Quetiapine and lithium showed comparable efficacy in one study, though lithium serum concentrations may have been suboptimal. Haloperidol was superior to quetiapine in efficacy at day 21 but similar at day 84. In the two trials evaluating quetiapine or placebo as adjunct therapy to lithium or divalproex, quetiapine was significantly more efficacious than placebo in one trial. In adolescents, quetiapine was more effective than placebo as an adjunct to divalproex. The most common adverse effects clearly attributable to quetiapine in these trials were somnolence and dry mouth. Quetiapine did not induce extrapyramidal effects, but weight gain was notable with the drug. CONCLUSION: While quetiapine treatment demonstrated efficacy in the majority of the studies, the robustness of its efficacy is questionable. The use of quetiapine as first-line therapy for acute mania is not recommended based on the available results and cost considerations. However, it may be a useful second-line agent, particularly when sensitivity to extrapyramidal symptoms limits treatment options.     

Gamma activity model for treatment-resistant bipolar psychotic mania

Objectives:The objective was to investigate the effect of clozapine on spontaneous gamma activity in treatment-resistant bipolar psychotic mania.Methods:Patients with treatment-resistant (TR) bipolar psychotic mania on clozapine monotherapy and nontreatment-resistant bipolar psychotic mania patients receiving lithium were prospectively studied for 6 weeks on severity of psychopathology and 30–49 Hz gamma spectral power.Results:Spectral power significantly increased in the lithium group and decreased in the clozapine group; no within group significant difference found.Conclusions:We propose a model highlighting the role of gamma spectral power and modulations of GABAergic neurotransmission in TR bipolar psychotic mania.KEY WORDS: Bipolar psychotic mania, gamma activity, spectral power, treatment resistance     

Predictors of response to treatment of acute bipolar manic episodes with divalproex sodium or placebo in 2 randomized, controlled, parallel-group trials

Identification and control of factors that are associated with placebo and drug response in acute mania may influence the design and analysis of future trials in this condition. We analyzed pooled data from 2 multicenter, placebo-controlled, randomized trials of divalproex sodium for the treatment of acute manic episodes, using linear and logistic regression to search for common and treatment-specific predictors of response. In both treatment groups, patients with greater numbers of prior hospitalizations, more severe baseline symptoms, or younger age at onset of illness were found to be significantly less likely to respond. The effect sizes associated with these factors were of comparable magnitude to the effect size associated with divalproex treatment. Stratification on the basis of these prognostic factors may improve the power of future trials for the treatment of acute mania and may help explain patient response to treatment.     

随机对照药物临床试验样本量估计

如何正确估计样本量是随机对照药物临床试验设计阶段的主要研究内容之一。本文在对随机对照临床试验样本量估计的影响因素一一分析的基础上,通过实例介绍临床试验样本量估计的分析过程,并讨论了临床试验样本量估计中的注意事项,为随机对照临床试验正确估计样本量提供参考。     

Anticonvulsants in the treatment of bipolar mania

A series of antiepileptic drugs have been investigated in terms of their ability to treat mania (with later applications for the treatment of bipolar depression and prevention of relapses). These include divalproex, carbamazepine, oxcarbazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate and zonisamide. Although these drugs are all antiepileptic in action, they bring about these effects by different mechanisms; in particular, their impact on GABA differs significantly. Perhaps for this reason, their impact on mania varies greatly, with double-blind significant results evident only for valproate, carbamazepine and oxcarbazepine. Only valproate and carbamazepine are approved by the US FDA for use in mania; oxcarbazepine has never been found significantly effective in large-scale studies. Of the other options, both gabapentin and topiramate failed in large-scale investigations; tiagabine failed in small sample reports. Although lamotrigine has been successful in the prevention of depression relapse in bipolar disorder, it has not been effective in treating mania. Finally, there are no findings of large scale double-blind studies on the use of levetiracetam and zonisamide. A review of the kinetics, side effects and complications of the antiepileptic drugs indicates that carbamazepine is useful, and has adverse event benefit over all other options. The potential of zonisamide awaits further testing.     

Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial

BACKGROUND: In an earlier 21-day, placebo-controlled trial, ziprasidone was efficacious in improving symptoms of mania and was well tolerated. To confirm these results, a similarly designed 21-day trial was conducted. METHODS: Inpatients with bipolar I disorder, manic or mixed, were randomized to ziprasidone (40 to 80 mg BID) or placebo. Efficacy rating scales were derived from the Schedule for Affective Disorders and Schizophrenia-Change Bipolar Scale (SADS-CB). SADS-CB-derived Mania Rating Scale (MRS) total score was the primary efficacy parameter. Secondary SADS-CB-derived efficacy parameters included Manic Syndrome and Behavior and Ideation Subscales, Hamilton Depression Rating Scale (HAM-D), and the Montgomery Asberg Depression Rating Scale (MADRS). The Clinical Global Impression-Severity Scale (CGI-S), the Global Assessment of Functioning (GAF), and the Positive and Negative Syndrome Scale (PANSS) were also assessed. RESULTS: Sixty-five placebo and 137 ziprasidone patients were evaluable for efficacy. Baseline-to-endpoint mean changes in MRS scores were -11.1 for ziprasidone and -5.6 for placebo (all patients, last observation carried forward [LOCF]; P < 0.01). Ziprasidone produced significantly greater improvements in Manic Syndrome (P < or = 0.01) and Behavior and Ideation Subscales (P < or = 0.001), CGI-S score, (P < or = 0.001), PANSS Total (P < or = 0.01) and Positive Subscale (P < or = 0.001) scores, and GAF (P < or = 0.001). With ziprasidone, significant improvements were observed from Day 2 onward for MRS and CGI-S at all time points except Day 4 for MRS. Treatment-related discontinuations due to adverse events were 5.8% for ziprasidone and 1.5% for placebo (P = 0.20). CONCLUSIONS: Ziprasidone was well tolerated, rapidly efficacious, and superior to placebo in improving symptoms and global illness severity in these inpatients with acute bipolar mania, both manic and mixed episodes.     

A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania

There are no rapid-acting intramuscular formulations of atypical antipsychotics available for quickly calming an agitated patient with bipolar disorder. In this study, 201 agitated patients with bipolar mania were randomly assigned to receive one to three injections of the atypical antipsychotic olanzapine (10 mg, first two injections; 5 mg, third injection), the benzodiazepine lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo, first two injections; olanzapine, 10 mg, third injection) within a 24-hour period. Agitation was measured at baseline, every 30 minutes for the first 2 hours, and at 24 hours after the first injection using the Positive and Negative Syndrome Scale-Excited Component subscale and two additional agitation scales. At 2 hours after the first injection, patients treated with olanzapine showed a significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo or lorazepam. At 24 hours after the first injection, olanzapine remained statistically superior to placebo in reducing agitation in patients with acute mania, whereas patients treated with lorazepam were not significantly different from those treated with placebo or olanzapine. Furthermore, no significant differences among the three treatment groups were observed in safety measures, including treatment-emergent extrapyramidal symptoms, the incidence of acute dystonia, or QTc interval changes. These findings suggest that intramuscular olanzapine is a safe and effective treatment for reducing acute agitation in patients with bipolar mania.     

Extended-release carbamazepine for acute bipolar mania: a review

In December 2004, an extended-release capsule formulation of carbamazepine was approved by the U.S. Food and Drug Administration for the treatment of acute manic or mixed episodes associated with bipolar I disorder. This formulation allows twice-daily dosing and minimizes plasma carbamazepine fluctuations. The efficacy, safety and tolerability of the product were demonstrated with two pivotal randomized, placebo-controlled, double-blind monotherapy trials. These studies showed efficacy in bipolar I mania in patients with acute manic or mixed episodes. Pooled post hoc analyses documented a significant onset of effect within seven days, an incremental response of about 25% over placebo and a moderate effect size of 0.61 with no treatment-emergent depression. Carbamazepine's mode of action in mania is unknown, but a variety of effects on receptors, neurotransmitters, ion channels and binding sites have been documented. It has a complex pharmacokinetic profile due to autoinduction and a long-acting active metabolite. Carbamazepine's most frequent adverse events comprise dizziness, somnolence, nausea and vomiting, although these tend to diminish over time. It is effectively weight neutral and can provide an acceptable and efficacious treatment option for bipolar I mania.     

