CNS Drugs
December 1, 2023
Niloufar Pouyan, Farnaz Younesi Sisi, Alireza Kargar et al.
12 citations
A review of 28 clinical studies with 477 participants examined how lysergic acid diethylamide (LSD) affects reward processing, using the National Institute of Mental Health's Research Domain Criteria (RDoC) framework. LSD produced dose-dependent mood improvement in 20 short-term and 3 long-term studies. Its subjective and neural effects were linked to the 5-HT2A receptor. Animal studies suggested LSD could mildly reinforce conditioned place preference without aversion and reduce responsiveness to other rewards. Findings on reward learning were inconsistent but hinted at potential enhancements in associative learning. Reward valuation measures indicated possible reductions in effort expenditure for other reinforcers. The review identified areas for future research but noted limitations including diverse study designs not initially RDoC-oriented and potential bias from open-label human studies.
Journal of Affective Disorders
April 1, 2025
Angela T H Kwan, Moiz Lakhani, Kayla M Teopiz et al.
11 citations
An analysis of the FDA Adverse Event Reporting System found that reports of hepatobiliary disorders differ between ketamine and esketamine. Compared to acetaminophen, ketamine was associated with disproportionately lower reporting of hepatitis, liver injury, drug-induced liver injury, hepatic failure, and acute hepatic failure, but disproportionately higher reporting of hepatic function abnormalities and hepatic cytolysis. For esketamine, there was no disproportionate reporting of most hepatobiliary toxicities relative to acetaminophen, except for disproportionately higher reporting of hepatic failure. The authors recommend periodic monitoring of liver function tests and clinical surveillance for signs of hepatobiliary disease in individuals receiving chronic ketamine or esketamine, though causality has not been established.
Psychiatry Research
January 1, 2022
Joshua D. Di Vincenzo, Orly Lipsitz, Nelson B Rodrigues et al.
11 citations
A small proportion of people with treatment-resistant depression experience clinically significant worsening of symptoms during a course of intravenous ketamine, but the rate is very low—between 1.83% and 5.49% across infusion time points—and similar to that seen with conventional antidepressants. In a retrospective analysis of 164 adults (142 with unipolar depression and 22 with bipolar depression) who received four ketamine infusions over two weeks, no individuals with bipolar depression reported worsening. The findings suggest that symptomatic worsening with ketamine is uncommon, though the study's uncontrolled, single-center design limits certainty.
CNS Spectrums
October 31, 2024
Sabrina Wong, Gia Han Le, Angela T H Kwan et al.
10 citations
A systematic review and meta-analysis of seven randomized controlled trials found that a single dose of esketamine given around childbirth significantly reduced the incidence of postpartum depression (PPD). Within one week of delivery, the odds of a PPD diagnosis were 70% lower for those who received esketamine compared to a control; between four and six weeks postpartum, the odds were 67% lower. The results suggest that esketamine may have preventive antidepressant effects during the postpartum period, with implications for both the mechanisms and clinical treatment of PPD.
CNS Spectrums
January 17, 2025
Roger S McIntyre, Gregory W Mattingly, Yordan Godinov et al.
9 citations
In adults with treatment-resistant depression, esketamine nasal spray combined with an oral antidepressant leads to higher remission rates than quetiapine extended-release combined with an oral antidepressant. Starting at week 8, 28.3% of esketamine-treated patients achieved remission compared to 18.6% on quetiapine, and by week 32, 55.7% versus 36.3%. Depressive symptoms improved more with esketamine from day 8 onward. Fewer patients stopped treatment due to side effects with esketamine (4.5%) than with quetiapine (10.1%). These results come from a secondary analysis of a randomized trial.
Psychedelic Medicine
November 18, 2024
Shakila Meshkat, Erica Kaczmarek, Zoe Doyle et al.
8 citations
In a small subgroup analysis of four adults with treatment-resistant depression associated with bipolar II disorder, two 25 mg doses of psilocybin combined with psychotherapy were associated with reductions in depressive symptoms. The average depression score on the Montgomery–Åsberg Depression Rating Scale dropped from 32.5 at baseline to 20.3 two weeks after the first dose, and to 19 two weeks after the second dose; at six months the average score was 21.3. Mania ratings remained stable, and no mania, hypomania, or psychosis occurred. The authors suggest psilocybin may improve depressive symptoms in bipolar II disorder but call for larger studies to confirm the findings.
