Translational Psychiatry
January 23, 2026
Stevan Nikolin, Clara Massaneda-Tuneu, Louise Brettell et al.
1 citation
Electroconvulsive therapy (ECT) leads to a faster reduction in depressive symptoms than ketamine for severe, medication-resistant depression. A meta-analysis of seven studies with 731 participants found that depression scores were slightly lower at baseline in the ketamine group. After adjusting for baseline differences, ECT produced an additional improvement of about 0.02 standardized mean difference per day, amounting to a predicted moderate advantage over ketamine after four weeks. This advantage falls within the range considered clinically meaningful.
Translational Psychiatry
November 24, 2025
Xin-Yu Li, Di Qiu, Ni Du et al.
1 citation
Patients with preexisting sleep disorders are at higher risk for postoperative sleep disturbance (PSD). In a randomized trial of 130 patients, intraoperative esketamine (0.3 mg/kg/h) reduced the incidence of PSD on postoperative day 1 (43.1% vs. 64.6%; odds ratio, 0.414) and lowered hydromorphone use. Preoperative oral microbiota profiles differed between patients who later developed PSD and those who did not, with specific bacterial taxa linked to sleep disturbance. The findings suggest esketamine may help prevent postoperative sleep disruption, possibly by modulating the oral microbiota.
Translational Psychiatry
November 17, 2025
Noah Stapper, Lindsay L Benster, Sahit Menon et al.
1 citation
A systematic review of 24 clinical trials examined neurophysiological biomarkers linked to treatment-induced changes in suicidal ideation. Most studies were published within the past five years but showed methodological heterogeneity, including non-randomized designs and concurrent interventions. Despite limitations, findings suggest that the anterior cingulate cortex is involved in the anti-suicidal effects of intravenous ketamine, an effect absent with oral ketamine, possibly explaining intravenous ketamine's superior clinical effects. Improvements in suicidal ideation following electroconvulsive therapy and magnetic seizure therapy were associated with activity in the prefrontal cortex. These patterns may indicate that acute effects of intravenous ketamine and sustained effects of seizure therapies involve differential modulation of these brain regions.
Translational Psychiatry
October 6, 2025
Hanna J Szkudlarek, Rajkamalpreet Singh Mann, Krystyna Wieczerzak et al.
1 citation
Adolescent exposure to THC, the main psychoactive component of cannabis, increases the risk of later neuropsychiatric symptoms, and the medial prefrontal cortex is a key brain region involved. The antioxidant N-acetylcysteine (NAC) prevented cognitive, synaptic, neuronal, and neurochemical deficits caused by chronic adolescent THC exposure in a rodent model. This suggests that THC-induced oxidative stress contributes to neuropsychiatric risk and identifies NAC as a potential preventive treatment.
Translational Psychiatry
March 8, 2025
Daiki Nakatsuka, Taro Suwa, Yuichi Deguchi et al.
1 citation
Aripiprazole, a partial dopamine receptor agonist, can suppress the dissociative side effects of the rapid-acting antidepressant ketamine without diminishing its antidepressant effects. Experiments in mice showed that aripiprazole blocked ketamine-induced psychotomimetic behaviors while preserving or enhancing antidepressant-like effects in the forced swim test, whereas the antagonist raclopride suppressed both. Brain mapping identified the ventral tegmental area as a key region. In a small clinical study of nine depressed patients, co-administering 12 mg of aripiprazole with ketamine reduced dissociative symptoms while maintaining antidepressant benefits. These findings suggest that combining aripiprazole with ketamine may offer a preferred therapy for treatment-resistant depression.
Translational Psychiatry
June 18, 2024
Matti Gärtner, Anne Weigand, Marvin Sören Meiering et al.
1 citation
Ketamine reduces spontaneous brain activity in three subregions of the anterior cingulate cortex (ACC) during administration in healthy people. Lamotrigine, which inhibits glutamate release, attenuates this effect only in the ventral ACC subregions, suggesting glutamate involvement there. ACC activity returns to baseline 24 hours later, though group differences persist between the lamotrigine and ketamine groups. Trait negative emotionality is closely linked to activity changes in the subgenual ACC after ketamine. These findings clarify how ketamine affects different ACC subregions and may relate to its antidepressant mechanisms.
Translational Psychiatry
July 20, 2026
Yong-Yu Yin, Si-Rui Sun, Hui-Ying Zhang et al.
Ketamine, a fast-acting antidepressant, works in part by blocking a signaling pathway between immune cells and neurons in the brain. In mice with depression-like symptoms caused by corticosterone, a single dose of ketamine (10 mg/kg) reversed behavioral deficits, reduced inflammation, and restored the structure of brain cells. Blocking the CX3CL1/CX3CR1 signaling pathway—either with a drug or by silencing the gene—eliminated both the behavioral and brain-cell benefits of ketamine. This suggests that this chemokine pathway is essential for ketamine's antidepressant effects and could be a new target for treating depression.
Translational Psychiatry
July 16, 2026
Celia Martín-Cuevas, Víctor Darío Ramos‐Herrero, Álvaro Flores‐Martínez et al.
A dual-hit mouse model combining prenatal immune activation with adolescent THC exposure produces schizophrenia-relevant behavioral and brain changes, particularly in males. Social deficits and repetitive behaviors emerged, along with reduced cortical thickness and decreased dendritic spine density in the prefrontal cortex and hippocampus. Reelin signaling pathway alterations occurred in a sex-dependent manner: males showed reduced Reelin levels mainly after THC exposure alone, while females had general reductions across treatment groups. The number of Reelin-positive cells also decreased. Adolescent THC exposure appears to be a major driver of Reelin alterations, with prenatal immune activation potentially modulating this effect. The findings highlight complex, domain-specific interactions between environmental risk factors in schizophrenia-related processes.
Translational Psychiatry
July 11, 2026
Moira G. Semple, Sarah E. Mennenga, Ryan Smith et al.
Ketamine and MDMA, compounds known as psychoplastogens, show therapeutic potential for mood and trauma-related disorders, but their molecular mechanisms are not fully understood. In a study analyzing blood samples from 20 ketamine-treated participants and saliva samples from 16 MDMA-treated participants, DNA methylation changes were examined using a Brain-Epigenome-Wide Association Study targeting brain-relevant genes. Ketamine was associated with 405 significantly altered genes and 169 functional networks, while MDMA was linked to 346 altered genes and 183 networks. Both compounds converged on pathways related to neuroplasticity and neuroimmune regulation, suggesting they induce peripheral epigenetic changes that engage molecular pathways relevant to psychiatric health.
Translational Psychiatry
July 4, 2026
Krisha Shah, Rubén Herzog, Alan C. Swann et al.
Ketamine rapidly reduces depression in some people with treatment-resistant depression, but the brain mechanisms are not fully understood. This analysis of a randomized, double-blind trial compared ketamine to midazolam in 30 older veterans with treatment-resistant depression. Using EEG data and a measure called O-information, which captures how brain regions interact in groups of three or more, the study found that ketamine caused dynamic changes in these interactions over time. The strongest effects occurred in alpha brain waves one hour after infusion, with changes shifting to theta waves by 24 hours and partially returning in beta and gamma waves by day 7.
Translational Psychiatry
June 24, 2026
Mauro Pettorruso, Giacomo D’andrea, Antonio Inserra et al.
Emerging clinical and preclinical evidence suggests that the therapeutic benefits of psychedelics for depression and anxiety may be separable from their consciousness-altering effects. Psychedelics produce profound brain changes, including suppression of the default mode network, leading to intense subjective experiences such as ego dissolution. These effects require extensive preparation and integration, exclude individuals with certain psychiatric vulnerabilities, and raise scalability concerns. Pharmacological strategies like serotonin 2A receptor antagonism and development of biased psychedelic analogues might retain therapeutic efficacy without psychedelic experiences. Preclinical data indicate that downstream molecular and network-level mechanisms could mediate therapeutic effects independently of subjective states. Confirming this dissociation could enable more scalable, accessible treatments for broader psychiatric populations.
Translational Psychiatry
June 13, 2026
Jillian L. King, Devin P. Effinger, Cameron Basquez-Pfeifer et al.
The head-twitch response (HTR) in mice, a standard test for hallucinogenic potential, fails to reliably indicate overall psychoactivity. Lisuride, which did not produce HTR, caused impaired movement, coordination, stress, cognitive disruption, and reduced prefrontal cortex EEG power. LSD, which triggered strong HTR, had minimal effects on these measures. Neither compound's effects beyond HTR depended on 5-HT₂A receptors. The HTR alone is insufficient and should be combined with other assessments.
