A good bipolar maintenance program makes all the difference in the world

In 2004, the World Federation of Societies of Biological Psychiatry (WFSB) published its Guideline for the Biological Treatment of Bipolar Disorders: Maintenance Treatment. This is the final installment in a trilogy that began with the publication of a 2002 Guideline for treating acute (initial phase) bipolar depression and followed with a 2003 Guideline for acute mania. "Although it is of great importance to control these acute manifestations as rapidly and effectively as possible," the WFSB notes, "the real key to treatment of bipolar disorder is successful maintenance treatment."

The Guideline and its predecessors are the result of a 55-member international task force headed up by Heinz Grunze MD of Ludwig-Maximilians-University (Munich), Siegfried Kasper MD of the University of Vienna, Guy Goodwin MD of the University of Oxford, and Charles Bowden MD of the University of Texas at San Antonio.

The aim of long term treatment, the Guideline states, is the prevention of new episodes and the maintenance of full remission. Since it is generally over-optimistic to expect any one agent to effectively combat all the symptoms of bipolar, combination therapy has become the strategy of choice. Unfortunately, the Guideline notes, controlled data on combination treatment is extremely limited, and thus clinicians must work out choices based on trials involving a single med (which in turn tend to be in short supply). Such are the pitfalls of evidence-based medicine.

Treatments such as talking therapy fall outside the scope of its review, the WFSB states. Where we stand ...

Bipolar I Without Rapid Cycling

Lithium - The WFSB cites both old and new long-term studies in support of the preventive efficacy of lithium, though early studies have over-stated the drug's effectiveness. A 2004 meta-analysis of five trials involving 770 patients by Geddes et al found lithium effective in preventing new episodes, particularly mania. A 1989 study by Gelenberg et al found that relapse rates were higher among patients with plasma levels maintained at 0.4 to 0.6 mEq/L than those with levels at 0.8 to 1.0 mEq/L. The catch is tolerability problems may limit higher doses over the long term.

Although the WFSB categorizes the evidence in favor of lithium as "Level A" (equating to first rate), these findings are not necessarily borne out in the real world, a situation that applies to the other agents as well. Co-occurring illness and poor adherence complicate treatment. Accordingly, the Guideline recommends taking into consideration likely predictors of favorable outcome such depression-free interval course, no rapid cycling, no alcohol or drug use, and iron-clad adherence.

Lamictal (Lamotrigine) - The evidence for long-term treatment is much stronger than for short-term treatment. Two 2003 studies by Calabrese and Bowden found that Lamictal was more effective over 18 months than lithium at preventing depressive episodes but less effective in preventing mania. The WFSB suggests the possibility of exploiting the complementary properties of both agents, but cautions that there are no controlled studies supporting this approach. (Supporting evidence: Level A.)

Depakote (Divalproex Sodium) - Although open studies looked promising, "the only randomized double-blind placebo-controlled study failed to establish a statistical benefit." (Lithium also flunked this trial, indicating it was the trial that failed rather than either med.) Secondary analysis of the data indicated Depakote's efficacy in preventing a new episode, especially depression (Bowden et al, 2000). A 2003 47-week extension of an acute mania trial by Tohen et al comparing Depakote to Zyprexa (Olanzapine) in a small number of remitted patients found no significant differences in number of relapses (41 percent for Zyprexa vs 50 percent for Depakote) or in time to relapse, though measures in affective stability and cognitive function favored Zyprexa. (Supporting evidence: Level B.)

Tegretol - The WFSB notes that early studies were methodologically suspect, but that two recent and impressive head-to-head comparisons with lithium (Greil 1997 and Hartong et all 2003) found that 1) for patients with a history of classical euphoric mania lithium was superior to Tegretol, and 2) although lithium patients had higher rates of relapse in the first six months, they performed better over two years. A secondary analysis of the 1997 study, however, showed those with "atypical" features (such as dysphoria rather than euphoria) responded better to Tegretol. The WFSB notes that Tegretol's interactions with other psychiatric meds pose a significant disadvantage. There was no discussion of the drug's chemical cousin Trileptal and its putatively cleaner action. (Supporting evidence: Level B.)

Atypical antipsychotics - The Guideline cites only Zyprexa as demonstrating long term efficacy, based on controlled trials. A 2002 study (Kasper et al) found efficacy in the drug over 12 months for both depression and mania, but especially mania. A 2004 study by Tohen et al found Zyprexa comparable to lithium, and perhaps superior in preventing mania. (Also keep in mind the Zyprexa-Depakote study.) Zyprexa as an add-on to lithium or Depakote also worked well for preventing mania over 18 months (Tohen et al, 2002). (Supporting evidence: Level A, but with the qualification that the maintenance studies were targeted at patients responsive to Zyprexa in the acute phase.)

Antidepressants - The WFSB recommends: "In bipolar patients where recurrent depressive episodes dominate the clinical course, the long-tem use of antidepressant in combination with a mood stabilizer may be considered." The Guideline also adds that these patients should have responded to an antidepressant during the initial treatment phase. Monotherapy with an antidepressant, because of the risk of switching into mania, should be regarded as taboo. SSRIs and other newer antidepressants may have lower switch rates than the old tricyclics. Naturalistic data from the Stanley Foundation Bipolar Network (Altshuler et al, 2003) supports the long term continuation of antidepressants for patients previously stabilized on antidepressants, but the Guideline notes that only 15 percent of the patients receiving antidepressants remained in remission for two months. A 2000 retrospective chart review by Ghaemi et al only partly supported these results, with reports of elevated risk of manic switches. (Supporting evidence: Level D.)

Other approaches - Calcium channel blockers, first-generation antipsychotics, ECT, psychosocial interventions.