Gabapentin as an Adjunct in Bipolar Disorder

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Bottom line: There is no evidence to suggest that Gabapentin is an effective adjunct for bipolar disorder.

Clinical Question: A 40 yo pt with bipolar disorder has multiple manic relapses on Lithium and Depakote. The pt's family inquires about Gabapentin. Is Gabapentin an effective adjunct for bipolar disorder?

Article : Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G., Gabapentin Bipolar Disorder Study Group.

Background: Despite increasing modalities in treating bipolar disorder, bipolar patients do poorly in long term follow up. Gabapentin has been described in several reports (including open label trials) as an effective adjunct for bipolar mania and depression.

Methods:

1. Design - 10 week, Double blind placebo controlled with a2-week single blind lead in. 117 outpatients in 14 centers with mania or hypomania. All pts received lithium and/or depakote for 2 weeks prior to randomization with levels greater than 0.5 (mEq/L for lithium and micrograms/ml for depakote). Qualified pts then randomized, and treatment arm given flexible gabapentin dosage between 600mg to 3600mg (split TID). Placebo arm continued on Lithium/ depakote or both.
2. Randomization - double blind with 2-week placebo single blind lead in. Exact randomization process not explained.
3. Inclusion - NO structured interview. DSM IV criteria. Exclusion -age under 16, YMRS <12.
4. Treatment and follow up - Pt's seen in 1 wk intervals for first 4 weeks, then 2 wk intervals for next 6 weeks. Li and Valproic acid dosages maintained after randomization unless pt safety in danger. Doesn't discuss what other meds pts were allowed.

Efficacy Variables: Ham D, YMRS, ISS, CGI, Ham A. Quality of Life Questionnaire.

Analysis: LOCF (ITT included all pts that received at least one dose of study medication).

Safety: Gabapentin generally well tolerated though there were reports of increased somnolence and dizziness (24% and 19%) compared to placebo. 13 patients had severe adverse events during study and 12 withdrew (5 in placebo, 7 in gabapentin).

Results:

1. 114 of 117 pts had a post randomization observation. 64 % of placebo and 53% of gabapentin arms completed trial. Pt's are rather similar at baseline. Many are hypomanic. See Table 1
2. On YMRS, pt's in the placebo arm fared better (see Table 2 - Mean change in YMRS -9.9 in placebo arm compared to -6.5 in gabapentin). Secondary efficacy factors were more similar between two arms (CGI, HAM D). See Table 2.
3. Somehow, it was determined that those pt's who had their lithium dosages altered during the 2 wk lead in disproportionately altered the data. The investigators removed the 16 patients who had such changes (12 in placebo arm, 4 in gabapentin arm) and report that the adjusted YMRS differences are no longer statistically significant.

Discussion:

The authors of the article attempt to justify the results by discussing issues with ethics (cannot withhold treatment, therefore Gabapentin not primary agent?) and study design.

Our question about therapy in the paper was, "Is Gabapentin an effective adjunct for bipolar mania/ hypomania?" The best evidence found was a medium sized, double blind placebo controlled study of Gabapentin adjunct tx vs. Lithium and/ or depakote only tx in hypomanic or manic bipolar outpts, which failed to show efficacy of Gabapentin as an adjunct as evidenced by mean changes in the Young Mania Rating Scale (CI -6.35 to -0.32). The trial's validity is limited by the study design and high drop out rate, which may have biased the results in either direction.

Given these limitations, the study gives fair evidence of no increased benefit with gabapentin adjunct therapy, and does nonsupport the use of Gabapentin in similar patients.