Translational Psychiatry
June 5, 2026
Samaneh Ahmadian-Moghadam, Shiva Roshan-Milani, Ehsan Saboory
Psilocybin-induced neuroplasticity could theoretically modulate stress-related neurodevelopmental risk pathways relevant to ADHD, but this remains a speculative hypothesis rather than an evidence-based intervention. Preclinical studies in non-ADHD models show psilocybin can induce rapid synaptic plasticity, alter cortical excitatory-inhibitory dynamics, and reverse stress-associated alterations. Human clinical trials in mood, trauma-related, and substance use disorders demonstrate durable changes in emotional regulation, cognitive flexibility, and brain network organization—processes overlapping with ADHD neural systems. Emerging preliminary, largely self-reported studies suggest potential benefits for inattention, impulsivity, and emotional dysregulation. Key mechanistic uncertainties and ethical considerations, especially for vulnerable populations, are emphasized as critical constraints on translation.
Translational Psychiatry
June 4, 2026
Mélusine Humbert‐droz, Anna M Becker, Jan Valenta et al.
A booster dose of MDMA prolongs the acute subjective drug effects compared with a single dose, without increasing peak effects. In a double-blind, randomized, placebo-controlled crossover study with 23 healthy volunteers, a 120 mg dose of MDMA followed by a 60 mg booster after 2 hours extended the duration of subjective effects to an average of 5.6 hours, versus 4.6 hours with a single dose. Adverse effects were more common after both MDMA conditions than placebo. Whether the prolonged effect translates into clinical benefit for MDMA-assisted psychotherapy remains unknown.
Translational Psychiatry
May 21, 2026
Francesco Bavato, Andrea E. Steuer, Anna M. Jacobsen et al.
Chronic users of methamphetamine (METH) and MDMA (Ecstasy) show distinct alterations in blood levels of tryptophan-related metabolites, which may help explain their different clinical effects. In a study of 36 chronic MDMA users, 33 chronic METH users, and 71 healthy controls, METH use was linked to depleted serum tryptophan and serotonin and broad activation of kynurenine pathways, whereas MDMA use was associated with selective activation of the OH-kynurenine branch. These metabolite changes correlated with the severity of depression and psychosis symptoms. The findings suggest that persistent changes in peripheral tryptophan metabolism may contribute to the substances' contrasting addiction and psychiatric profiles.
Translational Psychiatry
May 12, 2026
Linda Bryant, Laith Alexander, Sergio Mena et al.
A machine-learning model using structural brain scans predicted which adults with treatment-resistant depression would respond to a single ketamine infusion. The model, trained on 99 participants, achieved 72% balanced accuracy in the discovery sample and 60% in two independent groups, with performance dropping to chance in a saline-treated control group. Greater gray matter volume in frontal regions predicted response, while greater cerebellar volume predicted non-response. The findings suggest that pre-treatment brain structure may help guide personalized treatment decisions for ketamine therapy.
Translational Psychiatry
April 21, 2026
Paul A Parcon, Amanda Bardhoshi, Amanda Olsen-Dufour et al.
Ketamine, a rapid-acting antidepressant, increases cyclic adenosine monophosphate (cAMP) activity in the brain within an hour of infusion, likely by affecting phosphodiesterase-4 (PDE4), an enzyme that normally terminates cAMP signaling. In rats given 10 mg/kg ketamine, binding of a radioligand to PDE4 increased by a mean of 24% (range 3%–42%); in rhesus macaques given 0.5 mg/kg, binding increased by a mean of 14% (range 12%–16%). A radioligand selective for the PDE4B subtype showed a mean increase of 28% (range 16%–37%) in monkeys. Control experiments ruled out blood-flow effects. The findings suggest that boosting cAMP activity through PDE4 inhibition, particularly the PDE4B subtype, may underlie ketamine's rapid antidepressant effects and point to a common pathway for antidepressant action.
Translational Psychiatry
April 14, 2026
Ryan J. Keenan, Rifa T Haque, Xiangjun Jin et al.
A single dose of psilocybin worsened diet-induced weight loss over four weeks in obese mice switched to low-fat chow, making them more likely to lose more weight. The effect came mainly from reducing food intake, not from changing energy expenditure. In obese mice kept on a high-fat diet, psilocybin did not affect body weight or food intake, suggesting it does not directly cause weight loss or reduce eating. Instead, it may help enable weight loss when combined with other weight-loss interventions. The findings support further research into psychedelic compounds as an add-on therapy for obesity, though more work is needed to understand the mechanisms.
Translational Psychiatry
March 27, 2026
Livio Erne, Lorenz Mueller, Isabelle Straumann et al.
