CHAPTER 48 Anticonvulsants
OVERVIEW: HISTORICAL CONTEXT
There has been great hope for the use of anticonvulsants in the treatment of bipolar disorder (BPD), but in this hope lies a cautionary tale. In the 1980s, work on BPD (especially that done by Robert Post, M.D., at the National Institute of Mental Health [NIMH]) suggested that the mood instability that characterized the illness bore a resemblance to the characteristics of epilepsy, and hypotheses about the pathophysiological origins of BPD evolved.1,2 Post and others have suggested that a stress model of kindling may be responsible for the onset of mood episodes, and that worsening of the course of illness over time may be due either to kindling or to sensitization phenomena.1,2 These hypotheses led directly to the use of carbamazepine (effective as a treatment for partial seizures) for the treatment of mania, and, later, to the use of valproate in BPD. Many anticonvulsants (with different mechanisms for seizure reduction in epilepsy) have been used in BPD, but only three—valproate, lamotrigine, and carbamazepine—have proved effective in any phase of the illness.
In spite of the lack of empirical evidence, the notion that anticonvulsants are effective in BPD remains attractive.3 The use of gabapentin as a treatment for BPD became popular in the late 1990s, propelled in part by the drug’s favorable qualities: no need for blood monitoring, few interactions with other drugs, simple metabolism, and the perception of good tolerability (at least compared to the established treatments, including lithium and valproate, for BPD). Even as studies demonstrated its ineffectiveness for mania (gabapentin was significantly worse than placebo as an adjunctive treatment for mania), its use persisted. Ultimately, Pfizer Incorporated (which had acquired Warner-Lambert, gabapentin’s original marketing company) settled a $430 million civil and criminal lawsuit with the United States Justice Department for the inappropriate marketing of the drug.4 Although the kindling hypothesis has not been abandoned with regard to an understanding of the pathophysiology of BPD, some data suggest that kindling may not be operative in the disorder. In the NIMH Collaborative Study of Depression, no evidence was found for cycle length shortening in a cohort of patients (followed prospectively) with BPD.5 It is likely that the efficacy of anticonvulsant drugs in BPD is independent of their efficacy in epilepsy, in that the mechanism of mood improvement and relapse prevention may not be the same as the one that makes these drugs prevent seizures.
VALPROIC ACID
The acute antimanic efficacy of valproic acid has been established by several controlled studies, as these randomized and placebo-controlled studies have found divalproex sodium to be an effective and safe treatment for a manic episode, even in cases where lithium treatment previously failed.6,7 The Food and Drug Administration (FDA) has approved divalproex sodium as a treatment for acute mania for up to 3 weeks. Contrary to earlier studies, there appears to be a linear relationship between valproate serum concentration and symptom response, and the target dosage with optimal response in acute mania is above 94 mcg/ml.8
The largest trial of valproate for the maintenance treatment of BPD (n = 372) failed to find a difference between valproate, lithium, and placebo for the primary outcome measure (time to any mood episode).9 Unfortunately, no other adequately powered maintenance studies of valproate exist to adequately answer this question; a small study comparing it to olanzapine (but not placebo) in a 47-week maintenance study found no differences between the two drugs in recurrence rates.10 Valproate is not approved by the FDA for the maintenance treatment of BPD. Despite this lack of evidence, it has been recommended as a first-line prophylactic treatment of BPD in multiple treatment guidelines.11–13
Anticonvulsants, including valproate, are often viewed as more effective in rapid cycling than is lithium. However, it appears that this may not be the case. In a rigorous and ambitious double-blind study, rapid-cycling patients were stabilized on open-label lithium and divalproex sodium and then randomized in a double-blind fashion to either lithium or divalproex and followed prospectively.14 Contrary to the original hypothesis, there were no significant differences between the lithium-treated or the valproate-treated groups in time to dropout or time to additional psychopharmacology.
