Ketamine produces rapid antidepressant effects in treatment-resistant depression, but the exact mechanisms remain unclear. This review examines evidence that ketamine's fast action involves more than just glutamate release and AMPA receptor activation in the medial prefrontal cortex (mPFC). It also affects GABA, serotonin, glial cells, and circuits connecting the mPFC to the dorsal raphe nucleus. The authors argue that ketamine shifts the excitatory/inhibitory balance in the mPFC and that its metabolites, such as (2R,6R)-HNK, may contribute. They integrate preclinical findings to guide future research on fast-acting antidepressants.
Ketamine shows rapid antidepressant effects in treatment-resistant depression, but side effects and misuse risk limit its use. Its two enantiomers, (S)- and (R)-ketamine, work through different mechanisms: (S)-ketamine affects mTORC1 signaling, while (R)-ketamine affects ERK signaling. Preclinical studies suggest divergent pathways, and clinical research indicates (R)-ketamine has a milder side effect profile and reduces depression scores. However, recent randomized controlled trials found (R)-ketamine had no significant antidepressant efficacy compared to placebo, so caution is needed when interpreting its therapeutic potential. Further research is required to optimize dosing, route, and administration for each enantiomer.