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.     

Quetiapine: a review of its use in acute mania and depression associated with bipolar disorder

Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder.Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of extrapyramidal symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania.     

Spotlight on quetiapine in acute mania and depression associated with bipolar disorder

Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder.Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of extrapyramidal symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania.     

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.     

Polytherapy in bipolar disorder

Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder. The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression. For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.     

Epidemiology, diagnosis and management of mixed mania

The presence of depressive symptomatology during acute mania has been termed mixed mania, dysphoric mania, depressive mania or mixed bipolar disorder. Highly prevalent, mixed mania occurs in at least 30% of bipolar patients. Correct diagnosis is a major challenge. The DSM diagnostic criteria, the most widely adopted clinical convention, require a complete manic and complete depressive syndrome co-occurring for at least 1 week. However, recent alternative categorical and dimensional studies of manic phenomenology have shown that there are certain depressive symptoms or constellations that have special clinical importance when describing mixed states, such as depressed mood and anxiety symptomatology that do not overlap with manic symptoms. Patients with mixed mania are over-represented in the subgroup with severe and treatment-resistant symptoms. The course and prognosis of mixed mania are worse than that of pure manic forms in the medium and long term, with higher recurrence rates, higher frequency of co-morbid substance abuse and greater risk of suicidal ideation and attempts. Moreover, mixed manic episodes are usually associated with increased depression during follow-up, greater risk of rapid cycling course and higher prevalence of physical co-morbidities, principally related to thyroid function. All these factors are very relevant to selection of treatment. There are three crucial steps in the treatment of mixed mania--making the correct diagnosis, starting treatment early, and considering not only the acute state but also maintenance treatment and the patient's long-term outcome. Although challenging, acute mixed episodes are treatable. To date there have been no controlled studies devoted exclusively to treatment of mixed mania, and the only controlled data available therefore derive from sub-analyses of randomised clinical trials. Both short-term and maintenance treatments of patients with mixed mania require experience and usually involve the combination of different treatments. As a general rule, there is some consensus about discontinuing antidepressants during mixed mania. Olanzapine, aripiprazole or valproate semisodium (divalproex sodium) are first-line drugs for mild episodes; severe episodes of mixed mania usually require treatment with a combination of valproate semisodium or lithium plus an antipsychotic, preferably an atypical agent. Carbamazepine is also useful for the treatment of mixed mania. High-dose medications are sometimes needed to control the episode, and time to remission is usually longer than in pure mania. Importantly, patients with mixed manic episodes have more adverse events of psychopharmacological treatment. In some cases, electroconvulsive therapy is required.     

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/fluoxetine: a review of its use in the treatment of acute bipolar depression

Olanzapine/fluoxetine (Symbyax) is an oral once-daily fixed-dose combination of the atypical antipsychotic olanzapine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine that is approved in the US for the treatment of depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine plus fluoxetine is effective in the treatment of patients with acute bipolar depression. The combination improves depressive symptoms and symptom severity in this patient population, with an efficacy greater than that of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is generally well tolerated. Although associated with weight gain and potential elevations in glucose, lipid and prolactin levels, the combination does not increase the risk of treatment-emergent mania. Additional placebo- and active comparator-controlled studies are required in order to confirm the efficacy of olanzapine/fluoxetine in the treatment of bipolar depression and to definitively position olanzapine/fluoxetine with respect to other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated first-line option for the treatment of acute bipolar depression.     

Spotlight on olanzapine/fluoxetine in acute bipolar depression

Olanzapine/fluoxetine (Symbyax((R))) is an oral once-daily fixed-dose combination of the atypical antipsychotic olanzapine and the SSRI fluoxetine that is approved in the US for the treatment of depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine plus fluoxetine is effective in the treatment of patients with acute bipolar depression. The combination improves depressive symptoms and symptom severity in this patient population, with an efficacy greater than that of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is generally well tolerated. Although associated with weight gain and potential elevations in glucose, lipid and prolactin levels, the combination does not increase the risk of treatment-emergent mania. Additional placebo- and active comparator-controlled studies are required in order to confirm the efficacy of olanzapine/fluoxetine in the treatment of bipolar depression and to definitively position olanzapine/fluoxetine with respect to other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated first-line option for the treatment of acute bipolar depression.     

