Asenapine: a review of its use in the management of mania in adults with bipolar I disorder

Asenapine is an atypical antipsychotic agent available in sublingual formulations (5 or 10 mg) and indicated in the US (Saphris) for the acute treatment, as monotherapy or adjunctive therapy, of manic and mixed episodes and in the EU (Sycrest) for the treatment of moderate to severe manic episodes, in adult patients with bipolar I disorder. In two large (both n = 480), well designed, 3-week trials in adult patients with bipolar I disorder, asenapine monotherapy was significantly more effective than placebo at improving mania symptoms, as assessed using the Young Mania Rating Scale total score (YMRS; primary endpoint), with significant differences between the asenapine and placebo groups occurring after 2 days of treatment. In both trials, Clinical Global Impression for Bipolar Disorder (CGI-BP) scale mania severity scores exceeded those of placebo. In one trial, response and remission rates exceeded those of placebo. In a 9-week extension study that recruited completers from the monotherapy trials, there were no significant differences between asenapine and olanzapine groups in terms in Montgomery-?sberg Depression Rating Scale (MADRS) scores, CGI-BP mania severity scores, YMRS response rates or YMRS remission rates during the extension phase. In the extension study, the efficacy of asenapine monotherapy appeared to be maintained over 40 weeks (total treatment duration of 52 weeks). In a 12-week trial of asenapine as adjunctive therapy to lithium or valproate, asenapine was more effective than placebo in improving manic symptoms, based on the difference between groups in the YMRS total score at week 3 (primary endpoint). Most adverse events associated with asenapine were of mild to moderate severity, with <7% of asenapine recipients experiencing serious adverse events (vs 7% with placebo). In a pooled analysis of the monotherapy trials, the most common adverse events (occurring in ≥ 5% of patients and at twice the incidence of placebo) reported during acute phase asenapine monotherapy for bipolar mania were somnolence, dizziness, extrapyramidal symptoms (EPS, other than akathisia) and increased bodyweight, which were similar in nature to those occurring during longer-term monotherapy with asenapine. EPS did not worsen in severity during longer-term asenapine monotherapy. Asenapine had minimal effects on plasma glucose, lipid and prolactin levels over both short- and longer-term treatment periods, and had little pro-arrhythmogenic potential. Further active comparator trials and longer-term tolerability and safety data are required. In the meantime, asenapine is a further option for the management of manic and/or mixed symptoms in patients with bipolar I disorder and may be of particular value for patients who are at high risk for metabolic abnormalities.     

Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension

In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks.     

Olanzapine in bipolar disorder

Olanzapine is currently marketed not only for the treatment of schizophrenia, but also for the treatment of acute mania and the prevention of relapse in patients successfully treated with this drug for a manic episode. A large body of good clinical trials supports these indications. In the mania trials, olanzapine was more efficacious than placebo, equal or more efficacious than valproate and more efficacious than lithium or valproate monotherapy when used in combination with either drug. A trial that compared olanzapine with haloperidol failed to show superiority of the atypical versus the conventional. Olanzapine showed a modest but statistically significant effect in the treatment of bipolar depression; this modest effect was substantially enhanced in combination with fluoxetine. The long-term trials showed that olanzapine was better than placebo in the prevention of manic and depressive relapse and not inferior to lithium or valproate. The combination of olanzapine with lithium or valproate was also more efficacious than lithium or valproate alone in the prevention of manic relapse in patients partially non-responding to monotherapy with lithium or valproate. All these trials suggest that olanzapine may be a valuable drug in the short- and long-term treatment of bipolar I disorder. However, there are some concerns about the safety and tolerability of olanzapine in this population, as far as weight gain and metabolic syndrome are concerned, which may be addressed in future pharmacovigilance studies.     

