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.
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.
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.
Drug discovery today
December 1, 2023
Taeho Greg Rhee, Pasha A Davoudian, Gerard Sanacora et al.
20 citations
Psychiatric disorders are the leading cause of disability globally, and interest in psychedelic substances as potential treatments has recently revived. This review examines the therapeutic potential and safety concerns of psilocybin, DMT, LSD, and MDMA, including their possible interactions with psychotherapy. It covers active and recently completed clinical trials drawn from published literature, conference abstracts, clinical trial registries, and press releases. The review suggests that these compounds may offer new avenues for treating psychiatric disorders, though safety considerations remain important.
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
July 15, 2025
Mina Ansari, Taeho Greg Rhee, Mia C Santucci et al.
4 citations
Patients with obesity were significantly more likely to respond to intranasal esketamine for treatment-resistant depression than non-obese patients. Among 190 patients treated at a single clinic, 34.2% were obese. Obese patients had a 63% higher chance of achieving at least a 50% improvement on the Montgomery-Åsberg Depression Rating Scale compared to non-obese patients. However, when BMI was analyzed as a continuous measure, no linear relationship with treatment response was found. The authors suggest that increased body fat may prolong the presence of lipid-soluble esketamine or its metabolites, but the underlying mechanisms remain unknown.
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.
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.
JAMA psychiatry
July 1, 2026
Sung Ryul Shim, Hye Su Jeong, Tanner J Bommersbach et al.
1 citation
A systematic review and meta-analysis of 26 randomized clinical trials with 1,166 patients experiencing a major depressive episode found that intravenous ketamine infusions significantly reduce suicidal and depressive symptoms in the acute phase. A single ketamine infusion lowered suicidal symptoms at 24 hours and at 1 month, and repeated infusions produced similar reductions. Depressive symptoms decreased significantly from 4 hours through 1 week after a single infusion and after repeated infusions. Serious adverse events were unrelated to the interventions, and other side effects were transient. Longer-term outcomes remain unclear.
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.
Pharmacopsychiatry
February 5, 2026
Tianyi Xu, Sabrina Wong, Gia Han Le et al.
Lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine activate the 5-hydroxytryptamine 2B receptor, a pathway known to cause drug-induced valvular heart disease. This systematic review of 17 studies found no research on psilocybin, dimethyltryptamine, or mescaline. Both lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine show high or moderate affinity for this receptor and promote signaling linked to fibrotic changes in heart valve tissue. In vivo studies confirm serotonin-induced valvulopathy, and chronic 3,4-methylenedioxymethamphetamine use has been associated with valve abnormalities in humans. No clinical cases of lysergic acid diethylamide-induced valvulopathy have been reported, but preclinical data suggest potential for fibrotic signaling under sustained exposure. Preliminary evidence supports the need for cardiac safety monitoring in psychedelic research.