One in two smokers will die from their addiction unless they quit (Banks et al., 2015; Doll et al., 2004; Siddiqi et al., 2020). People with major depressive disorder (MDD) are up to three times more likely to smoke than those without MDD, highlighting the urgent need to address this public health challenge. Smoking prevalence in people with depression is 17.6% in the USA (Beth et al., 2022), with some studies suggesting rates up to 33% in other high-income nations (e.g., the UK (Taylor et al., 2020).
While people with mental health conditions are motivated to quit smoking (Siru et al., 2009), their odds of successfully quitting are 19% lower than those without mental illness (Hitsman et al., 2013). Due to these inequalities, individuals with depression are nearly twice as likely to die from smoking-related diseases (Correll et al., 2017; Plana-Ripoll et al., 2019).
The evidence linking smoking to mental health is striking. Not only may smoking cause depression (Wootton et al., 2020), but cessation has been shown to improve mental health (Taylor et al., 2021). Yet, a sense of therapeutic nihilism prevails in the treatment of smoking among those with mental illness. For example, varenicline, an effective smoking cessation aid, is less likely to be prescribed in this population than other medicines, like nicotine replacement therapy (NRT) (Taylor et al., 2020), and it has been laden with cautions to prescribers (British National Formulary), despite no clear evidence of harm (Anthenelli et al., 2016; Taylor et al., 2020; Thomas et al., 2022; Thomas et al., 2015; Wu et al., 2023).
Smoking rates and, consequently, smoking-related diseases are high among those with depression, creating a pressing public health challenge—time for better elf-care and access to effective smoking cessation treatments like varenicline.
This secondary analysis of the EAGLES randomised controlled trial (RCT) (Anthenelli et al., 2016; Kypriotakis et al., 2024) focused on:
- Individuals with current or historical major depressive disorder (MDD) and,
- Individuals with no psychiatric diagnosis (n= 6,653).
Eligible participants smoked >10 cigarettes/day and were motivated to quit. Participants were randomised to 12 weeks of varenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine replacement therapy (NRT) (transdermal nicotine patch 21 mg per day with taper), or placebo (placebo condition acted as a comparator for each individual medicine condition), with brief behavioural counselling at each visit. The 12-week treatment phase was followed by a 12-week non-treatment phase. Participants were asked to complete up to 15 face-to-face visits and 11 telephone visits during the 24-week trial. The trial was double-blinded, and outcome data were analysed as intention to treat.
Outcomes included moderate to severe neuropsychiatric adverse events (NPSAEs) and biologically verified, continuous abstinence at weeks 9–12 and weeks 9–24. Mental health changes were assessed using the Hospital Anxiety and Depression Scale (HADS), measuring anxiety and depression.
Participants
Results were presented by treatment condition, and further stratified by mental health subgroup:
- Past major depressive disorder (MDD) (n=2,174).
- Current MDD (n=451).
- Those without psychiatric diagnosis (n=4,028).
At baseline, the current-MDD cohort had a higher proportion of females and higher nicotine dependence, worse mental health according to the HADS and suicidal ideation history, higher use of psychotropic medications (e.g., antidepressants, anxiolytics, hypnotics, sedatives, antipsychotics, and mood stabilisers), and a longer smoking history.
Neuropsychiatric adverse events (NPSAEs)
The incidence of NPSAEs was low across all groups, with most symptoms occurring at frequencies ≤0.9%. Importantly, there were no treatment-related differences in suicidal ideation or related behaviours, or treatment discontinuations between the depression cohorts. Suicidal ideation was higher in the current-MDD cohort (3.3%) compared to the past-MDD (2.2%) and non-psychiatric (0.7%) cohorts, reflecting their baseline history of suicidal ideation. The incidence of treatment-emergent suicidal behaviour was very low, with no strong evidence for differences across cohorts or medications.
Safety analyses revealed no clear evidence for differences in the incidence of NPSAEs across the depression cohorts. The non-psychiatric cohort reported fewer NPSAEs compared to both the past-MDD and current-MDD cohorts. There was no strong evidence for differences in treatment-emergent NPSAEs between active treatments and placebo between the cohorts.
Efficacy: Smoking abstinence
In terms of efficacy, abstinence rates from smoking during weeks 9–12 were similar between the depression cohorts for varenicline. However, the current-MDD cohort had lower abstinence with bupropion and NRT compared to past-MDD and non-psychiatric cohorts. Within the past-MDD group, varenicline had higher abstinence rates than bupropion and placebo. For continuous abstinence (weeks 9–24), varenicline was particularly effective in the current-MDD cohort, outperforming both NRT and placebo, and bupropion outperformed NRT. Both the past-MDD and current-MDD cohorts had lower abstinence rates compared to the non-psychiatric cohort.
Anxiety and depression symptom changes
Changes in anxiety and depression symptoms were assessed, and results showed evidence for reductions in symptoms from baseline to week 6, stabilising by week 24. The current-MDD cohort showed improvements in both anxiety and depression, especially with varenicline. Varied improvements in anxiety and depression were observed across treatment groups, with varenicline showing the most substantial positive impact on outcomes in the current-MDD cohort.
Exploring how smoking cessation impacts mental health—when it comes to quitting, varenicline gives those with depression a much-needed helping hand.
The study makes an important contribution to our understanding of the safety and efficacy of smoking cessation medicines among individuals with MDD. Varenicline plus behavioural counselling is highlighted as an effective option, particularly for those with major depressive disorder (MDD), when compared to single-NRT, bupropion, or placebo.
