Key Concepts for the Use of Antiepileptic Drugs (AEDs) for Bipolar Disorder

Concepts Derived From Drug Effectiveness Review Project Report

Current evidence supports the conclusion that three AEDs (carbamazepine, valproic acid/valproate and lamotrigine) are efficacious in achieving and maintaining remission for outpatient adults with primary diagnoses of bipolar I disorder with recent mania or mixed episodes.
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- The overall magnitude of benefit obtained with AEDs in bipolar I disorder with recent mania or mixed episodes was an absolute improvement of the probability of attaining remission ranging from 7-28%; the relative rate of attaining remission was between 1.17-2.87, compared to placebo. The strength of evidence for this indication is low (GRADE criteria). [provide link to GRADE criteria]
- Data from multiple small trials provide only modest evidence for the efficacy of carbamazepine as a maintenance treatment in bipolar I disorder (GRADE strength of evidence: Low), and this medication may be a second-line choice compared with other efficacious agents.
- Evidence is stronger for lamotrigine in prevention of depressive than manic episodes.
- No acceptable evidence to support choice of one agent over another based on speed of onset in attaining remission.
Current evidence provides only modest support for the efficacy of the same three AEDs in achieving and maintaining remission in outpatient adults with bipolar I disorder with recent depressive episode or in bipolar II disorder.
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- The overall magnitude of benefit obtained with AEDs relative to placebo in bipolar I disorder with recent depressive episode was an absolute improvement in attaining remission of 11%, with a relative rate of attaining remission of 1.44, compared to placebo. The GRADE [provide link to GRADE criteria] strength of evidence for use of AEDs for this indication is low.
- The overall magnitude of benefit in bipolar II disorder is an absolute difference of 15%, with a relative rate of 1.58, of attaining remission compared to placebo. The GRADE [provide link to define GRADE criteria]strength of evidence for use of AEDs for this indication is low.
Efficacy of these agents in maintaining remission is generally based on the percentage of patients who do not experience symptomatic recurrence or prematurely discontinue study treatment because of symptoms.
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- There is great variability among the methods used to measure symptoms and functional status in these populations. Evidence indicating improvement in manic or depressive symptoms is much less clear because of difficulties in comparing different symptom scores and functional status measures in these populations.
- Most available evidence does, however, demonstrate improvement in symptom scores compared with placebo. The level of absolute improvement in reducing recurrence ranged from 1-23%, with a risk reduction ranging from 0.63-0.96. The GRADE [provide link to define GRADE criteria] strength of evidence for use of AEDs for this indication is low.
Carbamazepine, valproic acid and lamotrigine appear to have similar magnitudes of benefit in inducing remission, although the risk of recurrence is substantial for all agents.
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- While carbamazepine, valproic acid and lamotrigine have similar magnitudes of benefit based on indirect comparisons, few studies directly compare these medications with each other.
- Therefore, these conclusions should be considered tentative. The GRADE [provide link to define GRADE criteria] strength of evidence supporting this conclusion is low.
The rates of achieving and maintaining remission during treatment with carbamazepine, valproic acid and lamotrigine are similar to those obtained with lithium treatment for bipolar I disorder. For outpatient adults with acute mania, carbamazepine and valproate were similar, relative to lithium, in terms of response rates.
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- The incidence of recurrence in the studies examined ranged between 16% and 70% with placebo and between 6% and 65% with medication treatment.
- The broad range of these estimates is due to the variable definitions of recurrence used and variable duration of follow-up.
- Recurrence is a significant problem for these patients even with treatment with AEDs.
The overall risk of adverse events resulting in medication discontinuation is similar among carbamazepine, valproic acid and lamotrigine, and the overall risk of adverse events for AEDs is similar to that for lithium across all clinical subtypes of bipolar disorder.
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- However, the types of adverse events encountered differ among the three AEDs and lithium. Serious adverse events, although uncommon, may occur with each agent.
- Meaningful comparisons of the rates of these serious events among agents could not be performed.
- Overall evidence regarding comparative adverse event rates is based on a small number of studies.
- Between 5% and 24% of patients discontinue an AED because of adverse events. The rates of serious adverse events are on the order of 0 to 10.3%. The GRADE strength of evidence for this finding is low.
The risk of suicide or suicide attempt is present in bipolar disorder. Evidence regarding protection against the risk of suicide attempt is limited and does not support a difference between valproate and carbamazepine.
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- Compared to placebo, patients treated with AEDs for psychiatric conditions may have a small increase in suicidal ideation. http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm
- Both valproate and carbamazepine have been associated with lower protective effect against suicide attempt than lithium in observational studies; however, the evidence of less protective effect is stronger for valproate.
- There is insufficient data to compare the risk of suicide attempt among other AEDs.
There is limited evidence showing that gabapentin is no more, and perhaps less, efficacious than placebo in the treatment of bipolar I disorder with recent mania and rapid cycling bipolar disorder. No acceptable evidence was found to support use of gabapentin in achieving remission or preventing relapse in bipolar disorder.
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- Evidence regarding efficacy of topiramate for any of the above conditions (bipolar I disorder with recent mania, hypomania, or mixed episodes and bipolar II disorder) is sparse.
- Current evidence regarding use of topiramate for acute mania shows no evidence of efficacy.
The available evidence regarding the potential differential efficacy among AEDs in the treatment of patients with rapid cycling and other patient subgroups is extremely limited.
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- Available evidence does not allow prediction of which patient subpopulations will respond to any given AED.
- Available evidence does not allow prediction of response to a subsequent AED based on response to an initial trial of therapy.
Little evidence is available regarding differential efficacy of carbamazepine, valproic acid and lamotrigine in subpopulations defined by gender, age, ethnicity or comorbidity.