The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000

Objectives: New treatments for bipolar disorder have been reported since we first published survey-based expert consensus guidelines in 1996. The evidence for these treatments varies widely; data are especially limited regarding comparisons between treatments and how to sequence them. We therefore undertook a new survey of expert opinion in order to bridge gaps between the research evidence and key clinical decisions.

Method: Based on a literature review, a written survey was prepared which asked about 1,276 options for psychopharmacologic interventions in 48 specific clinical situations. Most options were scored using a modified version of the RAND Corporation 9-point scale for rating appropriateness of medical decisions. We contacted 65 national experts, 58 of whom (89%) completed the survey. Consensus on each option was defined as a non-random distribution of scores by chi-square test. We assigned a categorical rank (first-line/preferred choice, second-line/alternate choice, third-line/usually inappropriate) to each option based on the confidence interval of its mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations.

Results: The expert panel reached consensus on many key strategies, including acute and preventive treatment for mania (euphoric, mixed, and dysphoric subtypes), depression, and rapid cycling, and approaches to managing the complications of treatment resistance and comorbidity. Use of a mood stabilizer is recommended in all phases of treatment. Divalproex (especially for mixed or dysphoric subtypes) and lithium are the cornerstone choices among this class for both acute and preventive treatment of mania. Regardless of which is selected first, if monotherapy fails, the next recommended intervention is to use these agents in combination. The combination can then serve as the foundation on which other medications are added, if needed. Carbamazepine is the leading alternative mood stabilizer for mania. Expert opinion regards other new anticonvulsants as second-line options (e.g., if the previously mentioned mood stabilizers fail or are contraindicated). For milder depression, a mood stabilizer, especially lithium, may be used as monotherapy. Divalproex and lamotrigine are other first-line choices. For more severe depression, a standard antidepressant should be combined with lithium or divalproex. Bupropion, selective serotonin reuptake inhibitors (SSRIs), and venlafaxine are preferred antidepressants, and should be tapered 2 to 6 months after remission. Divalproex monotherapy is recommended for initial treatment of either depression or mania with rapid cycling. Antipsychotics are recommended for use with the above regimens for mania or depression with psychosis, and as potential adjuncts in non-psychotic episodes. Atypical antipsychotics, especially olanzapine and risperidone, were generally preferred over conventional antipsychotics. Recommendations are also given concerning the use of electroconvulsive therapy (ECT), clozapine, thyroid hormone, stimulants, and various novel agents for patients with treatment-refractory illness.

Conclusions: The experts reached high levels of consensus on key steps in treating bipolar disorder despite obvious gaps in high-quality data. To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data; however, their recommendations are generally conservative. Experts reserve strongest support for initial strategies and individual medications for which there are high-quality research data, or for which there are longstanding patterns of clinical usage. Within the limits of expert opinion and with the understanding that new research data may take precedence, these guidelines provide clear pathways for addressing common clinical questions in a manner that can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions.