Association Between e-Cigarette Use and Depression in the Behavioral Risk Factor Surveillance System, 2016-2017

Key Points Question What is the association between electronic cigarette (e-cigarette) use and depression? Findings In this cross-sectional study of 892 394 participants in the Behavioral Risk Factor Surveillance System from 2016 to 2017, e-cigarette users had higher odds of reporting a history of clinical diagnosis of depression compared with participants who never used e-cigarettes. In addition, increased frequency of e-cigarette use was associated with incrementally higher odds of reporting depression. Meaning These findings highlight the need for longitudinal studies to examine the association between e-cigarette use and depression, which may be bidirectional.


Introduction
2][3] They are marketed as less harmful nicotine delivery devices; however, their contents are largely unregulated and vary widely, with nicotine concentrations ranging from 0 to 59 mg/mL. 4,5Many products also contain potentially toxic metals, such as arsenic and lead, as well as propylene glycol.When used, e-cigarettes may generate volatile organic compounds, including acetaldehyde and formaldehyde, especially at high temperatures. 4,6 2016, 10.8 million adults (4.5%) in the United States reported current e-cigarette use, more than half of whom were younger than 35 years. 1 Among current e-cigarette users, 3.6 million (33.5%) reported daily use, with 54.6% also reporting traditional cigarette smoking. 1 Among individuals with mental health conditions (MHCs), who make up 36.4% of the US population, 7 smoking rates are estimated to be 70% greater than in the general US population, 8 with these individuals consuming approximately 56.4% of all cigarettes sold in the United States. 7garette smokers with MHCs also tend to smoke more heavily and find it harder to quit smoking. 7,9e prevalence of depression in the population varies widely, from 6.7% to 16.6%, 10,11 and a recent study found that prevalence of current e-cigarette use among those who reported having depression was 9.1%, compared with a prevalence of 4.5% in the general population. 1 The popularity of e-cigarettes among the general population and their appeal to those who are susceptible to MHCs, including younger adults, raises a question regarding the association between e-cigarette use and mental health.3,12 To test our hypotheses that e-cigarette users might be more likely to have depression and that depressed individuals might be more likely to use e-cigarettes, we sought to examine the cross-sectional association between the use of e-cigarettes and depression in a large representative sample of adults in the United States.

Study Population
The Behavioral Risk Factor Surveillance System (BRFSS) is a nationwide, telephone-based survey of randomly sampled US residents older than 18 years, established by the US Centers for Disease Control and Prevention to collect information on health-related risk behaviors, chronic medical conditions, and the use of preventive health services. 13The survey includes participants in all 50 states as well as Washington, DC, and 3 US territories, making it the largest dynamic telephone-based health survey in the world. 13e BRFSS is a publicly available data set containing deidentified data.Thus, based on the code of federal regulations revised common rule, 14 our analysis of the data set was exempt from institutional review board review.Each section of this report was prepared using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Inclusion and Exclusion Criteria
To examine the association between e-cigarette use and depression, we pooled data from the 2016 and 2017 BRFSS surveys, which included 936 319 participants.Of the participants in the data set, we excluded participants with missing data on e-cigarette use (n = 39 729 [4.2%]), self-reported history of clinical diagnosis of depression (n = 3818 [0.4%]), and both (n = 378 [0.1%]), leaving a total sample size of 892 394 (95.3%).

Use of e-Cigarettes
Participants were categorized as ever or never e-cigarette users based on their response to the question, "Have you ever used an e-cigarette or other electronic vaping product, even just 1 time, in your entire life?"Those who answered yes were then further classified into occasional or daily users based on their response to the question, "Do you now use e-cigarettes or other vaping products

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Association Between e-Cigarette Use and Depression every day, some days, or not at all?"We classified e-cigarette smokers into 4 statuses, as follows: everyday e-cigarette user, some days e-cigarette user, former e-cigarette user, and non-ecigarette user.

