Zenodo (CERN European Organization for Nuclear Research)
March 30, 2026
A therapist manual for psilocybin-assisted therapy developed for the EPIsoDE trial provides a structured psychotherapeutic framework for treating treatment-resistant depression. The manual outlines therapist qualifications, training, and a therapist dyad model, along with guidance on preparatory, dosing, and integration sessions. It emphasizes set and setting, describes the acute psilocybin experience including beneficial and challenging states, and offers self-regulation techniques like breathing exercises. A distinctive feature is the structured use of music during dosing sessions via a phase-specific block system. The manual also includes safety monitoring procedures and standardized checklists to enhance transparency and reproducibility in psychedelic research.
Psychopathology
March 27, 2026
Xiaoran Ding, Yaping Wu, Juan Yang et al.
1 citation
Ketamine is a rapid-acting antidepressant, especially for treatment-resistant depression, working through multiple targets in the glutamatergic system. It blocks NMDA receptors, which disinhibits dopamine reward pathways and increases BDNF expression via eEF2K suppression, activating the mTOR pathway and enhancing synaptic plasticity. Neuroimaging shows ketamine rapidly reshapes prefrontal-limbic connectivity and normalizes brain activity. It has a fast onset and broad therapeutic window, but enantiomers and metabolites differ in effects. Long-term safety, dependence risk, and cognitive effects require monitoring. Future work should explore synergistic treatments and safer ketamine derivatives for precision psychiatry.
Scientific reports
March 27, 2026
Gianmauro Palombelli, Valentina Zecca, Marta Boffa et al.
1 citation
In a rat model of treatment-resistant depression (Wistar-Kyoto rats exposed to chronic mild stress), brain scans revealed metabolic and structural changes distinct from non-depressed controls. Magnetic resonance spectroscopy showed reduced glutamate, glutamine, and taurine in the prefrontal cortex and decreased glutamine and choline compounds in the hippocampus, along with increased myo-inositol in the prefrontal cortex. Diffusion tensor imaging indicated higher mean diffusivity in both regions, consistent with demyelination or axonal loss, and lower fractional anisotropy in the hippocampus, suggesting compromised white-matter integrity. These findings mirror depression- and stress-related brain changes in humans, supporting the model's use for testing novel treatments like rTMS and psychedelics.
Medicine Advances
March 27, 2026
Thomas Edward Cutting, Richard Evans Hartman
Ketamine and its stereoisomers show efficacy for PTSD and treatment-resistant depression, with (R)-ketamine having fewer side effects. The therapeutic mechanisms involve specific brain regions: the dentate gyrus, prefrontal cortex, CA3 region of the ventral hippocampus, dorsal raphe nucleus, and the prelimbic–dorsal raphe nucleus circuit. For PTSD, ketamine attenuates serotonin signaling in the dorsal raphe nucleus and activates that circuit. When given before stress, it increases purine and pyrimidine metabolism, potentiates inhibitory neurotransmitters, and dampens excitatory ones except glutamic acid. Brain-derived neurotrophic factor activation of tropomyosin-related kinase B appears necessary for treatment effects, but N-methyl-D-aspartate receptor antagonism may not be.
Mindfulness
March 26, 2026
Céline Stinus, Sophie Berjot
A randomized controlled trial compared two meditation styles—focused-attention and self-inquiry—against a wait-list control group among 147 participants. Both meditation types reduced depressive symptoms and identity threat more than no meditation, with similar effectiveness. Focused-attention meditation also reduced dysfunctional attitudes more than self-inquiry or the control. Cognitive decentering (the ability to observe thoughts without identification) mediated the benefits of focused-attention meditation, while self-inquiry meditation showed exploratory links to increased feelings of connectedness to humanity and nature. The findings suggest that different meditation practices improve well-being through partially distinct psychological mechanisms, though the connectedness results require cautious interpretation.
Frontiers in Cell and Developmental Biology
March 25, 2026
Mizuki Yamamoto, Haruka Hirakata, Koji Toda
5 citations
Major depressive disorder affects many people across their lives, but its biological causes are still not fully understood. Older theories focused on imbalances in monoamine neurotransmitters like serotonin, leading to common antidepressants such as selective serotonin reuptake inhibitors. These drugs can take weeks to work, must be taken continuously, and fail to help about one-third of patients, while also carrying risks like increased suicidal thoughts in some groups. Newer findings show that ketamine and psychedelic compounds can produce rapid antidepressant effects by acting on glutamate signaling, synaptic plasticity, and immune-brain interactions, challenging the older models. This review covers both historical and emerging views on antidepressant development, describes major animal models of depression, and discusses recent translational research that is reshaping treatment approaches.
JAMA Psychiatry
March 25, 2026
Wiesław Jerzy Cubała, Malek Bajbouj, Michael Bauer et al.
