FMC

Treating bipolar disorder

Evidence-based guidelines for family medicine

Roger S. McIntyre, MD, FRCPC    Deborah A. Mancini, MA, CCRC    Peter Lin, MD, CCFP    John Jordan, MD, MCLSC, CCFP, FCFP

This article has been peer reviewed. Cet article a fait l’objet d’une évaluation externe. Can Fam Physician 2004;50:388-394.

Dr McIntyre is an Assistant Professor in the Department of Psychiatry at the University of Toronto and is Head of the Mood Disorders Psychopharmacology Unit at the University Health Network in Toronto, Ont. Ms Mancini is a Clinical Research Coordinator in the Mood Disorders Psychopharmacology Unit at the University Health Network. Dr Lin is Director of the Health and Wellness Center at the Scarborough Clinic of the University of Toronto. Dr Jordan is an Associate Professor in the Department of Family Medicine at the University of Western Ontario in London.

Bipolar spectrum disorders are increasingly recognized as prevalent in both community psychiatric and primary care populations.1-3

Bipolar disorder is a biphasic, chronic disorder. Therapeutic objectives include suppression of acute mania, treatment of acute depression, and protection from relapse (prophylaxis).4 Available treatments for bipolar disorder vary in their effectiveness and in patients’ tolerance while achieving these objectives. For example, some treatments for bipolar disorder are better at suppressing affective symptoms “above the baseline” of wellness (ie, bipolar hypomania or mania) while others are more effective in relieving symptoms of illness “below the baseline” (ie, bipolar depression). Unfortunately, no single medication is reliably effective at accomplishing all therapeutic objectives. This realization has revealed a need for safe and rational combination regimens for most patients with bipolar disorder.

Most people with bipolar disorder, however, remain undiagnosed or misdiagnosed in family practice.1-3,5-11 Recently, a screening instrument has been validated and could assist family physicians in detecting bipolar disorder.1-16 (See Piver et al1 for a helpful review of diagnostic and screening devices in bipolar disorder for general practitioners.) This article is intended to review the quality of evidence of the efficacy of available medications for bipolar disorder. Practical suggestions for medication combinations are also presented.

Quality of evidence

Articles were selected from MEDLINE from 1990 to 2003 using the key words “bipolar disorder,” “antiepileptics,” “antipsychotics,” “antidepressants,” and “mood stabilizers.” Treatment of bipolar disorder involves three domains: acute mania, acute depression, and prophylaxis. Level I evidence exists for lithium treatment in all three domains. Level I evidence exists for divalproex and carbamazepine treatment for acute mania, level II evidence for prophylaxis. Lamotrigine has level I evidence supporting its use for acute depression and prophylaxis and level II evidence supporting its use for acute mania. Level I evidence supports using oxcarbazepine for acute mania.

Level I evidence supports using some conventional antipsychotics (ie, haloperidol) for acute mania and level II evidence for prophylaxis. Level III evidence shows that conventional antipsychotics are ineffective for bipolar depression. Level I evidence supports using novel antipsychotics (eg, olanzapine, risperidone, and quetiapine) for acute mania; level I evidence supports using olanzapine for bipolar depression and maintenance.

Use of some antidepressants for acute bipolar depression is supported by level II evidence; however, the risk of an antidepressant mobilizing a patient into mania or rapid cycling is a serious liability (level I evidence).

Bipolar treatment

Table 1 shows current treatments for bipolar disorder and presents current levels of evidence for pharmacologic agents and clinical recommendations for their use.

Lithium. Isolated in the early 1800s, lithium remains a commonly prescribed mood stabilizer. Lithium’s efficacy in the various phases of this disorder is unequivocally established. Moreover, emerging data indicate that lithium also bestows an antisuicide effect independent of its ability to offer symptom relief.4,16-18 Lithium, however, is not a panacea. Naturalistic (or real-world) studies repeatedly have noted lower response rates with lithium. These lower rates might be due in part to enrolling patients who are less likely to respond to lithium (Table 2).19,20 People likely to respond to lithium typically exhibit “classic bipolar disorder” in which recurrent mania and depression are uncomplicated by comorbidity or rapid cycling.

