Lithium And Antiepileptic Drugs In Bipolar Depression

By | January 19, 2015

Lithium has been the gold standard for the treatment of bipolar illness for over 50 years (). There is more clinical and research experience with this drug than any other used to treat bipolar illness. Its utility in depression has been demonstrated in older studies and is generally underappreciated by the current generation of psychiatrists.

For over two decades, antiepileptic drugs (AEDs) have been integral to the treatment of bipolar illness. Historically, the introduction of antiepileptic drugs into the pharmacopeia was a consequence of Robert Post and James Ballenger’s translational work of the kindling hypothesis to the clinical setting (). The initial studies with carbamazepine led to widespread use, particularly in Europe () and paved the way to the subsequent introduction of valproic acid (). Several antiepileptic drugs are now in widespread clinical use, with some being used as mood stabilizers while others are used for their anxiolytic () or anorectic () properties.

The expert consensus guidelines () and the American Psychiatric Association bipolar treatment guideline (2002) both propose that lithium and mood-stabilizing antiepileptic drugs be the first-line treatment for bipolar depression prior to the introduction of antidepressant medications. This chapter reviews the available research regarding the use of these agents in bipolar depression.


Bipolar Depression

Lithium has been used for acute bipolar depression since its introduction for use in bipolar illness (). Controlled studies in bipolar patients invariably show significant improvement in the majority of acutely depressed bipolar patients (68%-100%, mean 68% response) (). This is very similar to what might be expected of an antidepressant for unipolar illness (), but is higher than the 51% efficacy rate of lithium in unipolar depression (). This clinically significant response rate stands in obvious contrast to general clinician experience with lithium. The discrepancy is explained by the fact that in the original controlled trials of lithium treatment, lithium levels were generally much higher (around 1.0 mM), than what is typically used by clinicians today (approximately 0.7 mM). There is ample evidence from lithium monotherapy studies () and studies of lithium coadministration with an antidepressant () that higher doses (and therefore blood levels) of lithium are more effective in treating and preventing depressive symptoms than lower doses. In their attempts to reduce the adverse-effect burden of lithium, clinicians are using it at doses that may be suboptimal for bipolar depression ().

Prophylaxis of Episodes

Lithium efficacy in preventing depressions in bipolar patients is not as clear. Early, long-term studies were not placebo-controlled, and have therefore been criticized regarding the methodology (). However, the best studies for the ability of lithium to prevent depressive relapse come from modern studies of lamotrigine, in which lithium is used as a positive control (). These studies are extraordinarily well designed, since minimum lithium serum levels were 0.8 mM or higher, and since they included patients that were either recently manic () or recently depressed (). This is an important characterization, since the polarity of the index episode appears to predict the polarity of the next episode (), and thus the outcome is different for the two groups (). In these studies, a total of 638 patients were randomly assigned to treatment with lithium (n = 167), lamotrigine (n=280), or placebo (n = 191) and followed for 18 months. Outcome was need for intervention (not meeting DSM-IV criteria for an episode). Lithium was not effective in preventing depressive relapse in these patients compared with placebo ().

Lamotrigine in Bipolar Depression

Valproic Acid in Bipolar Depression

Carbamazepine in Bipolar Depression


Despite being poorly studied with respect to bipolar illness, oxcarbazepine has made it into the American Psychiatric Association practice guideline for bipolar treatment (2002). Its utility in bipolar depression is even more poorly studied than in mania and hypomania. The observation that oxcarbazepine reverses abnormal behavior in two rat models of depression () suggests that it may indeed have antidepressant properties. In a group of 56 bipolar patients presenting with depression (n = 23), mania (n = 19), or psychosis (n = 14), there were no differences in outcome between any of the groups, suggesting that the study measures were inadequate. Twenty percent experienced no clear benefit (). As noted earlier, the antidepressant effect of carbamazepine has been associated with the cerebrospinal fluid concentrations of the 10,11-epoxide metabolite (). Since oxcarbazepine does not have that metabolite, it may also lack an antidepressant effect in bipolar illness.


Topiramate is an anticonvulsant with several interesting properties (): it is associated with weight loss, may be an effective anti-obesity agent (), and may actually increase insulin sensitivity (), possibly making it useful in the management of weight gain and obesity, which frequently accompany bipolar disorder (). Furthermore, topiramate may be effective in reducing binge-eating behavior (), bulimia (), and alcohol consumption (). For these reasons, topiramate is a frequently used drug in bipolar patients. However, initial reports that topiramate is an effective mood stabilizer have not been borne out by more extensive double-blind, placebo-controlled studies. Unfortunately, many of these reports remain unpublished and therefore cannot be critically reviewed.

Two studies have been performed with topiramate in depressed bipolar subjects. In one, 36 patients with either type I or II bipolar disorder were randomly assigned to receive either topiramate or bupropion slow release added to current medication. Fifty-six percent of topiramate-treated patients and 59% of bupropion-treated patients improved at least 50% on the Ham-D (). In an unpublished study, Hussain et al. (2001) studied long-term (3-year) topiramate use in 65 depressed type I and 18 depressed type II bipolar subjects. Sixty-three percent of the patients achieved remission (Ham-D<10) by the end of the study.

