Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale

Abstract

The gabapentinoids, gabapentin, and pregabalin, target the α₂δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.

Fig. 1. PRISMA diagram.

Flowchart of included and excluded studies.

Fig. 2. Forest plots showing the efficacy of gabapentinoids versus placebo across the anxiety spectrum.

CI Confidence interval, IV Inverse variance, SD Standard deviation.

Fig. 3. Subgroup analysis of empirically guided high (>600 mg; including 1200 mg (green), 900 mg (red) and 800 mg (yellow)) versus low doses (600 mg, purple) of gabapentin vs. placebo [46] in preoperative anxiety.

CI Confidence interval, IV Inverse variance, SD Standard deviation.

Fig. 4. Subgroup analysis of empirically guided high (300 mg, green) versus low doses (≤150 mg; including 75 mg (yellow) and 150 mg (purple)) of pregabalin vs. placebo [45] in preoperative anxiety.

CI Confidence interval, IV Inverse variance, SD Standard deviation.