LAMOTRIGINE
Lamotrigine is an anticonvulsant that inhibits voltage-gated sodium channels and reduces glutamate levels. Given the prominence of depression and depressive relapses in BPD, lamotrigine offers a significant advance in the long-term management of bipolar depression.15–19 Lamotrigine is approved for the maintenance treatment of BPD, and is efficacious when compared to placebo in maintenance studies. Long-term studies found an overall reduction in bipolar depressive relapse compared with placebo.20 In a key study in which patients who were most recently depressed were first stabilized on lamotrigine and randomly assigned to maintenance treatment with lamotrigine, lithium, or placebo, the overall sustained response rate was 57% with lamotrigine, compared with 46% for lithium, and 25% for placebo; this indicates that lamotrigine is effective in the prevention of relapse to depression when compared to placebo.17,21
The efficacy of lamotrigine for the treatment of acute bipolar depression has not been definitively determined. No single trial of the drug for acute bipolar depression found the drug better than placebo on the primary outcome measure of the study. One widely referenced study found that while lamotrigine was not statistically different from placebo for total Hamilton Depression Rating Scale (HDRS) scores, it was superior on several other measures, including the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression Improvement (CGI-I) scale.15
This effect has never been replicated in individual trials, but a recent meta-analysis of pooled individual data from all five acute lamotrigine trials in bipolar depression (both bipolar I and II disorders) found that response (defined as a ≥ 50% decrease in scores) on both the HDRS and the MADRS was significantly greater than for placebo and that remission was greater than placebo on the MADRS, but not the HDRS.22 The antidepressant effect of lamotrigine was greatest in the most severely ill subjects in a subgroup analysis. These data suggest that the individual trials were not adequately powered to find a difference between drug and placebo, and that, nonetheless, there may be an acute antidepressant effect of lamotrigine.
Lamotrigine has not demonstrated efficacy for the acute treatment of mania. No single trial found benefit for lamotrigine in the prevention of manic episodes, but pooled analyses revealed a small effect size for the prevention of mania.17,20,23 While lamotrigine is more effective than lithium in the prevention of depressive episodes, lithium is more effective than lamotrigine in preventing manic episodes; pooled data from two lamotrigine maintenance trials found a small, but significant, effect in favor of the drug in preventing relapse to mania.
No validated treatments for treatment-refractory bipolar depression exist, but a small, randomized, open-label trial of adjunctive lamotrigine, risperidone, or inositol in subjects who had depression in spite of trials of two consecutive standard antidepressants of adequate dose and duration was conducted as part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). An equipoise randomization process allowed subjects to chose to be randomized to any pair of the study treatments.24 While no differences were found in primary pairwise comparisons in randomized patients (n = 66), a secondary, post-hoc analysis found that 8 weeks of sustained recovery were seen in 23.8% of the lamotrigine-treated patients, 17.4% of inositol-treated patients, and 4.6% of risperidone-treated patients. Recovery rates for lamotrigine were statistically significantly better than for the inositol and risperidone groups. These data must be viewed cautiously, as they are from a secondary analysis, but they do represent the only data at all for the treatment of refractory bipolar depression.
CARBAMAZEPINE
Carbamazepine was the first anticonvulsant studied as a treatment of mania. More than 19 studies (most of which were small case series or open trials) evaluated carbamazepine for the treatment of mania, and until recently it was used in BPD despite little scientific support for its use. Recently, however, carbamazepine (in extended-release form) was found to be effective for acute mania in a large, placebo-controlled trial.25 No large-scale trials have compared it with other antimanic drugs, so its relative efficacy is unknown. There are no data establishing carbamazepine as an effective maintenance treatment in BPD, although some have suggested that carbamazepine may be more effective in rapid cycling, dysphoric mania, mixed states, and “ultra-rapid cycling.” The lack of direct evidence from adequately powered trials that examined these effects makes these assertions speculative. At present, there are insufficient data to suggest that carbamazepine is more effective in these patients than any other treatment.
