Personalized use of ketamine and esketamine for treatment-resistant depression.

Treatment-resistant depression accounts for a large share of the burden of major depressive disorder. Intravenous ketamine and intranasal esketamine are rapid-acting antidepressants that can effectively treat this condition, but response varies. Reliable predictors of response are urgently needed. Clinical predictors of a robust response to ketamine include a family history of alcohol use disorder and a history of childhood trauma. A promising brain-based biomarker is an increase in gamma power in frontoparietal regions measured by EEG. Blood-based biomarkers have shown limited usefulness, with small-effect increases in BDNF being the most consistent indicator. Dissociative symptoms during treatment are not typically associated with response. Most predictors have modest effect sizes, so multivariate models will be needed.

Study at a glance

Abstract

A large and disproportionate portion of the burden associated with major depressive disorder (MDD) is due to treatment-resistant depression (TRD). Intravenous (R,S)-ketamine (ketamine) and intranasal (S)-ketamine (esketamine) are rapid-acting antidepressants that can effectively treat TRD. However, there is variability in response to ketamine/esketamine, and a personalized approach to their use will increase success rates in the treatment of TRD. There is a growing literature on the precision use of ketamine in TRD, and the body of evidence on esketamine is still relatively small. The identification of reliable predictors of response to ketamine/esketamine that are easily translatable to clinical practice is urgently needed. Potential clinical predictors of a robust response to ketamine include a pre-treatment positive family history of alcohol use disorder and a pre-treatment positive history of clinically significant childhood trauma. Pre-treatment versus post-treatment increases in gamma power in frontoparietal brain regions, observed in electroencephalogram (EEG) studies, is a promising brain-based biomarker of response to ketamine, given its time of onset and general applicability. Blood-based biomarkers have shown limited usefulness, with small-effect increases in brain-derived neurotrophic factor (BDNF) being the most consistent indicator of ketamine response. The severity of treatment-emergent dissociative symptoms is typically not associated with a response either to ketamine or esketamine. Future studies should ensure that biomarkers and clinical variables are obtained in a similar manner across studies to allow appropriate comparison across trials and to reduce the signal-to-noise ratio. Most predictors of response to ketamine/esketamine have modest effect sizes; therefore, the use of multivariate predictive models will be needed.