Combination therapies outperform monotherapy for treatment-resistant depression, achieving an additional 6.5% reduction in depression scores over 12 weeks. The most effective combinations were olanzapine with fluoxetine and quetiapine with SSRIs/SNRIs. Injectable treatments, particularly ayahuasca, produced rapid effects, with a 77% reduction in depression scores at 15 days. Intranasal treatments reached efficacy sooner than oral ones, with 28-day efficacy similar to the 12-week efficacy of the olanzapine-fluoxetine combination. Dropout rates due to adverse events were similar across methods (4.5%-5.2%), but total dropouts were highest for oral (17.9%) and lowest for intranasal routes (10.6%). There was considerable variation in headache, dizziness, and nausea incidence across administration routes.
Ketamine is a rapid-acting antidepressant, especially for treatment-resistant depression, working through multiple targets in the glutamatergic system. It blocks NMDA receptors, which disinhibits dopamine reward pathways and increases BDNF expression via eEF2K suppression, activating the mTOR pathway and enhancing synaptic plasticity. Neuroimaging shows ketamine rapidly reshapes prefrontal-limbic connectivity and normalizes brain activity. It has a fast onset and broad therapeutic window, but enantiomers and metabolites differ in effects. Long-term safety, dependence risk, and cognitive effects require monitoring. Future work should explore synergistic treatments and safer ketamine derivatives for precision psychiatry.