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.
Brain Connectivity
December 5, 2016
Lauren Mak, Luciano Minuzzi, Glenda Macqueen et al.
354 citations
The default mode network (DMN) is a set of brain regions active during rest and self-referential thought. This review of studies up to August 2016 examined how DMN functional connectivity varies in healthy people by age, sex, cognitive function, and analysis method. DMN connectivity follows an inverse U-shape across the lifespan: strongest in adulthood, lowest in children and the elderly. Cognitive function positively correlates with DMN connectivity. Females show stronger intranetwork connectivity than males. Effects of analysis type were inconclusive. A voxel-wise meta-analysis for age confirmed an immature network in children versus adults and a stronger network in adults versus the elderly. Defining normal variation may help identify DMN changes in pathology.
The Canadian Journal of Psychiatry
November 11, 2020
Jennifer Swainson, Alexander McGirr, Pierre Blier et al.
109 citations
A systematic review by the Canadian Network for Mood and Anxiety Treatments evaluated evidence for racemic ketamine in treatment-resistant depression. Single intravenous infusions have Level 1 evidence for efficacy in adults, while multiple or maintenance infusions have only Level 3 evidence. Adverse events include dissociative symptoms and hypertension. Non-IV formulations have Level 3 or 4 evidence. Single-dose IV racemic ketamine is a third-line recommendation; repeated use requires careful case-by-case risk-benefit assessment. Oral and other formulations should be limited to specialists with ketamine expertise at tertiary centers due to limited evidence and risk of misuse.
The Canadian Journal of Psychiatry
August 17, 2022
Joshua D. Rosenblat, Muhammad Ishrat Husain, Yena Lee et al.
58 citations
Serotonergic psychedelics are being reconsidered as potential treatments for major depressive disorder. A Canadian task force systematically reviewed clinical trials from 1990 to 2021 and found that only psilocybin and ayahuasca have been tested in contemporary studies. Two pilot studies of single-dose ayahuasca for treatment-resistant depression showed preliminary positive effects (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy for major depressive disorder showed superiority to waitlist controls and comparable efficacy and safety to escitalopram with supportive psychotherapy, with additional trials showing efficacy in cancer-related depression (Level 3 evidence).
Psychedelic medicine (New Rochelle, N.Y.)
June 1, 2024
Ryan Yermus, John Bottos, Nathan Bryson et al.
13 citations
Ketamine-assisted psychotherapy (KAP) produces sustained reductions in anxiety, depression, and PTSD symptoms lasting up to 5 months after the last session. In a retrospective study of adults with treatment-resistant major depressive disorder, generalized anxiety disorder, or PTSD who received KAP across 11 North American clinics, large treatment effects were detected at 3 months (Cohen's d = 0.75-0.86) and sustained at 6 months (d = 0.61-0.73). Case reductions ranged from 39% to 41% at 3 months and 29% to 37% at 6 months. However, high attrition rates (82% at 3 months, 95% at 6 months) may limit validity of the results.
medRxiv
January 17, 2023
Ryan Yermus, Michael Verbora, Sidney H. Kennedy et al.
2 citations
preprint
Ketamine-Assisted Psychotherapy (KAP) produced large and sustained reductions in depression, anxiety, and PTSD symptoms for up to six months after treatment. In a retrospective trial of 1806 adults with treatment-resistant depression, anxiety, or PTSD, effect sizes at three months ranged from 0.75 to 0.86 and were maintained at six months (0.61 to 0.73). Between 39% and 41% of patients showed case reductions at three months, and 29% to 37% at six months. A minimal clinically important difference was reported by 50% to 75% at three months and 48% to 70% at six months. The treatment involved 4 to 6 guided ketamine sessions with psychotherapy.
Psychopharmacology
July 1, 2026
Sarah Ann Smith, Haseeb Mohammad, Lik Hang N Lee et al.
A review of 20 studies examined whether psychedelic drugs can affect social cognition in people with psychiatric or neurodevelopmental disorders that involve cognitive impairment. The drugs studied were ketamine, MDMA, psilocybin, LSD, and ayahuasca, tested in depressive disorders, anxiety disorders, autism spectrum disorder, and post-traumatic stress disorder. Findings included neural activation patterns suggesting that ketamine and psilocybin may modulate processes relevant to social perception, especially facial emotion processing, in depressive disorders. MDMA was linked to improvements in self-reported psychosocial functioning, self-awareness, and self-compassion in participants with PTSD. Direct evidence of improved social-cognitive functioning remains limited.
BJPsych Open
September 12, 2025
Karim S Ladha, Jiwon Lee, Gabriella Mattina et al.
A pilot trial tested the feasibility of a four-week course of nitrous oxide compared with midazolam (an active placebo) for treatment-resistant depression. Forty participants were randomly assigned to weekly one-hour inhalations of either 50% nitrous oxide or 50% oxygen plus intravenous midazolam. Recruitment, withdrawal, adherence, and missing data rates met feasibility criteria. Depression severity, measured by the MADRS scale, changed by -20.5% in the nitrous oxide group and -9.0% in the placebo group. Adverse events were mostly mild to moderate and transient. The results support conducting a full-scale trial.
Experimental and Clinical Psychopharmacology
April 1, 2023
Brett Melanson, Michael Wolter, Zion Leatham et al.
Exposure to a context previously paired with the effects of ketamine reduced immobility in the forced-swimming test in male rats, indicating a conditioned antidepressant-like response. This effect was not observed with bupropion, but was comparable to escitalopram. The response was not due to changes in general activity or conditioned incentive or aversive states, as no group differences appeared in a place-conditioning test. The findings suggest that drug-environment interactions may contribute to ketamine's sustained antidepressant effects in clinical settings.
Acta Psychiatrica Scandinavica
August 1, 2022
Helen Liu, Jaimie Kerzner, Ilya Demchenko et al.
A systematic review of published studies and ongoing clinical trials on nitrous oxide (N2O) for psychiatric disorders identified five published articles, four of which focused on depression. Three randomized controlled trials (RCTs) for treatment-resistant depression and major depressive disorder suggest that N2O has preliminary feasibility with rapid-acting effects on depressive symptoms. Ten ongoing trials are exploring N2O for depression, post-traumatic stress disorder, bipolar disorder, obsessive-compulsive disorder, and suicidal ideation. Typical treatment involves a single session of 50% N2O for 60 minutes, though 25% is also being tested. Larger-scale RCTs with repeated doses and follow-up beyond one month are needed to confirm efficacy and sustainability.