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.
Journal of Affective Disorders
July 23, 2025
Joyce Xu Hao Jin, Heidi Ka Ying Lo, Iris Wai Tung Tsui et al.
2 citations
In people with major depressive disorder (MDD) and bipolar disorder (BD), positive psychological traits such as mindfulness and grit interact with negative affect to influence positive mental health. Over two weeks, 29 people with MDD, 29 with BD, and 30 healthy controls reported their negative affect, pleasure attainment, and meaning in life five times daily. Lower negative affect strengthened the link between mindfulness and meaning in life in the MDD group but not in the BD or control group. Higher grit reduced the harmful effect of negative affect on pleasure attainment in the BD group but not in the other groups. These findings highlight complex relationships between positive traits and mental health in mood disorders.
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.
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.
Journal of Affective Disorders
April 1, 2026
Kayla M Teopiz, Gia Han Le, Sabrina Wong et al.
A systematic review of 13 preclinical studies and 1 human study found that dextromethorphan (DXM), a glutamatergic modulator with antidepressant properties, attenuates reward-seeking behavior in rats, as measured by conditioned place preference and behavioral sensitization. In the single human study involving 20 healthy participants, self-reported drug-liking for DXM (400 mg/70 kg) was significantly lower compared to psilocybin (20 mg and 30 mg) 7 hours after dosing. The review highlights a paucity of human studies and suggests that future research should investigate DXM's effects on reward function using validated paradigms in people with anhedonia.
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.
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.
Journal of Psychiatric Research
June 1, 2026
Kyle Valentino, Hana Ballum, William Cheung et al.
About 80% of people with major depressive disorder (MDD) report insomnia. This systematic review examined how glutamatergic modulators, especially ketamine, affect sleep in preclinical and clinical studies. Preclinical work showed ketamine alters EEG delta power during NREM sleep and normalizes clock suppressor gene expression, while esketamine enhances delta power but arketamine does not. mGlu2/3 activators reduce REM sleep. Clinical studies indicate that improved sleep can mediate ketamine's antidepressant effects in MDD. The authors suggest that sleep-related mechanisms are potential targets for depression treatment.
Journal of Affective Disorders
February 1, 2026
Kayla M Teopiz, Sabrina Wong, Gia Han Le et al.
Reward processing disruptions in major depressive disorder (MDD) may relate to altered frontostriatal brain activity. Glutamatergic modulators might improve reward function. This systematic review examined 11 fMRI studies testing glutamatergic agents—ketamine (9 studies), nitrous oxide (1), and memantine (1)—on frontostriatal activity in people with MDD or healthy controls. Preliminary evidence suggests intravenous ketamine may alter functional connectivity in striatal regions, potentially relevant to improved reward function in treatment-resistant depression. More research is needed on how these modulators affect reward-related brain structures, the timing of effects, and baseline characteristics predicting antidepressant response.
Expert Opinion on Drug Metabolism & Toxicology
January 1, 2026
Yang Jing Zheng, Christine E. Dri, Sabrina Wong et al.
Dextromethorphan/bupropion (DXM/BUP) received breakthrough FDA approval in August 2022 as a rapid-acting antidepressant. DXM/BUP is a noncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, combined with bupropion, a norepinephrine/dopamine reuptake inhibitor and CYP2D6 inhibitor. DXM alone has long been misused due to its metabolism into the psychoactive metabolite dextrorphan (DXO). The article discusses the pharmacodynamics and pharmacokinetics of DXM and DXO, highlights the abuse potential of DXM alone, and presents preclinical, clinical, and pharmacovigilance findings that support reduced abuse liability of DXM/BUP. The formulation demonstrates clinically meaningful improvement within one week of initiation. Given its safety, efficacy, and novelty, this glutamatergic modulator is a promising candidate for global approval. Future research should examine its potential in bipolar depression and trauma-associated MDD.
CNS Drugs
October 1, 2023
Dania Akbar, Taeho Greg Rhee, Felicia Ceban et al.
A systematic review of five studies found that AXS-05, a combination of dextromethorphan and bupropion, rapidly reduces depression severity in adults with major depressive disorder who do not respond to standard antidepressants. Depressive symptoms measured on the MADRS scale decreased significantly compared to placebo as early as one week and compared to an active control at two weeks. The treatment effect was maintained for up to 12 months, with an average 23-point reduction from baseline. The therapy was well-tolerated with only transient side effects. These results support the role of glutamatergic and sigma-1 signaling pathways in depression.
Journal of Affective Disorders
December 1, 2022
Anastasia Levinta, Shakila Meshkat, Roger S McIntyre et al.
Ketamine rapidly reduces depressive symptoms in people with treatment-resistant depression, but its effectiveness may diminish as the number of prior failed treatments increases. A systematic review of 18 randomized controlled trials found that ketamine and esketamine worked at both lower and higher stages of treatment resistance, yet effect sizes and duration of benefits were greater in studies involving patients with fewer prior antidepressant failures. Variability in how studies defined treatment resistance and measured outcomes prevented clear comparisons of efficacy across different resistance stages. The authors conclude that while ketamine remains broadly effective, more failed treatment trials may reduce its efficacy, and participant-level data are needed to clarify the relationship between resistance level and response.