Monthly research recap
Esketamine research: September 2026
What September 2026's 20 new studies found, synthesized from the papers below. All Esketamine research →
The synthesis
Synthesized from 19 studies in the library · AI-generated, grounded in the abstracts below
Found by searching the library for Esketamine, S-ketamine, spravato, esketamine nasal spray, then ranked by relevance.
Research indexed in September 2026 on esketamine is dominated by observational and review work rather than new large randomized trials. The most consistent findings are symptomatic improvement in treatment-resistant depression (e.g., mean MADRS reductions of roughly 7-8 points, quality-of-life gains, and reduced hopelessness), but effects on suicidality-specific outcomes are inconsistent, and one large retrospective cohort found no statistically distinguishable difference in suicide attempt or self-harm. Evidence on cognition, biomarkers, and durability remains mixed or preliminary, and most studies are small, uncontrolled, or short-term.
Evidence by study
Direction is which way each study's own result points, not our rating of the study. All 20 matching studies were reviewed; the 19 that directly address the question are shown here.
What the directions mean
- Supports:
- the study found the intervention worked, or its hypothesis held.
- Opposes:
- it found the opposite, no benefit or a harm.
- No effect:
- no significant difference either way.
- Mixed:
- effects in both directions within the same study.
- Unclear:
- the abstract does not report a direction.
| Study | Design | Sample size | Direction | Finding |
|---|---|---|---|---|
| Peripheral Biomarkers of Response to Ketamine and Esketamine Treatment in Unipolar Depressive Disorder—A Scoping Review 2026 | systematic review | 46 | Mixed | Across 46 studies, the most examined peripheral biomarkers (BDNF, inflammatory markers, kynurenine metabolites) showed inconsistent associations with ketamine or esketamine response, and no biomarker was judged ready for clinical use. |
| The Era of Rapid-Acting Antidepressants: Clinical Insights Into Ketamine, Esketamine, and Scopolamine 2026 | systematic review | 7 | Supports | Rapid-acting antidepressants produced rapid antidepressant responses, with the most consistent evidence for intravenous ketamine (onset about 110 minutes, response rates up to 70% at 24 hours, duration 1-2 weeks) and maintenance intranasal esketamine (MADRS reduction over four weeks, relapse HR 0.49). |
| Feasibility and tolerability of virtual reality during esketamine treatment: A pilot study. 2026 | pilot feasibility and tolerability study | 26 | Mixed | Auditory and visual discomfort were common during ketamine treatment and most surveyed patients were open to virtual reality, but among five patients who used VR during an esketamine session, glasses wearers had difficulty and nausea and all showed reduced altered-state scores. |
| A circuit dissection of perception-action decoupling in S-ketamine-induced hallucination-like states. 2026 | preclinical experimental study | Supports | S-ketamine induced auditory false alarms and behavioral disorganization through dissociable striatal pathways, and dexmedetomidine restored pathway-level temporal dynamics without simply suppressing activity. | |
| Esketamine for treatment of depression in Huntington's disease: A case report 2026 | case study | 1 | Mixed | Nasal esketamine was followed by rapid mood improvement (BDI 29 to 5 after three treatment days), but depression worsened again by three months (BDI 20). |
| Cognitive effects of ketamine and esketamine treatment for major depressive and bipolar disorder: a systematic review. 2026 | systematic review | 2441 | Mixed | Single-dose ketamine or esketamine showed inconsistent cognitive effects in randomized trials (some improvements, null findings, and impaired memory recall and processing speed), while open-label maintenance ketamine was associated with within-group cognitive improvements whose independence from antidepressant response or practice effects is uncertain. |
| EFFECTS OF KETAMINE AND ESKETAMINE ON SUICIDAL IDEATION WITHIN THE FIRST 24 HOURS IN ADULTS WITH DEPRESSIVE DISORDERS: VARIABILITY IN CLINICAL FINDINGS AND INTERPRETATIVE CHALLENGES - A NARRATIVE REVIEW 2026 | narrative review | Mixed | Intravenous ketamine showed rapid reductions in suicidal ideation in some trials but not others, and intranasal esketamine improved depressive symptoms at 24 hours without significant differences in clinician-rated suicidality in either ASPIRE trial. | |
| Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder with Comorbid Treatment-Resistant Depression: A Six-Month Case Report 2026 | case study | 1 | Supports | Over six months of intranasal esketamine, MADRS fell from 38 to 17 and Y-BOCS from 33 to 14, though the authors state the observation cannot distinguish a direct anti-obsessional effect from depression improvement or nonspecific factors. |
| 507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review 2026 | case study | 1 | Opposes | About three years of intranasal esketamine maintenance was temporally associated with subsequent ketamine use disorder escalating to 2-3 g/day, with initial depression improvement (CGI-S 7 to 4) followed by worsening; the authors state causality cannot be inferred from a single case. |
| 384. S-ketamine, but not R-ketamine, increases the spontaneous firing rate and the AMPA-evoked response of pyramidal neurons in the rat prefrontal cortex 2026 | preclinical electrophysiological study | Supports | S-ketamine and ifenprodil increased spontaneous firing of medial prefrontal cortex neurons by 63% and 50%, and ketamine and S-ketamine increased AMPA responsiveness, while none altered NMDA responsiveness. | |