Olanzapine in bipolar disorder

Olanzapine is currently marketed not only for the treatment of schizophrenia, but also for the treatment of acute mania and the prevention of relapse in patients successfully treated with this drug for a manic episode. A large body of good clinical trials supports these indications. In the mania trials, olanzapine was more efficacious than placebo, equal or more efficacious than valproate and more efficacious than lithium or valproate monotherapy when used in combination with either drug. A trial that compared olanzapine with haloperidol failed to show superiority of the atypical versus the conventional. Olanzapine showed a modest but statistically significant effect in the treatment of bipolar depression; this modest effect was substantially enhanced in combination with fluoxetine. The long-term trials showed that olanzapine was better than placebo in the prevention of manic and depressive relapse and not inferior to lithium or valproate. The combination of olanzapine with lithium or valproate was also more efficacious than lithium or valproate alone in the prevention of manic relapse in patients partially non-responding to monotherapy with lithium or valproate. All these trials suggest that olanzapine may be a valuable drug in the short- and long-term treatment of bipolar I disorder. However, there are some concerns about the safety and tolerability of olanzapine in this population, as far as weight gain and metabolic syndrome are concerned, which may be addressed in future pharmacovigilance studies.     

Extended-release carbamazepine capsules as monotherapy in bipolar disorder : pooled results from two randomised, double-blind, placebo-controlled trials

OBJECTIVES: Recently, two large, 3-week, randomised, double-blind, placebo-controlled trials using nearly identical protocols demonstrated that monotherapy with carbamazepine extended-release capsules (CBZ-ERC) was effective for the treatment of acute mania in patients with bipolar I disorder. By pooling data from these two trials, a more highly powered analysis of the efficacy and safety of CBZ-ERC in bipolar I disorder could be conducted. METHODS: Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Clinical Global Impression (CGI)-Severity (CGI-S) scale, the CGI-Improvement (CGI-I) scale and the Hamilton Depression Rating Scale (HDRS). A sub-analysis of the data based on manic versus mixed presentation was performed, as well as sub-analyses by age, sex and ethnicity. RESULTS: Of the 443 randomised patients in the pooled population, 240 completed the studies. Forty-two percent of CBZ-ERC-treated patients did not complete the studies, compared with 50% of placebo-treated patients (p=0.087). Ten percent of patients given CBZ-ERC withdrew because of lack of efficacy, compared with 22% of patients given placebo (p<0.001). At endpoint, CBZ-ERC compared with placebo was associated with significant improvements in mean YMRS total scores in patients experiencing both manic (p<0.0001) and mixed (p<0.01) episodes, using last-observation-carried-forward analyses. CGI-I and CGI-S scores also showed significant improvements from baseline for both manic and mixed patients at endpoint. In patients with mixed episodes, at endpoint there was a mean improvement in HDRS total score of 4.8 points with CBZ-ERC, compared with 2.3 points with placebo (p<0.05). Ninety percent of patients given CBZ-ERC experienced an adverse event, compared with 64% of those patients given placebo. Discontinuation because of adverse events occurred in 10.8% of patients taking CBZ-ERC, compared with 5.5% of patients taking placebo. CONCLUSIONS: These results confirm previous findings that CBZ-ERC is effective in the treatment of bipolar I disorder patients with either acute manic or mixed episodes. These data suggest that further randomised controlled studies are warranted to delineate the effect of CBZ-ERC on depressive symptoms in patients with bipolar disorder.     

Acute dysphoric mania: treatment response to olanzapine versus placebo

A substantial number of patients with mania have significant concomitant depressive features, and they may respond differently to mood stabilizers than patients with pure mania. This post-hoc analysis explored the response characteristics of olanzapine versus placebo in bipolar I manic patients with dysphoric and nondysphoric mania (differentiated by baseline Hamilton Depression Rating Scale [HAM-D] score of >20). Two similar, double-blind, randomized trials comparing olanzapine, 5-20 mg, to placebo were pooled for these analyses (N = 246). Mean changes in Young-Mania Rating Scale (Y-MRS) and HAM-D scores during 3 weeks of treatment were examined. Twenty-eight percent of patients had dysphoric mania (olanzapine, n = 33; placebo, n = 35). Among these patients, olanzapine-treated patients had greater improvement within 1 week than did placebo-treated patients on both mania ratings (Y-MRS: -9.7 vs. -3.0 points; = 0.011) and depressive symptom ratings (HAM-D: -9.9 vs. -5.4 points; = 0.025). Among those manic subjects without prominent depressive symptoms (olanzapine, n = 91; placebo, n = 87), mean Y-MRS improvement from baseline to endpoint with olanzapine (-11.5 points) versus placebo (-6.13 points) was comparable to the improvement seen with olanzapine versus placebo in the dysphoric mania subgroup ( = 0.476, test of interaction). In acutely ill manic patients with significant depressive symptoms, olanzapine demonstrated a broad spectrum of efficacy, effectively treating both manic and depressive symptoms. The magnitude of the antimanic response appears similar, regardless of baseline depressive features. Additional experience with putative mood stabilizers and atypical agents in mixed mania should include an exploration of their efficacy in treating both manic and depressive mood symptoms.     

Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania

This exploratory analysis was performed to compare the efficacy and tolerability of risperidone when added to two different mood stabilizers (lithium or valproate) for mania in bipolar disorder. Patients receiving lithium or valproate at baseline were drawn from the database of a 12-week, open-label risperidone study. The primary efficacy measure was the Young Mania Rating Scale (YMRS). Other assessments included the Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI) of improvement, and safety measures. The analysis included 33 patients on lithium plus risperidone and 46 patients on valproate plus risperidone. Both subgroups had comparable baseline YMRS scores (lithium 28.2, valproate 28.7) and both had significant reductions in score by week 1 (P<0.0001). Comparable reductions in score continued for both subgroups until the end of the study (YMRS scores at week 12: lithium 4.6 and valproate 6.7). There were no significant differences in response rates (> or =50% improvement on YMRS) or remission rates (YMRS score < or = 8) between the two subgroups. At week 12, 88% of the lithium plus risperidone patients and 80% of the valproate plus risperidone patients were in remission. Similarly, HAM-D scores were significantly and comparably reduced in both subgroups, and improvement in CGI was the same. There was no difference between subgroups in the incidence of adverse events or weight gain. These data suggest that risperidone can be safely combined with either lithium or valproate, and that the efficacy is similar regardless of the mood stabilizer used.     

A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode

On the basis of 3-week studies, lithium and valproate are both recommended for first-line treatment of acute mania. It is, however, also important to demonstrate that antimanic efficacy can be maintained. This study has been designed to compare the efficacy and tolerability of valproate and lithium over 12 weeks in the treatment of acute mania in patients with type I bipolar disorder. Three hundred patients with bipolar I disorder presenting with acute mania were randomized to open treatment with lithium (starting dose: 400 mg/day) or valproate (starting dose: 20 mg/kg/day) for 12 weeks. The primary efficacy criterion was remission (YMRS score or=2 on the CGI-BP severity scale). Remission rates were 65.5% (lithium group) and 72.3% (valproate group). Noninferiority of valproate with respect to lithium was demonstrated [between-group difference: 6.78% (95% confidence intervals: -3.80 to 17.36%)]. Remission rates assessed by the secondary mixed model repeated measures analysis were significantly greater with valproate than with lithium. Adverse events were reported in 44% of patients in both groups. Valproate and lithium showed comparable efficacy and tolerability in the treatment of acute mania over 12 weeks.     

Divalproex in the treatment of bipolar disorder

Valproate is commonly used as a first-line agent for the treatment of acute bipolar I mania. Its efficacy in the treatment of acute mania has been established in randomized, controlled trials versus placebo, lithium, haloperidol, and olanzapine. Only preliminary data regarding the efficacy of valproate in acute bipolar depression are currently available. The efficacy of valproate in the maintenance treatment of bipolar disorder has not been definitively established but most evidence from randomized, controlled trials suggests that it may have comparable efficacy to lithium and olanzapine. The results of randomized, controlled trials of valproate in the treatment of bipolar disorder are reviewed along with their implications for clinical practice.     

Risperidone: a review of its use in the treatment of bipolar mania

Risperidone (Risperdal) is an atypical antipsychotic with high affinity for 5-hydroxytryptamine (5-HT)2A, dopamine D2 and alpha1- and alpha2-adrenergic receptors. Risperidone is now approved in the UK and the US for use in bipolar mania. Risperidone < or =6 mg/day, as monotherapy or adjunctive therapy with first-line mood stabilisers, significantly improves moderate and severe bipolar mania and improves global functioning over 3 weeks. Improvements in Young Mania Rating Scale (YMRS) scores in double-blind trials were greater with risperidone than with placebo over 3 weeks, and similar to those with haloperidol over 3 and 12 weeks. Risperidone was reasonably well tolerated. Limited data are available on the combination of risperidone and carbamazepine. Risperidone, as monotherapy or combined therapy with lithium or valproate semisodium, is an effective treatment option in bipolar mania.     

