Antiepileptic Drugs, 5th Edition



Clinical Efficacy and Use in Psychiatric Disorders

John H. Greist MD

Distinguished Senior Scientist, Madison Institute of Medicine; and Clinical Professor of Psychiatry, University of Wisconsin, Madison, Wisconsin

The utility of nonbenzodiazepine anticonvulsants in the treatment of bipolar illness has been shown in controlled studies (1). The notion that anticonvulsants may be useful in psychiatric conditions other than bipolar illness (e.g., anxiety or psychotic disorders) has not enjoyed the same benefit of controlled research. Although claims of anxiolytic effects have been made for phenytoin, carbamazepine, and valproate, little evidence exists to support such use. The improved tolerability of newer anticonvulsant agents has renewed interest in exploring their psychiatric uses.

Gabapentin was introduced in the early 1990s and is of interest for its potential psychotropic effects. Early studies in seizure disorders indicated that gabapentin possessed minimal cognition-impairing effects such as those commonly associated with the older antiepileptic drugs (2, 3, 4, 5, 6). Additionally, improvements in mood and well-being among epileptic patients who were taking gabapentin were reported in a retrospective data analysis (7) and were subsequently confirmed in a prospective study (8).

The published open-label reports to date on the utility of gabapentin for the treatment of anxiety and bipolar disorders are noted in Table 32.1. Numerous reports of patient series successfully treated with gabapentin for various psychiatric conditions have been presented at various scientific meetings but are not included here. Despite the multitude of published reports, systematic evaluation of the psychiatric uses of gabapentin has not been carried out, and gabapentin is not approved by any government agency in the United States for such uses.


Preclinical data gathered early in the development of gabapentin showed anxiolyticlike effects in several animal models (9). Isolated anecdotal reports emerged over the years (10,11) and indicated the successful use of gabapentin to treat anxiety symptoms. Contemporaneously, we conducted two controlled clinical studies to test the hypothesis that gabapentin may be anxiolytic.

The first study (12) compared gabapentin and placebo in outpatients (n = 69) who were diagnosed with social phobia, according to the criteria of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), and who were treated for 14 weeks in a randomized, double-blind study design. Gabapentin was administered with doses given in a flexible escalating manner between the range of 900 and 3,600 mg/day. Using the Liebowitz Social Anxiety Scale as the primary measure of efficacy, this study found that patients taking gabapentin showed a significantly greater reduction in Liebowitz Social Anxiety Scale scores than those receiving placebo. The improvement seen with gabapentin was significantly greater than that observed with placebo after 1 week of treatment, and the superiority continued at each subsequent evaluation.

The second study (13) treated outpatients with DSM-IV-diagnosed panic disorder, with or without agoraphobia, in a randomized double-blind study lasting 8 weeks. Gabapentin was given in flexible doses of between 900 and 3,600 mg daily. The primary efficacy measure was the baseline to end point change in the total score of the Panic and Agoraphobia Scale (14), which is a composite measure of five domains of symptomatic and functional impairment in panic disorder. The protocol-specified analysis of efficacy did not show a difference between drug and placebo on the change in Panic and Agoraphobia Scale score. However, the same analysis on a subset of patients with at least a moderate severity of symptoms (as defined by a baseline total Panic and Agoraphobia Scale score of 20 or more) found that the drug-treated group showed a significantly greater improvement than the placebo-treated group.

The results of these studies, along with the experience of clinicians as mentioned in published case reports, provide preliminary evidence for the anxiolytic effects of gabapentin. Yet many unanswered questions remain. In addition to confirmation of the controlled trial results, a primary question centers on the dose-response curve in anxiety disorders. The doses used in the controlled trials were adjusted based on response and tolerability in the range of 900 to 3,600 mg daily given in three divided doses. Nearly two-thirds of the patients received doses >3,000 mg daily. Although these doses were well tolerated in both studies, the dose-response curve for anxiolytic effect can be definitively established only by fixed-dose studies. Anecdotal reports from experienced clinicians suggest that much smaller doses, perhaps in the range of 600 to 1,200 mg, may be sufficient to treat anxiety symptoms.





