In this issue, Kypriotakis and colleagues (
1) present novel data from the EAGLES trial (Evaluating Adverse Events in a Global Smoking Cessation Study) demonstrating the safety of varenicline, bupropion, and nicotine replacement therapy (NRT) for cessation of cigarette smoking for people with a current or past diagnosis of major depressive disorder (MDD). Because the authors examined current and past MDD separately, they were able to demonstrate that all three pharmacological treatments improved cessation outcomes compared to placebo for people with past MDD. Only varenicline, however, demonstrated improved cessation outcomes compared to placebo for people with current MDD. Similarly, in Cinciripini and colleagues’ (
2) analysis of the EAGLES data, 31.2% of people with depression (a combined group with past and/or current MDD) reported continuous abstinence using varenicline, representing the best outcome of the four conditions (compared with 23.0% receiving bupropion, 22.6% receiving NRT, and 13.4% receiving a placebo). These findings have important clinical implications for determining first-line tobacco treatments for people with current MDD.
These data add to the evidence that pharmacological treatments for tobacco cessation are safe for people with depression and that mental health symptoms not only do not worsen but improve with tobacco cessation (
3–
5). We are unaware of any pharmacological properties of varenicline that would suggest that it has a direct effect on depressive symptoms. It is reasonable to assume that varenicline’s superior effect on quitting is associated with decreased depressive symptoms. One study, however, found that depressive symptoms decreased for participants with schizophrenia spectrum disorders who received varenicline treatment and behavioral interventions for cigarette smoking cessation regardless of their cessation status (i.e., quit smoking vs. continued smoking) (
6), thus indicating that it is not simply quitting cigarette smoking that accounts for the decreased depression. It remains possible, however, that the behavioral intervention, rather than the varenicline itself, contributed to the effect on depression.
The Kypriotakis et al. study and other EAGLES trial data (
7) demonstrate the safety of varenicline for individuals with psychiatric comorbidity, and the U.S. Food and Drug Administration removed the black box warning for varenicline related to suicidal thoughts and behaviors in 2015 (
8); however, many prescribers remain hesitant to prescribe varenicline to individuals with psychiatric comorbidity (
9). This hesitation is not limited to varenicline, as few prescribers provide general tobacco treatment for their patients. Indeed, a survey of U.S. psychiatrists found that only a minority reported that they assist with a quit plan (15.9%), with time constraints and competing factors commonly named as barriers to discussing tobacco use cessation (
10). It will be critical to find ways that allow psychiatrists to integrate tobacco treatment into their settings while minimizing barriers to providing this type of care. It may be useful for psychiatrists to develop partnerships that allow them to work collaboratively with other mental health professionals, especially those who may provide counseling, to aid the integration of tobacco treatment into their patients’ care.
As seen in Cinciripini and colleagues’ results (
2), summarized above, even with the best outcomes from pharmacological treatment, the majority of people with depression do not achieve abstinence from tobacco, meaning that we need to continue to work to develop treatment plans that improve outcomes. Consistent with most cigarette smoking treatment trials, participants in the EAGLES trial received only 10 minutes of counseling at each of the 12 study visits. Although the 2008 Public Health Service guideline (
11) reports that up to 10 minutes of counseling per session is associated with 1.6 times the chances and more than 10 minutes of counseling with 2.3 times the chances of cigarette abstinence as compared to no contact, 10 minutes of counseling per session is a much smaller dose of counseling compared to what would be expected for other substance use disorders, especially when comorbid depression is present. There are multiple types of counseling that have demonstrated efficacy for both depression and tobacco use disorder independently (e.g., acceptance and commitment therapy, cognitive-behavioral therapy, behavioral activation). In research examining whether integrating depression-focused treatment with tobacco cessation–focused treatment yields improved abstinence outcomes for people with depression compared to tobacco cessation–focused treatment alone, there has been only mixed support (
12–
14); however, given the support for varenicline and depression, it makes sense to examine the pairing of varenicline with more intensive doses of these counseling approaches as compared to a brief, 10-minute dose of cessation counseling for individuals with depression. One study examining varenicline and intensive counseling (eight 45-minute sessions) for individuals with depression who smoked cigarettes found that quit rates were 32.3% among those who attended at least 75% of their counseling sessions and only 2.7% for those who attended fewer sessions (
15). While directionality cannot be inferred from these data, this finding suggests the need for further research on varenicline paired with intensive psychosocial interventions that are relevant to both depression and tobacco use.
