Efficacy and safety of esketamine for smoking cessation among patients diagnosed with lung cancer and major depression disorder: A randomized, placebo-controlled clinical trial

Cigarette smoking remains a major global health threat, and prevalence among cancer survivors is high despite overall declines in smoking. Quitting at the time of a cancer diagnosis substantially reduces mortality and risk of subsequent cancers, but cessation is often complicated by coexisting major depressive disorder (MDD). Previous research indicates a bidirectional relationship between smoking and depression, and cessation can provoke or worsen negative affect and anxiety, making quitting particularly challenging for people with MDD. Esketamine (ESK), an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects and regulatory approval for treatment-resistant depression, has not been established as a smoking cessation aid. Hong and colleagues therefore designed a multicentre, double-blind, randomised, placebo-controlled clinical trial to test whether intranasal ESK could increase smoking cessation rates in patients concurrently diagnosed with lung cancer and MDD. The study aimed to assess: efficacy for continuous smoking abstinence, changes in depression and anxiety severity, cognitive function and smoking-related symptoms, and the safety and tolerability of ESK in this high-risk population.

This trial was conducted at eight medical centres in Zhejiang province, China, between February 2023 and April 2024, with ethics approval and registration (ChiCTR2300068591). Adults aged 18–65 with a recent diagnosis of lung cancer scheduled for thoracoscopic surgery, current daily smokers (≥10 cigarettes/day for ≥6 months), and DSM-5-defined MDD with inadequate response/intolerance to at least two prior adequate treatments in the current episode were eligible. Key exclusions included schizophrenia or uncontrolled psychosis, recent major cardiac events, current use of smoking cessation medications, significant cognitive impairment, recent suicide attempt, pregnancy/breastfeeding, participation in other cessation programmes, and certain endocrine disorders. A sample size target of 236 (118 per group) was set using an effect size d = 0.5 for 95% power; allowance was made for approximately 10% drop-out. Participants were randomised 1:1 by a central system to intranasal esketamine (0.5 mg/kg) or saline placebo. Blinding measures included identical disposable nasal spray devices, preparation of study drug by a nurse not involved in assessments, and addition of a bittering agent to placebo to mimic taste. Treatments were given once weekly for eight sessions; the first dose was scheduled three weeks before surgery to align with recommended preoperative cessation timing. Participants continued existing antidepressant regimens and received cessation counselling after the initial session and standard WeChat-based support during follow-up. The primary clinical outcome was continuous smoking abstinence assessed 8 months after the first treatment (2 months of treatment plus 6 months of follow-up), defined as self-reported abstinence since last visit confirmed by expired-air carbon monoxide (CO) < 10 parts per million; missing data or CO > 10 ppm were classified as non-abstinent. Secondary outcomes included changes in depression (HDRS-24, QIDS-SR16), anxiety (GAD-7, VAS-A), cognitive function (MoCA), nicotine dependence (Fagerström Test), urge to smoke (strength and frequency scores), and respiratory symptoms (cough, phlegm, shortness of breath, wheeze). Safety assessments recorded treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs); psychotomimetic and dissociative symptoms were monitored using BPRS and CADSS, sedation with the MOAA/S scale, and predefined thresholds for clinically significant haemodynamic or respiratory change. Analyses used a modified intention-to-treat (mITT) principle including participants who received at least one treatment and had one post‑session assessment; last observation carried forward was used for missing scores. Statistical tests included t-tests or Mann–Whitney U tests for continuous data, chi-square for categorical variables, and two-sided significance set at p < 0.05.

