In treatment-resistant depression, repeated ketamine infusions showed greater antidepressant effects than the active placebo midazolam after five doses, but when compared head-to-head against a single ketamine infusion added to midazolam over two weeks, the difference was not statistically significant. Fifty-four participants completed all six infusions. The primary outcome, change in depression severity measured by the Montgomery-Åsberg Depression Rating Scale at 24 hours after the last infusion, did not differ significantly between the six-ketamine group and the single-ketamine group. Remission and response rates favored six ketamine after the fourth and fifth infusions, respectively, compared to midazolam before the single ketamine.
Psychedelic compounds such as ketamine, MDMA, and psilocybin show promise for treating post-traumatic stress disorder by modulating synaptic plasticity and enhancing memory processing and extinction. These interventions may overcome limitations of conventional therapies and, when combined with existing psychotherapies, produce rapid and lasting improvement in chronic symptoms. The review discusses how modern methods for predicting treatment response could enable personalized precision medicine approaches, using quantitative evidence to tailor psychedelic interventions to individual patients.
In a rodent model of antidepressant resistance, combining lithium with ketamine produced a robust antidepressant-like effect, as shown by reduced immobility and shorter latency to immobility in the forced swim test. The combination also increased blood levels of mTOR and insulin. In the prefrontal cortex, the treatment altered signaling proteins differently in two subregions: mTOR and Akt phosphorylation increased in the infralimbic area, while mTOR phosphorylation decreased in the prelimbic area. These findings suggest lithium may augment ketamine's effects in treatment-resistant conditions, linked to peripheral insulin and region-specific prefrontal signaling.