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.
The American journal of psychiatry
January 1, 2025
Roger S McIntyre, Angela T H Kwan, Rodrigo B. Mansur et al.
23 citations
Psychedelics show promise for treating difficult-to-treat psychiatric disorders like major depressive disorder, treatment-resistant depression, and posttraumatic stress disorder, with preliminary evidence also supporting efficacy in tobacco and alcohol use disorders. However, concerns exist about the interpretability and translatability of study results due to insufficiently characterized short- and long-term safety, abuse liability, and the essentiality of the psychedelic experience and psychological support. This overview reviews methodological aspects affecting inferences and interpretation of extant psychedelic studies and provides guidance for future research and development critical to study interpretation and clinical implementation.
Journal of psychopharmacology (Oxford, England)
March 1, 2023
Takesha Cooper, Michael David Seigler, Stephen M Stahl
18 citations
Several new drugs for depression work much faster than traditional antidepressants, sometimes after a single dose. These agents target three different brain systems: NMDA glutamate receptors, GABA A neurosteroid and benzodiazepine sites, and serotonin 2A/2C receptors. Despite their different targets, all trigger rapid neuroplasticity—the brain's ability to reorganize—which correlates with their fast antidepressant effects. Some of these drugs, called neuroplastogens, induce neuroplasticity without altering mental state. Others, called psychoplastogens, cause dissociation or hallucinatory experiences. There is debate whether these mental changes are necessary for the antidepressant effect or are unwanted side effects. These new treatments are expected to transform the management of major depressive disorder.
Pharmaceuticals (Basel, Switzerland)
January 24, 2025
John E Donello, Roger S McIntyre, Donald B Pickel et al.
14 citations
Plastogens are a class of therapeutics that rapidly promote changes in neuroplasticity. Ketamine, a notable example, is an N-methyl-D-aspartate receptor (NMDAR) antagonist with rapid and long-term antidepressant effects but also psychotomimetic and dissociative side effects. Stinels—rapastinel, apimostinel, and zelquistinel—are plastogens with improved safety and tolerability profiles. This review clarifies the mechanism of stinels, defining them as positive allosteric modulators of NMDAR activity with a novel regulatory binding site, contrasting with earlier descriptions of glycine-like partial agonists. The review presents the rationale for targeting NMDARs in treatment-resistant depression and other psychiatric conditions.
General Hospital Psychiatry
July 3, 2025
Kush V. Bhatt, James D Asuncion, Al Alam et al.
4 citations
Classical psychedelics show therapeutic promise for mental health conditions, but their acute subjective effects—while possibly enhancing outcomes—also pose clinical challenges. This review examines the phenomenology, benefits, risks, and implementation issues tied to these subjective experiences. Emerging research on nonhallucinogenic analogues may preserve neuroplastic benefits without inducing intense subjective effects. The authors argue that a debate over the necessity of acute subjective effects may be avoidable, and clinical psychiatry should accommodate both approaches. Future research should explore both the role of subjective experience and alternative compounds to expand treatment options.
CNS Spectrums
January 1, 2025
Emma O’leary, Seetal Dodd, Stephen M Stahl
Psychoactive substances like psychedelics, cannabis, and stimulants are being reconsidered for therapeutic use, but their histories in non-medical contexts raise ethical and regulatory challenges. This review examines the ethical issues shaping research and prescribing, highlighting diverse perspectives from Indigenous, philosophical, psychiatric, and user communities. Key concerns include balancing therapeutic benefits against misuse risks, ensuring rigorous science, and addressing sociopolitical factors that influence public perception and policy. The article calls for evidence-based frameworks that prioritize patient safety and recognize social and commercial determinants of health, extending ethics beyond prescribing. It critically assesses the promise and limitations of repurposing these substances for contemporary psychiatric practice.
International Journal of Molecular Sciences
October 13, 2022
Stephen M Stahl, Sara de Martin, Andrea Mattarei et al.
Esmethadone (REL-1017) and other uncompetitive NMDAR antagonists may rapidly relieve depression by preferentially blocking hyperactive GluN2D subtypes, restoring physiological neural plasticity. In major depressive disorder, upregulated tonic calcium currents through GluN2D subtypes reduce homeostatic availability of synaptic proteins, contributing to depressive behaviors. Low-potency NMDAR antagonists' selectivity for GluN2D may explain their rapid antidepressant effects without dissociative side effects.