Of 2,636 patients screened, 286 met inclusion criteria and 242 consented; 236 participants were randomised equally to esketamine (ESK, n = 118) or placebo (PLA, n = 118). During treatment 4 ESK participants discontinued due to side effects and 1 PLA participant discontinued for an unknown reason; during follow-up 5 ESK and 3 PLA participants were lost to follow-up. A total of 224 participants (94.9% of 236) completed all treatment sessions and 6 months of follow-up. Results were reported using the mITT approach described in Methods. Primary outcome: Among 236 participants, 222 (94.1%) provided 6‑month self‑report follow-up and 66 (29.7% of 222) claimed abstinence; 63 underwent CO verification and 43 (68.3% of 63) had self‑report confirmed. In the mITT analysis the 6‑month self‑reported continuous quit rate was 44.1% (52/118) in the ESK group versus 12.7% (15/118) in PLA, an estimated difference of 31.4% (95% CI 7.8% to 54.2%); odds ratio 5.21 (95% CI 1.96–7.82; p < 0.001). The 6‑month CO‑verified continuous quit rate was 28.8% (34/118) for ESK versus 7.6% (9/118) for PLA, an estimated difference of 21.2% (95% CI 4.3% to 36.1%); odds ratio 4.88 (95% CI 1.92–6.57; p < 0.001). Emotional and cognitive outcomes: Baseline depression scores indicated moderate–severe MDD (mean HDRS‑24 24.08, QIDS‑SR16 16.02). HDRS‑24 in the ESK group fell from 24.22 (SD 3.11) at baseline to 8.42 (SD 3.65) at 8 months, whereas PLA decreased from 23.92 (SD 3.32) to 16.73 (SD 3.79); the estimated between‑group HDRS difference at 8 months was −8.31 (p = 0.013, SE = 1.46). QIDS‑SR16 analyses showed similar group differences. Anxiety (GAD‑7) decreased from 13.85 (SD 3.05) to 6.11 (SD 2.96) in ESK versus 14.21 (SD 3.18) to 12.45 (SD 2.88) in PLA; the estimated between‑group difference at 8 months was −6.34 (95% CI −9.66 to −3.21; p = 0.021, SE = 1.31). Cognitive function by MoCA was higher in ESK at 8 months (mean 27.12, SD 1.86) than PLA (mean 25.21, SD 1.83); estimated difference 1.91 (95% CI 0.26 to 3.77; p = 0.031, SE = 1.07). Smoking‑related symptoms and dependence: Baseline respiratory symptoms were common (cough 59.3%, phlegm 49.6%). By 8 months, ESK significantly reduced incidence of cough (to 28.0%; p < 0.001) and phlegm (to 23.7%; p < 0.001); nausea and throat irritation were also reported less often in ESK (p < 0.05). No between‑group differences were observed for shortness of breath or wheeze. Fagerström scores indicated lower nicotine dependence in ESK (p = 0.022, SE = 0.65), and urge‑to‑smoke strength, frequency and composite scores were reduced in ESK versus PLA (p < 0.05). Safety: Common TEAEs (≥10%) included dizziness, somnolence, headache, nausea and dissociation. Most events were mild, transient and occurred during or shortly after dosing, resolving within 2 hours. Moderate or greater sedation (MOAA/S ≤4) occurred in 16.1% (19/118) of ESK participants versus 0.85% (1/118) in PLA; sedation typically began ~15 minutes after dosing and peaked at ~45 minutes. BPRS and CADSS scores peaked 30–60 minutes post‑dose and returned to baseline by 2 hours. TEAEs tended to decline with repeated dosing. Nasopharyngitis during follow‑up was more frequent in ESK. Three participants died during follow‑up from lung cancer‑related causes (two PLA, one ESK); no other SAEs or psychosis were reported. Blinding assessment found 14.4% of participants believed they knew allocation. No clear evidence of withdrawal after treatment cessation was observed.

Hong frames the findings as evidence that intranasal esketamine, delivered once weekly for eight sessions, increased continuous smoking abstinence at 6 months and produced substantial improvements in depressive and anxiety symptoms among patients with lung cancer and MDD. The investigators highlight concurrent reductions in nicotine dependence, urge to smoke and some smoking‑related respiratory symptoms, and report that most adverse events were transient and manageable without treatment‑related serious adverse events. The authors compare the CO‑verified 6‑month abstinence rate for ESK (28.8%) with published figures for other cessation interventions (reported within the paper as bupropion 23.1%, varenicline 27.0%, e‑cigarettes 18.0%, nicotine replacement 9.9%, and an FDA‑approved standard treatment 21.5), noting that ESK's effect size is broadly comparable to existing pharmacotherapies in this context. They underscore the rapid and robust antidepressant properties of ESK as a possible mechanism aiding cessation, and discuss neurobiological hypotheses linking nicotine dependence and depression, including habenular circuitry and multiple neurotransmitter systems (dopamine, serotonin, AMPA, opioids). On cognitive outcomes the authors propose several contributory factors: reversal of tobacco‑related cognitive impairment following cessation, improvement in depression‑related cognitive deficits, and better sleep quality postoperatively and after ESK, all of which may have contributed to MoCA gains. Strengths they cite include the trial's novelty in directly testing ESK for smoking cessation in this clinical population, multicentre conduct, 6‑month follow‑up to assess persistence of effects, and use of WeChat to reduce observer bias in self‑report questionnaires. Limitations acknowledged by the investigators include the short follow‑up with respect to cancer outcomes (they did not assess recurrence, survival or second primary cancers), limited geographic representation (all centres in eastern China) affecting generalisability, inability to disentangle changes in mood related to surgery from preexisting MDD over follow‑up, and potential partial unblinding due to characteristic sedative effects of ESK. The authors conclude that intranasal ESK is an efficacious and feasible treatment for cigarette smoking cessation in lung cancer patients with MDD, with concurrent improvement in mood and an acceptable safety profile.