Neuropsychiatric Disease and Treatment
January 1, 2020
Daphne Voineskos, Zafiris J Daskalakis, Daniel M. Blumberger
430 citations
Treatment-resistant depression (TRD) is a form of major depressive disorder that does not respond to standard first-line treatments. Although no consensus definition exists, all models require an inadequate response to at least two trials of antidepressant medication. This review compiles meta-analyses, trials, and reviews on TRD challenges and management. It discusses confounds in definitions and staging, difficulties in assessment, and pharmacological augmentation strategies (lithium, triiodothyronine, second-generation antipsychotics, switching antidepressant class). Somatic therapies (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation), psychotherapeutic approaches, and novel treatments (ketamine, psilocybin, anti-inflammatories) are reviewed. The evidence indicates that further large-scale work is needed to understand appropriate treatment pathways and prescribe effective options.
Frontiers in Psychiatry
February 10, 2023
Muhammad Ishrat Husain, Nicole Ledwos, Elise Fellows et al.
47 citations
A narrative review examined the neurobiological mechanisms that may explain the rapid antidepressant effects of serotonergic psychedelics such as psilocybin, LSD, and ayahuasca. The drugs act as agonists or partial agonists at serotonin 5HT2A receptors, and their rapid effects may involve downregulation of these receptors. They also influence brain-derived neurotrophic factor and immune responses. Neuroimaging studies suggest that psychedelics may disrupt the default mode network, a brain system involved in self-referential thinking that is overactive in major depressive disorder. The review concludes that multiple competing theories are being investigated and more research is needed to identify the most robust evidence.
BJPsych Open
July 1, 2023
Muhammad Ishrat Husain, Nicole Ledwos, Elise Fellows et al.
41 citations
A proof-of-concept randomized controlled trial will test whether combining the psychedelic psilocybin with risperidone, a drug that blocks the serotonin 2A receptor, can block psilocybin's psychedelic effects while preserving its antidepressant action in adults with treatment-resistant depression. Sixty participants will be randomly assigned to receive psilocybin plus risperidone, psilocybin alone, or placebo plus risperidone, all with 12 hours of manualized psychotherapy. Feasibility and tolerability will be assessed through recruitment, retention, and adverse events. If successful, this approach could make psilocybin therapy more acceptable and accessible by eliminating the need for a psychedelic experience and continuous monitoring.
Psychedelic Med (New Rochelle)
March 12, 2024
Alexander Wen, Nikhita Singhal, Brett D. M. Jones et al.
36 citations
Blinding is especially difficult in randomized controlled trials of psychedelics because these drugs produce noticeable changes in consciousness. This systematic review of 50 papers from 48 clinical trials published between 1963 and January 2023 found that most studies were double-blinded, used within-subjects designs, and employed inert placebos. The majority did not report on whether blinding procedures were successful, and in those that did, blinding failed. To reduce unblinding and expectancy effects, the authors recommend using active placebos and dose-response or active comparator designs.
Journal of Clinical Psychopharmacology
Nicole Ledwos, Joshua D. Rosenblat, Daniel M. Blumberger et al.
16 citations
A critical appraisal of clinical trials on serotonergic psychedelics for major depressive disorder and end-of-life distress finds that current evidence is low-level due to methodological limitations. Small randomized trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy to an active comparator, with similar preliminary positive effects for single-dose ayahuasca in treatment-resistant depression and lysergic acid diethylamide for end-of-life distress. Adverse events were mild and transient. However, small homogenous samples, expectancy bias, functional unblinding, and lack of standardized psychotherapy limit all studies. Psychedelics should remain experimental interventions used within clinical trials.
Journal of Affective Disorders
July 18, 2025
Mary E. Kittur, Mingyao Liu, Brett D. M. Jones et al.
12 citations
Psilocybin therapy shows promise for rapid and lasting clinical benefits when paired with psychological support, but the field lacks standardized therapeutic guidelines. A systematic review of 22 recent trials across conditions like depression, substance use, and obsessive-compulsive disorders found broad consistency in the structure of therapy sessions—before, during, and after psilocybin administration. However, trials varied widely in therapeutic intensity, diagnostic adaptations, and use of evidence-based psychotherapies. Fewer than half reported standardization measures such as manualized procedures, specific training, or adherence monitoring. These gaps undermine replicability and generalizability, and until support protocols are clearly defined, mechanistic understanding and clinical adoption will remain limited.