Antiepileptic drugs. Antiepileptic drugs (AEDs) are categorized as first, second, and third generation (Table 3). Divalproex and carbamazepine are unequivocally effective for acute mania. Their acute antidepressant and prophylactic efficacy, however, is modest and unreliable.21 Both agents are often effective alone or in combination for many patients less likely to respond to lithium (ie, with prominent comorbidity). Second-generation AEDs are, however, limited by being poorly tolerated (eg, weight gain, somnolence) and by a need to monitor plasma levels as well as hematologic and hepatic indices. Numerous drug-drug interactions also complicate their use.

Lamotrigine, a novel third-generation AED, is established as effective for acute and prophylactic treatment of bipolar depression. When prescribing lamotrigine (and other third-generation AEDs), blood monitoring is unnecessary. Lamotrigine is generally well tolerated but up to 10% of treated cases are complicated by cutaneous reactions, and 0.1% of patients with rash progress on to develop Stevens-Johnson syndrome. Risk of serious cutaneous syndrome is higher in preadolescent subjects, with rapid titration, and when lamotrigine is combined with other agents that interfere with its metabolism (eg, divalproex). Family physicians should consult the product monograph for dosing recommendations. The usual therapeutic dose of lamotrigine (without divalproex) is 200 to 300 mg daily. A lower dose (100 to 200 mg daily) is recommended when lamotrigine is coadministered with divalproex.

Gabapentin has not been established as a reliable treatment for any phase of bipolar disorder but has been effective for some anxiety and neuropathic pain syndromes.24,25 Anxiety frequently complicates bipolar disorder, and gabapentin is often useful as an alternative to benzodiazepines to manage anxiety symptoms.24

Topiramate, a fructose derivative, is under active investigation for several medical disorders. A recent controlled study compared topiramate with an antidepressant for treatment of mild bipolar depression. Topiramate was effective and well tolerated. Subjects in this study lost a mean of 5.8 kg across 8 weeks of treatment. Topiramate has been associated with substantial weight loss and is effective for binge eating disorder and bulimia nervosa, which frequently complicate mood disorders. More rigorous data for using topiramate for depression are awaited.27

Oxcarbazepine, the keto-analog to carbamazepine, has been approved in several countries, including Canada, as an antiepileptic agent. Preclinical data suggest that this agent has some antidepressant effect. Oxcarbazepine is reported to be better tolerated than carbamazepine. Oxcarbazepine has a more favourable pharmacokinetic profile, as it does not appear to produce the 10-11 epoxide metabolite (which contributes to tolerance difficulties and not efficacy). Further, it has fewer side effects affecting the central nervous system than carbamazepine and fewer drug interactions.28

Preliminary evidence, largely from open trials, has suggested that oxcarbazepine suppresses symptoms among bipolar patients. Some data suggest an anti-manic and perhaps also an anti-mixed and antidepressant profile. Dosing for bipolar disorder requires further clarification (Table 3).

Conventional antipsychotics. Conventional antipsychotics (ie, haloperidol) have been used frequently to treat bipolar mania. As a class, however, these agents are without proven reliable antidepressant or prophylactic efficacy.29,30 Moreover, patients often report dysphoria when taking these agents, and the risk of acute extrapyramidal syndrome and long-term risk of tardive dyskinesia are cause for concern.29 Bipolar patients taking conventional antipsychotic agents are reported to be at greater risk of antipsychotic-associated extrapyramidal syndrome than patients with schizophrenia.31

Novel antipsychotics. Novel antipsychotics (NAPs) (eg, olanzapine, risperidone, and quetiapine) have supplanted conventional antipsychotics as recommended first-line pharmacologic treatment for schizophrenia. Available NAPs are both structurally and pharmacologically distinct from older conventional antipsychotics (and from each other), which could give these agents different profiles of efficacy and tolerance.

Although categorized as antipsychotic, some NAPs appear to offer a direct antidepressant effect in people with schizophrenia, bipolar disorder, and major depression.32-36 Over the past several years, psychiatrists have been increasingly prescribing these agents as adjunct therapy or alternative strategies for people with nonpsychotic unipolar disorder. The role of NAPs in treatment-resistant depression has recently been elucidated in the Canadian Psychiatric Association’s guidelines on treatment of depressive disorders.37

Several investigations confirmed the antimanic efficacy of each of the available NAPs in bipolar disorder (as monotherapy and as adjunct strategies).14,38 It is noteworthy that the antimanic efficacy offered by these agents is independent of their antipsychotic effect. This response pattern suggests NAPs have a direct mood-stabilizing effect on patients with mood disorders. The effective dose of NAPs in bipolar disorder overlaps with dosing in schizophrenia. Many bipolar patients might benefit from lower relative dosing (eg, olanzapine, 10-15 mg; risperidone, 2-4 mg; quetiapine, 400-800 mg).

