Update on bipolar disorder: How to better predict response to maintenance therapy

These findings were consistent with earlier placebo-controlled studies of lithium maintenance treatment and a recent crossover comparison trial with carbamazepine.⁹ Lithium was also recently compared with carbamazepine in a 2.5-year maintenance multisite study in Europe.¹⁰ There was no significant difference in efficacy between the two in time to hospitalization, the primary outcome measure. On other outcome measures, including time to relapse or need for additional medication, lithium was superior to carbamazepine.

Pooled results from a number of naturalistic studies, which mirror clinical practice, indicated that approximately one-third of patients maintained on lithium had good functional outcomes without relapses and only minimal symptoms.¹¹ In general, these studies found higher rates of relapse with longer durations of follow-up.

Valproate maintenance treatment has been studied in two randomized, controlled trials (one vs. placebo,⁷ and one vs. olanzapine¹²) and two open-label comparison studies against lithium.^13,14 In the placebo-controlled trial, which also included a lithium comparison group described earlier, there was no significant difference in the time to development of any mood episode among the three treatment groups.⁷ However, divalproex was superior to placebo on a number of other outcome measures, including rate of study termination for any mood episode, termination for depression, and termination for noncompliance.

Divalproex was superior to placebo in patients who received divalproex in the open-label treatment phase before randomization. This is clinically relevant, as this group reflects expected relapse rates in patients treated initially with divalproex for acute mania who then remain on the drug for maintenance therapy. Patients receiving divalproex had significantly lower rates of intolerance and noncompliance compared to those treated with lithium.

In the second comparison study, 167 patients initially randomized and responding to divalproex or olanzapine in a 3-week acute bipolar mania trial continued in a double-blind 44-week extension study.¹² There were no significant differences in relapse into mania between the two groups (olanzapine 41%, divalproex 50%, p = 0.4) or time to manic relapse (olanzapine 270 days, divalproex 74 days, p = 0.4). There was no significant difference in tolerability between the two.

Two open-label studies compared valproate with lithium. In an 18-month study conducted in France, patients randomized to the valpromide formulation of valproate displayed a 20% lower relapse rate than those receiving lithium.¹³ The second open-label comparison trial found comparable efficacy between lithium and divalproex in a 1-year naturalistic pharmacoeconomic study that allowed additional medications as needed for recurrent symptoms.¹⁴

Carbamazepine has been evaluated in a limited number of studies for maintenance treatment of bipolar disorder. The results of many early randomized, controlled maintenance trials were criticized on methodologic grounds.¹⁵ But two recent comparison trials with lithium, as noted earlier, provided clinically important data regarding carbamazepine’s prophylactic efficacy.^9,10 Several additional clinically relevant observations emerged from analyses of secondary outcome measures in these two trials.

In the first study, 52 patients with bipolar I or II disorder received lithium or carbamazepine for 1 year, crossed over to the alternate drug the second year, and received both drugs the third year.⁹ There was little difference in relapse rates during the first year between the lithium (31%) and carbamazepine (37%) groups. Similarly, in the overall trial, there was little difference in the percentage of patients who were rated as having a moderate or better response—33% on lithium, 31% on carbamazepine, and 55% on the combination. A higher proportion of patients receiving carbamazepine withdrew due to side effects. In the second trial, significantly more patients receiving carbamazepine required additional medications for breakthrough symptoms and experienced side effects requiring treatment discontinuation.¹⁰

Lamotrigine has been studied in two placebo-controlled, randomized maintenance studies in patients with bipolar disorder.^8,16 The first evaluated bipolar I patients who had experienced a manic or hypomanic episode within 60 days of entry into an open-label treatment phase with lamotrigine.⁸ Patients who, in turn, improved or remained stable during the open-label treatment phase were then randomized to treatment with lamotrigine 200-400 mg/d, lithium, or placebo for up to 18 months. Both lamotrigine and lithium were superior to placebo on the primary outcome measure, which was time to need for additional medication for a mood episode. The median time until 25% of patients relapsed was 72 weeks for lamotrigine, 58 weeks for lithium, and 35 weeks for placebo.

Table 2

PUTATIVE PREDICTORS OF RESPONSE TO MAINTENANCE MEDICATIONS