Depression and Mental Health
The dependent variable of interest was depression, defined as a self-reported history of clinical diagnosis if participants answered yes to the question, "Has a physician ever told you have a depressive disorder (including depression, major depression, dysthymia, or minor depression)?" 15,16 separate supporting analyses, subjective poor mental health was explored as an alternative outcome, defined by evaluating participants' response to the question, "Now thinking about your mental health, which includes stress, depression, and problems with emotions, for how many days during the past 30 days was your mental health not good?" 17

Covariate Assessment
Baseline demographic factors, including age, sex, race/ethnicity, marital status, education, and employment status, were self-reported according to BRFSS protocol.Income was defined using federal poverty line cutoffs for each state, taking into account the number of adults and children in the household for each state. 18Data on alcohol and combustible cigarette use were also collected.
Heavy alcohol use was defined as more than 14 drinks per week for men and more than 7 drinks per week for women.Combustible cigarette smoking status was categorized as current, former, and never.

Statistical Analysis
The BRFSS uses design weighting and iterative proportional fitting to ensure representativeness of the data. 19These weights were applied in all analyses done with the data set.
Sociodemographic and risk factor characteristics were described according to e-cigarette use categories by applying sampling design elements and using the svy subpop command.Multivariable logistic models were used to assess the association between e-cigarette use and depression, adjusting for age, sex, race/ethnicity, income, marital status, employment, education, heavy alcohol use, and combustible cigarette smoking.The prevalence of depression in the data set was high at 18.9%; thus, supplemental analyses were also performed using Poisson regression models to test the stability of the estimates.Given the known high prevalence of use of e-cigarettes among the younger population as well as among smokers, we performed subgroup analyses among college students and among combustible cigarette users.
Formal effect modification was tested using interaction terms for e-cigarette use and sex, age, race/ethnicity, and cigarette smoking.Stratified analyses were then performed and presented by these variables.
To further test our estimates, subjective mental health was explored as an alternative outcome.
We compared those reporting 1 or more days of poor mental health with those reporting no days of poor mental health.
All analyses were conducted using Stata statistical software version 14.2 (StataCorp) with the significance level set at a 2-sided P < .05.Data analysis was conducted in May 2019.

Discussion
In this cross-sectional analysis of a large nationally representative survey of adults in the United States, we found that former and current e-cigarette users were more likely to report a history of clinical diagnosis of depression compared with never users.In addition, we found a graded association between frequency of use and depression.We further explored subgroups defined by age and race and found no significant differences in the association between e-cigarettes and depression or mental health, suggesting that the association between e-cigarettes and these mental health outcomes was similar across these broad segments of the population.
Our study provides additional evidence to establish an association between e-cigarette use and depression, which could have potentially significant implications for public health, clinical practice, and health policy.Our results are supported by findings from a small longitudinal study by Lechner et al 20 conducted among adolescents in Los Angeles, California, which showed that sustained e-cigarette use was associated with an increase in depression symptoms over a 12-month period.
While cross-sectional, our sample size was larger, enabling us to conduct important subgroup analyses.
Similar to a study that was conducted in France in 2019, 21 we also found that the association between e-cigarettes and depression did not differ significantly by sex or among current and former   Abbreviations: e-cigarette, electronic cigarette; OR, odds ratio.
a Adjusted for age, sex, race/ethnicity, income, marital status, education, employment, heavy alcohol use.
cigarette smokers.However, while that study found no association between e-cigarettes and depression in nonsmokers, we found that never cigarette smokers who used e-cigarettes had twice the odds of reporting a clinical diagnosis depression compared with those who did not use e-cigarettes, an estimate similar to that found among dual users.
Previous work has shown that college students are more likely to explore new products, including e-cigarettes, and it is not uncommon for this group to be targeted by tobacco companies' marketing strategies. 22,23Therefore, we explored the association between e-cigarette use and depression in the subpopulation and found that current e-cigarette users also had twice the odds of reporting depression compared with never users in the same category.This highlights the potential susceptibility of e-cigarette users in this group to depression.
Prolonged nicotine exposure has been shown to disrupt the cerebral dopamine pathway, amplify stress sensitivity, and distort the coping mechanisms that buffer against depressive symptoms. 20As many e-cigarettes contain nicotine, 4,24 this explain the graded association seen with increased frequency of use and depression, suggesting a potential dose-response relationship.In addition to nicotine, e-cigarettes contain varying amounts of trace metals including arsenic, aluminum, and lead, [25][26][27] many of which are on the priority pollutant list of the Agency for Toxic Substances and Disease registry, with known adverse health effects. 26In particular, lead and aluminum affect the central and peripheral nervous systems and may potentially contribute to the observed association between e-cigarettes and depression. 27aditional cigarette smoking affects the metabolism of a number of psychiatric medications, mainly via the induction of metabolic enzymes, leading to reduced blood levels and reduced therapeutic effectiveness. 28,29Analyses of e-cigarette contents have shown that they also contain tobacco-specific nitrosamines and some volatile organic compounds, although in less quantity than observed in traditional cigarettes. 30,31This raises further concern about the use of e-cigarettes among individuals with MHCs, as their use might complicate the treatment of psychiatric conditions.
Furthermore, a higher frequency of regular cigarette smoking has been reported among people with major depression compared with individuals who have never had major depression or any psychiatric illness, 32,33 and a brief prospective study done in adolescents found smoking to increase the risk of developing an episode of major depressive disorder. 34Among traditional cigarette smokers, patients with depression are less likely to successfully quit smoking, possibly because of worsening depressive symptoms during quitting attempts and poor tolerance of nicotine withdrawal symptoms. 21Smoking has also been shown to be highly predictive of future suicidal behavior, making it particularly concerning in individuals with a history of depression. 35Considering the similarities between e-cigarettes and traditional cigarettes, individuals with depression might be more susceptible to sustained use of e-cigarettes and may find it harder to reduce or quit their e-cigarette use.Furthermore, e-cigarette use might predispose users to developing major depression in the long term.
Consistent evidence of the gateway theory of an association between e-cigarette use and subsequent cigarette smoking initiation has been reported in a meta-analysis done by Soneji et al. [36][37][38] This theory, as well as the well-established addictive nature of nicotine, 39,40 make the rapid uptake of e-cigarettes among teenagers-described as an epidemic by the US Food and Drug Administration 41 and the US Surgeon General 42 -particularly concerning, especially because our findings show no difference in association between e-cigarette use and depression among younger and older adults.
Our findings, if confirmed in other study designs with longitudinal follow-up, may provide data to inform policies that could protect populations susceptible to depression.For example, the association between e-cigarette use and depression might justify further regulation of advertisements and marketing strategies, appropriate warning labels that highlight the potential risk of depression associated with e-cigarette use, and public health education about the potential effects of e-cigarettes, especially among those with MHCs.This association could also inform clinical practice by providing information that physicians could consider in counselling patients seeking

