The newer antiepileptic drugs pose a sometimes bewildering range of options for bipolar disorder treatment. Which work best for acute bipolar I mania? Which are best suited for maintenance in patients with mixed episodes, or for those with a history of rapid cycling? What about prevention of depressive episodes? And how do the antiepileptics compare with lithium?
For many patients with bipolar disorder, lithium is still the drug of choice. For others, however, an increasing body of evidence supports the efficacy of some antiepileptics and atypical antipsychotics.
The mood-stabilizing properties of two antiepileptic agents, carbamazepine and valproate, were demonstrated some years ago in randomized controlled trials in patients with bipolar disorder. Since then, there has been considerable interest in the potential thymoleptic properties of the new antiepileptic drugs.1 In recent years gabapentin, lamotrigine, topiramate, oxcarbazepine, zonisamide, tiagabine, and levetiracetam have been approved in the United States for the treatment of various types of epilepsy. These medications have diverse pharmacological properties that distinguish them from earlier agents and from one another.
Do these new agents have anything to offer patients? For the most part, the evidence is not yet in hand, but we will examine what’s available, starting with the most recent trial data regarding the efficacy of valproate and carbamazepine.
Carbamazepine for bipolar mania
Five randomized, controlled trials2 have shown the efficacy of carbamazepine in patients with acute bipolar I mania. Carbamazepine was superior to placebo and comparable to chlorpromazine and lithium. Pooled data reveal an overall response rate (defined as the proportion of patients experiencing > 50% reduction in manic symptoms) of 50% for carbamazepine, 56% for lithium, and 61% for chlorpromazine (differences in overall response rates are not significant).
Until recently, the efficacy of carbamazepine as a maintenance therapy for bipolar disorder was controversial.3 However, two recent large randomized, controlled maintenance studies that compared carbamazepine with lithium validated use of the agent for that purpose.4,5
In the first study, 144 patients received either drug and were followed for up to 2 1/2 years.4 The study showed no significant differences between the two groups in time-to-mood episode recurrence or hospitalization. However, significantly more patients receiving carbamazepine required treatment discontinuation for side effects and additional medications for breakthrough symptoms than did the patients receiving lithium.
Patients without both comorbid disorders and mood-incongruent delusions responded better to lithium, whereas those with mixed episodes and bipolar II disorder or NOS appeared to respond better to carbamazepine.
In the second trial, 52 patients with bipolar I or II disorders received either lithium or carbamazepine for one year, crossed over to the alternate drug the second year, and received both drugs during the third year.5 No significant differences were reported in relapse rates during the first year between lithium (31%) and carbamazepine (37%), or in the percentage of patients who experienced a moderate or better response: 33% on lithium, 31% on carbamazepine, and 55% on the combination. On a variety of other measures, lithium was superior to carbamazepine. But patients with a history of rapid cycling responded significantly better to the combination (56%) than to lithium (28%) or carbamazepine (19%) alone.
As in the previous study, a higher proportion of patients receiving carbamazepine withdrew after experiencing side effects. Both studies found that while carbamazepine is efficacious, lithium is superior overall. But since neither study included a placebo group, carbamazepine’s efficacy in maintenance treatment cannot be determined.
Carbamazepine also was evaluated in three randomized, controlled trials in patients with bipolar depression.2 These small trials suggest that carbamazepine’s antidepressant activity may be less robust than its antimanic effects. Response rates (>50% improvement in depressive symptoms) ranged from 32% to 34%, although many patients who participated had treatment-resistant bipolar depression.
Comparing the known efficacy of antiepileptic agents in bipolar disorder
| Drug | Mania | Depression | Maintenance | Comments |
|---|---|---|---|---|
| Valproate | ◊◊◊◊ | ◊ | ◊◊◊ | New Depakote ER formulation |
| Carbamazepine | ◊◊◊ | ◊◊ | ◊◊◊ | 2 new maintenance studies v. lithium |
| Gabapentin | – | ◊ | ◊ | 2 negative placebo-controlled studies in mania |
| Lamotrigine | × | ◊◊◊ | ◊◊◊ | Antidepressant activity in several controlled trials |
| Topiramate | ◊ | ◊ | ◊ | Dose-related weight loss |
| Oxcarbazepine | ◊◊ | ◊ | ◊ | Improved tolerability & pharmacokinetics |
| Zonisamide | ◊ | ND | ND | May produce weight loss in some patients |
| Tiagabine | × | ND | ND | More data needed regarding tolerability and efficacy |
| Levetiracetam | ND | ND | ND | Data needed regarding efficacy and tolerability |
Key
◊◊◊◊ efficacy demonstrated in ≥2 placebo-controlled trials
◊◊◊ efficacy demonstrated in one placebo-controlled or two large, active comparator trials
◊◊ efficacy in two small or one large active comparator trial
◊ efficacy only in open trials and case series
× conflicting evidence of efficacy in available studies
– lack of efficacy demonstrated in randomized, controlled trials
ND no data presently available
Based on the studies reviewed above, carbamazepine is considered a second-line agent for bipolar mania and maintenance treatment with very limited data regarding its antidepressant effects.6