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.
CNS Spectrums
July 11, 2022
Seetal Dodd, Trevor R. Norman, Harris A. Eyre et al.
61 citations
Psilocybin, a tryptamine alkaloid found in Psilocybe mushrooms, is metabolized into the active compound psilocin, which produces psychoactive effects primarily by partially activating the 5HT2A receptor. Psilocin also binds to other receptor subtypes, though these actions are not fully understood. Clinical trials have tested psilocybin at hallucinogenic doses for addictive disorders, anxiety, and depression. This review assesses psilocybin and psilocin as potential neuropsychiatric treatments, weighing therapeutic benefits against potential harms. The authors conclude that careful evaluation of the number needed to harm versus the number needed to treat will determine clinical viability, and they call for a responsible path forward in this field.
Australian & New Zealand Journal of Psychiatry
March 21, 2021
Daniel Perkins, Jerome Sarris, Susan L. Rossell et al.
53 citations
Psychedelic substances such as psilocybin, ayahuasca, LSD, and MDMA are gaining renewed medical interest due to the need for new psychiatric treatments and promising study results. This viewpoint reflects on the Royal Australian and New Zealand College of Psychiatrists' Clinical Memorandum on Psychedelics and notes regulatory developments, including applications for down-scheduling and access approvals. The authors argue that rigorous research is needed to assess benefits, safety, and therapeutic mechanisms. They summarize recent findings on mechanisms of action and the psychedelic-assisted psychotherapy model, suggesting medicinal psychedelics could become a new class of psychiatric treatments when used under medical supervision with psychotherapeutic support. However, sufficiently powered trials and safety protocols are required before clinical use, and untrained practitioner access could be harmful.
The British journal of psychiatry : the journal of mental science
January 7, 2025
Natalie T Mills, Stevan Nikolin, Nick Glozier et al.
3 citations
Anxiety disorders and treatment-resistant major depressive disorder (TRD) often occur together. In a randomized controlled trial comparing subcutaneous ketamine to midazolam in 174 people with TRD, ketamine reduced anxiety only when given at flexible, response-guided doses (0.5-0.9 mg/kg). At a fixed low dose (0.5 mg/kg), the reduction in anxiety was not statistically significant. The anxiety-reducing effect was linked to overall depression improvement and was not sustained four weeks after treatment ended. The findings suggest that adequate dosing is necessary for ketamine's anxiolytic effect in this population.
Journal of affective disorders
October 15, 2025
Mary Lou Chatterton, Johana Kevin Perez, Thao Thai et al.
2 citations
Subcutaneous ketamine appears cost-effective for treatment-resistant depression from a health sector perspective when the costs of the control treatment (midazolam) are included, but not from a societal perspective. A cost-utility analysis alongside a randomized controlled trial with 174 participants compared ketamine to midazolam given twice weekly for four weeks. At the end of the trial, quality of life scores were significantly higher for ketamine. When control arm costs were included, ketamine was less costly and more effective, with an 89% probability of being cost-effective at a $50,000 per quality-adjusted life year threshold. Excluding those costs made ketamine not cost-effective, highlighting the importance of comparator choice.
The British Journal of Psychiatry
July 6, 2026
Nick Glozier, Richard W. Morris, Elizabeth Stratton et al.
A 4-week course of subcutaneous racemic ketamine produced short-term clinical benefit in a minority of people with treatment-resistant depression, with response rates declining substantially after treatment cessation. Among 130 participants, 30% responded at treatment end (Montgomery-Åsberg Depression Rating Scale reduction ≥50%), but only 17% remained responders 4 weeks later, and over 50% experienced less than a 25% reduction in depression scores. No difference in response was found between fixed and flexible dosing regimens. Prior ketamine treatment during an earlier randomized trial did not affect later outcomes. No suicides or suicidal behavior requiring admission occurred, and only expected side effects were observed.
Archives of suicide research : official journal of the International Academy for Suicide Research
May 9, 2026
Gregory Carter, Maree Hackett, Stevan Nikolin et al.
Ketamine's effect on suicidal ideation in adults with treatment-resistant depression remains uncertain. In a phase III double-blind randomized trial comparing subcutaneous racemic ketamine to midazolam over four weeks, one cohort showed no significant difference between groups on either the MADRS item 10 or the C-SSRS measure of suicidal ideation. A second cohort showed a non-significant reduction on the MADRS item 10 but a significant reduction on the C-SSRS. Baseline suicidal ideation scores were low in both cohorts. Adverse events requiring clinical review occurred in 13.8% of all treatment sessions. The authors suggest flexible-dose subcutaneous racemic ketamine may have beneficial effects on suicidal ideation scores, but future studies need to be powered for suicidal ideation as a primary outcome.