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Association Between e-Cigarette Use and Depression information about the use of e-cigarettes, especially those with depression.At the very least, our findings warrant careful and thorough evaluation of e-cigarette use in both youth and adults with depression.Physicians should consider routine collection of information pertaining to e-cigarette use during clinic visits, especially in patients with depression, and routine counseling for those who use e-cigarettes, offering support to those who express willingness to quit.

Strengths and Limitations
To our knowledge, this study was the first to examine the association between e-cigarette use and depression across several subpopulations in the largest nationally representative database in the United States.However, our study has limitations.It was observational and cross-sectional, and therefore, we can neither infer causality nor ascertain the direction of the association, which we submit might be bidirectional.Furthermore, we lacked granular information on product characteristics, such as the brands of e-cigarettes used, and detailed exposure characterization, including frequency or duration of vaping.We also cannot exclude the possibility of residual confounding.Finally, data on both the exposure and outcome were self-reported, which might lead to nonrandom misclassification.

Conclusions
Our results suggest a strong association between e-cigarette use and depression, and this may have potential implications for regulation of e-cigarettes.Our results also highlighted the need for longitudinal studies to investigate the risk of depression associated with e-cigarette use and the potential bidirectionality of the association between e-cigarette use and depression.

Figure 2 .
Figure 2. Association Between Electronic Cigarette Use and Subjective Poor Mental Health

Table 2 .
Association Between e-Cigarette Use and History of Clinical Diagnosis of Depression and Subjective Poor Mental Health a Adjusted for age, sex, race/ethnicity, income, marital status, education, employment, heavy alcohol use, and combustible cigarette use.Odds ratios are adjusted for age, sex, race/ethnicity, income, marital status, education, employment, heavy alcohol use, and combustible cigarette use.Point estimates are represented with dots, and 95% CIs represented with upper and lower horizontal bars.

Table 3 .
Association Between e-Cigarette Use and Depression by Combustible Cigarette Smoking Status