Olanzapine: new indication. New indication in acute mania: just another neuroleptic

(1) Lithium is the first-line treatment for patients with acute mania. For patients with psychosis or intense agitation, an oral neuroleptic can be added (haloperidol or chlorpromazine, the best-assessed drugs of this class). (2) The licensed indications for oral olanzapine, a neuroleptic, explicitly mention the treatment of acute mania. (3) The clinical evaluation dossier on olanzapine in this setting (10 mg to 15 mg/day) is not particularly impressive. In particular, clinical trials included patients with a variety of associated psychotic symptoms. (4) The only comparative trial against another neuroleptic, haloperidol at a high starting dose (10 mg), showed that olanzapine was no more effective. The same applies to a trial comparing olanzapine with disodium valproate. (5) One placebo-controlled trial tested olanzapine as an additional treatment in patients who did not respond adequately to lithium or valproate disodium. Olanzapine potentiated the antimanic effects of the original treatment but also increased the incidence of adverse effects. (6) In patients with acute mania, the main adverse effects of olanzapine are drowsiness, weight gain, dizziness, and dry mouth. In the trial comparing olanzapine with haloperidol, olanzapine caused fewer extrapyramidal side effects but more weight gain than haloperidol. (7) Olanzapine costs 20 times more than haloperidol in France. (8) In practice, olanzapine is just another neuroleptic approved for the treatment of acute mania in patients with psychotic symptoms and agitation. There is no evidence that olanzapine has the best risk-benefit ratio in this category.     

Efficacy of Antimanic Treatments: Meta-analysis of Randomized, Controlled Trials

We conducted meta-analyses of findings from randomized, placebo-controlled, short-term trials for acute mania in manic or mixed states of DSM (III–IV) bipolar I disorder in 56 drug–placebo comparisons of 17 agents from 38 studies involving 10 800 patients. Of drugs tested, 13 (76%) were more effective than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperdone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone. Their pooled effect size for mania improvement (Hedges'' g in 48 trials) was 0.42 (confidence interval (CI): 0.36–0.48); pooled responder risk ratio (46 trials) was 1.52 (CI: 1.42–1.62); responder rate difference (RD) was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat of 6 (all p<0.0001). In several direct comparisons, responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate, or carbamazepine; lithium did not differ from valproate, nor did second generation antipsychotics differ from haloperidol. Meta-regression associated higher study site counts, as well as subject number with greater placebo (not drug) response; and higher baseline mania score with greater drug (not placebo) response. Most effective agents had moderate effect-sizes (Hedges'' g=0.26–0.46); limited data indicated large effect sizes (Hedges'' g=0.51–2.32) for: carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen. The findings support the efficacy of most clinically used antimanic treatments, but encourage more head-to-head studies and development of agents with even greater efficacy.     

Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. European Valproate Mania Study Group

To compare the efficacy of sodium valproate administered as adjunct to neuroleptic medication for patients with acute mania with the efficacy of neuroleptics alone, the authors conducted a 21-day, randomized, double-blind, parallel-group, placebo-controlled trial. The study design closely reflected a clinical psychiatric setting in Europe where patients with acute mania commonly receive neuroleptic medication. In this trial, 136 hospitalized patients met the ICD-10 criteria for acute manic episodes; these patients received a fixed dose of 20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel GmbH, Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably haloperidol and/or perazine. The primary outcome measure was the mean dose of neuroleptic medication (after conversion into haloperidol-equivalents) for the 21-day study period. Severity of symptoms was measured using the Young Mania Rating Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression Scale. Intent-to-treat analysis was based on 69 patients treated with valproate and 67 patients who received placebo. Groups were comparable with regard to demographic and clinical baseline data. Premature discontinuations occurred in only 13% of the patients. The mean neuroleptic dose declined continuously in the valproate group, whereas only slight variations were observed in the placebo group; the difference was statistically significant (p = 0.0007) for study weeks 2 and 3. The combination of neuroleptic and valproate proved superior to neuroleptics in attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement rate shown on the YMRS) was higher for the combination with valproate than for the group receiving only neuroleptics (70% vs. 46%; p = 0.005). Adverse events consisted of those known for valproate or neuroleptics; the only adverse event was asthenia, which occurred more frequently with the combination therapy. Valproate represents a useful adjunct medication for the treatment of acute manic symptoms. Valproate is beneficial because it allows the administration of fewer neuroleptic medications and produces improved and quicker remission of manic symptoms.     

