Atypical antipsychotics in bipolar disorder: systematic review of randomised trials

Background: Atypical antipsychotics are increasingly used for treatment of mental illnesses like schizophrenia and bipolar disorder, and considered to have fewer extrapyramidal effects than older antipsychotics. Methods: We examined efficacy in randomised trials of bipolar disorder where the presenting episode was either depression, or manic/mixed, comparing atypical antipsychotic with placebo or active comparator, examined withdrawals for any cause, or due to lack of efficacy or adverse events, and combined all phases for adverse event analysis. Studies were found through systematic search (PubMed, EMBASE, Cochrane Library), and data combined for analysis where there was clinical homogeneity, with especial reference to trial duration. Results: In five trials (2,206 patients) participants presented with a depressive episode, and in 25 trials (6,174 patients) the presenting episode was manic or mixed. In 8-week studies presenting with depression, quetiapine and olanzapine produced significantly better rates of response and symptomatic remission than placebo, with NNTs of 5-6, but more adverse event withdrawals (NNH 12). With mania or mixed presentation atypical antipsychotics produced significantly better rates of response and symptomatic remission than placebo, with NNTs of about 5 up to six weeks, and 4 at 6-12 weeks, but more adverse event withdrawals (NNH of about 22) in studies of 6-12 weeks. In comparisons with established treatments, atypical antipsychotics had similar efficacy, but significantly fewer adverse event withdrawals (NNT to prevent one withdrawal about 10). In maintenance trials atypical antipsychotics had significantly fewer relapses to depression or mania than placebo or active comparator. In placebo-controlled trials, atypical antipsychotics were associated with higher rates of weight gain of ≥7% (mainly olanzapine trials), somnolence, and extrapyramidal symptoms. In active controlled trials, atypical antipsychotics were associated with lower rates of extrapyramidal symptoms, but had higher rates of weight gain and somnolence. Conclusion: Atypical antipsychotics are effective in treating both phases of bipolar disorder compared with placebo, and as effective as established drug therapies. Atypical antipsychotics produce fewer extrapyramidal symptoms, but weight gain is more common (with olanzapine). There is insufficient data confidently to distinguish between different atypical antipsychotics.© 2007 Derry and Moore; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Citation: Derry, S. & Moore, R. A. (2007). 'Atypical antipsychotics in bipolar disorder: systematic review of randomised trials', BMC Psychiatry, 7:40. [Available at http://www.biomedcentral.com/1471-244X/7/40]

Aggression among 216 patients with a first-psychotic episode of bipolar I disorder

Background: Aggression by patients with bipolar I disorder (BD-I) is not uncommon. Identifying potential risk factors early in the illness-course should inform clinical management and reduce risk. Methods: In a study sample of 216 initially hospitalized, first-psychotic episode subjects diagnosed with DSM-IV-TR BD-I, we identified recent (within 1 month before hospitalization) aggression by ratings on the Brief Psychiatric Rating Scale-Expanded and review of detailed clinical research records. We compared subjects with versus without aggressive behavior for associations with selected demographic and clinical factors. Results: Aggression was identified in 23/216 subjects (10.6%). It was associated significantly with recent suicide attempt (OR = 4.86), alcohol abuse (OR = 3.63), learning disability (OR = 3.14), and initial manic episode (OR = 2.59), but not with age, sex, onset-type, personality disorder, time to recovery, or functional status. Conclusions: Among first-major episode BD-I patients with psychotic features, recent serious aggression towards others was identified in 10.6%. The odds of aggression increased by 4.9-times in association with a recent suicide attempt, more than 3-times with alcohol-abuse or learning disability, and by 2.6-times if the episode polarity was manic. The findings encourage closer management of alcohol misuse, suicide risk, and manic symptoms, and early detection of learning problems in BD-I patients

Factors modifying drug and placebo responses in randomized trials for bipolar mania

Factors modifying drug and placebo responses in randomized trials for bipolar mania. Yildiz A, Vieta E, Tohen M, Baldessarini RJ. Source Department of Psychiatry, Dokuz Eylül University, Izmir, Turkey. [email protected] Abstract Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for bipolar mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects' age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo-treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95% CI 5.77-7.76) and ineffective (7.61, 95% CI 5.47-8.75) drugs. Lesser placebo responses (MD) and greater drug-placebo differences (Hedges' g) were associated with fewer study sites, younger patients' age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drug-associated improvement (MD) and drug-placebo contrast (Hedges' g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for mania, fewer sites may limit placebo response and enhance drug-placebo contrasts

Identifying patterns in treatment response profiles in acute bipolar mania: a cluster analysis approach

