Pharmacology, biochemistry, and behavior
June 30, 2026
Lucie Ladislavová, Viera Kútná, Kristýna Mazochová et al.
Chronic microdosing of psilocin (0.05 or 0.075 mg/kg) in adult male Wistar rats over five weeks did not alter locomotor activity, depressive-like behavior, sociability, or novelty seeking, and did not increase cell proliferation in the dentate gyrus of the hippocampus. A small anxiogenic effect was detected in the Elevated Plus Maze. The findings suggest that, under this dosing schedule, psilocin microdosing produces limited behavioral effects and does not enhance hippocampal progenitor proliferation.
International Journal of Drug Delivery Technology
June 30, 2026
Angelin Grace Thomas, Dhivyaprasath Palaniappan, Sagar Guruswamy et al.
Esketamine nasal spray reduces depressive symptoms more effectively than a placebo or other treatments like quetiapine for people with treatment-resistant depression. Many patients felt better within days, and some benefits lasted weeks or months after stopping treatment. Most side effects, such as dizziness, nausea, and blood pressure changes, were mild to moderate and resolved within two hours. No serious side effects or deaths were reported. Gathering patient feedback during treatment helped doctors create better care plans. Some studies had small sample sizes, and long-term effects beyond 12 months are not well documented. Ongoing phase 3 studies aim to clarify optimal dosages and long-term outcomes.
Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater
June 30, 2026
Cielo A Estela-Fernandez, Reem Mohamed Yousif Elsheikh, Dal Bianco Beatrice et al.
Psychedelics show significant potential for treatment-resistant depression (TRD) by promoting neuroplasticity, corticolimbic function, and epigenetic changes beyond serotonergic agonism. Psilocybin-assisted therapy induces short-term symptom improvement lasting weeks to months. Ketamine, in intravenous, subcutaneous, and oral forms, produces rapid and robust reductions in depressive symptoms and relapses without impairing cognitive function. Esketamine yields early, clinically meaningful improvements in function and productivity. Ayahuasca demonstrates fast and sustained effects with higher remission rates and good safety. Despite encouraging findings, large, well-designed studies are needed before psychedelics become standard recommendations for TRD.
Asian Journal of Medical Sciences
June 30, 2026
Raja Suhail Shounthoo, Ajaiz Rasool, Athar Un Nisa Quraishi et al.
Ketamine, a dissociative anesthetic developed in the 1960s, is experiencing a resurgence as a treatment for depression and pain. Unlike standard antidepressants that target monoamine systems, ketamine works by modulating glutamate, a key neurotransmitter, and enhancing synaptic plasticity. It shows rapid antidepressant effects in treatment-resistant depression and effectiveness for both acute and chronic pain. However, significant concerns remain about long-term safety, lack of standardized protocols, and potential for misuse. This review examines ketamine's expanding roles in anesthesia, psychiatry, and pain medicine, highlighting its mechanisms, clinical uses, safety issues, and gaps in current evidence.
European archives of psychiatry and clinical neuroscience
June 30, 2026
C Hohoff, T Lange, L Steinbach et al.
Treatment resistance in major depressive disorder affects a substantial minority of patients and is hard to recognize early, delaying intensified care. The EMBER-MDD study is a non-interventional, in-vitro investigation that will analyze biospecimens from approximately 420 adults with major depressive disorder—about 210 who received esketamine nasal spray and 210 who received treatment as usual. Using genomics, epigenomics, transcriptomics, and proteomics/metabolomics, the study aims to discover individual-omic and integrated multi-omic biomarkers and signatures associated with treatment resistance risk and molecular correlates of clinical response. All outputs are research-only and will not support individual clinical decision-making. The study will deliver robust biosignatures and mechanistic hypotheses to guide future validation and inform stratified intervention strategies in subsequent trials.
Journal of affective disorders
June 29, 2026
Yao Ge, Lijuan Chen, Yu Shen et al.