Evidence of the antidepressant efficacy of NAPs in bipolar disorder is beginning to emerge.39 A recent large placebo-controlled study (N = 833) noted the combination of olanzapine and fluoxetine (mean dose approximately 10 mg and 50 mg, respectively) offered a robust symptomatic benefit in acute bipolar depression. Evidence of anti­depressant efficacy for the remaining NAPs is also beginning to surface.39,40

The optimal duration of adjunct NAP therapy for bipolar disorder is not empirically established. Some guidelines and bipolar experts recommend discontinuing the adjunct NAP after resolution of the acute episode (eg, approximately 1 to 2 months). In clinical practice, however, this is often impossible for many reasons (eg, insufficient acute response on mood-stabilizer monotherapy, immediate symptom breakthrough after NAP discontinuation). Several uncontrolled investigations of naturalistic practice have noted that most people with bipolar disorder treated with antipsychotic agents use the antipsychotic for lengthy periods.41

Evidence from placebo-controlled trials currently supports use of olanzapine for maintenance treatment of bipolar depression. A recent study suggests that, when patients are maintained on adjunct olanzapine therapy (with lithium or divalproex) rather than mood-stabilizer monotherapy, relapse rates are significantly reduced.

There is no conclusive evidence that NAPs are associated with a greater risk of tardive dyskinesia. They are, however, associated with clinically significant weight gain. Weight and metabolic monitoring is recommended when prescribing these agents. Weight gain is greater with olanzapine than with risperidone and quetiapine. The risk of glucose dysregulation and lipid abnormalities suggests routine weight and metabolic monitoring in patients receiving these treatments.43

Novel antidepressants. Somewhat surprisingly, little evidence supports use of antidepressants as reliably effective in bipolar depression. Moreover, antidepressants can induce manic episodes or rapid cycling in predisposed patients. Of the available classes, tricyclic antidepressants are believed more likely to switch patients than novel agents (ie, selective serotonin reuptake inhibitors, venlafaxine, bupropion).44,45 Short-term treatment with antidepressants, to be discontinued after 2 months of remission if possible, is promoted for treatment of many bipolar patients. Office counseling and psychoeducation is recommended for most patients with bipolar disorder. Formalized and structured education and lifestyle modification can beneficially influence the course of the illness. This review has focused on medical management. Patients with bipolar disorder often do not comply with treatment and often struggle with accepting being ill and coping. These concerns highlight the possible use of structured psychosocial interventions for some patients with bipolar disorder.47

Choosing a treatment regimen

The algorithm in Figure 1 attempts to provide a rational sequence for administering and combining treatments for bipolar disorder. Monitoring patient progress with a mood diary is further recommended as a careful, systematic, and quantifiable measure of patient progress.

Conclusion

An expanding array of treatments for bipolar disorder is changing the current standard of care for this condition. Some newer treatments are considered mood stabilizers and represent new therapeutic alternatives. Optimal treatment of this illness often requires a combination of both medications and psychosocial interventions. Current levels of evidence and clinical recommendations for treatment of bipolar disorder are changing based on new information from clinical trials. Several agents now being studied could further affect treatment.

Competing interests

Dr McIntyre works as a consultant and member of the Speakers Bureau for Wyeth-Ayerst Canada, Organon, Lundbeck, Lilly, Oryx, AstraZeneca, Pfizer, Janssen-Ortho, and GlaxoSmithKline. He receives research support from GlaxoSmithKline, Merck Frosst Canada, Wyeth-Ayerst, and Servier.

Correspondence to: Dr Roger McIntyre, University Health Network, 399 Bathurst St, ECW-3D-008, Toronto, ON M5T 2S8; telephone (416) 603-5279; fax (416) 603-5368; e-mail rmcintyr@uhnres.utoronto.ca

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