Modern electroconvulsive therapy (ECT) and nasal esketamine have significantly improved treatment for treatment-resistant depression (TRD), defined as non-response to at least two adequate antidepressant courses. This literature review presents evidence on efficacy and safety, comparing advantages, disadvantages, and response rates. Both treatments are highly effective for TRD. The choice between esketamine nasal spray and ECT should consider contraindications, age, severity, psychotic symptoms, patient preference, and accessibility. Pragmatically, esketamine is chosen before ECT when both are indicated, but studies on ECT in ketamine non-responders are missing.
Between 2013 and 2026, neuropsychopharmacology advanced from stagnation to momentum, producing several first-in-class treatments: rapid-acting drugs for treatment-resistant depression (intranasal esketamine), psychedelic-assisted therapy for PTSD and depression, neuroactive steroid GABA-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression, non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia, orexin receptor antagonists for insomnia, and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease.
A chronic, low-dose application of MK-801, a selective noncompetitive NMDA receptor antagonist, in animals produces changes that parallel those seen in schizophrenia. The treatment altered NMDA receptor subunit expression and reduced the number of GABAergic parvalbumin-positive interneurons, matching post-mortem findings from schizophrenic patients. This led to altered inhibition of pyramidal cells and cognitive deficits similar to those in schizophrenia. The findings suggest this animal model may help understand psychosis and aid in developing new treatments.