World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
American Journal of Psychiatry
August 29, 2018
Nolan Williams, Boris D. Heifets, Christine Blasey et al.
510 citations
Blocking opioid receptors with naltrexone dramatically reduced the antidepressant effect of ketamine in adults with treatment-resistant depression, while leaving ketamine's dissociative effects unchanged. In a double-blind crossover trial, 12 participants received either placebo or 50 mg of naltrexone before a ketamine infusion. Seven of 12 met the response criterion (≥50% reduction in depression scores) after ketamine plus placebo, but depression score reductions were significantly smaller when naltrexone was given. The trial was halted at an interim analysis because naltrexone blocked the antidepressant effect. The findings indicate that ketamine's acute antidepressant effect requires opioid system activation, while its dissociative effects do not.
medRxiv Preprint Server
April 28, 2023
Theresa R. Lii, Ashleigh E. Smith, Josephine R. Flohr et al.
28 citations
preprint
A single dose of intravenous ketamine (0.5 mg/kg) delivered during surgical anesthesia did not reduce depressive symptoms more than placebo in adults with major depressive disorder. In a triple-masked, randomized trial of 40 patients, depression severity scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) did not differ between the ketamine and placebo groups at 1, 2, or 3 days after infusion. Clinical response rates were similar (60% versus 50% on day 1). Only 36.8% of participants correctly guessed their treatment assignment, indicating successful masking. One serious adverse event occurred in each group, unrelated to ketamine. The findings suggest that ketamine's acute psychoactive effects may contribute to previously reported antidepressant results through subject-expectancy bias.
Psychopharmacology Bulletin
August 12, 2025
Alan F. Schatzberg, D Charles
15 citations
Several innovative psychiatric drugs have recently been approved or are nearing approval. Auvelity (bupropion/dextromethorphan) speeds antidepressant response and remission more than bupropion alone. Zuranolone, a 14-day oral treatment for postpartum depression, improves symptoms at day 15 and through day 45. Gepirone, a 5HT1a partial agonist, was approved for major depression based on positive trials and a favorable side effect profile. Cariprazine was approved as an adjunctive treatment for resistant major depression at 1.5 mg daily. MDMA-assisted psychotherapy for PTSD led to over 70% of subjects no longer meeting PTSD criteria, compared to 46% with psychotherapy and placebo. Xenomeline/tropsium (KarXT), a muscarinic M1M4 agonist, effectively treats positive and negative schizophrenia symptoms without dopamine antagonism. Lecanemab, a monoclonal antibody targeting beta-amyloid, slowed cognitive decline by 27% in early Alzheimer's disease.
medRxiv
August 7, 2025
Ben Deverett, Duan Li, Theresa R. Lii et al.
preprint
Ketamine produces dissociative, analgesic, and antidepressant effects, but it is unclear whether its underlying neurophysiological signatures can be separated. In this observational cohort study, 52 participants (healthy volunteers, elective surgery patients, and patients with depression) received a subanesthetic infusion of ketamine or placebo, with or without general anesthesia. When ketamine was given under general anesthesia, its characteristic low-frequency brain wave augmentation was absent, while high-frequency power modulation was preserved. This selective modulation suggests a method for investigating the distinct roles of high- and low-frequency neural activity in ketamine's behavioral effects.