The study offers important reassurance that smoking cessation medications are safe for this population, particularly in relation to neuropsychiatric events, mental health symptoms, and adverse effects. This includes any treatment-related risk of suicidal thoughts or behaviours. However, concerns remain in this particular trial about missing data for these outcomes, and the potential impact of industry funding.
Varenicline in combination with counselling may be an effective approach to safe smoking cessation for people with depression.
This study is the largest of its kind, focusing on smokers with current MDD, and offers an important comparison between smokers with past and current MDD diagnoses. By analysing data from the largest RCT in this population to date, the study advances our understanding of smoking cessation among individuals with varying MDD status. However, the analysis is still underpowered to detect differences between the past-MDD and current-MDD subgroups, which could have been augmented by applying methods like Bayes factors. Despite this, the trial data provide causal insights into the effects of smoking cessation medicines on main effectiveness outcomes like smoking cessation and depression and anxiety symptoms.
This study finds that smoking cessation medications are unlikely to increase adverse events, including treatment-emergent suicidal ideation and suicidal behaviours. This reassuring result supports their safety for people with MDD, a critical public health insight. However, concerns arise over missing mental health outcome data. In the original trial, 42 out of 4,116 participants in the psychiatric cohort had incomplete safety data, but the distribution of data missingness across clinical subgroups was not reported. The authors do not clarify this missing data or describe imputation methods. Similarly, the authors did not discuss missing data for the HADS.
The authors conclude that:
Varenicline plus behavioural counselling may be the best treatment for persons with past or current MDD.
While this underscores varenicline’s effectiveness, it disregards alternative options. For example, combination NRT is when one uses two types of NRT together, such as a nicotine patch plus a faster-acting NRT product like gum or lozenges. Systematic reviews suggest that combination-NRT is at least as effective, if not more so, for smoking cessation (Chang et al., 2015; Lindson et al., 2023), although evidence specific to individuals with MDD is limited.
Finally, potential commercial involvement raises concerns. While no direct financial benefits were disclosed, the author list includes scientists employed by pharmaceutical and consulting companies. Such links might influence research decisions and interpretations of treatment effectiveness and safety (Lundh et al., 2017).
This study gives us a clearer picture of smoking cessation in MDD, but like an ‘elf’ with a missing shoe, some gaps in data need to be filled for a full view.
The evidence on varenicline and smoking cessation in people with mental illness highlights the urgent need to address high smoking prevalence among individuals with depressive disorders, who face increased risks of smoking-related diseases and lower quit success rates. Kypriotakis et al.’s (2024) study reinforces that varenicline, combined with behavioural counselling, is a safe and effective treatment for smoking cessation in individuals with MDD. This study, along with other research on varenicline’s safety, supports lifting cautionary warnings for its use in people with mental illness, which could increase prescribing rates and help reduce smoking prevalence in this population.
The exclusion of combination-NRT, despite its proven efficacy, highlights the need for its inclusion in future research. Mental health benefits from smoking cessation likely stem from quitting itself rather than medication effects; combination-NRT’s higher quit rates could lead to even greater mental health improvements. Expanding evidenced-based treatment options and addressing biases in prescribing practices are essential to reduce smoking-related health inequalities among people with mental illness.
The evidence supports lifting mental health warnings around varenicline. Prescribers often fear lawsuits or believe it is unsafe for people with depression. Smoking is a leading cause of death in individuals with mental illness, who are far more likely to die from smoking-related diseases than from smoking cessation medication side effects. Yet, society continues to overlook the severe and devastating consequences of smoking in this population.
This issue is deeply personal to me. I have witnessed these consequences firsthand, with my father near the end of his life, suffering from multiple cancers, including lung cancer. Watching this has been heartbreaking. I reflect on all the times my dad visited the doctor—whether his smoking was overlooked, normalised, or deprioritised by a system unprepared to intervene until he quit at 60, on the day I graduated with a PhD focused on smoking cessation. After quitting, he told me it felt like “a black cloud had been lifted.” But sadly, quitting came too late. Ten years later, the effects of a lifetime of smoking are painfully clear.
In terms of next steps, the evidence base in this area is substantial, including findings from the current study, Cochrane reviews, and cohort studies. A network meta-analysis comparing combination-NRT and varenicline in individuals with MDD on cessation and mental health outcomes (if data are available) could provide additional clarity. Ideally, a well-designed, publicly funded RCT comparing these treatments in people with depression would conclusively “seal the deal,” strengthening the evidence and addressing any remaining gaps.
Addressing smoking in individuals with depression requires lifting outdated warnings, expanding treatment options, and acknowledging the personal and public health benefits of smoking cessation.
Dr Gemma Taylor has no financial interests in the study discussed in this blog and has no direct involvement with the researchers or the publication of this study. Dr Gemma Taylor is the Chief Investigator of smoking cessation trials for individuals with mental health conditions and holds academic positions at the Universities of Bristol and Bath. Dr Gemma Taylor is funded by CRUK and NIHR and is a member of the Society for Nicotine and Tobacco Research. Dr Gemma Taylor received funding from Pfizer in 2015 (via the GRAND scheme) to conduct epidemiological research on varenicline while employed at the University of Bristol. Dr Gemma Taylor has prior experience working as a statistical consultant to the pharmaceutical industry from 2022-2024.
Primary paper
Kypriotakis, G., Cinciripini, P., Green, C., Lawrence, D., Anthenelli, R., Minnix, J., Beneventi, D., Morris, C., Karam-Hage, M., & Blalock, J. (2024). Effects of Varenicline, Bupropion, Nicotine Patch, and Placebo on Treating Smoking Among Persons with Current or Past Major Depressive Disorder: Secondary Analysis of a Double-Blind, Randomised, Placebo-Controlled Trial. The American Journal of Psychiatry.
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