medRxiv Preprint Server
May 31, 2026
Yves Martins Varela, Patrícia Cavalcanti-Ribeiro, Geovan Menezes de Sousa et al.
preprint
Ketamine rapidly reduces depression symptoms in treatment-resistant depression, but its effects may be enhanced by combining it with psychotherapy. The drug induces neuroplasticity and psychological openness, which could help patients process emotions, restructure thoughts, and maintain improvements. However, research has not yet thoroughly examined whether adding structured psychotherapy to ketamine treatment provides additional benefits.
Pharmaceuticals (Basel, Switzerland)
May 31, 2026
Wenting Zhang, Xin Guo, Jiping Zhang et al.
Combining the herbal formula Dajianzhong Decoction (DJZT) with ketamine produces synergistic antidepressant effects in a mouse model of depression. The combination restores levels of short-chain fatty acids (SCFAs), particularly acetic acid and isobutyric acid, in the gut. These SCFAs activate the FFAR2 receptor in the brain's medial prefrontal cortex, which suppresses NLRP3-IL-1β-driven neuroinflammation and reverses synaptic deficits. Blocking FFAR2 with the inhibitor GLPG0974 eliminates these benefits. The findings suggest that the SCFA-FFAR2-NLRP3-IL-1β axis mediates the prolonged antidepressant action of the combined treatment, pointing to microbiota-modulating strategies for improving ketamine therapy.
Journal of pain & palliative care pharmacotherapy
May 29, 2026
Yogendra Singhal, Pavan Gaurav R, Sreeharsh Saji et al.
Depression is common among cancer patients and harms quality of life, treatment adherence, and prognosis. Standard antidepressants take weeks to work, but ketamine may offer rapid relief. This systematic review of 14 studies (randomized trials, cohort studies, and case-control designs) found that ketamine quickly reduces depressive symptoms, often within hours to days, and also improves anxiety, pain, and quality of life. Short-term side effects include fatigue, dizziness, and dissociation; long-term safety data are limited. Ketamine appears promising as a short-term option for depression in cancer patients, especially those with treatment-resistant depression, but more research is needed on long-term outcomes and optimal dosing.
Transl Psychiatry
May 29, 2026
The way NMDA antagonists alter negative affective biases in male rats could predict how well these drugs will work in humans with major depressive disorder.
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.
Psychotherapy and psychosomatics
May 27, 2026
Lea J Mertens, Felix Betzler, Manuela Brand et al.
A single 25 mg dose of psilocybin, or two such doses given six weeks apart, combined with psychotherapy produced a stable and clinically meaningful reduction in depression symptoms for up to twelve months in people with treatment-resistant depression. The average improvement on the Hamilton Rating Scale for Depression was about 7.9 points at six months and 7.7 points at twelve months, with no significant difference between dosing groups. Restarting standard antidepressant medication during follow-up was strongly linked to higher depression scores. This naturalistic follow-up of a phase 2b trial is the largest and most complete long-term assessment of psilocybin for depression to date.
May 27, 2026
James Phelps
A randomized trial found that serial intravenous ketamine was not significantly more effective than the active placebo midazolam in reducing depressive symptoms or improving quality of life. The improvement in MADRS scores fell short of the minimal clinically important difference. The study had a small sample size of 63 participants and faced blinding failures, with 78% of patients and 90% of raters correctly identifying the ketamine group, suggesting results may have been influenced by unblinded expectations. Further research that controls for non-specific effects is needed.
Australian & New Zealand Journal of Psychiatry
May 26, 2026
1 citation
Novel treatments for treatment-resistant depression, such as ketamine, esketamine, transcranial magnetic stimulation, and psilocybin-assisted therapy, are available in Australia but mostly through commercial clinics that require out-of-pocket payment, leaving many patients without access. The authors identify barriers including difficulty diagnosing treatment-resistant depression, lack of clinician training, and regulatory and economic hurdles. They propose establishing specialist treatment-resistant depression clinics, particularly in the public sector, to improve access and build expertise.
