Mood stabilizers should lower the risk of episode recurrence, reduce symptoms overall, and improve our patients' daily function - Journal of Family Practice, March, 2003 by Paul E. Keck, Jr., MD

Bipolar disorder is a persistent, severe, sometimes lethal, and lifelong illness. Therefore, it is important to prevent recurrent mood episodes and suppress intercurrent symptoms. (1) Evidence from randomized, controlled trials supports the efficacy of lithium, carbamazepine (Tegretol), divalproex (Depakote), olanzapine (Zyprexa), and lamotrigine (Lamictal) in long-term treatment of patients with bipolar disorder. As more treatments become available, expectations increase regarding the potential impact of mood stabilizers--in combination with psychotherapeutic interventions--on patients' lives.

Lithium

Alter more than 50 years, lithium remains the cornerstone of bipolar disorder treatment. (2) Lithium is one of the best-studied drugs in acute and long-term treatment, and it remains useful for many patients. On the other hand, new drugs are being developed for maintenance treatment of bipolar disorder because lithium is not effective for everyone and is associated with bothersome side effects for many patients. (2,3)

Goodwin and Jamison found about one-third of patients on lithium monotherapy remained episode-free for about 2 years. (4) Other naturalistic outcome studies of lithium maintenance therapy found somewhat more pessimistic results. A substantial subgroup of patients with bipolar disorder does well on lithium, but we now see greater numbers of patients who do not respond.

These findings imply the question, "What do we expect from mood-stabilizing drugs?" Do we expect complete prevention of mood episodes? These agents are certainly more useful if we define efficacy as a relative reduction in risk of episode recurrence, overall symptom reduction, and improvement in function.

Many factors associated with acute response to lithium--reviewed by Dr. Frye et al in this monograph--are also associated with long-term response. Patients with bipolar I illness--especially with euphoric or elated mania--tend to have better long-term outcomes with lithium than do other patients. Those who have done well on lithium in the past tend continue to do well on lithium, although the number of prior episodes is an important predictor of response.

Carbamazepine

Numerous studies have examined the use of carbamazepine in bipolar disorder maintenance treatment. (6) In a critical analysis by Dardennes et al of maintenance trials comparing carbamazepine with lithium, three of four studies found the agents comparable in efficacy, and one found lithium more effective than carbamazepine. (7) Limitations inherent in these early maintenance trials led to two recent studies.

Denicoff et al compared the efficacy of carbamazepine, lithium, and the combination in 52 outpatients with bipolar I disorder. (8) Patients received randomized, double-blind treatment with carbamazepine or lithium in year 1, were crossed over to the alternate agent in year 2, and received the combination in year 3. Adjunctive use of antipsychotics, antidepressants, and benzodiazepines was permitted.

Mean time to a new manic episode was significantly longer with combination therapy (179 days) compared with lithium (90 days) and carbamazepine (66 days) alone. Patients were significantly less likely to experience a manic episode during the combination phase (33%) than with lithium (11%) or carbamazepine (4%). Most patients required adjunctive treatment during each study phase.

Greil et al compared lithium and carbamazepine in an open-label, randomized trial for up to 2.5 years. (9) Some interesting differences between the two medications were noted:

* no significant difference in hospitalization rate, though more carbamazepine-treated patients (55%) than lithium-treated patients (37%) required hospitalization.

* a trend suggesting that carbamazepine was not quite as effective as lithium in preventing recurrence--59% versus 40% (Figure 1).

On the other hand, lithium-treated patients had better outcomes on two measures:

* number of patients who had mood episode recurrence or required an antimanic or antidepressant drug

* mood episode recurrence, need for additional medicine for manic or depressive symptoms, or dropout because of adverse effects.

A post hoc analysis found that patients with bipolar II illness or atypical features--mood incongruence, psychiatric comorbidity, psychotic symptoms and dysphoric mania--tended to do better with carbamazepine than with lithium. (10) These findings are interesting because relatively few predictors of response are found in the literature for carbamazepine maintenance treatment. Taken in total, this study suggested that lithium overall was associated with a better long-term outcome than carbamazepine.

Valproate

Three studies have addressed long-term efficacy of valproate formulations in treating patients with bipolar disorder.

Lambert and Venaud conducted an open comparison trial of valproinide versus lithium in >140 patients. (11) During 18 months, the number of episodes per patient was slightly lower with valpromide (0.5) than with lithium (0.6).

Bowden et al conducted the only placebo-controlled, randomized, maintenance study of valproate in patients with bipolar I disorder (Figure 2). (12) In this 1-year trial, patients received divalproex, lithium, or placebo. The primary outcome measure was time to relapse of any mood episode.

The inclusion of patients with relatively mild bipolar illness probably explains the lack of any significant difference in efficacy among the three treatment groups. Approximately 40% of the patients had never been hospitalized for a manic episode.

Post hoc analysis found divalproex was significantly more effective than placebo in preventing relapse among patients who started divalproex before randomization and then were randomized to divalproex or placebo. This group is representative of clinical practice.

The third maintenance study, which compared divalproex with olanzapine, is described later in this article. (13)