No. Patients



Ryback et al., 1997

Bipolar disorder


Variable, up to 3,600 mg/day

Good response in 67

Schaffer and Schaffer, 1997

Bipolar disorder


33-2,700 mg/day (mean, 539)

Good response in 18

Young et al., 1997

Bipolar depression


Flexible dosing

Full or partial response in 8

McElroy et al., 1997

Bipolar disorder (hypomanic, manic, or mixed)

9 consecutive

Adjunctive 300-4,800 mg/day

Moderate or marked improvement in 7 by 1 mo, in 1 by 3 mo; of these eight, six maintained their response at 1-7 mo follow-up

Stanton et al., 1997

Acute mania


3,600 mg/day

Marked improvement

Bennett et al., 1997

Bipolar disorder schizoaffective


Adjunctive 600-2,400 mg/day

Marked or moderate improvement in 4

Chouinard et al., 1998

Schizophrenia, schizoaffective disorder, bipolar disorder, generalized anxiety disorder


Adjunctive 100-4,400 mg/day

Improved sleep and reduced anxiety in all patients

Erfurth et al., 1998

Acute mania


1,200-4,800 mg/day alone or in combination

BRMAS 38 to 8 in add-on group (n = 6); 27 to 9 in 4/8 solo group (n = 8)

Soutullo et al., 1998

Acute mania and ADHD


1,500 mg/day added on to carbamazepine

Marked response within 1 mo

Ghaemi and Katzow, 1998

Bipolar or unipolar MDD


100-5,600 mg/day (mean 1,597 mg/day)

Moderate to marked efficacy in 15 (30%)

Knoll et al., 1998

Bipolar disorder


Adjunctive gabapentin, median top dose = 2,400 mg/day

Marked response in 1, moderate response in 7, mild response in 2 and no response in 2

Brown and Hong, 1999

Bipolar disorder with antidepressant-induced bruxism



Complete resolution of bruxism

Young et al., 1999

Non-rapid-cycling bipolar disorder type I and II


Adjunctive, up to 6 mo

Significant reduction in manic and depressive symptoms

Grunze et al., 1999

Bipolar disorder type I



BRMAS score declined significantly in patients with moderate mania, but gabapentin was not efficacious in patients with very severe mania

Cabras et al., 1999

Bipolar disorder schizoaffective


Adjunctive, flexible dosing (mean dose, 1,440 mg/day)

Positive response in 19 (76%)

Hatzimanolis et al., 1999

Acute mania


Adjunctive, flexible dosing

Moderate improvement after 2 wk of treatment

Maurer et al., 1999

MMD with somatoform pain disorder


Adjunctive, 1,800 mg/day

Remission of depression and pain

Perugi et al., 1999

Bipolar type I (mixed)


300-2,000 mg/day for 8 wk (mean dose, 1,130 mg/day)

Marked improvement in 4, moderate improvement in 6, mild worsening in 1; improvements maintained for 4-12 mo; HAMD decrease significantly

Sokolski et al., 1999

Bipolar disorder (mixed)


Adjunctive, flexible dosing

HAMD and BRMAS declined rapidly and significantly over 1 mo; improvement in insomnia

Hardoy et al., 1999

Schizoaffective and bipolar disorder with antipsychotic-induced movement disorder


Adjunctive, flexible dosing

14 patients showed improvement of movement disorders

Wang et al., 2000

Bipolar depression


Adjunctive, flexible dosing

60% response in mild to moderate depression, little or no response in severe depression

Vieta et al., 2000

Bipolar disorder type I and II


Flexible dosing (mean dose, 1,310 mg/day)

Two-point improvement on CGI-BP among 8 of 16 patients who completed 12 wk of treatment; those with anxious or depressive symptoms had the most improvement

ADHD, attention deficit/hyperactivity disorder; MDD, major depressive disorder.



The safety of gabapentin among patients with epilepsy is now well known (15, 16, 17, 18, 19), but the safety of the drug in anxious patients is less well described. Both the controlled studies showed a profile of adverse events consistent with that previously reported among epileptic patients. The most frequent adverse events were somnolence and dizziness that dissipated with continued treatment. Fewer data are available on adverse effects associated with cessation of gabapentin treatment. In both controlled anxiety studies, gabapentin was discontinued at the end of the trial by a rapid taper-down over 6 days. No overt withdrawal phenomena were observed, a finding suggesting that, unlike some other anxiolytics, gabapentin may not produce tolerance and withdrawal effects. One case report, however, suggested that rebound anxiety may occur after withdrawal of high-dose gabapentin among patients with obsessive-compulsive disorder (20). Until more data accrue on this issue, following the general clinical principle of withdrawing any antiepileptic agent gradually seems advisable.


The data on the use of gabapentin in the treatment of bipolar disorder are more complicated. Several clinical reports first suggested that gabapentin, like other anticonvulsants, may be clinically useful in treating patients with bipolar disorder who are partially responsive to conventional mood stabilizers (21,22). Numerous case series (23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35) were subsequently reported, confirming that therapeutic benefit was associated with the addition of gabapentin to combination drug regimens in patients with bipolar illness who were refractory to other treatments (Table 32.1).

