What are we trying to accomplish in the maintenance treatment of patients with bipolar disorder? Given that the disorder recurs in more than 90% of patients who experience a manic episode,1 there are 5 important goals:
- Prevention of recurrent episodes;
- Amelioration of subsyndromal symptoms;
- Reduction of suicide risk;
- Compliance enhancement;
- Optimization of interpersonal, social, and vocational functioning.
There is a great premium on preventing mood episode recurrence in patients with bipolar disorder. Mood episodes themselves produce substantial morbidity, but morbidity is not confined to these episodes alone. Full recovery of functioning often lags many months behind remission of symptoms.2 Recurrent mood episodes also may lead to progressive loss of function between episodes. Mood episodes also carry risks of mortality from suicide, violence, and impulsive risk taking.
Clearly, mood-stabilizing medications form the cornerstone of maintenance treatment,3,4 along with a strong therapeutic alliance between patient and clinician and targeted psychosocial therapies. In the Expert Consensus Guidelines for medication treatment of bipolar I disorder, maintenance treatment was recommended for 1 year following an initial manic or mixed episode; longer (indefinite) treatment was recommended for patients with a family history of bipolar disorder or if 2 episodes occurred.3
Compared with clinical trials of agents for acute bipolar mania (and mixed episodes), there are relatively few randomized controlled trials of medications for the maintenance phase of bipolar disorder. Some naturalistic studies have provided data on relapse rates associated with treatment with a variety of different agents. Even fewer studies have examined psychosocial interventions designed specifically to reduce relapse rates.
But new data are beginning to emerge regarding the efficacy of divalproex, lamotrigine, and olanzapine as maintenance therapies. A number of clinical predictors of response to these agents have begun to be identified, as well as to lithium and carbamazepine. Eliciting these characteristics is important when making recommendations to patients about available drug therapies.
In addition, effective maintenance treatment often requires combinations of mood-stabilizing, antidepressant, and antipsychotic agents to control or eliminate subsyndromal and breakthrough symptoms.
In this review, we will cover the available new data on pharmacologic maintenance treatments of bipolar disorder and their clinical implications.
What the studies show
Lithium has been the mainstay of therapy for bipolar disorder for more than 35 years. Most randomized, controlled trials of lithium maintenance therapy were conducted in the 1960s and 1970s5 (Table 1). Unfortunately, these studies had several design limitations that inflated the expectations of lithium’s efficacy as a maintenance treatment.6 These included discontinuation designs in which patients stabilized on lithium were abruptly switched to placebo; exaggerated early placebo relapse rates; enrollment of both unipolar and bipolar patients; lack of specific diagnostic criteria; and reported results only for patients completing studies. Pooled data from these trials indicated that lithium reduced the risk of relapse fourfold compared with placebo at 6 months and 1 year.5
Two contemporary randomized, placebo-controlled maintenance studies utilizing more rigorous designs provided further evidence of lithium’s superiority over placebo in extending time to manic relapse.7,8 Both studies enrolled patients who were currently or had recently been manic and had been stabilized in open-label treatment that included study medications.
In the first study, comparing 1-year relapse rates among patients randomized to lithium, divalproex, or placebo, lithium extended time to recurrence of mania by 55% compared with placebo.7 In the second, an 18-month trial comparing lithium, lamotrigine, and placebo, lithium significantly increased the time to intervention for recurrence of mania compared with placebo.8 The overall manic relapse rates were 17% for lithium-treated patients and 41% for those on placebo. However, lithium did not significantly extend time to depressive relapse or intervention for depressive relapse, respectively, in either study. Moreover, in the first study, patients who received lithium tended to have greater subthreshold depressive symptoms.8
Table 1
What works in maintenance treatment of bipolar disorder (ranked by number of randomized, controlled trials)
| Medication RCTs (n) | Trial results | Strong evidence | Some evidence |
|---|---|---|---|
| Lithium (15) | Equal to divalproex and lamotrigine; equal to or better than carbamazepine; better than placebo | 4-fold reduction of relapse risk vs. placebo at 6, 12 months; more efficacious in mania than in depression; higher lithium level correlated with lower relapse rates, but more side effects | |
| Carbamazepine (7) | No significant benefit vs. lithium; better than placebo | May be more efficacious in mania than in depression; may be less tolerable than lithium; no data on serum levels | |
| Divalproex (4) | Equal to lithium and olanzapine; better than placebo | May be more efficacious in mania than in depression; may be more tolerable than lithium; data on serum levels pending | |
| Lamotrigine (2) | Better than placebo | More efficacious in depression than in mania | Dosage 200-400 mg/d |
| Olanzapine (1) | Equal to divalproex | Data on dosage and differential efficacy related to dosage pending | |
| Clozapine (1) | Better than treatment as usual | Efficacy in treatment-resistant mania (bipolar schizoaffective disorder, bipolar type) |