<p>Abstract</p> <p>Background</p> <p>Patients with acute mania respond differentially to treatment and, in many cases, fail to obtain or sustain symptom remission. The objective of this exploratory analysis was to characterize response in bipolar disorder by identifying groups of patients with similar manic symptom response profiles.</p> <p>Methods</p> <p>Patients (n = 222) were selected from a randomized, double-blind study of treatment with olanzapine or divalproex in bipolar I disorder, manic or mixed episode, with or without psychotic features. Hierarchical clustering based on Ward's distance was used to identify groups of patients based on Young-Mania Rating Scale (YMRS) total scores at each of 5 assessments over 7 weeks. Logistic regression was used to identify baseline predictors for clusters of interest.</p> <p>Results</p> <p>Four distinct clusters of patients were identified: Cluster 1 (n = 64): patients did not maintain a response (YMRS total scores ≤ 12); Cluster 2 (n = 92): patients responded rapidly (within less than a week) and response was maintained; Cluster 3 (n = 36): patients responded rapidly but relapsed soon afterwards (YMRS ≥ 15); Cluster 4 (n = 30): patients responded slowly (≥ 2 weeks) and response was maintained. Predictive models using baseline variables found YMRS Item 10 (Appearance), and psychosis to be significant predictors for Clusters 1 and 4 vs. Clusters 2 and 3, but none of the baseline characteristics allowed discriminating between Clusters 1 vs. 4. Experiencing a mixed episode at baseline predicted membership in Clusters 2 and 3 vs. Clusters 1 and 4. Treatment with divalproex, larger number of previous manic episodes, lack of disruptive-aggressive behavior, and more prominent depressive symptoms at baseline were predictors for Cluster 3 vs. 2.</p> <p>Conclusion</p> <p>Distinct treatment response profiles can be predicted by clinical features at baseline. The presence of these features as potential risk factors for relapse in patients who have responded to treatment should be considered prior to discharge.</p> <p>Trial registration</p> <p>The clinical trial cited in this report has not been registered because it was conducted and completed prior to the inception of clinical trial registries.</p

Antidepressant efficacy of cariprazine in bipolar disorder and the role of its pharmacodynamic properties:A hypothesis based on data

The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of cariprazine fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of cariprazine. The original model suggests that a constellation of effects on different receptors is necessary and that serotonin reuptake inhibition does not appear to play a significant role in acute bipolar depression. On the contrary, norepinephrine activity seems to be necessary. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition appears essential to sustain it. Overall, the properties of cariprazine fit well the proposed model and add to its validity. A point that needs further clarification is norepinephrine reuptake inhibition which is not yet fully studied for cariprazine.</p

Ritanserin as an adjunct to lithium and haloperidol for the treatment of medication-naive patients with acute mania: a double blind and placebo controlled trial

BACKGROUND: Bipolar disorder is a lifelong episodic condition characterized by mood swings between mania and depression. Several lines of evidence suggest that serotonin is likely to play a pivotal role in the pathophysiology of bipolar disorder. Ritanserin, a 5-HT(2 )receptor antagonist, has been reported to have antipsychotic activity. In this 6-week double blind, placebo controlled study involving moderate to severe manic patients, we assessed the effects of ritanserin plus haloperidol in combination with lithium. METHODS: 45 patients aged between 21–43 were eligible to participate as they met the DSM-IV criteria for a current manic episode, on the basis of a clinical interview by an academician psychiatrist. In addition, a score of at least 20 points on the Young Mania rating Scale was required representing moderate to severe mania. Patients were randomly allocated lithium (1–1.2 mEq/L) + haloperidol (10 mg/day)+ ritanserin (10 mg/day) (Group A) or lithium (1–1.2 mEq/L)+ haloperidol (10 mg/day) + placebo (Group B) for a 6-week, double-blind, placebo-controlled study. Patients were assessed by a third year psychiatry resident at baseline and 3, 7, 14, 21, 28 and 42 days after the medication started. All patients entered the hospital were not previously under any medication. The mean decrease in the Young Mania Rating Scale score from baseline was used as the main outcome measure of response of mania to treatment. The extrapyramidal symptoms were assessed using the Extrapyramidal Symptoms Rating Scale. Side effects were systematically recorded throughout the study and were assessed using a checklist. RESULTS: Young Mania Rating Scale total scores improved with ritanserin. The difference between the two protocols was significant as indicated by the effect of group and the between-subjects factor (F = 5.02, d.f. = 1, P = 0.03). The means Extrapyramidal Symptoms Rating Scale scores for the placebo group were higher than the ritanserin group and the difference was significant in day 42. The difference between the two groups in the frequency of side effects was not significant CONCLUSIONS: The efficacy of ritanserin to obtain a better improvement in patients with mania seems to support the 5-HT hypothesis of bipolar disorder

Pure Red Cell Aplasia after 13 Years of Sodium Valproate, and Bone Marrow Suppression after 17 Years of Carbamazepine

A 38-year-old woman presented with acute hematological toxicity from her anticonvulsants, even though she had been taking them for many year