Journal of affective disorders
July 1, 2024
Cameron N Calder, Angela T H Kwan, Kayla M Teopiz et al.
31 citations
Ketamine is effective for adults with treatment-resistant depression. A systematic review of 21 placebo-controlled randomized trials with 2042 participants calculated the number needed to treat (NNT) for racemic ketamine: 7 at 4 hours, 3 from one day to one week, and 9 at four weeks. Esketamine had an NNT of 2 at one day and 11 at four weeks. Numbers needed to harm indicated low risk. The NNTs under 10 across observation intervals are considered highly clinically meaningful for this difficult-to-treat disorder. Limitations include potential functional unblinding and selective reporting bias.
Journal of affective disorders
June 15, 2024
Gia Han Le, Sabrina Wong, Sebastian Badulescu et al.
25 citations
A systematic review examined how serotonergic psychedelics (psilocybin, LSD) and ketamine affect brain wave patterns measured by EEG and MEG in people with major depressive disorder, treatment-resistant depression, and healthy controls. Ketamine and psychedelics both increase theta power in depressed individuals. In healthy controls and depressed persons, both drug classes decrease alpha, beta, and delta power. Ketamine also increases gamma power in both groups. Theta power specifically rises in those with major depressive disorder when given psychedelics. The studies varied in patient populations, dosing, and measurement devices. The findings support disease models involving altered network connectivity and may guide future treatment discovery.
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 affective disorders
April 1, 2024
Sabrina Wong, Angela T H Kwan, Kayla M Teopiz et al.
19 citations
A systematic review of randomized controlled trials compared the clinical efficacy of psilocybin and esketamine in adults with treatment-resistant depression. 25 mg of psilocybin significantly reduced depressive symptoms at 21 days post-dose, with a number needed to treat (NNT) of 5. Psilocybin-induced nausea had a number needed to harm (NNH) of 5. Fixed doses of esketamine (56 mg and 84 mg) showed significant effects at 28 days post-dose, with NNTs of 7. Esketamine-induced headache, nausea, dizziness, and dissociation had NNHs below 10. The preliminary results may reflect only a small portion of the patient population and require replication and longer-term studies. Both agents showed clinically meaningful NNT estimates and acceptable NNH profiles, underscoring their clinical relevance for treatment-resistant depression.
Journal of affective disorders
October 15, 2024
Angela T H Kwan, Joshua D Rosenblat, Rodrigo B Mansur et al.
13 citations
Ketamine and esketamine are increasingly prescribed for treatment-resistant mood disorders and suicide risk, but ketamine is also misused. Analyzing reports in the World Health Organization pharmacovigilance database up to January 2024, ketamine showed elevated reporting odds ratios for alcohol abuse (3.24), substance dependence (12.48), substance use disorder (170.44), substance abuse (2.94), drug dependence (2.88), drug use disorder (11.54), and drug abuse (2.85). Esketamine had reduced odds for substance abuse (0.41), drug dependence (0.083), and drug abuse (0.052), and no increased odds for any alcohol or substance misuse parameter. These associations do not establish causation.
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.
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.
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.
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.
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.
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.
Journal of affective disorders
December 15, 2024
Sabrina Wong, Gia Han Le, Rodrigo 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.
The Journal of clinical psychiatry
July 7, 2025
Angela T H Kwan, Moiz Lakhani, Joshua D Rosenblat et al.
2 citations
In a global pharmacovigilance analysis of adverse event reports from the World Health Organization's VigiBase database, esketamine was associated with higher reporting odds for suicidal ideation compared to lithium (5.13 times) and fluoxetine (3.34 times), while ketamine showed lower reporting odds for suicidal ideation, suicide attempt, and completed suicide relative to both reference drugs. Both drugs had lower reporting odds for suicide attempts and completed suicides. The authors caution that causality cannot be determined from these observational data.