Multimodal predictors of response to intravenous ketamine in treatment-resistant depression: toward personalized treatment in major depressive and bipolar disorders.

Intravenous ketamine is a rapid-acting intervention for treatment-resistant depression (TRD) in adults with major depressive disorder and bipolar disorder (BD). While efficacy is established, a comprehensive integration of clinical, neurophysiological, biomarker, metabolic, and cognitive predictors remains lacking, limiting precision CNS-targeted therapy. To synthesize recent evidence on multimodal predictors of intravenous ketamine response in TRD and propose a preliminary clinical framework to guide personalized treatment. Following PRISMA guidelines, Scopus, PubMed, EMBASE, and MEDLINE were searched for English-language, peer-reviewed studies published within the last 5 years. Eligible studies included adults receiving intravenous ketamine for depressive disorders. Data were descriptively synthesized to identify consistent predictors, evidence clusters, and research gaps. The review included 150 studies. Key predictors of ketamine response included baseline depressive severity, comorbid anxiety, atypical depression and sleep phenotypes, inflammatory and neuroplastic biomarkers (eg, monocyte count, BDNF), metabolic factors (BMI, vitamin B12), genetic/epigenetic variants, neurophysiological signatures (EEG, TMS, fMRI connectivity), cognitive performance, and early symptomatic improvement. Integrative analysis suggests that glutamatergic, circadian, and inflammatory mechanisms interact to shape interindividual variability. Limitations include methodological heterogeneity and scarce long-term outcome data. Intravenous ketamine response in TRD is multifactorial, reflecting clinical phenotype, CNS biomarkers, neurophysiology, metabolism, and genetics. This review proposes a preliminary research framework and pilot clinical questionnaire intended to facilitate future investigation of individualized treatment approaches. However, most proposed predictors remain exploratory and require prospective validation before clinical implementation.