3 citations
A single day of treatment with an inhaled synthetic formulation of mebufotenin (GH001) significantly reduced depression symptoms in adults with treatment-resistant depression compared to placebo. In a randomized, double-blind trial of 81 patients, those receiving up to three escalating doses of GH001 showed an average 15.5-point greater improvement on the Montgomery-Åsberg Depression Rating Scale by day 8 than those on placebo. Remission rates were 57.5% for GH001 and 0% for placebo. No severe or serious adverse events occurred. The findings suggest GH001 may be a rapid-acting, well-tolerated treatment option for treatment-resistant depression.
CNS Drugs
March 24, 2026
A proof-of-concept trial tested intranasal 5-MeO-DMT combined with an SSRI in people with treatment-resistant depression. The treatment was generally well tolerated and showed preliminary signals of antidepressant effects, though the small, uncontrolled design limits conclusions.
Mini reviews in medicinal chemistry
March 24, 2026
Shivaputra A Patil, Holly C Hunsberger
Psilocybin, a naturally occurring psychedelic derived from Psilocybe mushrooms, is experiencing renewed interest for treating mental health disorders, addiction, and cancer-related depression, and its benefits are expanding into brain injury and lifespan due to its ability to enhance neuroplasticity. Its psychoactive effects arise from psilocin acting as a partial agonist at the 5-HT2A receptor. After the FDA's breakthrough therapy designation for treatment-resistant depression in 2018 and major depressive disorder in 2019, large-scale synthesis became a major challenge, requiring complex multi-step processes with strict temperature control and hazardous reagents. Modified versions of Hofmann's original method now enable kilogram-scale production for clinical trials. This mini review covers the history, chemistry, pharmacology, and therapeutic use of psilocybin in depression.
Journal of clinical psychopharmacology
March 24, 2026
Riccardo Guglielmo, Emma Laura Facchinetti, Daniele Cioci et al.
Treatment-resistant depression, affecting up to one third of people with major depressive disorder, often involves lasting cognitive problems that hinder recovery. A systematic review of six studies found that esketamine does not appear to cause cognitive decline in adults aged 18 to 80. Improvements in attention and processing speed were the most frequent and robust findings, seen in both randomized trials and naturalistic studies. Memory remained stable in short-term studies but improved with longer follow-up. Executive functions improved mainly in participants with baseline impairments and in long-term assessments. Overall, esketamine appears cognitively safe and may offer selective cognitive benefits, particularly in attention and processing speed, potentially supporting functional recovery.
Journal of psychopharmacology (Oxford, England)
March 21, 2026
J García-jiménez, D Nuñez-arias, G Carretero Merelo et al.
In a real-world clinical setting across three Spanish centers, esketamine nasal spray produced progressive improvements in depressive symptoms and functioning in adults with treatment-resistant depression. Among 50 patients, significant reductions in depression severity and disability were observed at every assessment from week 2 through discharge, with notable gains during weeks 8–16. The median time to response was 8 weeks, and to remission 16 weeks; overall response and remission rates reached 70% and 68%. Suicidal risk shifted early toward lower categories, with no suicide attempts during treatment. Higher refractoriness, measured by the Maudsley Staging Model, independently predicted lower odds of response and remission.
Nan fang yi ke da xue xue bao = Journal of Southern Medical University
March 20, 2026
Zhuoning Zhang, Xinyu Hao, Fuyang Cao et al.
Esketamine produces antidepressant effects in mice subjected to chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex. In a study of 150 male C57BL/6J mice, those treated with esketamine showed reduced immobility in tail suspension and forced swim tests and increased sucrose preference compared with saline-treated controls. Immunofluorescence staining indicated higher c-Fos expression in glutamatergic neurons after esketamine treatment. Chemogenetic activation of these neurons mimicked the antidepressant effects, while their inhibition blocked esketamine's benefits.
The journal of ECT
March 19, 2026
Jennifer Sjödin, Karin Zimmer, Max Bell et al.
Electroconvulsive therapy (ECT) is effective for severe or treatment-resistant major depressive disorder, but anesthesia may reduce its impact by raising the seizure threshold. A review of 59 studies found that ketamine and etomidate produce longer seizures than other anesthetics, though etomidate suppresses cortisol synthesis and ketamine can cause perceptual disturbances. Lower anesthetic doses and longer intervals between anesthesia and ECT are linked to longer seizures and better response, but this has not been confirmed in randomized trials. Clinical outcomes are broadly similar across anesthetics, though ketamine may speed ECT's effect. Anesthetic choice should consider patient factors like cardiovascular health.
JAMA Psychiatry
March 18, 2026
9 citations
A phase 2b randomized clinical trial tested 25 mg of psilocybin with psychotherapy against a 5 mg dose and a placebo (nicotinamide) in 144 adults aged 25 to 65 with treatment-resistant depression who had stopped antidepressants. The primary outcome—a 50% or greater reduction in depression scores at six weeks—was not statistically significant: 17.0% of those receiving 25 mg responded, versus 12.5% on 5 mg and 10.6% on placebo. Exploratory analyses suggested a clinically meaningful reduction in depressive symptoms with the 25 mg dose. The treatment was generally well tolerated, but safety signals included higher reports of suicidal ideation on dosing days and two serious adverse reactions, one case of hallucinogen persisting perception disorder.
