Ketamine and psilocybin both provide rapid relief from major depressive disorder by enhancing synaptic plasticity in mood-regulating circuits, but through distinct initial mechanisms: ketamine blocks NMDA receptors while psilocybin primarily activates 5-HT2A receptors. A shared downstream pathway involves BDNF-TrkB signaling, which promotes spinogenesis and synaptogenesis critical for sustained antidepressant effects. The review also discusses 5-HT2A receptor biased agonism as a potential strategy to separate therapeutic benefits from hallucinogenic effects. Understanding how serotonergic, glutamatergic, and neurotrophic systems converge may guide development of fast-acting, durable, and non-hallucinogenic antidepressants.
Auditory hallucinations affect 60-80% of schizophrenia patients and often resist antipsychotic treatment. This randomized, sham-controlled trial tested whether real-time fMRI neurofeedback targeting the superior temporal gyrus, combined with mindfulness meditation, produces specific neural changes beyond placebo. Twenty-three adults with medication-resistant hallucinations practiced mindfulness meditation while receiving neurofeedback from either the superior temporal gyrus or motor cortex. Both groups reported reduced hallucinations after neurofeedback, with no group differences in symptom reduction. However, real neurofeedback produced greater reductions in secondary auditory cortex activation and connectivity between auditory cortex and cognitive control regions (dorsolateral prefrontal cortex and anterior cingulate), which persisted in a crossover condition. Mindfulness meditation independently reduced primary auditory cortex activation. Region-specific neurofeedback targeting modulates auditory-cognitive control networks, potentially restoring the balance between bottom-up sensory processing and top-down control.