Pharmacological interventions for the prevention of relapse in bipolar disorder: a systematic review of controlled trials

We conducted a systematic review and meta-analysis of randomised and quasi-randomised controlled trials evaluating all clinically relevant pharmacological interventions for the prevention of relapse in people with bipolar disorder. Thirty-four trials were included in the review. Direct comparisons with placebo and with lithium were available for most drugs. In addition, there were direct comparisons of valproate vs. olanzapine, imipramine vs. lithium plus imipramine, olanzapine plus mood stabilisers vs. mood stabilisers and perphenazine plus mood stabilisers vs. mood stabilisers. Methodological quality varied across studies and the strength of evidence was not equal for all treatments or for all comparisons. There is evidence from placebo-controlled trials for the efficacy of lithium, valproate and lamotrigine as maintenance therapy for the prevention of relapse in bipolar disorder. Three drugs have a significant effect in the prevention of manic relapses (lithium, olanzapine and aripiprazole) and three in the prevention of depressive symptoms (valproate, lamotrigine and imipramine). Imipramine is little used in practice, because of concern about adverse effects. The significant effects of olanzapine and aripiprazole were demonstrated in selected responsive bipolar I patients only. Despite widespread use in clinical practice, there is little evidence to support the efficacy of combination therapy.     

Olanzapine: a review of its use in the management of bipolar I disorder

Olanzapine is an atypical antipsychotic that is approved in the US and Europe for the oral treatment of acute manic episodes in patients with bipolar I disorder, and for maintenance therapy to prevent recurrence in responders.Oral olanzapine is effective in the treatment of bipolar mania, both as single agent therapy and as adjunctive therapy in combination with lithium or valproate semisodium. In the treatment of acute episodes, olanzapine is superior to placebo and at least as effective as lithium, valproate semisodium, haloperidol and risperidone in reducing the symptoms of mania and inducing remission. Additional comparative studies are required to determine the efficacy of olanzapine relative to newer atypical antipsychotics, such as quetiapine, ziprasidone and aripiprazole. Olanzapine is also effective at delaying or preventing relapse during long-term maintenance therapy in treatment responders, and is currently the only atypical antipsychotic approved for this indication. Current evidence suggests that olanzapine may be more effective than lithium in preventing relapse into mania, but not relapse into depression or relapse overall. Olanzapine is generally well tolerated, and although it is associated with a higher incidence of weight gain than most atypical agents, it has a low incidence of extrapyramidal symptoms (EPS). Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the acute treatment of manic episodes and the long-term prevention of relapse into manic, depressive or mixed episodes associated with bipolar I disorder.     

喹硫平联合碳酸锂或丙戊酸钠治疗双相躁狂的多中心随机对照研究

目的:探讨喹硫平合并碳酸锂或丙戊酸钠治疗双相躁狂的疗效和安全性。方法:将符合CCMD-3和DSM-IV的双相障碍诊断标准的100例研究对象随机分成2组,53例喹硫平组应用喹硫平合并碳酸锂或丙戊酸钠,47例对照组单一使用碳酸锂或丙戊酸钠,治疗观察6 wk。采用Beck-Rafaelsen躁狂量表(BRMS)评定疗效,以副反应量表(TESS)及实验室有关辅助检查评价安全性。结果:喹硫平组的45例(85％)和对照组的40例(85％)完成了6 wk的治疗观察,喹硫平组在治疗wk 1末的减分率比对照组显著,这种差异在1～6 wk一直存在,而且wk 6结束后的临床有效率(BRMS减分率≥50％)、痊愈率(BRMS<11)也显著高于对照组。喹硫平合并碳酸锂或丙戊酸钠常见的不良反应有头晕、头痛、嗜睡、心悸、口干、直立性低血压、便秘。结论:喹硫平合并碳酸锂或丙戊酸钠治疗双相躁狂的疗效比单一使用心境稳定剂好。     

Olanzapine compared to lithium in mania: a double-blind randomized controlled trial

Neuroleptics are of established efficacy in mania. Controlled data on the use of olanzapine in mania is however, absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly allocated to receive either olanzapine or lithium in a 4 week double-blind randomized controlled design. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2, olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P = 0.025). Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine appears to be at least as effective as lithium in the treatment of mania.     

