Zenodo (CERN European Organization for Nuclear Research)
February 28, 2026
Kshirsagar Pankaj*, Misal Shivdarshan, Dr. Giri Ashok
About one-third of people with major depressive disorder or bipolar depression do not get better with standard antidepressants, a condition called treatment-resistant depression. Ketamine and esketamine, which modulate the glutamate system by blocking NMDA receptors, can produce rapid antidepressant effects within hours when given intravenously at low doses. Esketamine nasal spray is approved for treatment-resistant depression and major depression with suicidal thoughts, based on clinical trials. These drugs offer a new approach focused on neuroplasticity rather than the older monoamine theory, but they require monitoring for side effects such as dissociation, sedation, and potential for misuse. Long-term safety and effective maintenance strategies still need to be established.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
February 27, 2026
Chris H. Miller, Angela Hickman, Caitlin Baten et al.
2 citations
Ketamine, originally developed as an anesthetic, has emerged as a novel treatment for major depressive disorder (MDD) and treatment-resistant depression (TRD). Its antidepressant properties were discovered serendipitously, leading to FDA approval for TRD and MDD with suicidal ideation. The drug acts primarily as an NMDA receptor antagonist, triggering a paradoxical AMPA-mediated glutamate surge that promotes synaptogenesis and neuroplasticity. Intravenous ketamine and intranasal esketamine differ in dosing, bioavailability, and onset. Common adverse effects include dissociation, sedation, and hypertension. Efficacy studies show mixed-to-positive results, with non-inferiority to established treatments like electroconvulsive therapy. Future research aims to develop predictive markers for personalized medicine.
Naunyn Schmiedebergs Arch Pharmacol
February 26, 2026
1 citation
Esketamine, a drug used for treatment-resistant depression, is associated with a range of adverse drug events, including psychiatric, neurological, and cardiovascular effects. Analysis of reports from the US Food and Drug Administration Adverse Event Reporting System identified the most common adverse events as dissociation, sedation, and increased blood pressure. Network toxicology analysis suggested that esketamine may interact with multiple biological targets and pathways, potentially explaining its toxicological mechanisms. The findings indicate that while esketamine is effective, careful monitoring for specific adverse events is warranted.
Pharmacopsychiatry
February 26, 2026
Ping-Chung Wu, Wei-Chen Lin, Tung-Ping Su et al.
A combination of clinical markers better predicts which patients with treatment-resistant depression and suicidal thoughts will respond rapidly and durably to a single low-dose ketamine infusion than any single marker alone. The markers include mild or moderate depression severity, a shorter current episode, no more than four prior antidepressant failures, low or moderate current suicide risk, and a history of suicide attempts. The analysis of 67 patients from previous trials used a decision-tree model to identify these predictors. Clinicians can use these findings to select patients most likely to benefit, though further confirmation is needed.
American Journal of Geriatric Psychiatry
February 24, 2026
Rachel Fremont, Amelia Karim, Tanya Peguero Estevez et al.
1 citation
In an open-label clinical trial, a single intravenous infusion of ketamine (0.5 mg/kg) was safe and well tolerated in 13 patients with mild cognitive impairment and major depressive disorder. No serious adverse events occurred. Depression severity, measured by the Montgomery-Asberg Depression Rating Scale, dropped from a mean of 27.4 before treatment to 5.7 at 24 hours after the infusion—a large-magnitude improvement. For 8 of the 13 patients, this improvement persisted for up to one month, with a mean score of 12.1 and at least a 50% reduction. These findings suggest ketamine may be effective for depression in this population, but larger randomized controlled trials are needed to confirm efficacy and assess cognitive effects.
J Affect Disord
February 23, 2026
In a randomized controlled trial, adolescents with major depressive disorder who received repeated esketamine infusions showed changes in multiple peripheral inflammatory markers compared to those who received a placebo. The treatment was associated with reductions in certain inflammatory markers, suggesting that esketamine may influence immune system activity in this population. The findings indicate a potential link between the antidepressant effects of esketamine and its impact on inflammation, though the exact relationship requires further investigation.
Journal of Clinical Medicine
February 20, 2026
Vassilis Martiadis, Fabiola Raffone, Serena Testa et al.
