Stress-induced disorders such as depression, anxiety, PTSD, and postpartum depression are increasingly common, yet current treatments are limited. This review examines ketamine as a potential preventive treatment, summarizing preclinical and clinical findings on (R,S)-ketamine and its metabolites (2R,6R)- and (2S,6S)-hydroxynorketamine. It explores underlying mechanisms involving brain regions, circuits, and glutamatergic, dopaminergic, serotonergic, and inflammatory processes. The review also notes limitations including age- and sex-specific efficacy, adverse effects, and legal and ethical concerns. Future research directions and clinical integration are discussed. The literature underscores the need for further study to weigh ketamine's benefits and risks as a prophylactic.
Ketamine shows rapid antidepressant effects in major depressive disorder, suicidal tendencies, and treatment-resistant depression, but these effects are transient and require repeated clinic visits. Repeated exposure raises concern because ketamine has abuse liability, and depression and addiction share overlapping neural circuitry and molecular mechanisms. The review outlines limited knowledge of ketamine's neurobiological underpinnings mediating antidepressant effects and correlates them to its abuse potential. Although speculative, repeated ketamine use for depression could lead to substance use disorder, warranting caution. The lack of understanding of long-term effects and mechanisms is a limiting factor that needs systematic investigation before repeated use in depressed patients.