What causes depression at the mechanistic level?

Major depressive disorder responds, on average, modestly to antidepressants. The 'serotonin hypothesis' is now widely considered too simple. Alternative mechanisms include neuroinflammation, HPA-axis dysregulation, neuroplasticity deficits and disrupted circuits.

Why ketamine and psilocybin produce rapid effects, and which patients will respond to which therapies, are pressing open questions.