Major depressive disorder (MDD), including treatment-resistant depression (TRD), is a highly prevalent psychiatric disorder. MDD is associated with severe suffering, burden and large economical costs. Although various conventional antidepressant treatments are available, a large portion of depressed people does not or not adequately respond to the first-line treatments (mostly SSRIs and SNRIs) and a substantial part (ca, 30%) completely fails to respond, leading to TRD. The last two decades of intense research into new drugs for major depression and TRD has led to two lines of development, namely, Typical (or serotonergic) psychedelics (psilocybin, ayahuasca) and atypical (glutamatergic/NMDA) psychedelics (ketamine, esketamine). Both approaches, via a different entrance mechanism, have a fast (immediate) onset, combined with a long-lasting antidepressant action, which cannot be explained by long-term biological presence of the drug in the brain. The psychedelic drugs acutely initiate short-lasting CNS-induced side effects but also lead to activation of downstream cortical processes that underlie the 'lasting' antidepressant effects. In the present chapter, the clinical developments that have led to the marketing of psilocybin and esketamine for major depression disorders has been described. The emergence of fast onset antidepressants for major depression and treatment-resistant depression is a huge step forward in treating major psychiatric disorders. The acute psychotomimetic (psilocybin) or dissociative (esketamine) effects heavily interfere with performing of 'blind' studies, making proper placebo effects challenging. The development of new medicines that are acutely effective in depressive disorders is, however, a real breakthrough in psychiatry, but has also led to a spur of new research activities into new mechanisms involved, and also in developing new research techniques involved in designing proper research methodologies to bring this exciting field into adulthood.
