Two large randomized, double-blind studies examined the utility of lamotrigine in the maintenance treatment of patients with bipolar I disorder (41, 42). Both studies were placebo controlled and included lithium monotherapy as an active comparator. In one study, patients had most recently suffered a depressive episode (41) and, in the other, a manic or hypomanic episode (42). Both studies involved an open-label stabilization period of 8–16 weeks followed by an 18-month trial of lamotrigine monotherapy, lithium monotherapy, or placebo in patients who had recovered and were stable.

In the study of recently depressed patients (41), both lamotrigine (200 mg/day or 400 mg/ day) and lithium (0.8–1.1 meq/liter) were superior to placebo in preventing any mood episode. Lamotrigine, but not lithium, was superior to placebo in preventing a depressive episode. Lithium, but not lamotrigine, was superior to placebo in preventing a manic, hypomanic, or mixed episode. With the exception of rash, there were no side effects of lamotrigine that exceeded placebo. There were no serious rashes. For the lithium group, the incidence of somnolence and tremor exceeded that of placebo.

In the study of recently manic or hypomanic patients (42), both lamotrigine (target dosage of 200 mg/day) and lithium (0.8–1.1 meq/liter) were superior to placebo in delaying onset of any mood episode. Lithium, but not lamotrigine, was superior to placebo in prevention of a manic episode, but neither agent was superior to placebo in preventing depressive episodes. There were no adverse events for which lamotrigine statistically exceeded placebo. Lithium exceeded placebo for diarrhea only.

When the data from both studies were pooled, lamotrigine was superior to placebo in time to intervention for any mood episode, as well as for prevention of depressive episodes and manic, hypomanic, or mixed episodes (43). Similarly, lithium was superior to placebo in time to intervention for a mood episode and for prevention of a manic, hypomanic, or mixed episode. Lithium was not superior to placebo in prevention of a depressed episode.

Given the results from these studies, both lamotrigine and lithium appear to have substantial utility in the maintenance treatment of patients with bipolar disorder. The utility of lamotrigine was somewhat greater for the prevention of depressive compared with manic episodes, and the opposite is true for lithium.

A 47-week, randomized, double-blind study of olanzapine versus divalproex for manic or mixed episodes was completed (44). The median time to remission was shorter for olanzapine than for divalproex, although the remission rates at the end of the study did not differ between agents. Adverse events for olanzapine included somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels, while adverse events for divalproex were nausea and nervousness.

A randomized, double-blind, controlled trial compared the efficacy of olanzapine and lithium for the prevention of relapse or recurrence of a manic or mixed episode (45). In this study patients currently experiencing a manic or mixed episode were treated acutely with olanzapine and lithium for 6–12 weeks. Patients who achieved remission were randomly assigned to 52 weeks of olanzapine or lithium monotherapy. A relapse into mania or depression occurred in 30% of the olanzapine-treated patients and in 39% of the lithium-treated patients—an insignificant difference. Olanzapine was superior to lithium in rates of symptomatic recurrence of mania or mixed episodes (14% vs. 28%), but rates of depression recurrence did not differ. Treatment-emergent insomnia was higher in the lithium group than in the olanzapine group. Among the lithium group, 26% discontinued treatment because of side effects, compared with 19% of the olanzapine group.

A randomized, double-blind, controlled study examined the utility of continued combination treatment with a mood stabilizer (lithium, carbamazepine, or valproate) and a first-generation (typical) antipsychotic (perphenazine) (46). Immediately following remission from a manic episode, patients were randomly assigned to remain on the combination therapy or to receive the mood stabilizer plus placebo. Among those on continued combination therapy, there was shorter time to depressive relapse, a higher rate of discontinuation, and higher rates of dysphoria, depressive symptoms, and extrapyramidal symptoms. The study concluded that there were no short-term benefits with the continuation of the first-generation antipsychotic with a mood stabilizer; in fact, its continued use was associated with the aforementioned detrimental effects.

However, a similar study of the second-generation antipsychotic olanzapine plus mood stabilizer versus mood stabilizer plus placebo had somewhat different results (47). In this randomized, double-blind, controlled study, patients who achieved remission after 6 weeks of treatment with olanzapine plus either lithium or valproate received continued lithium or valproate plus olanzapine or plus placebo for 18 months. There were no differences in time to relapse into mania or depression between the monotherapy and combination therapy groups, but combination therapy was significantly better for prevention of symptomatic relapse. Combination therapy was associated with increased somnolence, weight gain, and tremor.

Knowledge of the utility of psychosocial interventions has expanded recently. Family-focused therapy is a manualized psychosocial program involving all available family members in which weekly psychoeducation, communication enhancement training, and problem-solving skills training occur adjunctively with pharmacotherapy. A 2-year randomized, controlled study of family-focused therapy plus pharmacotherapy versus a crisis management intervention and pharmacotherapy (supported by grants from the National Institute of Mental Health, the National Alliance for Research on Schizophrenia, and the MacArthur Foundation) found that postepisode symptomatic adjustment and drug adherence were enhanced with the family-focused therapy and pharmacotherapy combination compared with the other (48). Patients in the group receiving family-focused therapy had fewer relapses and longer survival intervals.

Another randomized, controlled study examined the utility of cognitive therapy in conjunction with pharmacotherapy over a 12-month period (49). Those treated with cognitive therapy and pharmacotherapy had significantly fewer bipolar episodes, days in an episode, and number of admissions.

Two controlled studies (supported by grants from the Stanley Medical Research Institute, the Instituto de Salud Carlos III, the Fundació Marató de TV3, and the Fundació María Francisca Roviralta) of a longitudinal (21-session) psychoeducational program were conducted in Spain (50, 51). In both studies psychoeducation reduced recurrences over 2 years. Psychoeducation enhanced lifestyle regularity and early syndrome detection.

A recent study (supported by grants from the National Institute of Mental Health) found that a psychosocial intervention focused on addressing interpersonal problems and regulating social rhythms during acute treatment in bipolar I patients extended the time to new episode and reduced the likelihood of recurrence (52).