Long-Term Treatment with Lithium, Valproate, or Carbamazepine: Lithium Best for Most Patients
Shannon Stepan, Eric Peselow and Nunzio Pomara from Maimonides Medical Center in Brooklyn, NY, have analyzed naturalistic observations of long-term maintenance treatment of bipolar disorder with valproic acid, lithium, and carbamazepine and found that patients on lithium went much longer before experiencing an episode of mania or depression than patients taking carbamazepine or valproate.
The team followed 225 outpatients for up to 124 months, or until they had a manic or depressive episode or dropped out of the study during a well phase. Ninety-eight patients took lithium, 78 took valproate, and 50 took carbamazepine. Fifty-two percent of the participants dropped out of the study during a well phase.
One hundred three patients (45.8%) had either a manic or depressive episode during the study. This included 36.7% of the patients taking lithium, 55% of patients taking valproate, and 50% of patients taking carbamazepine. Median time until a first episode was 45 months for the entire sample, 36 months for those patients on valproate, 42 months for those on carbamazepine, and 81 months for those on lithium. A statistical analysis known as a Cox regression model indicated that patients taking valproate had a significantly higher risk of having a manic or depressive episode than those taking lithium.
Editor’s note: These naturalistic data are highly consistent with a number of more controlled clinical studies. In particular, the BALANCE study by Geddes et al. (2010) reported that lithium was superior to valproate on most outcome measures in a two-year randomized study, and that the combination of lithium and valproate was significantly better than valproate alone.
These data are particularly noteworthy because valproate is used much more often than lithium in the US (while lithium remains the main mood stabilizer in most European countries).
There is even more evidence that lithium is a more successful treatment in most patients with bipolar disorder. In the Bipolar Collaborative Network, in which I am an investigator, we found that a treatment regimen that included lithium was associated with long-term stabilization for at least six months in a higher percentage of patients than a treatment regimen that included valproate. Lithium also was associated with greater long-term success than valproate in a study comparing US patients with those from the Netherlands and Germany.
The data from all of these sources is in agreement. It suggests that clinicians in the US should return to lithium as the first-choice mood stabilizer for patients with bipolar illness, since valproate has now been shown to be less successful in long-term prophylaxis in several naturalistic and controlled studies.
The shift toward greater use of valproate was based in part on the randomized placebo-controlled data of Bowden and colleagues, which showed that valproate had better antidepressant effects than lithium, although neither lithium nor valproate response exceeded that of placebo on the main outcome measure of time to relapse into a manic episode. Patients in that study had fairly inactive illnesses, and only 25% of the patients on placebo relapsed during the study. Inexplicably, lithium was inferior to placebo in preventing depressive relapse. The conclusions from that study differ greatly from meta-analyses that indicate lithium is highly effective in preventing both manic and depressive episodes when compared with placebo. The study by Bowden et al. appears to be an outlier that likely resulted from the stringent selection criteria, which required long periods of wellness prior to entering the trial, making relapse on any agent, including placebo, highly unlikely.
I should note that valproate is, in fact, helpful for some subgroups of patients who are not responsive to lithium, and it has a better profile of efficacy than lithium in those with dysphoric as opposed to euphoric mania, and possibly in those with higher levels of comorbid anxiety as well.
Similarly, carbamazepine appears to be effective in many of the subgroups that are less responsive to lithium, including those with more rapidly recurrent or continuously recurrent episodes, comorbid substance use, mood-incongruent delusions (consistent with a schizoaffective presentation) and those with a negative family history of mood disorders in first-degree relatives.
Lithium in combination with these drugs may be useful for difficult-to-stabilize bipolar illness. Lithium in combination with lamotrigine would also be useful in those with predominantly depressive recurrences. In the absence of a good prophylactic response to these combinations, the addition of a well-tolerated atypical antipsychotic is often the next option.
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