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.
JAMA Psychiatry
March 1, 2017
Gerard Sanacora, Mark A Frye, William M. Mcdonald et al.
577 citations
Ketamine can produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. However, existing studies have relatively small sample sizes, lack longer-term data on efficacy, and provide limited data on safety. Despite these limitations, ketamine is increasingly used off-label for mood and other psychiatric disorders. This review and consensus statement provides an overview of the data, highlights limitations, and offers suggestions to facilitate evidence-based clinical decision-making and patient safety.
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.
The American journal of psychiatry
March 1, 2025
Konstantinos N Fountoulakis, Athanasios Saitis, Alan F. Schatzberg
78 citations
Intranasal esketamine, approved as an add-on therapy for treatment-resistant major depression with acute suicidal thoughts, shows only modest benefit for depression and no effect on suicidality itself. A systematic review and meta-analysis of 87 studies found a weak but significant positive effect on depression at weeks 2-4 (effect size 0.15-0.23), similar to adding atypical antipsychotics. However, the effect on suicidality was not significant at any time point. The authors highlight esketamine's abuse potential, unknown long-term effects, and alarming signs of deaths and emerging suicidality during testing, urging caution in light of these regulatory and safety concerns.
The American journal of psychiatry
March 1, 2025
Marjorie R Levinstein, Reece C Budinich, Jordi Bonaventura et al.
49 citations
Ketamine, a racemic compound used as an anesthetic, analgesic, and recreational drug, is being investigated for treating refractory depression and comorbid conditions like anxiety, obsessive-compulsive disorder, and opioid use disorder. Although ketamine is traditionally classified as an NMDA receptor antagonist, this review argues its pharmacology should be redefined to include opioid receptors and the endogenous opioid system. The authors propose that ketamine's antidepressant effects may arise from bifunctional, synergistic interactions involving both NMDA and opioid receptors.
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.
American Journal of Psychiatry
May 1, 2020
Alan F. Schatzberg
19 citations
No Summary
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.
The American journal of psychiatry
June 1, 2026
Jason M Tucciarone, Igor D. Bandeira, Christine Blasey et al.
5 citations
Ketamine rapidly reduces suicidal thoughts in major depressive disorder, but the effect is short-lived. In this trial, adults with major depression and active suicidal ideation received a single ketamine infusion, then were randomly assigned to take either low-dose buprenorphine or a placebo daily for four weeks. Suicidal thoughts dropped significantly more in the buprenorphine group (average decrease of 11.6 points on the Scale for Suicide Ideation) than in the placebo group (average decrease of 6.3 points). Depression scores did not differ between groups. No serious side effects occurred. Buprenorphine appears to sustain and boost ketamine's antisuicidal effects, offering a potentially safe, scalable option for suicide prevention.
JAMA Psychiatry
June 1, 2026
Ben Deverett, Duan Li, Theresa R. Lii et al.
1 citation
Ketamine produces distinct brain-wave patterns that may be linked to its therapeutic effects. General anesthesia selectively blocks one of these patterns—theta oscillations—while leaving another pattern, beta-gamma oscillations, intact. In 52 participants, ketamine given during anesthesia preserved beta-gamma power increases but eliminated the characteristic theta augmentation seen during awake administration. This suggests that different neurophysiologic effects of ketamine can be separated, offering a way to investigate which brain-wave changes underlie its antidepressant, analgesic, or dissociative properties.
Journal of Affective Disorders
July 15, 2025
Theresa R. Lii, Josephine R. Flohr, Robin L. Okada et al.
1 citation
The endogenous opioid system may influence the placebo antidepressant response. A post hoc analysis of a randomized, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery tested whether baseline opioid use affected antidepressant responses. The analysis found that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, pain intensity, and ethnicity. The findings, based on a small sample, require confirmation by prospective controlled studies. Opioid use at baseline attenuated the placebo antidepressant response independently of pain, while the antidepressant response was preserved in opioid users who received ketamine.
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.
medRxiv : the preprint server for health sciences
November 2, 2024
Theresa R. Lii, Josephine R. Flohr, Robin L. Okada et al.
preprint
The placebo antidepressant response was weaker in depressed patients who were already taking opioid medications, independent of their pain levels. In a re-analysis of a randomized trial, patients on chronic opioid therapy who received a placebo showed depression scores 10 points higher on the Montgomery-Åsberg Depression Rating Scale (MADRS) across 1 to 14 days after treatment, indicating less improvement. When measured as percent change, opioid users experienced 38.4% less improvement than non-users. For patients who received ketamine, baseline opioid use did not significantly affect depression scores. Pain intensity did not predict depression outcomes, and the link between depression and pain was negligible. These results come from a small, unregistered post hoc analysis and require confirmation.