Brain-derived neurotrophic factor Val66Met and CYP2B6 polymorphisms as predictors for ketamine effectiveness in patients with treatment-resistant depression.

Background: Converging lines of evidence indicate that ketamine is a rapid antidepressant for individuals with treatment-resistant depression. Hitherto, no reliable a priori predictors of ketamine response have been reported. Pharmacogenetic biomarkers have yielded mixed results regarding potential candidate genes associated with ketamine's biochemistry as reliable predictors of response.

Aims: No studies have examined the effects of Val66Met and CYP2B6 genotypes on patients receiving repeated infusions of intravenous ketamine.

Methods: In all, 85 participants with major depressive disorder who had previously received four infusions of intravenous ketamine were recruited to the foregoing study. Buccal swabs were collected and genotype variants across the Val66Met and CYP2B6 genes were analyzed. A repeated measures mixed linear model was used to assess change in depressive symptoms, suicidality, and anxiety, correcting for sex and age. Multiple regression was run to determine whether these genetic markers were associated with treatment efficacy for depressive severity, suicidal ideation, anxiolytic response, and degree of dissociation to intravenous ketamine.

Results: Participants experienced significant overall reductions in depression, suicide, and anxiety. Overall, 25% met the response criteria and 15% met the remission criteria. However, Val66Met and CYP2B6 did not significantly predict changes in symptoms of depression, suicide, anxiety, or average dissociation.

Conclusions: This study contributes to the growing literature that ketamine efficacy is unlikely to be predicted by single genes, and a pleiotropic approach may likely be necessary for developing reliable predictors of clinical benefits.