Bipolar Treatment for the Long-Haul

A good maintenance program makes all the difference in the world

by John McManamy
McMan's Depression and Bipolar Web
Sept 26, 2004

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 - 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 - 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 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.

Bipolar I with Rapid Cycling

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Lithium - The WFSB cites a 1974 Dunner and Fieve study that found rapid cyclers were less responsive to lithium, but argues that the drug has been given a bad rap in that other meds aren’t exactly magic bullets, either. Moreover, the Dunner and Fieve study did show that lithium appeared to prevent new manic episodes (but had no effect on new depressive episodes). Small open trials have demonstrated a small preventive effect, but inferior to Lamictal. (Supporting evidence: Level C.)

Depakote - Open studies show efficacy against new episodes of mania, mixed states, and to some degree bipolar depression. (Supporting evidence: Level C.)

Lamictal - Open data appears to support its use, but a large trial (Calabrese, 2002) showed an effect only for the bipolar II patients in the study. Another large trial (to date unpublished) failed to show improvement. (Supporting evidence: Level D.)

Tegretol - Contradictory open studies. (Supporting evidence: Level D.)

Calcium channel blockers - Two double-blind studies by Pazzaglia et al (1993, 1998) show evidence for Nimotop (nimodipine), even in refractory patients. The drug’s short half-life necessitates a daily dosage of usually more than 240 mg, equating to eight tablets given in three doses. (RxUSA cites a unit cost of $7.50 per pill, which adds up to $60 per day, so please check your health plan before getting your hopes up.) (Supporting evidence: Level B.)

Atypical antipsychotics - Small studies indicating some efficacy for Clozaril. No adequate data for the other atypicals. (Supporting evidence: Level D.)

Combination treatment - The WFSB says that with rapid cycling, combination treatment is the rule. A 1997 study by Denicoff et all assigned 52 bipolar patients to either lithium or Tegretol, then crossed them over to the opposite medication and finally to both drugs over the course of three years. About a third improved on each drug, but 55.2 did better on the combination. For patients with a past history of rapid cycling, the results were more dramatic: 28 percent responded to lithium and 19 percent to Tegretol, but 56.3 responded to the combination. (Supporting evidence: Level C.)

Bipolar II Without Rapid Cycling

Although there is new interest in bipolar II, there are very few studies, with current guidelines making no specific recommendations to its treatment. In the words of this Guideline: "Currently, only lithium reaches a Level C classification, and the evidence for [Tegretol] is no better than Level D criteria."

Bipolar II With Rapid Cycling

Level C for Lamictal (based on the Calabrese 2002 secondary analysis and open studies), Level D for Depakote.

Schizoaffective Disorder

Because diagnosis is notoriously unreliable and owing to the fact that in studies of this population the data tends to come from schizophrenia trials directed at resolving psychosis symptoms, the WFSB acknowledges treatment recommendations are problematic. Nevertheless, the Guideline ventures that lithium may be more effective in patients with the mood-dominant type of this illness than the schizophrenia-dominant type, and that augmenting with Tegretol may be successful. (Supporting evidence: Level C.) Open trials indicate the effectiveness of Depakote. (Supporting evidence; Level D). The WFSB recommends combination mood stabilizer-antipsychotic treatment.

When to Start Maintenance Treatment

Although there are no controlled prospective studies to indicate when maintenance treatment should start, several retrospective chart analyses suggest that with every episode the length of the subsequent symptom-free interval decreases. Although the WFSB finds maintenance treatment prudent, it also notes that unwilling patients suddenly discontinuing their treatments may do themselves more harm than had they never been on long term treatment, particularly lithium users.

Many European guidelines, the WFSB notes, recommend waiting for at least a second episode of the illness while US guidelines favor beginning maintenance treatment with the first manic episode. The Dutch strike a balance by taking the individual patient into account. There is consensus that once preventive treatment is started it should be life long, though there are no discontinuation studies targeting this question.

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