| 457. Intensive longitudinal monitoring of symptoms in response to treatment with intranasal esketamine 2026 | prospective longitudinal observational study | 15 | Mixed | Across 202 weekly self-reports, rumination decreased significantly while depression symptoms increased significantly, and anxiety and functional disability did not change significantly. |
| The effect of ketamine on mitochondrial bioenergetics, viability, and function: A systematic review. 2026 | systematic review | 13 | Mixed | Lower ketamine or esketamine concentrations generally did not adversely affect mitochondrial membrane potential, oxidative phosphorylation, respiration, or bioenergetics, whereas higher concentrations or prolonged exposure induced dysfunction in some models. |
| Metabolic Burden and Response to Repeated Intranasal Esketamine in Treatment-Resistant Depression: A Longitudinal Multidomain Biomarker Study 2026 | observational cohort | 30 | Supports | Esketamine was associated with a mean 7.7-point MADRS reduction, greater baseline metabolic burden predicted greater improvement, and fasting glucose fell by 1.58 mmol/L without weight change, while inflammatory and neurotrophic composites were not associated with symptom change. |
| Beyond symptom reduction: Intranasal esketamine is associated with improved quality of life in treatment-resistant depression. 2026 | observational cohort | 35 | Supports | Intranasal esketamine plus an oral antidepressant was associated with significant improvements over 6 months in depressive symptoms, hopelessness, suicidal ideation, and quality of life, with the quality-of-life improvement exceeding the threshold for clinical meaningfulness and no significant SSRI versus SNRI subgroup differences. |
| Esketamine Use and Attempted Suicide or Intentional Self-Harm Among Individuals with Treatment-Resistant Depression: A Retrospective Cohort Study. 2026 | retrospective cohort study | 23140 | No effect | Current esketamine exposure was not associated with a statistically distinguishable difference in recorded nonfatal, medically attended suicide attempt or intentional self-harm (HR 1.017, 95% CI 0.670-1.544), with the interval compatible with both benefit and harm. |
| 374. Intranasal esketamine in treatment-resistant bipolar depression maintained on long-acting aripiprazole 2026 | case series | 4 | Supports | Four patients achieved complete remission of depressive symptoms after add-on intranasal esketamine 84 mg, though the authors note limited existing data on esketamine in bipolar disorder. |
| 551. Esketamine in neuropsychiatric long COVID: a retrospective analysis 2026 | review | Unclear | Argues that Long COVID's neuropsychiatric manifestations overlap clinically and neurobiologically with depressive and anxiety disorders and that converging evidence implicates neuroinflammation; the abstract reports no primary findings. | |
| Esketamine for Postoperative Anxiety After Major Abdominal Tumor Surgery: A Randomized Clinical Trial 2026 | randomized controlled trial | 180 | No effect | Esketamine did not reduce postoperative anxiety: response rates on postoperative day 3 were 39.5% with esketamine versus 42.5% with placebo, and anxiety scores were similar at days 3 and 30, though esketamine was associated with lower depressive symptom scores at day 30. |
| 575. A scoping review: ketamine or esketamine when used to assist psychotherapy or in combination with psychotherapy for the management of depression 2026 | systematic review | Unclear | Argues that evidence for ketamine-assisted psychotherapy in depression is sparse and cannot be separated from ketamine's pharmacological antidepressant effects, and that only limited data support ketamine combined with psychotherapy. |
Points of agreement
- Intranasal esketamine added to oral antidepressants is consistently associated with reduced depressive symptoms in treatment-resistant depression across reviews and observational cohorts.
- Improvements extend to some secondary outcomes such as hopelessness and quality of life in observational studies.
- Biomarker and cognitive findings are repeatedly described as inconsistent or preliminary.
- Acute subjective and dissociative effects are common and shape tolerability and clinical management.
Conflicts
- Suicidality outcomes diverge: some trials and cohorts report reductions in suicidal ideation, while a large retrospective cohort found no statistically distinguishable difference in suicide attempt or self-harm and the ASPIRE trials showed no significant clinician-rated suicidality differences.
- Cognitive effects are mixed, with randomized trials showing improvements, null findings, and impairments, while open-label maintenance studies show within-group improvements.
- One longitudinal monitoring study found depression symptoms increased over treatment even as rumination improved, contrasting with cohorts reporting sustained symptom reduction.
- One case report describes ketamine use disorder emerging after long-term esketamine maintenance, contrasting with the generally favorable safety picture in reviews.
Gaps
- Durability of antidepressant response beyond a few weeks to months is poorly characterized.
- No peripheral biomarker is yet consistent enough for clinical implementation.
- Evidence in special populations (bipolar disorder, Huntington's disease, obsessive-compulsive disorder, Long COVID) rests on case reports, small case series, or argumentative reviews.
- Whether cognitive and quality-of-life gains are independent of antidepressant response or reflect practice effects is unresolved.
- Long-term safety, misuse risk, and optimal monitoring strategies are not established.
- Whether psychotherapy adds benefit beyond esketamine's pharmacological effect remains untested with adequate comparison groups.