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.
Expert Review of Neurotherapeutics
September 21, 2020
Hartej Gill, Barjot Gill, David Chen‐li et al.
62 citations
Psychedelics like psilocybin and MDMA show promise as a new type of therapy for mental health disorders. Evidence suggests they may work with just one dose, produce rapid effects, and be effective for treatment-resistant conditions, possibly serving as a standalone treatment. More clinical trials are needed to test their safety, tolerability, and effectiveness in real-world patient populations.
CNS drugs
November 1, 2024
Roger S. McIntyre, Rakesh Jain
58 citations
Glutamate signaling has emerged as a promising target for treating major depressive disorder (MDD), a chronic condition where standard monoamine antidepressants often have delayed effects and low remission rates. This narrative review describes how glutamate dysregulation is linked to depression, based on preclinical evidence and the rapid improvement seen with ketamine in a proof-of-concept trial. While many NMDA-targeted therapies have been investigated in phase 2 or 3 trials, most were discontinued. However, two glutamate-targeted antidepressants are now FDA-approved: nasal esketamine (Spravato) for treatment-resistant depression and MDD with suicidal ideation, and oral dextromethorphan-bupropion (Auvelity) for MDD in adults. These approvals highlight glutamate's role and offer new treatment options.
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).
American Journal of Psychiatry
March 22, 2023
Joshua D. Rosenblat, Marisa Leon-Carlyle, Shaun Ali et al.
53 citations
Psilocybin, a hallucinogen derived from certain mushrooms, shows promise in treating mental health disorders. In a sample of 400 participants, 70% reported significant reductions in depression symptoms after psilocybin therapy. The treatment demonstrated an effect size of 1.5, indicating a substantial impact on psychological well-being. This innovative approach could reshape psychiatry and enhance complementary medicine practices, potentially influencing fields like business and computer science through improved employee mental health. The findings highlight the potential for psychedelics in therapeutic settings.
Current Psychiatry Reports
April 1, 2024
John L. Havlik, Syed Wahid, Kayla M. Teopiz et al.
30 citations
Treatment-resistant depression (TRD) has historically had very limited options, but recent advances have expanded knowledge of effective interventions. Psychotherapy can help as an add-on but not alone. Adjunctive non-antidepressant drugs like buprenorphine and antipsychotics show little recent support; side effects and high discontinuation rates may outweigh benefits. Strong recent evidence supports interventional approaches: electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation. Research on TRD should use internationally defined inclusion criteria for generalizable results.
Expert Opinion on Drug Safety
August 15, 2023
Roger S. McIntyre
26 citations
The text discusses concerns about psilocybin, lysergic acid diethylamide (LSD), and ecstasy in relation to valvular heart disease, focusing on 5HT2B receptor agonism and FDA guidance. It highlights the potential risk of these substances to cause heart valve damage through activation of the 5HT2B receptor, a mechanism linked to certain drugs. The abstract underscores regulatory considerations from the FDA regarding this safety issue, suggesting that agonism at this receptor may be a key factor in assessing the cardiac risks of psychedelic compounds.
Expert Opinion on Drug Safety
August 28, 2023
Roger S. McIntyre
16 citations
The article reviews the pharmacology and therapeutic potential of psychedelics such as psilocybin and lysergic acid diethylamide, focusing on their mechanisms of action and regulatory status. It discusses how these compounds influence neurotransmitter receptors and their possible applications in treating mood disorders, including depression. The authors highlight the growing interest in psychedelic-assisted therapy and note that the FDA has granted breakthrough therapy designation for some psychedelic treatments, suggesting a shift in the medical and regulatory landscape toward these substances as antidepressants.
Current Treatment Options in Psychiatry
April 26, 2024
Noah Chisamore, Erica Kaczmarek, Gia Han Le et al.
8 citations
No Summary
Psychiatry Research
August 15, 2025
Sipan Haikazian, Roger S. McIntyre, Shakila Meshkat et al.
7 citations
Ketamine infusions, given intravenously at sub-anesthetic doses, reduced depression and suicidality scores in patients with treatment-resistant major depressive disorder and treatment-resistant bipolar depression. Improvements from an acute course persisted during maintenance infusions over weeks and months, with no cases of suicidal behavior or addiction. One bipolar patient (4%) experienced an affective switch that stabilized. These results provide preliminary support for the long-term use of maintenance ketamine infusions.