Treatment of mixed bipolar states

Mixed bipolar states are associated with more severe symptoms and outcome. Our aim is to review the literature examining their treatment. We conducted a literature search of randomized clinical studies and post-hoc analyses on mixed bipolar states' treatment. Remarkably, there is only one double-blind, placebo-controlled trial, recruiting a mixed episode cohort, and one post-hoc analysis of this trial, while most data come from post-hoc analyses of trials including both manic and mixed patients. Improvement of manic symptoms in mixed episodes is similar to that seen in pure manic episodes and independent of baseline depressive features. The magnitude of response to manic symptoms' treatment probably exceeds that of depressive symptoms, which appear to resolve later. Valproate and carbamazepine are effective in acute mixed episodes, but the efficacy of lithium appears questionable. Atypical antipsychotic monotherapy improves both manic and depressive symptoms. Mood-stabilizer-atypical antipsychotic combination increases this effect. Atypical antipsychotic-antidepressant combination against acute mixed depression does not increase the risk for mania, although its superior efficacy vs. atypical antipsychotic monotherapy cannot be supported by current data. As regards prophylaxis, atypical antipsychotic monotherapy is associated with a lower incidence of and a longer time to relapse of any kind. The augmentation of lithium or divalproex with atypical antipsychotics increases prophylactic efficacy. Lithium or divalproex monotherapy have not been associated with significant prophylactic benefits following mixed mania. New, randomized prospective trials involving homogeneous cohorts of mixed bipolar patients are needed in order to delineate the appropriate pharmacological treatment of mixed states.     

Olanzapine: new indication. Prevention of bipolar disorder: unconvincing trials

(1) Lithium, the standard preventive treatment for patients with bipolar disorder, reduces the number of relapses and suicide attempts. (2) Olanzapine is the first neuroleptic to be approved in France for prevention of relapse in patients with bipolar disorder. Many neuroleptics are already used for this indication but their efficacy has not been established in comparative clinical trials. (3) One placebo-controlled double-blind trial involved 361 patients who were treated just after recovering from a manic episode. The trial was supposed to last 48 weeks, but only 146 patients were treated for more than 8 weeks. Therefore, the trial results, including an observed effect on mania, cannot be interpreted to imply long-term prevention. (4) One double-blind trial compared olanzapine plus a mood stabiliser with placebo plus a mood stabiliser in 344 patients who had recovered from an acute episode. Only 21 patients completed the 12-month trial, and the percentage of patients who had relapses (manic or depressive) did not differ significantly between the groups. (5) In a third double-blind trial, 431 patients in remission from a manic episode after treatment with olanzapine + lithium were treated for 12 months with lithium or olanzapine. This trial suggested that olanzapine was more effective in preventing depressive and manic relapses (30% of patients, compared to 38.8% with lithium), but only 171 patients completed the trial. Most dropouts were due to adverse events (19% with olanzapine, 26% with lithium). The impact of treatment on suicide risk was not studied. (6) In a fourth study, 101 patients in remission from a mixed or manic episode continued their initial treatment with olanzapine or sodium divalproate in double-blind manner for 11 months. The risk of relapse was not significantly different between the groups, but the study sample size was too small to tell whether or not the treatments were equally effective. (7) Trials focusing on prevention of relapse in patients with bipolar disorder confirmed the known adverse effects of olanzapine, including weight gain and QTc prolongation. Olanzapine was associated with more weight gain and sedation than lithium. Hyperglycaemia occurring on olanzapine can cause life-threatening ketoacidosis. (8) Lithium remains the standard treatment for preventing recurrent bipolar disorder. There is no firm evidence that olanzapine is more effective than a mood stabiliser after lithium failure, or that it boosts the efficacy of lithium.     

