International journal of psychiatry in clinical practice
April 29, 2026
David Eckert, Siegfried Kasper
A narrative review presents a decision-making framework for three pharmacological augmentation strategies for treatment-resistant depression: lithium, quetiapine, and esketamine. The agents differ in pharmacological profile, monitoring requirements, and clinical application, though their mechanisms appear to converge on neuroplasticity pathways. Treatment selection may be guided by psychiatric presentation, somatic comorbidity, and practical feasibility. Validated predictive markers for differential response are currently lacking.
Naunyn-Schmiedeberg's archives of pharmacology
April 28, 2026
Yunsheng Liu, Rongde Zhong, Fenyong Yao et al.
Since 1975, research on ionotropic glutamate receptors (iGluRs) in depression has grown 7.31% annually, with the United States and China leading publication output. The field has shifted from basic synaptic mechanisms to clinical applications, particularly NMDA receptors and treatment-resistant depression. Ketamine therapy exemplifies a successful translation from preclinical models to rapid-acting antidepressants. A bibliometric analysis of 6,843 publications maps this evolution, identifies key collaborative networks, and highlights knowledge gaps to guide future development of next-generation antidepressants.
Zenodo (CERN European Organization for Nuclear Research)
April 27, 2026
Ryan Malone
A new mechanistic model called the Thalamic Filter Model (TFM) proposes that depression may involve chronically elevated inhibitory tone in the thalamic reticular nucleus, which narrows conscious bandwidth and produces cognitive rigidity and rumination. Ketamine's rapid antidepressant effect may work by temporarily reducing this thalamic over-filtering. Baseline EEG features—including vigilance stage distribution and spectral dynamics—predict ketamine response in treatment-resistant depression. A review of six independent EEG biomarker studies (total n > 200) found that lower baseline vigilance, lower gamma power, and higher alpha power all predict better response, consistent with the model's prediction that higher baseline filter impedance predicts greater benefit. The model generates three falsifiable predictions and proposes lag-1 autocorrelation as a practical baseline biomarker.
BMC psychiatry
April 26, 2026
Sergi López-rodríguez, Cinto Segalàs, Eva Real et al.
In eight adults with treatment-resistant obsessive-compulsive disorder and comorbid major depressive disorder, twelve weeks of intranasal esketamine (56-84 mg per session) substantially improved depressive symptoms, with MADRS scores decreasing by 48.8%. Obsessive-compulsive symptoms showed a more modest and heterogeneous reduction, with Y-BOCS scores decreasing by 30.3%. Half of participants achieved depression response, and half met OCD response criteria. Depressive symptoms improved earlier, while OCD symptoms followed a slower and more variable trajectory. These preliminary findings suggest that repeated intranasal esketamine may offer a therapeutic window for this severe subgroup, supporting further controlled studies.
Scientific Reports
April 25, 2026
Audrey G. Evers, Elizabeth C. Stade, Aadesh Salecha et al.
1 citation
Media coverage of psychedelics as mental health treatments is more positive and less cautious than coverage of FDA-approved antidepressants. An analysis of 6,805 newspaper articles from 2017 to 2024 found that positive emotion and sentiment were more strongly associated with psychedelic coverage, while negative emotion and risk language were more strongly associated with antidepressant coverage. Contrary to expectations, reward language was more linked to antidepressants, and negative sentiment appeared more in psychedelic coverage. This imbalance may shape patient expectations, treatment adherence, and outcomes.
Psychedelics
April 25, 2026
Juliet Meccia, David Casimir, Sisi Li et al.
Over the past 25 years, informal and underground use of 5-MeO-DMT has generated substantial, though underrecognized, knowledge about its potential to alleviate depressive symptoms. Traditional drug development, with structured trials and regulatory milestones, rarely incorporates findings from these alternative routes. Legal and regulatory barriers have delayed formal clinical investigation, while public channels and Indigenous knowledge have driven grassroots support and anecdotal evidence of therapeutic benefit. The article identifies critical communication gaps hindering integration of 5-MeO-DMT into mainstream psychiatry and advocates for transparent data-sharing models that incorporate existing informal knowledge.
Pharmaceuticals (Basel, Switzerland)
April 24, 2026
Pietro Carmellini, Alessandro Cuomo, Maria Beatrice Rescalli et al.
