| Summary: | <p>The gabapentinoids, gabapentin and pregabalin, target the α<sub>2</sub>δ 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. A systematic review and meta-analysis of the evidence for three of their common psychiatric uses – bipolar disorder, anxiety disorders/states, and insomnia – was carried out. Published and unpublished literature were searched and a random-effects pairwise meta-analysis was performed for each outcome where possible. Efficacy and acceptability were assessed using only double-blind randomised controlled trials. Assessment of tolerability also included single blind or open-label trials and non-randomised evidence. Where a quantitative synthesis could not be conducted, results were presented narratively. 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 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 state anxiety, with gabapentin showing a dose effect. In insomnia, results were inconclusive. There is moderate evidence of efficacy of gabapentinoids in state anxiety and anxiety disorders, 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. It may be possible to develop modified α<sub>2</sub>δ ligands, targeting particular subtypes or isoforms, with a more beneficial therapeutic profile. A future direction for clinical research would be to explore the targeted treatment of comorbid anxiety in bipolar disorder using gabapentinoids or modified α<sub>2</sub>δ ligands.</p>
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