In people with major depressive disorder, the balance between excitation and inhibition across the brain's cortex is disrupted, particularly in the parietal and prefrontal-cingulate regions. Using resting-state functional magnetic resonance imaging data from 254 patients and 451 healthy controls, the Hurst exponent—a proxy for excitation-inhibition balance—was found to be significantly reduced in patients. This imbalance was linked to specific gene expression related to neuronal structure, metabolism, and mitochondrial function, as well as to neurotransmitter systems including GABA, opioid, serotonin, and synaptic density. In a separate trial of 32 patients with treatment-resistant depression, ketamine increased the Hurst exponent in the anterior cingulate and medial prefrontal cortices, suggesting that restoring excitation-inhibition balance may underlie ketamine's antidepressant effects.
Asian J Psychiatr
June 28, 2026
A single adolescent with treatment-resistant depression, severe obesity, and pseudo-Cushing syndrome showed rapid improvement in depressive symptoms after a single intravenous infusion of ketamine. The patient's depression scores dropped substantially within 24 hours, and the improvement persisted for at least one week. This case suggests that ketamine may be a rapid-acting option for adolescents with complex, treatment-resistant depression, even when accompanied by significant medical comorbidities.
The Brown University Psychopharmacology Update
June 28, 2026
A phase 2b trial found that a single, individualized vaporized dose of the psychedelic mebufotenin (5-MeO-DMT) improved depressive symptoms more than placebo in adults with treatment-resistant depression over seven days. No serious adverse events occurred during the study. The results were published in JAMA Psychiatry.
Academic Journal of Neuropsychiatry and Neuropsychology
June 27, 2026
Abdullah Burak Uygur, Kadir Karakuş, Selime Çelik Erden et al.
Esketamine, a novel treatment for depression, works through NMDA receptors and intracellular signaling pathways, moving beyond traditional monoamine-based antidepressants. The article reviews its mechanism of action, clinical adverse effects, contraindications, safe administration protocols, and treatment process. Esketamine offers a rapidly acting option for depression, but its use requires careful management due to potential adverse effects and specific contraindications.
bioRxiv (Cold Spring Harbor Laboratory)
June 26, 2026
Paulina Clara Dagnino, Irene Acero-Pousa, Robin Carhart‐Harris et al.
A central challenge in neuroscience is understanding how the human brain is organised to support optimal functioning and adaptability. One approach to characterise complex brain dynamics is by artificially perturbing whole-brain models. Here, we asked whether whole-brain organisation under perturbation in major depressive disorder (MDD) changes after intervention with psilocybin and escitalopram. First, we built whole-brain models of pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) and obtained an initial generative effective connectivity (GEC) matrix for each individual.
Journal of psychopharmacology (Oxford, England)
June 25, 2026
Joost C Van Mechelen, Tobias A Wieles, Laura G J M Borghans et al.
Oral S-ketamine (S-KETPO) has poor bioavailability (9-12%) and produces much lower peak concentrations of S-ketamine but higher levels of its active metabolites norketamine and hydroxynorketamine compared to intravenous S-ketamine (S-KETIV). In 16 healthy participants, S-KETIV caused sedative, psychomotor, and psychotomimetic effects along with reductions in brain electrical activity, while the higher oral dose (0.45 mg/kg) showed limited psychotomimetic effects and smaller brain activity reductions, and the lower oral dose (0.20 mg/kg) had no effects. Safety was similar across treatments. These pharmacokinetic and pharmacodynamic differences may affect dose selection and therapeutic outcomes in treatment-resistant depression.
Molecular psychiatry
June 25, 2026
Clotilde Guidetti, Maurizio Fava, George I. Papakostas
Major depressive disorder and treatment-resistant depression affect many people, and over half of patients do not respond adequately to first-line antidepressants. This review examines promising rapid-acting treatments, including psychedelic compounds like psilocybin, which is in late-stage trials, and neuroplastogen compounds. It also discusses repetitive transcranial magnetic stimulation, including the SAINT protocol, which has shown rapid antidepressant effects and is FDA-cleared for treatment-resistant depression. The ALTO-300 trial is evaluating an adjunctive treatment guided by an EEG biomarker, and a Phase 2 study reports outcomes varying by genotype, suggesting potential for genetically personalized interventions. Challenges include unblinding in psychedelic trials, scalability of neuromodulation, and need for validated biomarkers.