Methodological issues associated with preclinical drug development and increased placebo effects in schizophrenia clinical trials

Recent failures to detect efficacy in clinical trials investigating pharmacological treatments for schizophrenia raise concerns regarding the potential contribution of methodological shortcomings to this research. This review provides an examination of two key methodological issues currently suspected of playing a role in hampering schizophrenia drug development; 1) limitations on the translational utility of preclinical development models, and 2) methodological challenges posed by increased placebo effects. Recommendations for strategies to address these methodological issues are addressed.     

Zonisamide for bipolar disorder, mania or mixed states: a randomized, double blind, placebo-controlled adjunctive trial

Objective

This is the first multicenter, double blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar mania or mixed state.

Experimental design

One hundred four patients with Bipolar Disorder, Type I, II or NOS, in a manic, hypomanic or mixed state of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases: a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. The primary outcome variable for manic and hypomanic patients was the Young Mania Rating Scale (YMRS) both the YMRS and Montgomery Asberg Depression Rating Scale (MADRS) served as primary outcome variables for patients in mixed states. Secondary outcome measures included the Clinical Global Impression for Bipolar Disorder (CGI-BP), the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also analyzed. Side effects were measured using the SAFTEE.

Principal observations

There were no statistically significant differences for any of the primary or secondary outcome measures between zonisamide and placebo-treated patients.

Conclusions

In contrast to previous studies that suggested efficacy of adjunctive zonisamide in bipolar mania or mixed state, these results were not confirmed in this double blind controlled study.     

Budgetary impact of treating acute bipolar mania in hospitalized patients with quetiapine: an economic analysis of clinical trials

ABSTRACT

Objective: To present a tool that allows estimation of the budget impact of treatments for acute mania in bipolar I disorder from a US healthcare payer perspective.

Methods: Using discrete event simulation, the course of individuals is simulated beginning with hospitalization. Discharge depends on symptom level measured by the Young Mania Rating Scale (YMRS). The treatment effect is determined using time-dependent regression equations derived from trial data, and decision rules obtained from clinical experts. Outcomes include: time to response and symptom resolution; proportion of subjects reaching each outcome; number of adverse events. Costs were obtained from hospital discharge databases, the National Medicare Physician Fee Schedule and RedBook. Different scenarios are examined, each describing the proportion of subjects on the various treatments (lithium, divalproex sodium, olanzapine, risperidone, and quetiapine – monotherapy and in combination with lithium). Analyses are intention-to-treat over 100 days, corresponding to follow-up in mania trials. Despite its flexibility and structural adaptability, the model has some important limitations related to the characteristics of the clinical trials. These include focus on inpatient management of acute mania, use of the YMRS as the model driver, polypharmacy restricted to two-drug regimens, no explicit consideration of titration and dose changes, and relatively short time horizon.

Results: Scenarios with a greater proportion of quetiapine users (5% vs. 40% and 100%) result in a smaller impact on the healthcare budget ($6912, $6277, and $5525 per patient, respectively) and improvements in patient outcomes (e.g., 43%, 47%, and 54% responding at day 21; 74%, 77%, and 80% remitting by day 84). Sensitivity analyses showed that the budget impact is influenced by drug prices, discharge criteria and side-effect management.

Conclusion: Results suggest that increased use of quetiapine for bipolar mania in the US is economically justified and improves health outcomes. In addition, this model illustrates that discrete event simulation is a useful and versatile tool for budget impact analyses.