Frontiers in Psychiatry
June 30, 2023
Colleen E. Charlton, Povilas Karvelis, Roger S. McIntyre et al.
7 citations
Suicide claims over 700,000 lives each year. Ketamine shows promise for treating suicidal thoughts and behaviors, but how it works is not fully understood. Computational psychiatry offers a framework to explore the dynamic interactions behind suicidality and ketamine's therapeutic action. This paper reviews current computational theories of suicidality and ketamine's mechanism, discussing modeling approaches that explain ketamine's anti-suicidal effect. It examines ketamine's potential through mismatch negativity and predictive coding, considering neurocircuits for learning and decision-making, and altered connectivity and receptor densities. Theory-driven models can integrate existing knowledge and extract parameters to identify patient subgroups and personalize treatment. Future studies should optimize task design and evaluate set, setting, and psychedelic-assisted therapy.
Frontiers in Psychiatry
June 30, 2023
Colleen E. Charlton, Povilas Karvelis, Roger S. McIntyre et al.
7 citations
Suicide claims over 700,000 lives each year. Ketamine shows promise for treating suicidal thoughts and behaviors, but how it works is not fully understood. Computational psychiatry offers a framework to explore the dynamic interactions behind suicidality and ketamine's therapeutic action. This paper reviews current computational theories of suicidality and ketamine's mechanism, discussing modeling approaches that explain ketamine's anti-suicidal effect. It examines ketamine's potential through mismatch negativity and predictive coding, considering neurocircuits for learning and decision-making, and altered connectivity and receptor densities. Theory-driven models can integrate existing knowledge and extract parameters to identify patient subgroups and personalize treatment. Future studies should optimize task design and evaluate set, setting, and psychedelic-assisted therapy.
JAMA Psychiatry
April 15, 2026
Diana Orsini, Sabrina Wong, Sara Di Luch et al.
4 citations
In randomized clinical trials of psychedelic drugs for psychiatric disorders, the drugs' strong subjective effects often reveal which treatment participants or raters think they received, a phenomenon called functional unblinding. A systematic review of 112 trials found that only 29.5% assessed whether blinding was maintained, yet 57.1% cited blinding as a limitation. Blinding failure exceeded 90% in psilocybin, LSD, and ayahuasca studies and 85% in MDMA trials with inert placebos. Ketamine trials rarely assessed blinding but fared better when midazolam was used as an active comparator. No control strategy consistently preserved ideal blinding, raising concerns about the validity of efficacy estimates.
Acta Psychiatrica Scandinavica
December 1, 2025
Liyang Yin, A. Imamog ̄lu, Gia Han Le et al.
3 citations
A single intravenous dose of ketamine may reduce symptoms of posttraumatic stress disorder (PTSD). The authors recommend future research to test whether combining ketamine with psychotherapy provides additional benefit and to investigate the biological mechanisms that explain symptom relief.
Journal of Psychiatric Research
October 30, 2025
Isabella S Ji, M Cheng, Kayla M. Teopiz et al.
2 citations
Esketamine reduces depressive symptoms and improves functioning, especially in workplace settings. Future research should treat functional outcomes as key secondary or co-primary endpoints to better capture recovery in treatment-resistant and major depressive disorder.
Journal of Affective Disorders
September 16, 2025
Sami George Sabbah, Sophie Li, Sabrina Wong et al.
2 citations
Psilocybin is linked to dynamic and temporally distinct neuroplastic changes that are associated with clinical improvement in depression. However, many studies reused overlapping datasets, had high exploratory flexibility, and risk of bias, which limits the generalizability of the results. Future research should use independent datasets, pre-registered imaging endpoints, and longitudinal designs to better understand the mechanisms of psychedelic therapy for depression.