Clinical Neuropsychopharmacology and Addiction
June 25, 2026
Luca Persico, Giacomo D’andrea, Clara Cavallotto et al.
Intranasal esketamine substantially reduced depression severity in 210 patients with treatment-resistant depression treated in routine clinical practice. Depression scores improved markedly over three months, and men showed a modest advantage over women by the end of treatment, with lower depression ratings and higher rates of response and remission. Among patients under 65 years, sex differences were small and not statistically significant; among those 65 and older, men appeared to benefit more numerically, but this difference did not hold up after statistical correction and remains uncertain. Discontinuation rates and safety outcomes were similar between sexes. The authors call for future studies to examine hormonal, vascular, inflammatory, and other factors that might explain the observed sex differences.
International Journal of Innovative Technologies in Social Science
June 24, 2026
Aleksandra Łoś, Kacper Szkodziński, Inga Jakubczyk et al.
Depressive disorders affect up to 16% of the population over a lifetime and are a leading cause of disability. For 20–50% of patients, standard treatments fail, leading to treatment-resistant depression (TRD). A review of studies on psilocybin-assisted therapy (PAT) for major depressive disorder (MDD) and TRD found that PAT offers a faster onset of action than traditional antidepressants, with symptom reduction often occurring within the first week and lasting 6–12 months. Many patients also improved in anhedonia, anxiety, and psychosocial functioning. Psilocybin represents a promising alternative for severe depression and TRD, with rapid and lasting effects.
International Journal of Innovative Technologies in Social Science
June 24, 2026
Irmina Grygutis, Oskar Mikołajczyk, Kornelia Julia Fimiarz et al.
Ketamine and its derivative esketamine are rapid-acting treatments for treatment-resistant depression, but the best way to give them depends on balancing effectiveness, safety, cost, and available healthcare resources. Intravenous (IV) ketamine works fastest and most strongly but requires infusion equipment and monitoring for temporary high blood pressure and dissociation. FDA-approved intranasal esketamine has strong long-term data but needs supervised in-clinic administration and blood pressure checks. Oral and sublingual forms are easier and cheaper but less effective and carry higher risk of misuse. Subcutaneous and intramuscular injections offer high absorption with minimal setup but have little supporting evidence. The choice of route should be tailored to each patient's situation.
European Psychiatry
June 23, 2026
Maximilian Preiß, Valentin Popper, Luna Helene Charlotte Faber et al.
No Summary
Journal of Psychopharmacology
June 23, 2026
Lenka Seillier, Alexandre Seillier, Morgan A. Zvolska et al.
Psilocybin produces rapid and sustained antidepressant-like effects in rats, as measured by reduced immobility and increased climbing in the forced swim test. Blocking the 5-HT2B receptor with the antagonist RS-127445 dose-dependently reversed these behavioral effects, indicating that 5-HT2B receptors are necessary for psilocybin's antidepressant-like activity. However, the same antagonist did not affect psilocybin-induced head-twitch responses, a proxy for psychedelic effects, suggesting that the antidepressant-like and psychedelic effects of psilocybin can be dissociated via different serotonin receptor subtypes.
medRxiv
June 23, 2026
Paulina Clara Dagnino, Anne Maj van der Velden, Henricus G. Ruhé et al.
In people with major depressive disorder, mindfulness-based cognitive therapy (MBCT) plus treatment as usual, compared to treatment as usual alone, increased the hierarchical organization of brain activity during rumination but not at rest. Greater hierarchy—meaning more directional information flow and less recurrent looping—was linked to improvements in clinical and behavioral outcomes. This shift away from self-reinforcing negative mental loops toward more differentiated cognitive and bodily cycles may help explain how MBCT interrupts ruminative thought patterns. Hierarchical brain dynamics could serve as a treatment-sensitive marker and potential mechanism of therapeutic change in MBCT for depression.
INNOVAPATH
June 22, 2026
Muhammad Bilal Akram, Ali Sher, Areena Fatima et al.