Journal of Psychoactive Drugs
August 24, 2023
Stanley Wong, An Yi Yu, Nicholas Fabiano et al.
11 citations
Interest in psychedelic therapies for mental and substance use disorders has grown, but evidence for non-psilocybin serotonergic psychedelics remains limited. A scoping review of mescaline, ibogaine, ayahuasca, DMT, and LSD identified 77 studies: 43 on LSD, 24 on ayahuasca, and 5 each on DMT, ibogaine, and mescaline. Reported benefits included improved mood, anxiety, insight, reduced substance use, better relationships, and fewer vegetative symptoms. Adverse effects were psychological, neurological, physical, and gastrointestinal; serious events like homicide and suicide appeared in LSD studies. The review concludes there is only low-level evidence supporting the safety and efficacy of these substances for mental and substance use disorders.
Therapeutic Advances in Psychopharmacology
September 1, 2025
Stanley Wong, Gray Meckling, Nicholas Fabiano et al.
6 citations
A systematic review and meta-analysis of nine randomized controlled trials involving 593 adults with psychiatric diagnoses found that psilocybin therapy led to a small but significant decrease in suicidal ideation compared to control conditions. No studies reported suicide attempts or deaths. The analysis showed low heterogeneity and no publication bias, though two studies had a high risk of bias. Current evidence is limited by small sample sizes, insufficient follow-up data, and inadequate assessment of blinding.
EClinicalMedicine
December 1, 2025
Tyler S Kaster, Yi Dai, Fidel Vila-Rodriguez et al.
5 citations
Both repetitive transcranial magnetic stimulation (rTMS) and intranasal esketamine are more effective than starting a new antidepressant medication for treatment-resistant depression. In a secondary analysis of individual patient data from two clinical trials involving 282 matched participants, rTMS reduced depression severity scores by 5.35 points and esketamine by 2.89 points more than medication alone. The difference between rTMS and esketamine was not statistically significant, but the results suggest rTMS may be at least as effective as esketamine. The analysis highlights the need for direct head-to-head trials comparing these two interventions.
General Hospital Psychiatry
December 9, 2025
Gerasimos Konstantinou, Joshua D. Rosenblat, Sarah Hales et al.
4 citations
Psilocybin-assisted therapy shows promise for treating late-life mental health conditions such as depression, loneliness, and existential distress, where conventional medications often have limited effectiveness and poor tolerability in older adults. The review describes neurobiological mechanisms including serotonergic modulation, enhanced neuroplasticity, and disruption of maladaptive default mode network activity. Clinical trials in general adult populations report sustained improvements in depressive symptoms, existential anxiety, and social connectedness following psilocybin administration. However, older adults are underrepresented in psychedelic research, creating gaps in knowledge about dosing, safety, and long-term outcomes. Age-specific protocols are needed to address pharmacokinetic complexities, cardiovascular risks, drug interactions, and ethical challenges around informed consent in cognitively impaired patients.
Ther Adv Psychopharmacol
October 16, 2025
Stanley Wong, Brett D. M. Jones, Mathura T. Thiyagarajah et al.
3 citations
A review of nine small clinical trials found that ayahuasca and psilocybin, when used to treat major depressive disorder and treatment-resistant depression, are associated with changes in several biological markers. These include increased serum brain-derived neurotrophic factor, decreased serum C-reactive protein, altered amygdala activation, and changes in functional connectivity between brain regions such as the ventromedial prefrontal cortex, anterior cingulate cortex, and posterior cingulate cortex. These associations suggest potential mechanisms of clinical response, but larger, longer-term studies are needed to confirm these findings.
BJPsych Open
December 15, 2025
Nicole Ledwos, Jenna Baer, Muhammad Ishrat Husain et al.