Other Anticonvulsants

Few of the other available anticonvulsants have been studied in bipolar depression. Not all anticonvulsants have mood-stabilizing properties and fewer have an antidepressant effect.


Gabapentin is an anticonvulsant with clinically meaningful efficacy in blinded, placebo-controlled studies in panic disorder () and generalized anxiety disorder (). Because of its anxiolytic effect and initial open series suggesting utility as a mood stabilizer (), it has been widely used in bipolar patients. However, its poor performance in blinded, placebo-controlled monotherapy () and adjunct studies (in which it was statistically inferior to placebo) suggests that it has a limited role in acute mania. Nonetheless, with efficacy in different types of anxiety disorders, the question remains of whether gabapentin can be effective in bipolar depression.

In the only placebo-controlled study that utilized a crossover design, 31 treatment-resistant bipolar patients did not experience any benefit from gabapentin compared with placebo in the treatment of depressive symptoms (). However, positive responses have been reported in open trials. For example, Vieta and collegues (2000) found that 8 of 22 type I and II bipolar subjects with residual symptoms (36.4%) had a good response, particularly in anxious symptoms. Wang et al. (2002) found that 50% of 22 depressed type I (n = 10) and type II (n = 12) bipolar subjects experienced a moderate to marked improvement when gabapentin was added to a mood stabilizer or an antipsychotic agent. Eight (36%) achieved remission: the more mildly depressed subjects were the ones that improved and severely ill subjects did not do well (). Perugi et al. (2002) gave gabapentin to 43 treatment-resistant DSM-III bipolar subjects. Eighteen (42%) responded and 17 of these subjects maintained the response for a full year. But the greatest improvement was experienced by those with anxiety, somatization, and alcohol abuse (). Ghaemi and Goodwin (2001) reviewed the records of 21 bipolar spectrum subjects treated with gabapentin (13 receiving monotherapy). They found that overall improvement in depressive symptoms was 27.6%. A subgroup with greater response (57.5% improvement) did not achieve statistical significance (P=0.1). Overall, these open studies are associated with placebo-like rates of response (30%-40% range) and improvement in mild or anxious symptoms, suggesting that gabapentin is not generally helpful in bipolar depression but may be helpful in mildly depressed, anxious individuals. A similar conclusion was reached in a more extensive review of the open data ().

A similar pattern is seen when patients have mild mixed symptoms. Sokolski et al. (1999) and Young et al. (1999) both reported a significant decrease in symptoms of hypomania and depression in mildly ill type I or type II bipolar disorder patients. Again, anxiety symptoms were not specifically measured, but may have accounted for most of the improvement.

More clear is the lack of prophylactic effect of gabapentin in long-term treatment. Montanes Rada and de Lucas Taracena (2001) openly followed nine bipolar patients receiving gabapentin monotherapy for 9 months. Overall the patients did worse after beginning gabapentin, with an increase in the number of relapses (from an average of 0.18/ month to 0.29/month). Similarly, in another study of 18 patients with an initial good response to gabapentin, only seven (39%) experienced ongoing benefit, while five relapsed (three dropped out) ().


Tiagabine is an approved antiepileptic agent (). Suppes and colleagues in the Stanley Bipolar Network (2002) examined tiagabine at an average dose of 8.7 mg/day in 17 refractory bipolar patients. Only three (23%) improved, the majority (77%) either experienced no change or worsened. Similarly, Schaffer et al. (2002) reported a small open series of 22 bipolar spectrum patients who received low-dose tiagabine (<8 mg/day) as an add-on to other mood stabilizers. At the end of 6 months only eight (36%) were considered responders.


Pregabalin is an antiepileptic compound related to gabapentin () that has significant anxiolytic effect in generalized anxiety disorder () and social phobia (). Bipolar studies are unpublished and are believed to be negative.


Levetiracetam is an antiepileptic agent () that has been preliminarily examined in depressed bipolar subjects. Post et al. (2005) described that only 31% of depressed patients had significant improvement after 8 weeks of treatment with 2,000-3,000 mg/day. The low response rates suggest that additional preliminary studies are still required.

Antiepileptic Drugs In Bipolar Depression: Summary

Lithium and anticonvulsants have a significant role in the treatment of bipolar depression. Lithium has extensive data supporting its utility in both acute bipolar depression and relapse prevention. Additionally, it has well-documented anti-suicide potency. Lamotrigine has been shown in placebo-controlled trials to improve acute depression and prevent depressive relapse in both types I and II bipolar subjects. Valproic acid has not been adequately studied in acute bipolar depression, and available evidence indicates suboptimal benefit. However, secondary analyses of a controlled relapse prevention study and open data suggest that it may have a role in the delay or prevention of depressive episodes in bipolar patients. Carbamazepine appears to have a modest acute and prophylactic antidepressant effect. Other agents have not been adequately studied in bipolar depression but may improve other associated symptoms (e.g., anxiety with gabapentin) to play a role in the management of bipolar depression.