Treatment-resistant depression (TRD) affects many people with major depressive disorder who do not get better after adequate medication. TRD is a varied condition driven by complex interactions among brain, immune, and social factors. Better understanding of its causes—including brain inflammation, problems with how brain cells communicate, and hormone imbalances—has helped identify possible markers for diagnosis and new treatments. This perspective discusses these underlying mechanisms, highlights promising biomarkers for diagnosis and treatment planning, and covers emerging therapies such as fast-acting antidepressants, brain stimulation, and psychedelic-assisted therapy. Combining these advances into medical care may allow more personalized and effective management of TRD.
Journal of Education Health and Sport
June 22, 2026
Urszula Szuleta, Wiktoria Zawada, Krystian Kaczmarek et al.
Major depressive disorder often resists current treatments; a reanalysis of the STAR*D study found a cumulative remission rate of about 41% after up to four treatment steps. Ketamine and its derivatives have attracted attention for their rapid antidepressant effects, especially in treatment-resistant depression. This review summarizes evidence on their efficacy, safety, and clinical use. Ketamine appears promising due to its fast onset of action, and some evidence suggests it may reduce suicidal ideation in high-risk patients. However, the authors emphasize the need for further large-scale, long-term studies to clarify the durability of benefit and long-term safety.
UNC Libraries
June 21, 2026
Verina Guirguis
Esketamine is an effective treatment for individuals with treatment-resistant depression, showing significant mood improvements shortly after administration. In a study of five participants with major depressive disorder, subjective feelings of 'Highness' increased by 31.73% and 'Happiness' by 22.75% within 15 minutes. A notable reduction in alpha power was observed, peaking at a decrease of 46.36% at 35 minutes post-administration. These changes correlate with mood fluctuations, suggesting dynamic brain network alterations during treatment.
Progress in neuro-psychopharmacology & biological psychiatry
June 20, 2026
Xin Ding, Kenji Hashimoto, Jian-Jun Yang
Xanomeline and ketamine, two mechanistically distinct antidepressants, partially converge on common molecular pathways despite acting through different upstream receptors. Network pharmacology and molecular docking identified 368 overlapping targets for xanomeline with major depressive disorder and 714 for ketamine. Three shared signaling pathways emerged: EGFR tyrosine kinase inhibitor resistance, Ras signaling, and Rap1 signaling. Three core proteins—EGFR, IGF1R, and SRC—were common to both drugs. Xanomeline associated more strongly with receptor tyrosine kinase and PI3K/AKT signaling, while ketamine linked more to synaptic transmission, NMDA receptors, and glutamatergic signaling. These hypothesis-generating findings suggest partial convergence on downstream plasticity-related signaling nodes.
Progress in neuro-psychopharmacology & biological psychiatry
June 20, 2026
Jen-Ping Chen, Chih-Wei Hsu, Yi-Ya Fang et al.
Esketamine initiation, compared with oral antidepressant monotherapy, was associated with a 26% lower risk of all-cause mortality over two years among adults aged 18–74 with cancer-related depression, according to a target trial emulation using electronic health records. After propensity score matching of 1,751 patients per group, esketamine also corresponded to lower risks of emergency room visits, intensive care unit visits, ischemic stroke, and psychotherapy utilization. Safety outcomes were generally comparable between groups. The associations were more pronounced in older patients. These real-world findings support esketamine as a potential therapeutic option for managing cancer-related depression.
Research Square
June 19, 2026
Aline Frick, Grace Blest‐hopley, Manesh Grin et al.
In a reanalysis of a six-week randomized controlled trial comparing psilocybin with escitalopram for moderate-to-severe major depressive disorder, sex-related patterns emerged for anxiety and anhedonia. Women receiving psilocybin showed greater reductions in anxiety than men, while women receiving escitalopram showed greater reductions in anhedonia than men. For other depressive symptoms, thought suppression, and well-being, sex differences were small and uncertain. Sexual dysfunction severity was lower overall in the psilocybin group than in the escitalopram group and lower in women than in men, though the treatment-by-sex interaction was not significant. These preliminary findings suggest that responses to these serotonergic treatments may differ between women and men, supporting the need for adequately powered, sex-balanced trials.