Expert Opin Investig Drugs
May 26, 2026
A review of a two-step approach for bipolar depression with acute suicidal ideation and behavior: an initial intravenous ketamine protocol for rapid symptom relief, followed by maintenance with D-cycloserine and lurasidone to prolong therapeutic effects. The strategy is mechanistically informed but uncertainties remain about which components drive efficacy, optimal dosing, and duration of benefits. Further studies are needed to refine maintenance strategies and translate insights into clinical practice.
Biomedicines
May 23, 2026
Dominik Jucha, Michał Klimas, Dominika Wiśniewska et al.
About 25% of people with bipolar disorder experience drug-resistant depression, where standard treatments fail. This paper reviews augmentation strategies and polypharmacotherapy for treatment-resistant bipolar depression. Atypical antipsychotics show limited efficacy and high side effects. Ketamine produces the fastest and strongest antidepressant effect with low risk of switching to mania. Pramipexole shows long-term promise but carries high risk of mania and impulse control disorders. Celecoxib, as anti-inflammatory therapy, significantly improved response and remission rates compared to escitalopram alone. Memantine showed only early, short-term benefit. The authors conclude that rational polypharmacotherapy targeting glutamatergic and inflammatory pathways is most promising, with ketamine having the greatest clinical potential.
Psychopharmacology (Berl)
May 22, 2026
A single subanesthetic-dose ketamine infusion shortens the global and regional path length of brain functional connectivity in people with treatment-resistant depression and suicidal ideation, suggesting a more efficient network organization. This change in connectivity may underlie the rapid antidepressant and anti-suicidal effects of ketamine.
Ther Adv Psychopharmacol
May 22, 2026
Among people with treatment-resistant depression, early changes in suicidal ideation after ketamine or esketamine treatment are linked to later emergency department visits for suicidality. The analysis indicates that reductions in suicidal thoughts during the first few weeks of treatment may lower the risk of subsequent emergency care for suicidality, though the relationship requires further study.
Current topics in medicinal chemistry
May 21, 2026
Guizhen Lyu, Dongbing Li
Depression affects over 300 million people worldwide and is a leading cause of disability. This review synthesizes recent advances in understanding depression across biological, cognitive, and psychosocial domains, highlighting innovations in diagnosis, pathophysiology, and treatment. It explores distinctions between major depressive disorder and bipolar depression, emphasizing biomarkers and neuroimaging to reduce misdiagnosis. Special attention is given to under-researched subtypes like postpartum, inflammation-related, and adolescent depression. Pathophysiological insights include dysregulated neurotransmitter systems, neuroinflammation, and disrupted neural connectivity, with genetic-environment interactions underscoring personalized approaches. Advances in treatment range from FDA-approved neurosteroid therapies for postpartum depression to psychedelic-assisted psychotherapy for treatment-resistant cases, advocating for precision psychiatry and interdisciplinary models to reduce healthcare disparities.
Pharmacol Rep
May 20, 2026
A retrospective analysis of patient-reported outcomes found that psychiatric adverse events emerged during ketamine treatment for major depressive disorder. The text does not specify the frequency, severity, or nature of these events, nor does it provide comparative data or a control group. The analysis suggests that such events can occur, but the magnitude and clinical significance remain unclear based solely on the abstract.
Scientific reports
May 20, 2026
Guan-Jie She, Wei-Chi Li, Chun-Hsiang Chou et al.
Ketamine infusion alters brain activity patterns in people with treatment-resistant depression, specifically in regions involved in sensory-cognitive integration, mood regulation, and cognitive control. In a study of 45 patients, those receiving ketamine showed changes in the timing and shape of hemodynamic responses in the bilateral olfactory cortex and right inferior parietal gyrus, compared to those receiving midazolam. Improvements in suicidal thoughts were linked to changes in the thalamus and superior frontal gyrus. Ketamine responders also had reduced time-to-peak in the left precuneus. These findings suggest ketamine's effects on suicidal ideation may involve neurovascular coupling dynamics.