Several of these reports involve patients with acute mania treated with gabapentin alone or in combination with other drugs (36, 37, 38, 39, 40). In the treatment of acute mania, the most important contribution comes from an open-label prospective study (36,37) using gabapentin either alone or in combination with other antimanic agents. These two reports involved 20 acutely manic inpatients treated with gabapentin either alone or added to other antimanic drugs. Clinical symptom severity ratings were collected prospectively using the Bech-Rafaelsen Mania Scale. The authors of this study concluded that patients receiving gabapentin as adjunctive treatment derived greater benefit than those who received it as monotherapy. This finding may suggest that gabapentin treats some component of acute mania (e.g., comorbid anxiety, insomnia) that responds incompletely to traditional antimanic treatments. In this respect, gabapentin may be complementary to, rather than a substitute for, established antimanic agents. This idea is supported by another report of the open-label treatment of 22 patients with type I or II bipolar disorder (41). Of the 16 patients who completed 12 weeks of treatment, eight showed at least a two-point improvement on the Clinical Global Impression (Bipolar). The greatest improvement seemed to occur in patients with anxious and depressive features.

Some data suggest that the best candidates for adjunctive gabapentin treatment may be patients with bipolar depression in the mild to moderate range of severity (35). In this group, the rate of response was noted to be about 60%, whereas patients with more severe symptoms had little or no response.

Two controlled studies of gabapentin in bipolar disorder have been conducted. In a crossover design, Frye et al. (42) tested the utility of high-dose gabapentin (≤4,800 mg/day) among patients with bipolar disorder who were refractory to treatment with conventional mood stabilizer treatment (i.e., lithium, valproate, or carbamazepine). The patients were entered into a crossover study that included three randomized 6-week treatment periods with gabapentin, lamotrigine, or placebo. Only a modest benefit of gabapentin over placebo was demonstrated in the initial parallel-group portion of the study. Overall, the rate of improvement in mood symptoms on gabapentin did not differ from placebo.

Another study (43) involved patients with bipolar disorder (n = 117) treated with lithium, valproate, or the combination of the two and who were still manifesting manic, hypomanic, or mixed manic-depressed symptoms. After a 2-week single-blind placebo stabilization period to adjust the doses of lithium or valproate, patients were randomized to treatment with adjunctive gabapentin (900 to 3,600 mg/day) or placebo for 10 weeks. Their clinical status was rated using the Young Mania Rating Scale, the Hamilton Depression Rating Scale, the Internal States Scale, the NIMH-Life Chart, and the Clinical Global Impression of Change.

The results of this study were surprising in light of the previously published anecdotal reports of the beneficial effects of gabapentin in patients with bipolar disorder. Patients who received adjunctive placebo showed significantly greater reductions in the total Young Mania Rating Scale scores than those receiving adjunctive gabapentin. This difference was not explained by worsening in the gabapentin-treated group but by a larger therapeutic effect


in the placebo-treated group. Further data exploration showed that the group randomized to placebo included a large number of patients whose background therapy (mainly lithium) was adjusted during the stabilization period. It is conceivable that this treatment optimization may have produced the greater therapeutic effect seen among patients receiving placebo during the randomized treatment phase. A fuller discussion of the methodologic problems with this study has been published (43).

The discrepancy between anecdotal reports and the controlled studies on the use of gabapentin in bipolar disorder is puzzling. It is possible that the patient population selected for the two controlled studies differed in some fundamental respect from the sort of patients selected by clinicians on a case-by-case basis and included in the published case reports. Alternatively, gabapentin may have a beneficial effect on some component of the bipolar disorder symptom picture (e.g., comorbid anxiety) that is not adequately treated by agents such as lithium and valproate and that was not adequately measured in the controlled studies.


A few published reports discuss the use of gabapentin for the control of behavioral disorders associated with dementia (44, 45, 46, 47). This could be a valuable use for a well-tolerated drug such as gabapentin. Unfortunately, current knowledge on the use of gabapentin in this population lacks support from controlled studies.

Another promising application of gabapentin is enhancing abstinence during treatment of alcohol or cocaine abusers (48). Based on the association between postdetoxification insomnia and the risk of alcoholic relapse, it is proposed that using gabapentin to improve sleep may help to minimize resumption of drinking (49).


The data to date suggest that gabapentin is superior to placebo in reducing anxiety symptoms among patients with social phobia and in a subset of patients with panic disorder. The anxiolytic effect of gabapentin was shown in the social phobia study to be apparent as early as the first week of treatment. This speedy effect could be clinically useful, especially among patients requiring more rapid relief than that provided by the antidepressant drugs.

The efficacy of gabapentin in bipolar disorder is unclear. Anecdotal reports involving over 200 patients with bipolar disorder report therapeutic benefit on gabapentin treatment. Yet controlled studies have failed to detect such an effect. Several potential explanations exist for such a discrepancy that can only be resolved through further studies. In summary, gabapentin may be useful in the treatment of psychiatric symptoms in anxiety and other disorders, but a great deal more controlled research is required before definitive recommendations for such use can be made.


Atul C. Pande, MD, graciously reviewed this manuscript, and I appreciate his thoughtful criticisms.


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