Depression likely arises from a mix of two interacting biological problems: imbalances in monoamine neurotransmitters (like serotonin) and disruptions in glutamate signaling that impair the brain's ability to adapt and form new connections. These two systems can combine in different ways across individuals, helping explain why some people respond to standard antidepressants while others do not. Rapid-acting treatments such as ketamine work by directly targeting the glutamate system to boost synaptic plasticity, offering faster relief, especially for treatment-resistant depression. A framework called the 'monoamine-glutamate continuum' may guide future precision psychiatry by matching treatments to each person's specific neurobiological profile.
Translational Psychiatry
April 24, 2026
Matt Butler, Ellen Moore, James Rucker et al.
1 citation
Hallucinogen persisting perception disorder (HPPD) involves episodes of altered perception after past psychoactive drug use, causing distress and impairment. In a large retrospective cohort study using electronic health records from 25,778 individuals diagnosed with HPPD, high rates of prior comorbidities were found, including depressive episodes (29.2%), anxiety disorders (26.2%), chronic pain (15.9%), headache syndromes (14.7%), post-viral fatigue (12.3%), ADHD (6.6%), and fibromyalgia (6.7%). Anxiety and functional somatic syndromes were more common in HPPD patients than in psychedelic-using controls. Anxiety (odds ratio 1.5) and post-viral fatigue (odds ratio 1.9) predicted HPPD development among psychedelic users. After diagnosis, HPPD was associated with increased risk of subsequent functional somatic syndromes (odds ratio 2.0) and psychiatric disorders (odds ratio 1.4) compared to psychedelic-using controls.
Journal of psychopharmacology (Oxford, England)
April 24, 2026
Marco Colizzi, Elisa Morandin, Veronica Croccia et al.
In adults with treatment-resistant depression, higher baseline levels of the inflammatory marker interleukin-6 (IL-6) were associated with more rapid symptom reduction after intranasal esketamine treatment, while lower IL-6 predicted greater symptom severity and higher disability. IL-6 levels themselves did not change over the 24-week open-label phase 2 trial. The finding suggests that inflammation may play a role in treatment resistance and that baseline IL-6 could help guide personalized treatment decisions.
Journal of psychoactive drugs
April 23, 2026
Brayan Jonas Mano-Sousa, Maria Clara Gama Fontes, Ana Clara Anacleto Gonçalves et al.
In people with treatment-resistant depression, ayahuasca—a traditional Amazonian psychedelic—rapidly reduces suicidal thoughts and depressive symptoms. A systematic review of five studies found consistent evidence of these effects, attributed to the synergistic action of β-carbolines and DMT. Neurobiologically, ayahuasca promotes neuroplasticity by upregulating Brain-Derived Neurotrophic Factor and decreasing Default Mode Network activity, enabling profound introspection and emotional processing. Despite promising results, large-scale, rigorous longitudinal studies are needed to establish safe clinical guidelines.
Open Access Indonesian Journal of Medical Reviews
April 21, 2026
Psilocybin-assisted therapy produces a large reduction in depressive symptoms, but the evidence is preliminary and limited by methodological problems. A meta-analysis of nine randomized controlled trials involving 514 participants found a large effect size (SMD = 1.270). However, the certainty of the evidence is rated low due to risk of bias, high heterogeneity, short-term follow-up, and publication bias. Effects were much larger when psilocybin was compared to a waitlist rather than an active placebo, and blinding is compromised by the drug's subjective effects. The authors conclude that robust Phase 3 trials are needed before routine clinical use.
Mental Wellness
April 21, 2026
Mohsen Khosravi, Domenico de Berardis, Massimo Tusconi
A systematic review and meta-analysis of 13 clinical trials with 606 participants found no statistically significant overall antidepressant effect of psilocybin-assisted psychotherapy for major depressive disorder and treatment-resistant depression. The pooled standardized mean difference was -0.79 with a 95% confidence interval from -3.98 to 2.40, and extreme heterogeneity across studies was observed. The type of control group accounted for most of the variation between studies, with waitlist and low-dose comparators exaggerating effect sizes. Session frequency moderated outcomes, with 2 to 5 sessions yielding larger effects and more intensive protocols reducing benefit. Psilocybin's antidepressant efficacy appears highly context-dependent rather than universally robust.