2 citations
Up to 60% of people with obsessive–compulsive disorder (OCD) do not respond to standard treatments such as selective serotonin reuptake inhibitors, antipsychotic augmentation, or cognitive–behavioural therapy. This open-label pilot trial will test whether a single 25 mg dose of psilocybin combined with psychological support is feasible, tolerable, and safe for ten adults with treatment-resistant OCD. Clinical improvement will be measured with the Yale–Brown Obsessive–Compulsive Scale. Exploratory brain imaging, electroencephalogram, and transcranial magnetic stimulation-electroencephalogram measures will examine changes in dynamic connectivity and brain dynamics before, during, and up to one week after dosing. Results will inform the design of larger randomized trials and help clarify neurobiological mechanisms of psilocybin-assisted therapy.
The Journal of Clinical Psychiatry
January 8, 2025
Ali Abdolizadeh, Brett D. M. Jones, Maryam Hosseini Kupaei et al.
2 citations
A systematic review of treatments for suicidality among psychiatric inpatients aged 18–65 found that intravenous ketamine produced the most consistent rapid reduction in suicidality among 14 pharmacologic trials. Among 35 nonpharmacologic trials—including chronotherapy, neurostimulation, and psychotherapies—results were mixed, with some interventions showing potential benefit, especially for mood, personality, and trauma-related disorders. Many studies had methodological limitations such as nonrandomized designs and lack of control groups. The review calls for larger, well-designed trials to confirm effectiveness.
PLoS One
January 1, 2025
Johny Bozdarov, Brett D. M. Jones, Madeha Umer et al.
2 citations
A 10-week trial of Mindfulness-Based Boxing Therapy (MBBT) for adults with major depressive disorder or generalized anxiety disorder showed high retention (89%), attendance (84%), and satisfaction (98%). Among eight outpatients in Toronto, depression scores dropped 54%, anxiety 51%, and distress 36%, while mindfulness increased 79%. Participants reported benefits including cathartic release, improved self-esteem, and a sense of community. The authors conclude that MBBT is feasible and acceptable as an exercise-based intervention, but caution that larger randomized trials are needed to confirm clinical benefits.
Journal of Affective Disorders
January 23, 2026
Reinhard Janssen-Aguilar, Jithin Joseph, Huda Al-Shamali et al.
In a retrospective chart review of 209 adults with treatment-resistant depression treated with intravenous ketamine, depressive and anxiety symptoms improved significantly over four or six infusions, but the improvements were modest and highly variable across individuals. Anxiety symptoms improved more slowly and less robustly than depressive symptoms. End-of-treatment response and remission rates were numerically higher after six infusions than after four, but the difference was not statistically significant. Four distinct patterns of symptom change emerged for both depression and anxiety, highlighting the heterogeneity of treatment response. Durability after six infusions could not be assessed because follow-up data were available only for the four-infusion group.
Biological Psychiatry
April 9, 2025
Mary E. Kittur, L. Martínez, Brett D. M. Jones et al.
No Summary
JMIR Research Protocols
January 27, 2023
Yuliya Knyahnytska, Reza Zomorrodi, Tyler S Kaster et al.
Suicide is a leading cause of death, and people with bipolar depression (BD) are at high risk. Ketamine has shown rapid antisuicidal and antidepressant effects, but its biological mechanisms are poorly understood. This open-label clinical trial tests the safety and feasibility of repeated ketamine infusions for acute suicidality in 30 adults with BD, aged 24-65, at a Toronto hospital. Ketamine is given intravenously over 40 minutes twice weekly for 4 weeks (8 sessions). The study also examines neurophysiological markers, such as cortical excitation and inhibition, and effects on suicidality, depressive symptoms, and quality of life. Recruitment is ongoing; 5 participants have completed the trial.
Frontiers in Aging Neuroscience
January 1, 2022
Magnus Bein, Myriam Lesage, Elena Dikaios et al.
Late-life depression affects up to 18% of older adults and is linked to elevated dementia risk. Mindfulness-based cognitive therapy (MBCT) may help treat depressive symptoms and cognitive deficits in this population, but a definitive randomized controlled trial has not yet been conducted. This protocol describes a multi-site blinded trial comparing MBCT to an active control, a Health Enhancement Program, in 213 patients with late-life depression. Changes in depression severity, processing speed, executive functioning, and brain biomarkers will be assessed at baseline, post-intervention (8 weeks), and 26 weeks after baseline. The study will evaluate MBCT's potential to improve depression, cognitive impairments, and neurobiological markers.