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.
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.
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.
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.
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.
Biological Psychiatry
April 9, 2025
Mary E. Kittur, L. Martínez, Brett D. M. Jones et al.
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