Journal of Affective Disorders
September 1, 2024
Angela T H Kwan, Joshua D. Rosenblat, Rodrigo B. Mansur et al.
8 citations
Ketamine and esketamine are effective for treatment-resistant depression and may help people with substance use disorder or alcohol use disorder when paired with behavioral therapy. However, concerns exist about their own abuse potential. Analyzing reports from the FDA Adverse Event Reporting System, ketamine showed significantly increased reporting odds for alcohol abuse, substance dependence, substance use disorder, substance abuse, drug dependence, drug use disorder, and drug abuse. In contrast, esketamine showed significantly reduced reporting odds for substance abuse, drug dependence, and drug abuse. Mixed results across different substance-related outcomes suggest possible beneficial effects, but causal links cannot be established due to data limitations.
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.
Psychiatry Research
May 8, 2025
Noah Chisamore, Lee Phan, Roger S McIntyre et al.
7 citations
A review of pre-clinical and clinical studies on non-hallucinatory psychedelics (NHPs) for mood and anxiety disorders found five animal studies showing antidepressant-like effects, assessed via forced swim test and open field test, without the head-twitch response that indicates hallucination. One case report described a patient who inadvertently combined trazodone and psilocybin and experienced potent antidepressant effects without psychedelic effects. These preliminary findings suggest that antidepressant benefits of psychedelics may be separable from hallucinatory effects, providing impetus for rigorous clinical trials in humans.
Expert Opinion on Drug Safety
June 21, 2024
Roger S McIntyre, Rodrigo B. Mansur, Joshua D. Rosenblat et al.
7 citations
Ketamine and esketamine reduce measures of suicidality in people with treatment-resistant depression, but whether they can worsen preexisting suicidality is unclear. Analysis of the FDA Adverse Event Reporting System from 1970 and 2019 through September 2023 found higher reporting odds ratios for suicidal ideation (7.58) and depression suicidal (14.19) with esketamine compared to lithium. In contrast, lower reporting odds ratios for suicide attempt were observed with both ketamine (0.15) and esketamine (0.57). The mixed results across different aspects of suicidality prevent any determination of causal effects, and the lower odds for suicide attempt cannot be interpreted as a direct therapeutic effect.
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.
Psychiatry Research
January 1, 2025
David C J Chen-Li, Rodrigo B. Mansur, Joshua D. Di Vincenzo et al.
6 citations
In a real-world clinic setting, a single ketamine infusion significantly reduced suicidal ideation among 96 adults with treatment-resistant depression, as measured by the Columbia Suicide Severity Rating Scale. The reduction shifted the group average from active toward passive suicidal thoughts. A mediation analysis showed that ketamine's antisuicidal effects are partially independent of its antidepressant effects, suggesting a direct benefit on suicidality beyond mood improvement. The findings support ketamine's effectiveness for suicidal ideation outside controlled clinical trials.
Translational Psychiatry
August 6, 2024
Chengyu Wang, Xiaofeng Lan, Weijian Liu et al.
6 citations
Non-improvement after four ketamine infusions, or three consecutive non-improvements after three infusions, reliably predicts overall non-response to a six-dose course of intravenous ketamine for depression. Among 135 individuals with major depressive or bipolar disorder in a current depressive episode, sensitivities for predicting non-response exceeded 90% using these early non-improvement criteria. Those who did not improve by these points showed no significant reduction in depressive symptoms from subsequent infusions. The findings suggest that early non-improvement can guide clinicians to discontinue treatment, avoiding ineffective continued dosing.
Expert Opinion on Therapeutic Targets
June 1, 2025
Naomi Xiao, Liyang Yin, Kayla M Teopiz et al.
5 citations
Sigma-1 receptors (S1Rs) may be a target and mediator of antidepressant activity. They regulate neurotransmitter release (including monoamines and glutamate), influence intracellular calcium levels, and affect immune inflammatory responses. In August 2022, the FDA approved dextromethorphan-bupropion, the first antidepressant whose hypothesized mechanism includes activity at S1Rs. The review synthesizes preclinical and clinical data on S1R physiology, pathophysiology, and function. Modulating sigma-1 systems is relevant to current FDA-approved treatments for major depressive disorder and may inform future therapeutic development. Whether sigma-1 modulation uniquely targets difficult-to-treat symptoms like anhedonia remains unknown.
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.
Journal of Affective Disorders
April 15, 2026
Gia Han Le, Sabrina Wong, Danica E. Johnson et al.