Bolus injections of DMT produce very strong subjective effects that peak within 2 minutes and subside completely within 12–30 minutes, consistent with a short elimination half-life of about 6–7 minutes. A ceiling effect for peak subjective effects occurred at the 15 mg dose, and no tolerance developed to the acute effects. Tolerability markedly improved when doses were escalated openly rather than given double-blind, and at equivalent doses the subjective effects were rated as less intense. These results indicate that blinding and expectancy influence the subjective experience and that individual dose-escalation may improve tolerability and guide dose selection in future DMT studies.
Translational Psychiatry
March 6, 2026
Ty Lees, Jason N Scott, Brian W. Boyle et al.
A single low dose of ketamine (0.5 mg/kg) reduced depressive, anhedonic, and ruminative symptoms 24 hours later in 24 people with treatment-resistant depression. The symptom improvement was not linked to changes in brain connectivity but was associated with connectivity patterns present before the infusion. After ketamine, participants showed broad increases in resting-state functional connectivity within and between the default mode and frontoparietal networks, as measured by EEG. The authors suggest these connectivity increases may reflect ketamine's synaptogenic effects, which can be short-lived. The study included 34 healthy controls who did not receive ketamine.
Translational Psychiatry
February 19, 2026
Luís Carlos Pereira, Wigínio Gabriel Lira-Bandeira, Andréa Silva Medeiros-Bandeira et al.
Chronic stress from social isolation in juvenile male marmosets reduces neuronal volume in the somatosensory cortex, a brain region implicated in depression. Ayahuasca, a psychedelic brew, given before and during isolation prevented this reduction, with treated animals showing neuronal volumes similar to non-stressed controls. Trends also suggested preserved cortical structure, though differences in neuronal density and overall cortical volume were not statistically significant. These results indicate ayahuasca may protect against stress-induced cortical atrophy and support further research into its therapeutic potential for stress-related psychiatric disorders, especially in adolescents.
Translational Psychiatry
January 31, 2026
Jesper L. Kristensen
Psilocybin is a prodrug that is rapidly converted in the body to psilocin, the active compound responsible for its subjective and therapeutic effects. The authors of the reviewed manuscript used computational network pharmacology and molecular docking to investigate how psilocybin might prevent suicide, but they incorrectly treated psilocybin as the active agent. In humans, psilocybin's effects correlate with psilocin plasma concentration and serotonin 2A receptor occupancy, and cryo-EM structures of psilocin bound to that receptor are available. Therefore, discussing psilocybin's binding to proteins is nonsensical for understanding its therapeutic actions in humans.
Translational Psychiatry
November 24, 2025
Assaf Oshri, Cullin J Howard, Steven M Kogan et al.
Socioeconomic hardship increases the risk of suicidal thoughts and behaviors in adolescents, partly through shorter sleep duration. A study of 11,878 youth from the Adolescent Brain Cognitive Development Study found that higher levels of hardship predicted more suicidal ideation and attempts. Shorter sleep acted as a pathway linking hardship to suicidal thoughts, but this indirect effect was weaker in adolescents with higher coherence in the brain's Default Mode Network. The findings suggest that sleep health is a mechanism connecting economic adversity to suicide risk, and that DMN coherence may serve as a neuroprotective factor supporting resilience.
Translational Psychiatry
November 21, 2025
Andrea Francesco Carluccio, Georg Northoff
Auditory verbal hallucinations (AVH) in psychosis and schizophrenia involve changes in brain connectivity and organization, but how these relate to the structure of subjective experience is unclear. This review proposes two neurophenomenological hypotheses. First, disruptions in connections between sensory, bodily, and language brain regions may cause temporal fragmentation in perception and thought, leading to hyperreflexivity—abnormal attention to isolated objects. Second, a reduced distinction between unimodal and transmodal brain regions may blur the boundary between outer social and inner mental spaces, causing confusion between interpersonal and intrapersonal experience. These hypotheses link brain changes directly to the structure of experience in AVH.
Translational Psychiatry
November 13, 2025
Bruna Giribaldi Cunha, David Nutt, Marieke Martens et al.
In a double-blind randomized trial, patients with long-standing moderate-to-severe depression received either two doses of 25 mg psilocybin plus daily placebo or two doses of 1 mg psilocybin plus daily escitalopram over six weeks. Both treatments comparably reduced negative bias in recognizing facial emotions, a measure of emotional information processing. However, changes in this bias were not linked to concurrent depression score changes. Only in the escitalopram group did a decrease in misclassifying positive faces as negative correlate with lower depression scores at a one-month follow-up. The findings suggest overlapping cognitive mechanisms between psilocybin and escitalopram, notable given psilocybin's short dosing regimen.