7 citations
Intranasal esketamine provides rapid symptom relief for treatment-resistant depression when standard antidepressants fail, but its real-world effectiveness depends on organizational and multidisciplinary factors beyond pharmacology. This narrative review synthesizes clinical and real-world evidence to propose a phase-based integration framework that specifies complementary roles for psychiatry, nursing, and psychotherapy across pre-treatment assessment, induction, session delivery, post-session integration, and maintenance phases. The framework emphasizes safety, continuity of care, and patient-centred monitoring, with measurable implementation indicators. While evidence supports esketamine's efficacy in reducing depressive symptoms, anhedonia, and suicidality, prospective implementation studies are needed to evaluate clinical effectiveness, feasibility, and cost-effectiveness of the proposed multidisciplinary approach.
Psychiatry Research
February 19, 2026
Trisha Menon, Andy Lu, Akhilan Arulmozhi et al.
Ketamine, esketamine, repetitive transcranial magnetic stimulation (rTMS), and electroconvulsive therapy (ECT) are associated with reductions in suicidal ideation in people with major depressive disorder. The strongest evidence from randomized controlled trials supports rapid, short-term effects, particularly for ketamine and esketamine. Further research is needed to characterize the durability of these antisuicidal effects and to determine whether reductions in suicidal ideation translate into reduced severity of suicidal behavior.
AJN American Journal of Nursing
February 19, 2026
Liz Braun, Alison Colbert
Ketamine, initially approved as an anesthetic in 1970, is increasingly used off-label for treatment-resistant depression, anxiety, and posttraumatic stress disorder. Its S-enantiomer, esketamine (Spravato), received FDA approval for treatment-resistant depression in 2019. Clinical applications include intranasal esketamine, IV infusions, ketamine-assisted psychotherapy, and at-home therapy, with varying oversight. The regulatory landscape remains fragmented, evidence is evolving, and vulnerable patients seek relief. This article provides clinical information for nurses advising patients about ketamine and discusses regulatory, ethical, and nursing implications.
Medical Science Monitor
February 18, 2026
Łukasz Grabarczyk, Sophia Rebekka Wolfermann, Hubert Oniszczuk et al.
Conventional antidepressants work in only about half of patients with treatment-resistant depression (TRD). Ketamine, a fast-acting NMDA receptor antagonist, offers an alternative. This non-systematic review of preclinical and clinical evidence found that both ketamine and esketamine show efficacy across several TRD subpopulations, including geriatric, psychiatric, neurologic, oncologic, pediatric, and obstetric patients. Key challenges include psychotomimetic effects, abuse potential, and cardiovascular side effects. Preliminary data on arketamine suggest possible longer-lasting benefits with fewer adverse effects. However, many findings come from very small samples, highlighting the need for larger trials to establish definitive safety and efficacy.
Molecular Psychiatry
February 18, 2026
1 citation
Esketamine, a fast-acting antidepressant, improves depression in both sexes among adults with treatment-resistant depression. However, females showed greater overall improvement and higher odds of treatment response than males toward the end of four-week trials, regardless of whether they received esketamine or placebo. Females also experienced more pronounced reductions in sadness, detachment, and neurovegetative symptoms at certain time points. In contrast, males showed a significant reduction in sadness symptoms two days after esketamine. These findings indicate that sex assigned at birth influences the trajectory and symptom profile of antidepressant response, highlighting its importance for personalized treatment strategies.
Research Square
February 17, 2026
Zofia Winczewska, Magdalena Górska‐ponikowska, Wiesław Jerzy Cubała
Ketamine at 25 ng/mL increased the viability of mouse hippocampal HT22 neuronal cells exposed to hydrogen peroxide, but only at the highest concentration tested (1000 µM H₂O₂). At that level, cell viability rose from 12% (±1.63%) without ketamine to 38% (±9.12%) with ketamine. This suggests a protective, nonlinear effect that depends on the intensity of oxidative stress, activating only at critical H₂O₂ overload typical of severe depression. The findings indicate a threshold antioxidant mechanism that may contribute to ketamine's antidepressant action and inform future predictive models for individualized treatment.