BMC Psychiatry
March 17, 2026
2 citations
In real-world clinical settings, intranasal esketamine shows effectiveness for treatment-resistant depression, with response varying based on patient characteristics. The text describes factors associated with treatment response but does not specify which factors or provide concrete numbers.
Frontiers in Computer Science
March 16, 2026
A computational model using explainable artificial intelligence can optimize single-dose psilocybin treatment protocols by creating personalized patient simulations. The framework, tested on three public datasets (7 participants from a neuroimaging dataset, 53 from a multimodal mental disorder dataset, and aggregated results from 10 clinical trials), achieved 94.7% prediction accuracy and 89.3% explainability scores in simulated environments. The model also demonstrated 92.8% precision in predicting treatment response patterns and a 73.4% reduction in carbon footprint. These results are entirely from simulated data and require clinical validation before any practical use.
Cureus
March 14, 2026
Suneha Shelke, Rusheeth Thummalapally
Treatment-resistant depression (TRD) affects up to a third of people with major depressive disorder who do not respond to standard antidepressants. Esketamine, a nasal spray approved for TRD in 2019, blocks NMDA receptors and may also reduce compulsive and addictive behaviors in patients whose depression and substance use disorders are linked. This review of randomized trials, cohort studies, systematic reviews, and animal research suggests that esketamine can reduce drug-seeking behavior, lessen cravings, and improve outcomes when paired with behavioral therapies like mindfulness. In rodent studies, esketamine reduced cocaine-seeking after abstinence, and clinical data hint at benefits for alcohol misuse. Esketamine may offer a dual treatment for depression and addiction, but larger studies are needed to confirm its effects and safety.
Clinics and practice
March 13, 2026
Alessandro Guffanti, Matteo Leonardi, Natascia Brondino et al.
In three young adults (ages 20–25) with mild to moderate autism spectrum disorder and treatment-resistant depression, intranasal esketamine added to standard antidepressants reduced depressive symptoms. Two patients achieved clinical remission at six months, and one showed partial response. Suicidal ideation decreased, but mentalization and social cognition improved only mildly. Subjective quality of life rose substantially for all three. No major side effects occurred. These preliminary observations require confirmation in controlled trials.
Pharmacological Reports
March 11, 2026
1 citation
People with both substance use disorders and treatment-resistant depression are more likely to respond to ketamine, which is effective for depression but also has misuse potential. The authors contrast a biological mechanism with a possible expectancy effect to explain this link, and advise weighing risks and benefits when using ketamine for these patients.
Int J Psychiatry Clin Pract
March 11, 2026
1 citation
In a real-world clinical setting, intranasal esketamine and accelerated repetitive transcranial magnetic stimulation (rTMS) showed comparable effectiveness for treatment-resistant depression. Both treatments led to significant reductions in depressive symptoms, with no statistically significant difference between the two approaches. The findings suggest that either option can be a viable fast-acting intervention for patients who have not responded to prior treatments.
Journal of Racial and Ethnic Health Disparities
March 10, 2026
Ya Yambao Yang, Mandy Yang, Tiffany Wing Lam Yip et al.
Hmong shamans understand and respond to depression through cultural beliefs and spiritual practices rather than biomedical frameworks. Nine of twelve shamans interviewed struggled to name depression, while eight attributed it to soul loss or spiritual imbalance. Displacement, war trauma, and poverty were identified as contributing factors by all participants. Coping strategies included family time, gardening, and healing from other shamans. Female shamans more openly shared struggles, while male shamans concealed emotions due to their household role. Only younger shamans had sought therapy; older shamans associated depression with stigma, mistrust, and fear of medication. This suggests a generational shift toward openness to mental health services.
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.
Journal of Emerging Technology in Teaching and Learning
March 10, 2026
Fadhilah Aini, Nurul Husna, Mutia Hidayati
Integrating BAKU (Good and Strong) culture into Islamic mindfulness therapy helps young Muslims in the Daarut Tauhiid Bandung environment better manage anxiety and depression. The qualitative phenomenological study involved digitally active young Muslims who regularly participate in religious activities. Thematic analysis of in-depth interviews showed that this culturally aligned approach improves resilience, psychological well-being, and emotional management skills. Because the therapy matches participants' spiritual and cultural values, it is more relevant and acceptable than standard interventions. The authors recommend developing mental health programs that combine Islamic mindfulness with local culture as both a preventive and curative solution for young Muslims in the digital era.
bioRxiv (Cold Spring Harbor Laboratory)
March 10, 2026
Gabriele Floris, Sarah J. Jefferson, Jocelyne Rondeau et al.
Combining psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) reduces psychedelic-like effects in mice—measured by head twitch response—while preserving antidepressant effects against chronic stress. Proteomic analysis of the medial prefrontal cortex revealed enhanced synaptogenesis and reduced GPCR signaling pathways with the combination versus psilocybin alone. This suggests a potential strategy for developing serotonergic antidepressants that maintain efficacy without the intense psychedelic experience, which currently limits scalability of psilocybin therapy.