Scientific reports
April 21, 2026
Rong Ding, Daojie Wang, Guoxin Wang et al.
Adding low-dose esketamine (1 mg/kg) to sufentanil patient-controlled analgesia (PCA) significantly reduces postoperative depression and anxiety in elderly colorectal cancer patients without improving pain control or increasing side effects. In a double-blind trial of 99 patients aged 65 and older, those receiving esketamine had lower anxiety and depression scores at 24 and 72 hours after surgery compared to those given only sufentanil; no dose-dependent difference was seen between 1 mg/kg and 2 mg/kg esketamine. Pain scores and need for rescue analgesia did not differ between groups. Patient satisfaction was higher with esketamine (77% and 90%) than with sufentanil alone (50%). Adverse events were similar across groups.
Current pain and headache reports
April 21, 2026
Navy C Coggins, Hanson A Chokr, Tricia A Meyer et al.
Ketamine, originally developed as a dissociative anesthetic, has expanded beyond procedural sedation to pain management and psychiatry. In pain medicine, its therapeutic rationale is grounded in noncompetitive antagonism of the NMDA receptor and modulation of central sensitization, key mechanisms underlying refractory neuropathic and centralized pain states. Evidence from preclinical studies and randomized clinical trials suggests intravenous ketamine may provide short-term analgesic benefit for resistant neuropathic pain, phantom limb pain, and complex regional pain syndrome. Low-dose perioperative administration has demonstrated opioid-sparing effects as part of multimodal analgesia.
bioRxiv : the preprint server for biology
April 17, 2026
Pasha A Davoudian, Quan Jiang, Cory A Knox et al.
Psilocybin, a classic psychedelic, alters the activity of specific inhibitory neurons in the mouse medial frontal cortex. It reduces firing of somatostatin-expressing interneurons while increasing activity of parvalbumin-expressing interneurons. This cell type-specific response depends on the 5-HT1A receptor on somatostatin interneurons, and contributes to the drug's long-term behavioral effects. The findings reveal that psilocybin changes cortical inhibition in a targeted manner, highlighting a mechanism beyond the commonly studied pyramidal cells.
Journal of intensive care medicine
April 16, 2026
Vrutti Patel, Saurabh Sujanyal, Lekhya Raavi et al.
Subanesthetic doses of ketamine improved specific depressive symptoms in critically ill intensive care unit patients without causing significant hemodynamic instability. In a retrospective study of 34 adults, including 18 solid organ transplant recipients, ketamine infusions (0.3-0.75 mg/kg over 40 minutes on three consecutive days) were associated with improvement in apparent sadness (90.0% vs 52.2%) and reported sadness (95.0% vs 59.1%). Among transplant recipients, improvement in apparent sadness remained significant (80.0% vs 41.7%). Heart rate increased transiently at 15-30 minutes post-infusion but returned to baseline by 60-90 minutes. Adverse effects included anxiety (12.5%), restlessness or agitation (10.4%), and dissociation (8.16%). These findings support ketamine's potential as a rapid-acting antidepressant in the ICU.
Journal of psychopharmacology (Oxford, England)
April 16, 2026
Minna Chang, Allan H Young, Mario F Juruena
Both electroconvulsive therapy (ECT) and ketamine show sustained therapeutic potential for treatment-resistant depression, with ECT possibly associated with longer remission. Higher doses, more frequent administration, and maintenance ECT or ketamine appear to prolong remission, and continuing oral antidepressants may extend it further. This systematic review of 13 studies found no direct head-to-head comparisons of time-to-relapse between the two treatments that met inclusion criteria, preventing formal statistical analysis. The review excluded studies involving psychotic depression, limiting generalizability to those populations.
Current neuropharmacology
April 16, 2026
Xiangying Wei, Shan Xu, Zhaoqiong Zhu
General anesthetics such as ketamine, propofol, isoflurane, and certain opioids show rapid and sustained antidepressant effects in both preclinical and clinical settings, offering a new therapeutic avenue for treatment-resistant depression, which affects about one-third of patients. These effects go beyond traditional monoamine regulation, involving modulation of glutamate and GABA signals and restoration of synaptic plasticity in damaged brain circuits. Despite the promise, balancing benefits against risks and establishing consistent treatment guidelines remain critical for developing new rapid-acting antidepressants for patients who do not respond to standard care.
