On secondary outcome measures, lamotrigine, but not lithium, was superior to placebo in delaying time to depressive relapse. In contrast, lithium, but not lamotrigine, was superior to placebo in delaying time to manic relapse. Finally, lamotrigine, but not lithium, was superior to placebo in time to discontinuation for any reason.
From this study, it appears that lamotrigine is most effective in preventing depressive relapse, whereas lithium is most effective in preventing manic relapse. Thus, lithium and lamotrigine may complement each other in maintenance treatment by preventing manic and depressive episodes in combination.
The findings of the first trial were consistent with those of the second placebo-controlled lamotrigine (100-500 mg/d) maintenance study conducted specifically in patients with rapid cycling bipolar I and II disorders.16 In this 6-month trial, there was no significant difference in time to need for additional medications, the primary outcome measure, between the lamotrigine and placebo groups.
Median survival time was significantly greater for the lamotrigine group (18 weeks) than for the placebo group (12 weeks). The lamotrigine group had significantly longer time to need for additional medications in bipolar II, but not bipolar I, patients. Patients with bipolar II disorder also displayed significantly greater improvement with lamotrigine on global scales compared with bipolar I patients. Because bipolar II disorder is characterized predominantly by depressive episodes, these findings suggest that lamotrigine was again more beneficial in preventing recurrent depression, in this case, specifically, in rapid cycling bipolar II patients.
Taken together, the results of these studies are also consistent with the results of two placebo-controlled trials of lamotrigine in the treatment of acute bipolar depression.17,18 Its efficacy in acute bipolar I depression was first demonstrated in a 6-week, double-blind, randomized, parallel-group trial in which patients received lamotrigine 50 mg/d, 200 mg/d (after gradual titration over the first 4 weeks), and placebo.17
Both dosage groups of lamotrigine displayed significantly greater improvement in depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (but not the Hamilton Depression Rating Scale) and by the Clinical Global Improvement Scale compared with the placebo group. There was a trend for the 200 mg/d group to have greater improvement than the 50 mg/d group, a trend that might have become significant had the study been longer, as the 200 mg/d group did not receive this dose for the full trial. There was no significant difference in the incidence of hypomanic or manic switches among the three study groups.
Frye and colleagues also found lamotrigine to be superior to placebo in global improvement in depressive (but not manic) symptoms in a crossover monotherapy trial in treatment-refractory bipolar I and II patients.18
Olanzapine, as described earlier, was comparable to divalproex in a head-to-head comparison 44-week extension trial in patients who responded to double-blind treatment in an acute mania study.12 These results were consistent with the preliminary findings of an open-label extension study of olanzapine.19 There are no placebo-controlled trials of olanzapine or any other atypical antipsychotic in the maintenance phase of bipolar disorder published to date.
Clozapine was more effective than “treatment as usual” (combinations of mood-stabilizers and typical antipsychotics) in patients with treatment-refractory bipolar and schizoaffective (bipolar subtype) disorders.20 Many patients with bipolar disorder now receive adjunctive maintenance treatment with typical antipsychotics, but the limited data from the few controlled trials of typical agents administered in combination with mood-stabilizers do not support the efficacy of this strategy.21 Moreover, some reports suggest that maintenance treatment incorporating typical antipsychotics may increase the frequency and severity of depressive episodes in patients with bipolar disorder.
Predicting response to pharmacologic treatment
Clinical experience and data from the randomized, controlled trials reviewed earlier have identified several tentative predictors of response—or nonresponse—to specific medications. Lithium, divalproex, and carbamazepine appear to have greater efficacy in the prevention of manic rather than depressive episodes.11 In contrast, lamotrigine appears to have greater efficacy in preventing depressive rather than manic episodes.
It is unclear whether olanzapine and perhaps other atypical antipsychotics may have a more favorable effect in preventing one pole of the illness over another (Table 2). The currently available atypicals (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) in general appear to differ from typical antipsychotics in having bidirectional (antimanic and antidepressant) effects on mood symptoms.
Atypicals may exert antidepressant effects via a number of different mechanisms, including 5HT2 receptor antagonism (a property shared by all atypicals and the antidepressants trazodone, nefazodone, and mirtazapine); alpha2-adrenergic antagonism (clozapine and risperidone); and 5HT1D antagonism, 5HT1A agonism, and 5HT and NE reuptake inhibition (ziprasidone).22
Patients with rapid-cycling bipolar disorder have a relatively poor response to lithium (response rates of approximately 20%).11 Patients with rapid-cycling bipolar I disorder may have a greater likelihood of response to combined treatment with lithium and carbamazepine,9 or divalproex.11 Alternately, patients with rapid-cycling bipolar II disorder have lower relapse rates on lamotrigine compared with placebo.16 Anecdotal reports and the results of acute treatment studies suggest that clozapine and olanzapine may be beneficial maintenance agents for rapid-cycling bipolar I patients.