Annals of Clinical Psychiatry
November 1, 2022
David Chen‐li, Leanna M.W. Lui, Joshua D. Rosenblat et al.
22 citations
Postpartum depression (PPD) is a severe mood disorder affecting mothers and children, and there is a need for rapid-acting treatments. This narrative review examined the available literature on ketamine for PPD, searching databases for preclinical studies, clinical trials, and reviews. Four clinical trials were identified. The review suggests that ketamine may be a favorable option due to its antidepressant and analgesic effects, short infusion time, and rapid clearance from the mother's bloodstream. However, evidence is insufficient to support its routine use, highlighting the need for more clinical research.
Journal of Psychopharmacology
October 11, 2020
Roger S. McIntyre, Nelson B. Rodrigues, Orly Lipsitz et al.
19 citations
Adults with treatment-resistant depression or bipolar disorder who also have high anxiety show greater improvement in depressive and anxiety symptoms after intravenous ketamine treatment than those with low anxiety. Among 209 patients receiving four ketamine infusions, the 94 with anxious-distress had a significantly larger drop in depression scores and a greater reduction in anxiety symptoms after three and four infusions. Both groups experienced a significant decrease in suicidal thoughts. The findings suggest that ketamine may be particularly effective for people with treatment-resistant mood disorders and prominent anxiety.
Expert Opinion on Drug Safety
May 3, 2022
Danica Nogo, Hana Nazal, Yuetong Song et al.
17 citations
Ketamine is an established treatment for treatment-resistant depression, but long-term adverse effects from repeated doses are not well characterized. Animal models and studies of people with substance use disorder who use high daily doses of ketamine show clear neurotoxic effects, including potential brain lesions. No studies have specifically evaluated the effects of the lower, infrequent sub-anesthetic doses typically prescribed for depression. It is difficult to separate ketamine's direct effects from other factors like comorbidities and dose differences. It remains unknown whether repeated sub-anesthetic dosing in adults with depression causes brain lesions or other neuropathologies. Practitioners should remain vigilant, recognizing that depression itself is linked to neurodegenerative processes.
CNS Spectrums
December 10, 2020
Nelson B. Rodrigues, Ashley Siegel, Orly Lipsitz et al.
17 citations
Intravenous (IV) ketamine effectively reduces symptoms of depression, suicidal ideation, anxiety, and anhedonia in adults with treatment-resistant depression, regardless of whether they have previously undergone neurostimulation. In a retrospective analysis of 238 patients, those without prior neurostimulation experienced an average 6.4-point reduction on a depression severity scale, while those with a history of neurostimulation showed a 4.3-point reduction. No significant differences emerged between the groups, indicating that IV ketamine benefits even highly intractable patients.
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.
Psychiatry Research
April 25, 2022
Hartej Gill, Parnian Puramat, Pankti Patel et al.
16 citations
Psilocybin shows promise as a treatment for major depressive disorder (MDD), potentially offering an alternative to conventional therapies. A systematic review of neuroimaging studies found that psilocybin administration decreased amygdala activity and reduced depressive symptoms in two studies involving MDD participants. In healthy populations, changes in functional connectivity and activation of prefrontal limbic structures, particularly the ventral medial prefrontal cortex and amygdala, were observed. However, high methodological heterogeneity across the thirteen included studies—ten in healthy populations and three in MDD participants—limits conclusions. Longitudinal research is needed to clarify psilocybin's long-term effects and sustained therapeutic potential for MDD.
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.
European Psychiatry
January 1, 2026
Andy Lu, Heidi Xu, Gia Han Le et al.
4 citations
Ketamine's antidepressant effects in treatment-resistant depression may be partially mediated by the opioid system, but the evidence is mixed. Because opioid receptor antagonists inconsistently reduce these effects, the opioid system likely acts as a context-dependent modulator rather than a primary mediator, especially at standard antidepressant doses.
Acta Psychiatrica Scandinavica
December 1, 2025
Liyang Yin, A. Imamog ̄lu, Gia Han Le et al.
3 citations
Intravenous ketamine may be efficacious in treating posttraumatic stress disorder (PTSD). A systematic review of seven randomized controlled trials involving 323 participants found that ketamine meaningfully improved PTSD symptoms in two trials, as measured by the Clinician-Administered PTSD Scale for DSM-5 and the Impact of Event Scale-Revised. Multi-infusion schedules achieved greater clinical outcomes than single-dose schedules. Preliminary evidence suggests repeated lower doses (0.2 mg/kg) were more efficacious in sustaining treatment effects than standard doses (0.5 mg/kg). Symptom improvement was associated with top-down inhibition of the amygdala originating in the ventromedial prefrontal cortex.
Journal of Psychiatric Research
October 30, 2025
Isabella S Ji, M Cheng, Kayla M. Teopiz et al.
2 citations
Ketamine and esketamine, NMDA receptor antagonists, are effective for depressive symptoms in major depressive disorder (MDD) and treatment-resistant depression (TRD), but functional impairments in work, social, and family life often persist even when mood improves. This systematic review of randomized controlled trials found no controlled studies on ketamine's effect on functional outcomes, highlighting a major gap. For esketamine, nine studies showed significant improvements: Sheehan Disability Scale scores dropped by an average of 13.6 points versus 9.4 for placebo, and workplace productivity loss, presenteeism, and activity impairment all significantly decreased. Esketamine thus improves both depressive symptoms and daily functioning, especially at work.
Can J Psychiatry
October 28, 2025
Jennifer Swainson, Elisa Brietzke, Atul Khullar et al.
2 citations
Interest in psychedelic agents for psychiatric conditions like PTSD, depression, and anxiety has grown, especially with the spread of ketamine clinics. However, the evidence is confusing because there are no standard definitions for what psychotherapy means in these treatments. Studies often fail to distinguish between using a manualized psychotherapy, providing general psychological support, or offering therapy specifically to integrate the drug experience. It is also unclear whether the drug works alone or if the psychedelic experience is needed for therapeutic effect.
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.
Research Square
May 27, 2026
Tychique T. Wasolua, Tanner J. Bommersbach, Roger S. McIntyre et al.
Ketamine and its S-enantiomer esketamine show both neurotoxic and neuroprotective effects depending on dose, duration, and experimental model. In preclinical studies, high or repeated doses can cause neuronal damage, while lower doses may protect against injury. Human studies are limited but suggest similar potential for harm and benefit. The systematic review highlights the need for careful dosing and monitoring in clinical use, especially for depression treatment.
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.
CNS Spectrums
April 1, 2023
Amanda Jones, Roger S. McIntyre, Mark Jacobsen et al.
AXS-05 (dextromethorphan-bupropion) rapidly and significantly reduced anhedonic symptoms in adults with major depressive disorder. In a 6-week randomized, double-blind, placebo-controlled trial with 327 participants, those receiving AXS-05 showed a mean reduction of 4.44 points on the MADRS anhedonia subscale at Week 1 versus 2.69 points for placebo, and a reduction of 9.70 points at Week 6 versus 7.22 for placebo. Response rates were significantly greater for AXS-05 from Week 1 onward. Common adverse events included dizziness, nausea, and headache.