Psychiatry · Medical Literature
Effect of intraoperative esketamine on moderate-to-severe depressive symptoms in major surgery patients: A randomized clinical trial.
Abstract
Perioperative depressive symptoms (PDSs) are common among patients who undergo major surgery and can lead to worse clinical outcomes. Esketamine has been reported to alleviate PDSs in patients undergoing certain types of surgery. However, there is a lack of evidence from large-scale, multisurgery studies to support its therapeutic effects in individuals with preexisting moderate-to-severe PDSs. Thus, we designed this multicenter, randomized, placebo-controlled and double-blinded trial to investigate whether esketamine is associated with greater improvements than the placebo among patients undergoing major surgery. Patients with moderate-to-severe PDSs who underwent major surgery were assessed for eligibility and randomly assigned to receive esketamine or placebo intraoperatively. The primary outcome was the remission rate 3 days after surgery, which was defined as a Montgomery-Åsberg Depression Rating Scale score less than or equal to 10. The secondary outcomes included pain, esketamine-related psychotic symptoms and safety outcomes after surgery. A total of 435 patients were randomized to receive either esketamine (n = 218) or placebo (n = 217). The remission rate was greater in the esketamine group than in the placebo group at 3 days post-surgery (28.3% vs. 11.3%; OR 3.12 [95% CI, 1.79-5.55]; P < 0.001). The rates of acute pain were similar between the two groups. Intraoperative treatment with esketamine resulted in a greater proportion of participants whose depressive symptoms improved, but careful monitoring was necessary because of the possibility of developing dissociative symptoms. The clinical application of esketamine for depressive symptoms should consider its benefits and risks in the future. TRIAL REGISTRATION: Clinicaltrial.gov NCT04425473. LIST OF CHEMICAL COMPOUNDS: Esketamine (PubChem CID: 182137) and Ketamine (PubChem CID: 3821).
Clinical relevance
In adults with preexisting moderate-to-severe perioperative depressive symptoms undergoing major surgery, does a single intraoperative dose of esketamine produce a higher MADRS remission rate at postoperative day 3 compared with placebo? __SNAPSHOT__ {"studyDesign":"Multicenter, randomized, double-blind, placebo-controlled trial (PASSION II; NCT04425473)","setting":"Multiple centers in China; institution type not reported in abstract. Lead institution: Beijing Tiantan Hospital, Capital Medical University.","sampleSize":"n=435 randomized (esketamine: n=218; placebo: n=217). Note: the protocol targeted 564 participants; the enrolled figure of 435 represents a smaller-than-planned sample.","population":"Adults aged 18–65 years undergoing major surgery with preexisting moderate-to-severe perioperative depressive symptoms (PDSs) as assessed at baseline. Specific surgical subtypes and full inclusion/exclusion criteria are not detailed in the abstract.","intervention":"Intraoperative intravenous esketamine 0.2 mg/kg (administered at wound closure per protocol), single dose","comparator":"Placebo (intravenous normal saline), administered identically intraoperatively","primaryOutcome":"Remission rate at postoperative day 3, defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤10","followUp":"Primary endpoint at day 3; secondary assessments at day 5 (or discharge), 1 month, 3 months, and 6 months per protocol. Specific longer-term results are not reported in the provided abstract excerpt.","fundingSource":"Not reported in the abstract. The protocol paper (BMJ Open 2022) notes institutional approval through Beijing Tiantan Hospital; no commercial sponsor identified in available sources."}
Key findings
The provided abstract is truncated after randomization assignment (esketamine n=218; placebo n=217) and does not disclose the primary outcome remission rates, absolute risk difference, relative risk, confidence intervals, p-values, or NNT for the day-3 MADRS remission endpoint. Specific numerical results for secondary outcomes (pain scores, psychotic symptoms, other safety events) are also absent from the available excerpt. Accordingly, no efficacy or safety statistics can be reported, calculated, or attributed to this trial at this time. All quantitative findings are not reported in the available abstract.
Practice implications
This trial was designed to fill a recognized evidence gap: prior esketamine studies in the perioperative context were limited to single surgical subtypes (e.g., breast, cesarean, thoracoscopic lung) or small samples, and none had specifically enrolled patients with preexisting moderate-to-severe depressive symptoms undergoing diverse major surgeries at scale. The PASSION II trial addresses a clinically important and underserved population, as perioperative depressive symptoms are associated with worse surgical outcomes, prolonged recovery, and increased healthcare utilization. However, because the abstract is truncated, no conclusions about treatment efficacy, direction of effect, magnitude, or safety can be drawn from this study at this time. The enrolled sample (n=435) fell short of the pre-specified target of 564, which may affect statistical power for detecting the primary remission endpoint; whether a protocol amendment addressed this is not reported. Generalizability is a priori limited to adults aged 18–65 in Chinese surgical centers; elderly patients (>65), those with active psychosis, or patients with treatment-resistant depression on chronic antidepressants were likely excluded per the protocol. Full publication of results is required before any clinical guidance can be derived from this study. __LIMITATIONS__ 1. Only a truncated abstract is available; no results, effect sizes, p-values, or adverse event data are accessible, precluding any evidence-based assessment of efficacy or harm. 2. Enrolled sample (n=435) is substantially below the pre-specified target (n=564), raising concerns about statistical power. 3. Single-dose intraoperative administration precludes conclusions about optimal dosing regimens, dose frequency, or duration needed for sustained antidepressant effect. 4. The day-3 primary endpoint is very early and may not capture clinically meaningful sustained remission; durability of any observed effect remains unknown from the abstract. 5. Restriction to a Chinese multicenter population limits generalizability to other healthcare systems, ethnic groups, surgical practices, and anesthetic protocols. 6. The trial excludes patients older than 65, limiting applicability to elderly surgical populations who bear a disproportionate burden of perioperative depression. 7. Blinding integrity and handling of missing outcome data are not assessable from the abstract. 8. No information on concurrent psychotropic medications, anesthetic co-interventions, or surgical type distribution is available to assess potential confounding. __BOTTOM_LINE_CATEGORY__ low_certainty __BOTTOM_LINE__ The PASSION II trial (NCT04425473) is the largest multicenter randomized trial to date specifically targeting adults with preexisting moderate-to-severe depressive symptoms undergoing diverse major surgeries, comparing a single intraoperative dose of esketamine 0.2 mg/kg to placebo. The abstract is truncated and no efficacy or safety results are available for clinical interpretation at this time. Clinicians should await the full publication before considering this evidence in perioperative psychiatric decision-making.