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.
Treatment-resistant depression (TRD) affects about one-third of people with major depressive disorder, but its molecular basis is unclear. In a mouse model, chronic social defeat stress was followed by sequential treatment with fluoxetine and ketamine, allowing classification into antidepressant-responsive and non-responsive animals. RNA sequencing of the nucleus accumbens and prefrontal cortex revealed distinct transcriptional signatures. Prior fluoxetine exposure primed some mice for molecular and behavioral response to ketamine, but this priming was absent in non-responders, indicating that resistance stems not from treatment failure alone but from a lack of adaptive molecular priming. Gene co-expression network analysis identified modules linked to stress susceptibility and antidepressant resistance, offering insight into gene networks underlying TRD.
Treatment-resistant depression (TRD) affects about a third of patients who do not respond to standard antidepressants, yet its molecular basis is poorly understood. In a mouse model of TRD, where chronically stressed mice failed to respond to fluoxetine, subsequent ketamine treatment produced behavioral and transcriptional changes in the nucleus accumbens. Failed fluoxetine treatment primed the mice for a positive response to ketamine, and specific gene networks linked to stress susceptibility and antidepressant resistance were identified. These findings illuminate molecular mechanisms behind antidepressant resistance and address a gap in preclinical TRD models.