Ther Adv Psychopharmacol
May 19, 2026
correction
No Summary
Acta pharmacologica Sinica
May 19, 2026
Jun-Nan Xu, Jing-Ting Li, Ru-Xia Xu et al.
Depressed mice show reduced motivation to explore in a new behavioral test called the Multilevel Exploration Test (MET), which breaks exploration into search, attend/investigate, and approach phases. Activating a specific neural circuit from the prelimbic cortex to the zona incerta restored exploratory deficits and alleviated other depression-like behaviors. A machine learning model using MET data predicted individual emotional states—normal, anxiety-like, or depression-like—with over 92% accuracy. The MET offers a high-throughput way to study motivation-related brain mechanisms and may help identify new antidepressant targets.
J Affect Disord
May 16, 2026
1 citation
A panel of experts from the American Society of Ketamine Physicians, Psychotherapists, and Practitioners used a Delphi process to develop consensus guidelines for administering intravenous ketamine infusions to treat depressive disorders. The guidelines provide recommendations on patient selection, dosing, safety monitoring, and treatment protocols, aiming to standardize clinical practice and improve patient outcomes. The consensus reflects agreement among specialists on best practices for this off-label use of ketamine.
Asian J Psychiatr
May 16, 2026
1 citation
A systematic review and meta-analysis of randomized controlled trials found that oral ketamine produces short-term antidepressant effects. The analysis synthesizes evidence from multiple trials, indicating that oral ketamine can reduce depressive symptoms more than placebo or control conditions over brief follow-up periods. The review notes that the evidence base is still limited and that longer-term efficacy and safety require further investigation.
JAMA Network Open
May 15, 2026
1 citation
A single 25 mg dose of psilocybin, combined with psychotherapeutic support, produced rapid antidepressant effects in people with moderate to severe recurrent major depressive disorder. Depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale, improved significantly more in the psilocybin group than in the placebo group by day 8, with benefits lasting through day 42 but not at one year. Self-reported depressive symptoms showed improvement as early as day 2 and persisted for over three months. The treatment was generally well tolerated, though two participants experienced persistent severe anxiety requiring medical attention. These findings suggest psilocybin may offer a rapid and relatively durable antidepressant effect.
Behavioral sciences (Basel, Switzerland)
May 14, 2026
Fabiola Raffone, Carlo Ignazio Cattaneo, Enrico Pessina et al.
Trauma-related autobiographical memories can become intrusive and distressing, contributing to post-traumatic stress disorder (PTSD) and depression, including treatment-resistant depression (TRD). Intranasal esketamine, an approved rapid-acting treatment for TRD, may create conditions that facilitate psychotherapeutic work on traumatic memories. This narrative review synthesizes evidence on ketamine and esketamine for PTSD and trauma symptoms, distinguishing intravenous ketamine studies, intranasal esketamine data, and combination approaches with psychotherapy.
J Affect Disord
May 14, 2026
Ketamine treatment alters the network structure of depression symptoms in people with treatment-resistant depression. The connections among symptoms, such as mood and sleep, shift after treatment, suggesting that ketamine may work by reorganizing how symptoms relate to one another rather than simply reducing overall severity.
Fortschr Neurol Psychiatr
May 13, 2026
1 citation
Esketamine, an NMDA receptor antagonist, is approved as a nasal spray for treatment-resistant major depression and for rapid symptom reduction in psychiatric emergencies. In the US it is also approved as a monotherapy for treatment-resistant depression. Acute treatment often causes dissociative effects, but a link between these initial symptoms and later therapeutic response is not sufficiently proven. A key methodological problem is functional unblinding, where characteristic side effects reveal group assignment. Proponents of ketamine-augmented psychotherapy suggest that ketamine-induced synaptic plasticity opens a 'therapeutic window' for psychotherapy, but current research methods cannot adequately test causal relationships due to unblinding and general limitations of psychotherapy studies.
BJPsych Open
May 13, 2026
This is a correction notice for a previously published study protocol. The original protocol describes a phase II double-blind placebo-controlled randomised partial crossover trial investigating microdosing psilocybin for major depressive disorder. No new findings or data are presented.