Expert opinion on therapeutic targets
January 28, 2026
Gia Han Le, Roger S. McIntyre
1 citation
Up to half of adults with major depressive disorder who do not respond to two or more standard antidepressants may have treatment-resistant depression (TRD). Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan are the first glutamatergic treatments to work rapidly and robustly for TRD, but their exact mechanisms are unclear. This review integrates evidence that elevated tonic NMDA receptor currents, mainly through NR2C/D subunits, underlie TRD. Ketamine, esketamine, and dextromethorphan selectively dampen these currents to produce rapid and sustained antidepressant effects. Ketamine and esketamine's affinity for NR2A/B subunits likely drives dissociative effects not seen with dextromethorphan. Future drug development should focus on subunit-biased ligands.
Clinical Pharmacology & Therapeutics
May 28, 2026
Gia Han Le, Sabrina Wong, Danica E. Johnson et al.
The serotonin 5-HT2B receptor sits at a crossroads between potential antidepressant effects in the brain and serious heart valve risks when activated peripherally. This narrative review of preclinical and clinical literature finds that peripheral activation of 5-HT2B receptors causes valvular heart disease through cell proliferation and scarring, as seen with older drugs like fenfluramine and some dopamine agonists. In the brain, the receptor's effects are mixed: astrocytic activation may support metabolism and plasticity, while neuronal blockade can normalize dopamine and glutamate activity. Several approved antidepressant adjuncts (aripiprazole, brexpiprazole, cariprazine) antagonize this receptor without observed heart valve problems. The authors propose developing centrally selective, periphery-sparing 5-HT2B antagonists for treatment-resistant depression, with early cardiac monitoring to ensure safety.
CNS Spectrums
March 10, 2026
Halima Faisal, Gia Han Le, Angela T.h. Kwan et al.
Ketamine rapidly alters brain reward circuitry in people with major depressive disorder, particularly in fronto-striatal and limbic networks. In a synthesis of 13 neuroimaging studies involving 623 participants (482 with depression, 141 controls), intravenous ketamine (typically 0.5 mg/kg over 40 minutes) changed resting-state connectivity in ventral striatal-prefrontal and default mode, salience, and executive networks within 2 to 48 hours, with some effects lasting up to 10 days. Task-based imaging showed altered ventral striatal responses during reward anticipation and feedback, and changes in medial prefrontal activity during emotion processing. PET scans indicated increased prefrontal-cingulate metabolism and region-specific serotonin receptor binding changes. Few studies directly measured anhedonia, suggesting the findings reflect broader antidepressant mechanisms.
Psychiatry Research
February 19, 2026
Trisha Menon, Andy Lu, Akhilan Arulmozhi et al.
Ketamine, esketamine, repetitive transcranial magnetic stimulation (rTMS), and electroconvulsive therapy (ECT) are associated with reductions in suicidal ideation in people with major depressive disorder. The strongest evidence from randomized controlled trials supports rapid, short-term effects, particularly for ketamine and esketamine. Further research is needed to characterize the durability of these antisuicidal effects and to determine whether reductions in suicidal ideation translate into reduced severity of suicidal behavior.
Journal of Affective Disorders
February 12, 2026
Erica Kaczmarek, Nelson Rodriguez, Noah Chisamore et al.
Anhedonia, a core symptom of depression that often resists standard treatments, may be reduced by psilocybin-assisted psychotherapy (PAP). In a secondary analysis of a randomized, waitlist-controlled trial, 30 adults with treatment-resistant depression (major depressive disorder or bipolar II disorder) received one 25 mg dose of oral psilocybin plus psychotherapy. Anhedonia severity, measured by the Snaith-Hamilton Pleasure Scale, decreased significantly at the 2-week primary endpoint, with clinically meaningful improvements persisting at 3 and 6 months. The analysis adjusted for sex and age. These preliminary results suggest PAP could be a promising intervention for anhedonia in treatment-resistant depression, though larger placebo-controlled trials are needed to confirm the findings and clarify underlying mechanisms.
Neuroendocrinology
October 30, 2025
Sabrina Wong, Gia Han Le, Jens Uhlig et al.
Blocking NMDA receptors improves the function and survival of pancreatic alpha and beta cells, which may help explain why certain NMDA antagonists like ketamine, esketamine, and dextromethorphan have antidepressant effects and could also address metabolic problems often seen in depression. The findings suggest a shared mechanism linking mood regulation and pancreatic hormone control. More research is needed on how low doses of these drugs affect pancreatic function and delta cells.