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

Aripiprazole (Abilify?) is an atypical antipsychotic indicated for the treatment of mania associated with bipolar I disorder. It is unique in its class, as it is a partial agonist of dopamine D(2) and D(3), and serotonin 5-HT(1A) receptors and a modest antagonist of 5-HT(2A) receptors. This article reviews the pharmacological properties, clinical efficacy and tolerability of oral aripiprazole in the management of mania associated with bipolar I disorder in adults. In well designed clinical trials in patients with recent manic or mixed episodes associated with bipolar I disorder, oral aripiprazole monotherapy or adjunctive therapy to lithium or valproate improved symptoms of mania following short-term (≤12 weeks) or maintenance (≤100 weeks) treatment. In addition, maintenance treatment with aripiprazole (as monotherapy or adjunctive therapy) prevented the recurrence of any mood episodes or manic episodes (but not depressive episodes) in patients who had previously been stabilized and maintained on aripiprazole. Aripiprazole was generally well tolerated in these studies and was associated with a low risk of prolactin elevation, corrected QT interval prolongation and metabolic disturbances. Extrapyramidal symptoms occurred in up to 28% of aripiprazole recipients, but after longer-term treatment (≤100 weeks), symptom severity did not differ significantly from that in placebo recipients. Aripiprazole treatment generally did not increase bodyweight to a clinically relevant extent; however, more patients receiving aripiprazole monotherapy than placebo had clinically significant bodyweight gain during 100 weeks' treatment. Additionally, in a comparative trial, aripiprazole monotherapy was at least as effective as haloperidol monotherapy in terms of improving symptoms of mania, but had the advantage of a lower incidence of some adverse events, such as extrapyramidal symptom-related adverse events. Further trials comparing aripiprazole with other agents, including atypical antipsychotics, would help to definitively position aripiprazole relative to these agents. Current guidelines recommend aripiprazole as a first-line option (as monotherapy or adjunctive therapy) for the short-term treatment of mania associated with bipolar I disorder, and as a first-line (as monotherapy) or second-line (as adjunctive therapy) option for preventing the recurrence of mood episodes during longer-term therapy.     

Antipsychotic drugs in bipolar disorder

Antipsychotic drugs are useful in the treatment of acute mania and as maintenance treatment. While both typical and atypical antipsychotic drugs are able to diminish manic symptoms, agitation and aggression in acute mania, the atypical antipsychotic drugs enjoy a number of advantages, including significantly less extrapyramidal symptoms, diminished risk of tardive dyskinesia, lack of increase in serum prolactin levels (with the exception of risperidone), improvement in cognition, and possible decrease in suicidality. Most of the atypical antipsychotic drugs have been found to be effective as an add-on treatment (with mood stabilizers and antidepressant drugs) and sometimes as monotherapy in treatment-resistant bipolar patients. Long-acting typical neuroleptic drugs may be useful in the treatment of non-compliant bipolar patients. A small number of patients with schizophrenia treated with risperidone, olanzapine, or quetiapine experience a first episode of hypomania or mania. It is not apparent if this is a true drug-induced event or coincidental. Side-effects of note with the atypical antipsychotic drugs are weight gain (most prominently with olanzapine and clozapine), sedation, and agranulocytosis (clozapine). Atypical antipsychotic drugs are recommended for use in bipolar disorder for acute treatment, maintenance treatment, and for treatment-resistant patients.     

Asenapine improves phencyclidine-induced object recognition deficits in the rat: evidence for engagement of a dopamine D<Subscript>1</Subscript> receptor mechanism

Rationale  

Cognitive deficits are common in schizophrenia. Asenapine is an atypical antipsychotic approved by the US Food and Drug Administration in adults for treatment of schizophrenia or acute treatment, as monotherapy or adjunct therapy to lithium or valproate, of manic or mixed episodes of bipolar I disorder.     

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.     

Iloperidone, asenapine and lurasidone: a primer on their current status

Introduction: Three newer atypical antipsychotic drugs were FDA-approved in 2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The three drugs are indicated for the treatment of acute schizophrenia. Asenapine is also approved for treatment of manic or mixed episodes associated with bipolar I disorder, for the maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Areas covered: This review compares and contrasts the current preclinical, clinical, safety and tolerability profiles of the three newer drugs, as reported in published preclinical and clinical studies, product labels, poster presentations and press releases. Expert opinion: Preclinical studies have reported that the three drugs have variable affinities for a wide range of neurotransmitter receptors, and are active in animal models predictive of antipsychotic activity. Asenapine is the first antipsychotic to be administered sublingually, whereas iloperidone requires titration to minimize orthostatic hypotension. Asenapine and lurasidone are associated with dose-related akathisia, whereas iloperidone is not. The three drugs appear to have relatively benign metabolic profiles. The availability of the three novel antipsychotics should provide additional options for improved treatment of schizophrenia and other psychotic disorders.     

Quetiapine for the treatment of acute bipolar mania, mixed episodes and maintenance therapy

INTRODUCTION: Bipolar disorder is characterized by mood instability, which can be challenging to manage. First-line pharmacological approaches usually involve lithium, anticonvulsants and antipsychotics. Over the past fifteen years, several second-generation antipsychotics have demonstrated benefits for various phases of this disorder. AREAS COVERED: This article examines the pharmacodynamics and pharmacokinetics of quetiapine ; its evidence base as an acute and maintenance monotherapy or adjunctive therapy for bipolar manic or mixed episodes is also discussed, along with the related issues of its safety and tolerability. EXPERT OPINION: In the context of bipolar disorder, quetiapine is the only agent approved as a monotherapy or adjunct therapy for acute manic/mixed episodes in adults and adolescents; as a monotherapy for acute depressive episodes in adults; and as an adjunctive maintenance therapy for bipolar I and II disorder in adults. In addition to its antipsychotic properties, this broad mood-stabilizing potential may simplify the management of select patients.     