4 citations
Ketamine and esketamine rapidly reduce depression in people with treatment-resistant depression and bipolar depression, but the synaptic mechanisms behind dosing and durability are unclear. This review of 61 clinical and 17 preclinical studies found that a single 0.5 mg/kg intravenous infusion produces antidepressant effects peaking at 24 hours and fading over 2-3 days. Early neurophysiological changes appear within 3-8 hours, consolidate by 24 hours, and are rarely detected beyond 3 days. Twice-weekly and thrice-weekly dosing produce comparable four-week outcomes, and weekly maintenance reduces relapse risk. Ketamine may open a plasticity window lasting about 2-3 days, and aligning dosing intervals with this window could optimize durability while minimizing drug exposure.
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.
CNS Spectrums
November 20, 2024
Angela T H Kwan, Moiz Lakhani, Gurkaran Singh et al.
4 citations
Ketamine shows potential for treating PTSD, OCD, and alcohol use disorders beyond its established use for depression. A systematic review and meta-analysis of 44 studies found that ketamine significantly reduced PTSD symptoms measured by the PCL-5 (average decrease of 28 points) and CAPS-5 (average decrease of 14 points), and OCD symptoms measured by the Y-BOCS (average decrease of 8 points). For alcohol use disorders, ketamine treatment was associated with reduced urge to drink, higher abstinence rates, and longer time to relapse. However, the small number of randomized controlled trials highlights the need for more research on ketamine's short- and long-term benefits and risks for these conditions.
Focus (American Psychiatric Publishing)
October 1, 2023
Farhan Fancy, Nelson B Rodrigues, Joshua D. Di Vincenzo et al.
4 citations
Repeated intravenous ketamine infusions significantly reduced depression, suicidal thoughts, and anxiety in patients with treatment-resistant bipolar I/II depression, and improved functioning. In an observational study of 66 patients receiving four infusions over two weeks, depressive symptoms dropped by an average of 6.08 points on the QIDS-SR16 scale. Response rate was 35% and remission rate 20%. Hypomania occurred in only 4.5% of patients, with no mania or psychosis. The findings suggest real-world effectiveness and tolerability of IV ketamine for bipolar depression.
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.
CNS Spectrums
August 12, 2025
Gia Han Le, Sabrina Wong, Stavroula Bargiota et al.
3 citations
G protein-coupled receptors (GPCRs) are involved in many bodily processes. Traditional drug classification divides ligands into agonists or antagonists. Biased agonism is a newer concept where a drug selectively activates one intracellular signaling pathway over another, such as G protein versus β-arrestin pathways. This narrative review of literature up to April 2025 describes distinct mechanisms of antagonism and agonism beyond conventional models. Biased agonism has shown potential for greater efficacy, as with the incretin receptor agonist tirzepatide, and improved safety, as with certain serotonergic psychedelics and opioids. Preclinical evidence suggests biased agonism could improve psychiatric and neurological treatments by differentially activating pathways, pending clinical validation.
Journal of Psychopharmacology
July 1, 2025
Ryan M Brudner, Erica Kaczmarek, Marc G Blainey et al.
3 citations
In a small sample of 31 individuals with treatment-resistant major depressive disorder or bipolar II disorder, those who reported more intense mystical experiences after their first dose of psilocybin-assisted psychotherapy showed greater reductions in depressive symptoms two weeks later. This link between mystical experiences and antidepressant benefit was not observed after the second or third psilocybin doses. The findings offer preliminary support for the idea that mystical-type experiences play a therapeutic role in psilocybin-assisted psychotherapy, extending prior work to a clinically complex population with treatment-resistant depression.
Journal of Affective Disorders
December 15, 2024
Sabrina Wong, Gia Han Le, Rodrigo B. Mansur et al.
3 citations
A review of preclinical and clinical studies examined whether ketamine affects metabolic parameters, particularly glucose-insulin homeostasis, in people with major depressive disorder (MDD) and treatment-resistant depression (TRD). In experimental diabetic conditions, ketamine did not disrupt glucose-insulin homeostasis. In adults with MDD, ketamine was associated with GLUT3 transporter upregulation and altered metabolomic signatures. In adults with TRD, ketamine increased brain glucose uptake in the prefrontal cortex. The available evidence suggests ketamine does not adversely affect metabolic parameters, though few clinical studies have evaluated its effects on glucose-insulin homeostasis in MDD. Ketamine appears safe regarding metabolic disturbances commonly seen with other augmentation therapies.
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.