Journal of affective disorders
April 15, 2026
Gia Han Le, Sabrina Wong, Danica E Johnson et al.
4 citations
Ketamine and esketamine rapidly reduce depression in people with treatment-resistant depression and bipolar depression, but the synaptic mechanisms behind dosing and durability are unclear. This review of 61 clinical and 17 preclinical studies found that a single 0.5 mg/kg intravenous infusion produces antidepressant effects peaking at 24 hours and fading over 2-3 days. Early neurophysiological changes appear within 3-8 hours, consolidate by 24 hours, and are rarely detected beyond 3 days. Twice-weekly and thrice-weekly dosing produce comparable four-week outcomes, and weekly maintenance reduces relapse risk. Ketamine may open a plasticity window lasting about 2-3 days, and aligning dosing intervals with this window could optimize durability while minimizing drug exposure.
Preprints.org
April 15, 2026
preprint
This review examines the potential therapeutic use of psilocybin in older adults for inflammation-driven disorders of aging, including depression and neurodegeneration. It discusses how psilocybin may modulate inflammatory pathways and promote neuroplasticity, offering benefits for age-related conditions where inflammation plays a key role. The authors suggest that psilocybin-assisted therapy could address both mood disorders and cognitive decline in this population, though they note the need for further research to establish safety and efficacy in older adults.
Journal of affective disorders
April 15, 2026
Jen-Ping Chen, Chih-Wei Hsu, Yi-Ting Chen et al.
Among adults with treatment-resistant depression, repetitive transcranial magnetic stimulation (rTMS) was associated with fewer medical complications than esketamine over the first year, including lower risks of hospitalization, arrhythmia, and any injury. Suicide-related outcomes were broadly comparable overall, though esketamine showed a protective advantage during the 30-90-day interval and among patients aged 45-65 years. The analysis used target trial emulation with propensity score matching on 50 covariates, drawing on electronic health records of 1,690 matched patients per treatment group. The findings suggest rTMS has a more favorable overall medical safety profile, while suicide risks were similar except for specific subgroups and time periods.
Frontiers in Psychiatry
April 13, 2026
Craig F. Ferris
Psychiatric drug development has stagnated for decades, with treatments for depression, schizophrenia, and PTSD offering only partial relief—remission rates of 30-40% for treatment-resistant depression and 60-70% of schizophrenia patients experiencing persistent symptoms. A paradigm shift proposes that mental illness stems from breakdowns in the brain's sensory filtering mechanisms, which gate irrelevant stimuli. The cerebellum is identified as a critical hub for bottom-up sensory gating, housing over half the brain's neurons and showing disrupted connectivity during PTSD symptom provocation. Psychedelic drugs may recalibrate these filters by disrupting entrenched filtering architectures and reopening plasticity windows. This framework extends predictive processing theory with a specific neural substrate and suggests novel therapeutic targets.
Transl Psychiatry
April 10, 2026
1 citation
A target trial simulation using real-world data suggests that esketamine, when added to standard antidepressant treatment, maintains effectiveness and safety over a sustained period for people with major depressive disorder. The analysis, designed to mimic a randomized trial, found that patients receiving esketamine showed continued improvement in depressive symptoms without unexpected safety concerns. The findings support the long-term use of esketamine as a treatment option for major depressive disorder.
BMC medical education
April 9, 2026
Nikita Sanati Morel, Dea Siggaard Stenbaek, Johan Lundberg et al.
Nine nurses completed a 15-week online and on-site training program to serve as facilitators in a trial of psilocybin treatment for depression in cancer patients. Subjective evaluations indicated the training supported knowledge and skill acquisition, but most nurses reported needing additional practical in-person training to feel adequately prepared. An objective assessment of verbal relational skills using role-plays showed a significant increase in only one of twelve measures, with medium to large effect sizes for six measures from pre- to post-training. The training model showed modest potential to improve outcomes, though effects were limited to role-play. The specific skills and qualifications needed for providing psychotherapeutic support in psilocybin treatment remain unclear.