The cost-effectiveness of lamotrigine in the maintenance treatment of adults with bipolar I disorder

OBJECTIVE: To present an economic model and cost-effectiveness estimates for lamotrigine in maintenance treatment of bipolar I disorder (BD-I) using outcomes from the pivotal lamotrigine trials. The main comparator treatments in the pivotal trials were lithium and .no maintenance. (acute-only) treatment. A comparison with olanzapine was included as an indirect analysis following publication of data during the course of our research. METHODS: A Markov model was built around the 3 health states of euthymia, mania, and depression. The base-case model simulates a cohort of 1,000 patients with BD-I who have recently stabilized after resolution of a bipolar mania episode. The cohort was modeled for a period of 18 months. Resource-use estimates were derived from best available published data, treatment guidelines, a physician survey, and published unit cost data. Outputs were measured in terms of costs per acute mood episode avoided, costs per euthymic day gained, and costs per quality-adjusted life-years (QALYs). Direct health care payer costs are used in the analyses. RESULTS: The base-case model for patients with a recent manic episode indicated that lamotrigine is the most effective treatment for avoiding both acute depression episodes and all types of acute episodes (depression and mania). It is also the most effective treatment in terms of number of euthymic days achieved (309 days per patient per year). Olanzapine is most effective for avoiding acute mania episodes. Total direct costs of treatment are lowest for the lithium treatment arm (Dollars 8,710 per patient for the 18-month period). All maintenance therapies were cost effective compared with the no-maintenance (acute-only treatment) arm. In the base case, lamotrigine had incremental cost-effectiveness ratios of Dollars 30 per euthymic day and Dollars 2,400 per acute episode avoided compared with lithium. A QALY analysis indicated that lamotrigine is cost effective in patients with a recent manic episode at Dollars 26,000 per QALY. The base-case model indicated that lamotrigine dominates olanzapine, (that is, lamotrigine costs less and is more effective than olanzapine) in patients with a recent manic episode. In a sensitivity analysis using outcomes from the pivotal trial of recently depressed patients, lamotrigine, in comparison with lithium, was not shown to be as cost effective as in the recently manic patients, but it was still cost effective compared with no maintenance treatment. CONCLUSIONS: For a defined cohort of patients with BD-I, the pharmacoeconomic model indicated that prevention of mood episodes with lithium and lamotrigine is cost effective in patients with a recent manic, mixed, or hypomanic episode. The conclusions with respect to the indirect comparison with olanzapine should be validated if and when direct trial data become available. Cost-effectiveness of maintenance treatments for patients with BD-I (recently depressed as well as recently manic) are likely to improve in models with a broader costing perspective and that take a longer time frame. Further research into the outcome implications of health-related quality of life and other BD subgroups are recommended.     

Resistance to lithium: What alternatives exist?

Lithium is highly valued for the treatment of mania and depression. Resistance may occur to one of its two main indications: firstly for the treatment of acute episodes of mania, and secondly for the prevention of relapse either of bipolar affective disorder (manic depression) or of unipolar affective disorder (recurrent depression). For the management of manic episodes, alternative possibilities include neuroleptics, carbamazepine, electroconvulsive therapy (ECT) and sodium valproate. Neuroleptics are effective, but may precipitate depression. Carbamazepine is effective either alone or as a supplement to the lithium. ECT is an impressively powerful treatment for mania. Valproate appears to be effective but more studies are desirable. Alternatives to lithium in the prevention of relapse of recurrent affective disorders include antidepressants, carbamazepine and ECT. For the prevention of relapses of bipolar affective disorder antidepressants have the disadvantage of increasing the frequency of manic episodes. In unipolar disorder they are a valid alternative to lithium but with some disadvantages. Carbamazepine is effective in the prophylaxis of bipolar affective disorder and should be considered especially in patients with rapid cycling or those with psychotic features. Only open studies are available on ECT and valproate as prophylactic agents. Preliminary work has been carried out on verapamil, flupenthixol, clonazepam, methylene blue, clorgyline, clonidine, tryptophan and 5-hydroxy tryptamine.