While people with depression are a key priority group related to tobacco disparities (e.g., greater prevalence of and/or consequences from tobacco use, greater difficulty in quitting tobacco use), it is also important to remember that there are individuals with depression who belong to additional tobacco-related disparity groups, such as women, individuals of sexual and gender minoritized status, individuals of racial and ethnic minoritized status, and individuals with lower socioeconomic status (
16,
17). In fact, the prevalence of tobacco use among people with depression varies by these factors (e.g.,
18–
20). For example, 2014 data from a national sample of individuals in the United States showed that, beyond a higher prevalence of cigarette smoking for people with depression (34.0%) compared to people without depression (19.9%), larger disparities were found when taking socioeconomic status into account (
20). Among individuals with depression, the prevalence of cigarette smoking was nearly two times higher for those with lower incomes (46.3%) compared to those with higher incomes (24.4%).
It is important to consider potential differences in treatment outcomes by sociodemographic subgroups to ensure that all individuals with depression benefit from the most efficacious and effective treatments for tobacco cessation. In the Kypriotakis et al. study, the majority of people with current and past MDD were women (65.9%–66.7%), and the majority of people in the full sample identified as White race (78.9%–83.9%). There are subgroup differences in cigarette smoking cessation by gender and race, with evidence that women and individuals identifying as Black race have more difficulty with cigarette smoking cessation (e.g.,
21,
22). With regard to pharmacological treatment efficacy by gender, data pooled from 32 clinical trials showed that the efficacy of varenicline, bupropion, and NRT was similar for men, while varenicline had better outcomes than bupropion and NRT for women (
23), with similar results found in a study of real-world effectiveness of pharmacological tobacco treatments (
24). With regard to race, a separate analysis of EAGLES data demonstrated that while varenicline, bupropion, and NRT had better efficacy than placebo for White individuals, only varenicline had better efficacy than placebo for Black individuals (
25). While these findings suggest the benefits of selecting varenicline as a first-line tobacco treatment across gender and racial groups, it is important to note that there is less evidence for how varenicline, bupropion, and NRT differ in efficacy or effectiveness for other priority tobacco-related disparity groups, such as those from lower socioeconomic status or those with sexual and gender minoritized identities.
Together, the existing data suggest that varenicline should be considered a first-line treatment for individuals with current MDD who smoke cigarettes. Varenicline not only appears to be efficacious for this population but also, importantly, is safe. Prescribers who experience barriers to providing tobacco cessation treatment can collaborate with mental health providers who may provide intensive counseling. Prescribers can also recognize the intersectional identities of their patients and the impact of these identities on tobacco use and tobacco-related disparities (
17), as well as the potentially important information provided by secondary analysis of clinical trials and treatment studies that focus on individuals from priority tobacco-related disparity groups. As alluded to above, counseling interventions that are appropriate for both tobacco cessation and the alleviation of depression may be reasonable targets for future research to further enhance treatment outcomes. In addition, the effects of varenicline on depressive symptoms in those who do and who do not quit smoking while using varenicline would be another area for further study. Such studies should control for the behavioral interventions provided and should also be conducted in individuals who are not trying to quit smoking cigarettes, in order to control for mood effects associated with successful quitting. Ultimately, these ongoing clinical and research efforts can help ensure that people with depression, a critical tobacco-related disparity group, receive the most efficacious and effective treatments to help them achieve long-term abstinence from tobacco and reduce tobacco-related consequences.