International Journal of Innovative Technologies in Social Science
February 16, 2026
Esketamine nasal spray, the first novel mechanism treatment for treatment-resistant depression in decades, has an acceptable safety profile under clinical supervision. Common adverse effects such as dissociation and sedation resolve within two hours, and blood pressure elevations normalize within 1.5 hours without intervention. Pre-approval concerns about bladder cystitis, cognitive decline, and abuse were not confirmed: no cystitis occurred despite years of exposure, cognitive function remained stable or improved, and misuse was rare (less than 0.01%). Serious adverse events were infrequent (less than 0.2% of sessions), mainly during initial treatments. Mortality rates matched background rates in treatment-resistant depression. Long-term studies up to 6.5 years found no organ damage, cognitive decline, or meaningful abuse problems.
Addiction
February 16, 2026
Cassie Bloy, Ananya Sarma, Bethan Marsh et al.
1 citation
People with alcohol use disorder experience changes in consciousness from 0.8 mg/kg intravenous ketamine administration. Ketamine's effects remain broadly consistent across three repeated infusions. Reductions in alcohol consumption linked to ketamine do not appear to be caused by the acute psychoactive effects of the drug.
Research Square
February 11, 2026
Jack Swain, Davis Carter, Leonardo Vando
Among 374 adults with moderate-to-severe PTSD who completed six sessions of at-home, telehealth-supported ketamine-assisted therapy, PTSD symptoms improved substantially. Mean PCL-5 scores dropped from 51.1 at baseline to 28.3 after session 6, a 44.6% reduction. The clinical response rate was 79.7%, and 60.7% achieved remission. Suicidal ideation resolved completely in 75.9% of those who reported it at baseline. Depression and anxiety scores also declined by about half. Side effects occurred in 4.3% of participants. Controlled trials are needed to confirm causality.
February 10, 2026
Jolien K. E. Veraart
Treatment-resistant depression is a poorly defined label that may harm patients' hope. Survey data show many individuals seeking ketamine treatment have long-standing depressive symptoms and dissatisfaction with standard therapies. Fixed low doses of oral esketamine were not effective in a randomized controlled trial, but higher, individualized dosing led to meaningful improvement in a subgroup. Ketamine was often effective and well tolerated in complex cases, including patients with psychotic symptoms, PTSD, or those on maintenance ECT, especially with supportive monitoring. Combining ketamine with psychotherapy appears promising but needs more research. A key pharmacological finding is that repeated oral use may speed up ketamine's own metabolism (auto-induction), potentially reducing long-term effectiveness.
bioRxiv (Cold Spring Harbor Laboratory)
February 10, 2026
Erdem Pulcu, Sara Costi, Pilar Artiach-Hortelano et al.
A single sub-anesthetic dose of ketamine reduces activity in the lateral habenula, a small midbrain structure involved in aversive learning, when healthy volunteers expect or experience unpleasant stimuli a day later. In a randomized trial with 70 adults, those who received ketamine showed attenuated habenula responses during an aversive Pavlovian conditioning task measured with 7-Tesla functional neuroimaging. Preliminary evidence suggests that reduced habenula activity during aversive learning may weaken the emotional impact of negative memories. These results support preclinical models of how ketamine may rapidly relieve depression by acting on the human habenula.
Brain Sciences
February 7, 2026
Miriam Olivola, Tiziano Prodi, Giada Versaci et al.
2 citations
During intranasal esketamine treatment for treatment-resistant depression, patients describe four distinct types of dissociative experiences: sensory alteration and perceptual flow (27.8%), time suspension and chronological drift (58.3%), body and space alteration (55.6%), and psychic distance from suffering (83.3%). Most patients frame these experiences as neutral or meaningful, often linked to temporary relief from rumination and depressive distress, though a minority report transient distress or loss of control. The findings suggest dissociation functions as a transitional subjective state whose clinical relevance depends on anticipation, framing, monitoring, and integration, supporting structured psychoeducation and in-session support in esketamine programs.
International journal of psychiatry in clinical practice
February 7, 2026
Daniel Pustay, Vishal Patel, Krista Ulisse et al.
