Off-label psychiatric prescribing of gabapentinoids not backed by evidence

UK: Widespread and often off-label psychiatric prescribing of gabapentinoids is not supported by strong evidence except for some anxiety states, according to results from a systematic review and meta-analysis published in Molecular Psychiatry. Thus, for their use caution is indicated despite the attractive genetic and pharmacological rationale, and further evidence of safety and efficacy is needed.

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. The authors 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 randomized controlled trials (RCTs) and 15 open-label studies were identified

Data results showed that,

• For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified by the research team but a quantitative synthesis could not be performed due to diversity in the study population, design, and outcome measures.

• Across the anxiety spectrum, a consistent but not universal effect in favor of gabapentinoids compared to placebo was seen (standardized mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55) and gabapentin (SMD -0.92) were more effective than placebo in reducing preoperative anxiety.

• In insomnia, results were inconclusive.

Finally, it was concluded by the authors that there is a lack of rigorous evidence to support the clinical efficacy of gabapentin and pregabalin for the treatment of acute mania or acutely depressed BD patients. It should not be used as monotherapy in the short- or long-term period, however, as adjunctive therapy, its effects on the long-term outcomes of BD remain to be clarified.

Authors indicate caution and further evidence of efficacy and safety of gabapentin, and pregabalin use, despite their attractive genetic and pharmacological rationale. It may also be possible to develop modified α2δ ligands, targeting particular subtypes or isoforms, with a more beneficial therapeutic profile.

Reference:

Hong, J.S.W., Atkinson, L.Z., Al-Juffali, N. et al. Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale. Mol Psychiatry 27, 1339–1349 (2022). https://doi.org/10.1038/s41380-021-01386-6