Elsevier

The Lancet

Volume 381, Issue 9878, 11–17 May 2013, Pages 1672-1682
The Lancet

Series
Treatment of bipolar disorder

https://doi.org/10.1016/S0140-6736(13)60857-0Get rights and content

Summary

We review recent developments in the acute and long-term treatment of bipolar disorder and identify promising future routes to therapeutic innovation. Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics. Substantial progress has been made in the development and assessment of adjunctive psychosocial interventions. Long-term maintenance and possibly acute stabilisation of depression can be enhanced by the combination of psychosocial treatments with drugs. The development of future treatments should consider both the neurobiological and psychosocial mechanisms underlying the disorder. We should continue to repurpose treatments and to recognise the role of serendipity. We should also investigate optimum combinations of pharmacological and psychotherapeutic treatments at different stages of the illness. Clarification of the mechanisms by which different treatments affect sleep and circadian rhythms and their relation with daily mood fluctuations is likely to help with the treatment selection for individual patients. To be economically viable, existing psychotherapy protocols need to be made briefer and more efficient for improved scalability and sustainability in widespread implementation.

Introduction

Bipolar disorders types I and II affect about 2% of the world's population, with subthreshold forms of the disorder affecting another 2%.1, 2 Even with treatment, about 37% of patients relapse into depression or mania within 1 year, and 60% within 2 years.3 In the STEP-BD cohort (n=1469), 58% of patients with bipolar disorder types I and II achieved recovery, but 49% had recurrences in a 2-year interval; twice as many of these recurrences were of depressive polarity (marked by sad mood, loss of interests, or fatigue) rather than of manic polarity (marked by elevated mood, grandiosity, and decreased need of sleep).4 After initial onset, patients with bipolar disorder have residual depressive symptoms for about a third of the weeks of their lives.5 In 2009, the direct and indirect costs of bipolar disorder were estimated to be US$151 billion.6 Patients also experience psychotic symptoms, impaired functioning, compromised quality of life, and stigma.7, 8

Treatment of bipolar disorder conventionally focuses on acute stabilisation, in which the goal is to bring a patient with mania or depression to a symptomatic recovery with euthymic (stable) mood; and on maintenance, in which the goals are relapse prevention, reduction of subthreshold symptoms, and enhanced social and occupational functioning. Treatment of both phases of the illness can be complex, because the same treatments that alleviate depression can cause mania, hypomania, or rapid cycling (defined as four or more episodes in 12 months), and the treatments that reduce mania might cause rebound depressive episodes.

We focus on contemporary issues in the acute and maintenance treatment of bipolar disorder. Developments in diagnosis and neurobiology are beyond the scope of this review and are mentioned only when they have direct implications for management. Despite a substantial expansion of research into bipolar disorder and potential treatments during the past 2 decades, true advances have been few. The development of effective treatments for bipolar disorder is hampered by our scarce knowledge of basic disease mechanisms and the consequent absence of validated pharmacological targets, and unconvincing animal or human experimental drug models (table 1 provides a summary of putative treatment targets). Most newly introduced treatments for bipolar disorder, whether pharmacological or psychological, have been based on an extension of use from another disorder—eg, antipsychotics in mania and antidepressants or cognitive-behavioural therapy for bipolar depression. However, lithium remains unique because its main therapeutic use is in bipolar disorder, and investigation of its mechanism of action has, and remains, crucially important in the identification of future targets.

Section snippets

Treatment of mania

The pioneering trials of lithium and chlorpromazine were done in the 1970s and were followed by a focus on antiepileptics (eg, valproate and carbamazepine) in the 1980s and 1990s. Few trials directly assessing the comparative efficacy of different second-generation antipsychotics exist, but a mixed treatments meta-analysis compared 13 agents studied in 68 randomised controlled trials (16 073 participants).9 This review found substantial and clinically important differences in terms of both

Treatment of bipolar depression

The treatment of bipolar depression is a major challenge, with few treatments of proven efficacy and, in particular, substantial controversy about the role of antidepressant drugs. Authors of guidelines and consensus statements on this topic often ponder why antidepressants are so commonly used despite the scarce evidence for efficacy.30, 31, 32 Until recently, after the work of Emil Kraepelin, bipolar depressive episodes were deemed phenomenologically and biologically similar to unipolar

Long-term maintenance treatment

Lithium, introduced by John Cade in 1949, remains the best established long-term treatment for bipolar disorder.49 Although the metal has been in clinical use for more than 50 years, the most convincing evidence of long-term efficacy comes from randomised clinical trials in which lithium was included as an active comparator.50 A meta-analysis of five placebo-controlled lithium maintenance trials (n=770) showed that lithium reduces the risk of manic relapses by 38% (RR 0·62, 95% CI 0·50–0·84)

Psychosocial treatments for bipolar disorder

Treatment guidelines increasingly suggest that optimum management of bipolar disorder needs integration of pharmacotherapy with targeted psychotherapy.30, 57 A recent randomised trial in Denmark has shown clinical benefits from this approach.58 Psychological approaches build on evidence that psychosocial stressors, including excessive family discord or distress, negative life events, or events that disrupt sleep and wake rhythms or accelerate goal attainment are associated with relapses and

Adjunctive psychotherapy in acute treatment

Patients in acute manic episodes are not likely to respond well to intensive psychotherapy because of insufficient insight or rejection of help.85 Some trials have examined whether psychotherapy enhances remission from acute depression.86 The STEP-BD study compared up to 30 sessions of family-focused therapy, interpersonal and social rhythm therapy, or cognitive-behavioural therapy (ie, intensive treatment) with a brief psychoeducational therapy (three individual sessions) for 293 patients with

Adjunctive psychotherapy in long-term maintenance

Most studies of psychotherapy for bipolar disorder are maintenance trials in which patients receive standard drugs and either an experimental psychosocial intervention or usual care (eg, brief treatment or a supportive treatment of equal frequency and duration; table 1). A meta-analysis of eight maintenance psychotherapy trials, which included family, individual, and group treatment trials, yielded effect sizes ranging from an odds ratio (OR) of 0·57 (95% CI 0·39–0·82) for reductions in any

Future directions

Advances in the pharmacological treatment of bipolar disorder have come mainly from the repurposing of drugs used in other neuropsychiatric disorders, and do not target the mood instability that characterises the disorder. Dopamine antagonism seems to be a potential target for antimanic treatments, but the scarce convincing evidence that increasing serotonergic transmission improves symptoms in bipolar depression shows the need for development of bipolar-specific validated targets for novel

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