A systematic review of 42 studies examined predictors of response to electroconvulsive therapy, repetitive transcranial magnetic stimulation, and ketamine-based treatments in adults with treatment-resistant depression. Predictive factors were grouped into clinical (symptom profile, illness duration), biological (IL-6, CRP, BDNF), and imaging (cingulate cortex activity, connectivity) categories. Inflammation markers and fronto-limbic network findings appeared across treatments but were inconsistent. Some predictors show promise, but clinical use remains limited by methodological differences and small sample sizes. Larger and comparative studies are needed to identify clinically useful predictors for treatment decision-making.
Psychopharmacology
February 7, 2026
Rebecca J Simpson, Mario F Juruena
1 citation
Ketamine-assisted psychotherapy (KAP) shows promise for treatment-resistant depression, with reductions in depressive symptoms sustained up to six months in some cases. However, among the three studies with control groups, no significant differences were found between KAP and control conditions. Methodological heterogeneity across the 11 included studies—including variability in treatment protocols, outcome measures, and study designs—limits the ability to draw firm conclusions or identify mechanisms driving KAP's effects. More rigorous research, particularly randomized controlled trials, is needed to better understand its efficacy and mechanisms.
Neuropsychobiology
February 5, 2026
Lavanya Seth, Jitendriya Biswal, Surjeet Sahoo et al.
Both electroconvulsive therapy (ECT) and intravenous ketamine, given alongside oral antidepressants, significantly reduce severe depression and suicidal thoughts in patients with major depressive disorder. In a trial with 64 adults, depression scores dropped from 27 to 1 with ECT and from 26 to 2 with ketamine by four weeks after treatment; suicidal ideation scores fell from 12.1 to 1.2 with ECT and from 12.6 to 2.0 with ketamine. Ketamine worked faster, while ECT had slightly more lasting effects. Side effects were mild: ECT caused temporary cognitive issues, ketamine caused minor dissociative and urinary symptoms. Ketamine is a promising rapid option for acute suicidal ideation.
Molecular neurobiology
February 5, 2026
Zofia Winczewska, Wiesław J Cubała, Piotr Radziwiłłowicz et al.
5 citations
Oxidative stress (OS) is increasingly recognized not only as a factor in depressive disorders but also as a potential biomarker for the severity and persistence of treatment-resistant depression (TRD). This review synthesizes current evidence linking OS to TRD's chronicity and symptom persistence, suggesting that OS severity may indicate treatment resistance. The authors discuss fast-acting antidepressants and a non-pharmacological nutraceutical approach aimed at reducing OS as a way to fill a therapeutic gap and improve recovery chances. An integrated strategy to lower OS may help overcome treatment resistance in severe TRD, modifying disease course and improving prognosis.
Journal of affective disorders
February 4, 2026
Raquel Kosted, Alli Waddell, Ken Adolph et al.
Depression symptoms improved over time in patients receiving five ketamine infusions, with faster initial improvement that slowed later. Higher scores on the Adverse Childhood Experiences (ACE) survey were linked to greater symptom reduction, regardless of whether patients received ketamine-assisted therapy or infusions alone. Younger adults showed a stronger response to infusions alone compared to ketamine-assisted therapy, while older adults showed the opposite pattern. The association between higher ACE scores and greater symptom reduction was particularly pronounced in younger adults and reversed in older adults. These findings suggest ketamine may offer a targeted benefit for people with early life stress, especially younger adults.
Brain Sciences
February 4, 2026
Katarina Savić Vujović, Sonja Vučković, Lara Samardžić et al.
Ketamine and a ketamine-magnesium sulfate combination lower body temperature in rats through serotonergic and adrenergic mechanisms, but not through GABAA receptors. Giving yohimbine, an α2-adrenergic blocker, deepened ketamine-induced hypothermia at doses of 0.5 and 1 mg/kg, while only the highest dose (3 mg/kg) enhanced the combination's effect. Methysergide, a serotonin blocker, had opposite effects depending on dose: 1 mg/kg worsened ketamine hypothermia, whereas 0.5 mg/kg reduced the combination's cooling effect. Bicuculline, a GABAA antagonist, did not change hypothermia from either treatment. These findings clarify neurotransmitter pathways involved in NMDA antagonist-related thermoregulation.