Spotlight on olanzapine in bipolar I disorder

Olanzapine is an atypical antipsychotic that is approved in the US and Europe for the oral treatment of acute manic episodes in patients with bipolar I disorder and for maintenance therapy to prevent recurrence in responders. Oral olanzapine is effective in the treatment of bipolar mania, both as single agent therapy and as adjunctive therapy in combination with lithium or valproate semisodium. In the treatment of acute episodes, olanzapine is superior to placebo and at least as effective as lithium, valproate semisodium, haloperidol and risperidone in reducing the symptoms of mania and inducing remission. Additional comparative studies are required to determine the efficacy of olanzapine relative to newer atypical antipsychotics such as quetiapine, ziprasidone and aripiprazole. Olanzapine is also effective at delaying or preventing relapse during long-term maintenance therapy in treatment responders and is currently the only atypical antipsychotic approved for this indication. Current evidence suggests that olanzapine may be more effective than lithium in preventing relapse into mania, but not relapse into depression or relapse overall. Olanzapine is generally well tolerated and, although it is associated with a higher incidence of weight gain than most atypical agents, it has a low incidence of extrapyramidal symptoms. Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the acute treatment of manic episodes and the long-term prevention of relapse into manic, depressive or mixed episodes associated with bipolar I disorder.     

Intravenous valproate loading in acutely manic and depressed bipolar I patients.

Recently, valproate has emerged as a drug of primary choice for the treatment of acute mania, especially mixed mania and, partially, rapid cycling. Because of its relative safety, it can be administered in high doses as an oral loading therapy, with approximately 60% to 70% of patients showing a favorable response. Here we report on seven bipolar I patients, two of which have euphoric mania, three have a mixed manic state (including one patient with ultra-rapid cycling and one with very prominent depressed features), and two have solely depressed mood. All but one of the manic patients showed a rapid and favorable response to intravenous valproate loading, which built up sufficient blood levels that were maintained by subsequent oral treatment. Of the two patients with solely depressed mood, however, one experienced only minor benefits and the other showed no change in the depressive symptomatology. Intravenous valproate was tolerated without problems and also led to a drastic reduction in and eventual withdrawal of benzodiazepine treatment in two cases. All of the patients showed a drastic remission of mania with valproate blood levels at or only slightly above 50 microg/mL (blood drawn 12 hours after last application). It is interesting to note that one patient who was previously nonresponsive to oral valproate loading responded well to intravenous valproate. Besides the obvious efficacy and safety of this treatment regimen, these findings may also imply that a difference in pharmacokinetics with intravenous loading may result in a quick saturation of plasma-binding proteins, and hence, peak concentrations of valproate may be reached rapidly, which could contribute to the beneficial action, even in patients previously nonresponsive to oral valproate.     

Novel treatments for bipolar disorder

Treatments other than lithium have recently emerged as equally important in the management of bipolar disorder. The spectrum of efficacy of newer treatments differs from lithium and among the novel drug treatments valproate, generally used as the better tolerated divalproex form, principally benefits manic symptomatology both acutely and in prophylaxis. Atypical antipsychotic drugs have demonstrated efficacy in reducing acute manic symptoms. No controlled evidence of efficacy in prophylaxis has been published. Lamotrigine has demonstrated efficacy in both acute bipolar depression and maintenance efficacy in rapid cycling bipolar patients, especially those patients with bipolar II disorder, which is principally manifested as depression. Randomised, double-blind, placebo- controlled studies provide good evidence that regimens of risperidone or olanzapine in combination with lithium or valproate provide greater improvement in acute mania than the mood stabilisers alone. Similarly, valproate combined with antipsychotics provided greater improvement in mania than antipsychotic medication alone and resulted in lower dosage of the antipsychotic medication. A positive but unclear placebo-controlled study of omega-3 fatty acids added to lithium in bipolar disorder needs confirmation in standard clinical trial paradigms. Several other drugs that were reported as beneficial in various facets of bipolar disorder in open trials have not differed from placebo when studied in randomised, placebo-controlled trials.