Smoking and exposure to tobacco smoke are a major risk factor of morbidity and mortality worldwide [1]. Evidence suggests that nearly 9 out of 10 current smokers initiated smoking before adulthood, and 98% of smokers first experience tobacco smoking until 26 years of age [2].

Some findings indicate that depression might be the strongest factor contributing to smoking initiation and substance use among university students [3]. At a global level, depression has been considered as a common mental health disorder among University students [4]. Conversely, in this particular population, smoking has been reported as a predisposing factor for the development of depressive symptoms [5, 6]. Depression is suggested to occur two times more frequently among current moderate smokers compared to non-smokers [7]. While reciprocal association between smoking and depression has previously been observed, the directionality of this association has not yet been addressed [8, 9]. However, a recent study found strong evidence to support a hypothesis that smoking could be a risk factor for development of depression for both lifetime smoking and smoking initiation [10].

Previous studies reported that, compared with current smokers, persons who had never smoked had significantly better health-related quality of life (HRQoL) and had less anxiety and depressive symptoms [11–13]. In most studies, the association of smoking with the mental health component of the HRQoL was stronger compared to that with the physical health component [13, 14]. Therefore, we hypothesized that depressive symptoms could be a mediator of the association between smoking and poorer HRQoL.

Over the last decades, factors associated with HRQoL among University students have been extensively studied [15, 16]. Furthermore, HRQoL is regarded as an important self-reported outcome measure and has been used in clinical studies focusing on subjective aspects of one’s health and functional status or well-being [17]. Even though the prevalence of chronic diseases among university students is low, and this population is considered overall healthy, the sensitivity of HRQoL measures allow for early detection of differences in health status between various students’ subgroups [15, 18].

The association of smoking with HRQoL among university students in low- and middle- income countries was rarely studied. The Republic of Serbia is classified as an upper middle-income country. Nevertheless, it is still in the process of political and economic transition [19]. In addition, Serbia is located in the Eastern Europe, a region with an overall high prevalence of tobacco smoking of > 25% [1]. In Serbia, about one third of students smoke cigarettes and this prevalence have been stable over time [20, 21].

There is scarcity of studies investigating a potential mediating effect of depression in the association between smoking and students’ HRQoL. The aim of this study was to assess the association between smoking and HRQoL among students in two different universities and the potential mediating effect of depression.

The study included 1,624 (964 first year, 660 third year) students from the Belgrade University and 514 (264 first year, 250 third year) students from the Kosovska Mitrovica University. In both populations, females were more prevalent, 63.0% and 53.7%, respectively. Average age of students in both populations was 20.8 years (Table 1).

Differences in MCS (Belgrade 71.0 ± 18.5; Kosovska Mitrovica 75.6 ± 17.3, p = 0.001) and in PCS (Belgrade 80.0 ± 13.4; Kosovska Mitrovica 81.5 ± 13.6, p = 0.023) of HRQoL were observed between the two study population.

Students who ever smoked had lower MCS compared to students who had never smoked in their lifetime in both student samples (Belgrade 67.3 ± 19.9 vs. 72.3 ± 17.8, p = 0.001; Kosovska Mitrovica 70.5 ± 19.7 vs. 77.6 ± 15.8, p = 0.001) and the some results was obtained for PCS (Belgrade 78.3 ± 14.7 vs. 80.6 ± 12.9, p = 0.004; Kosovska Mitrovica 77.6 ± 15.9 vs. 83.2 ± 12.2, p = 0.001). Generally, scores of HRQoL related to mental health were lower compared with scores of domains related to physical health (Table 2).

In both student samples, students who ever smoked had higher BDI score compared to students who had never smoked (Belgrade 8.17 vs. 6.19, p = 0.001; Kosovska Mitrovica 6.16 vs. 2.67, p = 0.001). In both student populations, proportion of depression among students who ever smoked was higher compared to students who never smoked (Belgrade 19.4% vs. 11.2%, p = 0.001; Kosovska Mitrovica 14.0% vs. 4.0%, p = 0.001) (Table 2).

In the first four models of the hierarchical regression analysis, after adjustment for socio-demographic, behavioral and health factors, smoking remained associated with poorer PCS in students from the Kosovska Mitrovica and poorer MCS in both populations of students (Tables 3, 4 and 5). An exception from this pattern was observed for “Behavior” and “Chronic diseases model” in students from the Belgrade when PCS was examined (Table 6). The first four models explained 10.5–14.7% of variance (p = 0.001) for PCS and MCS score in both populations. In both samples, we observed that the magnitude of the association between smoking and HRQoL becomes weaker after adjustment for additional covariates.

In the Belgrade sample, after addition of BDI in the full model, the association of smoking with HRQoL was lost. The “Depression model” explained 32.3% of variance of PCS and 42.0% of MCS (p = 0.001). This means that having more depressive symptoms was associated with poorer HRQoL and modified the association of smoking with HRQoL among students from Belgrade. Similarly, in Kosovska Mitrovica after inclusion of the BDI score in the final “Depression model”, the association between smoking and MCS and PCS was lost. The “Depression model” in the hierarchical regression analysis of the Kosovska Mitrovica sample explained 32.4% of variance for PCS and 38.7% for MCS (p = 0.001).

Preacher and Hayes’s method showed that a higher BDI was a mediator of the association between smoking and HRQoL. In both populations, smoking was associated with poorer MCS and PCS indirectly through higher level of depressive symptoms, while direct effect of smoking on HRQoL was not found (Belgrade: MCS direct effect 1.12, 95% CI -0.57, 2.80 and indirect effect 2.26, 95% CI 0.95, 3.53 and PCS direct effect 0.39, 95% CI -1.71, 0.92 and indirect effect 1.40, 95%CI 0.59, 2.24; Kosovska Mitrovica: MCS direct effect 0.77, 95% CI -2.06, 3.60 and indirect effect 4.28, 95%CI 2.18, 6.58 and PCS direct effect 0.56, 95% CI -1.75, 2.87 and indirect effect 2.73, 95%CI 1.42, 4.23) (Fig 1).

In this research we observed a strong association between smoking and poorer physical and mental health components of the health-related quality of life that persisted after adjusting for participants’ socio-demographic, behavioral and health factors. However, the associations with both PCS and MCS were explained by a mediation effect of the depressive symptoms. The mediating effect of depressive symptoms remained consistent across two student populations, six years apart, in two cities with socio-politically and economically diverse environment within the same country. Strong association between BDI score and PCS and MCS score was found across all five quantile scores.

In a sample from the Belgrade University, the PCS of students who never smoked was 2.3 points higher than PCS of students who ever smoked, and the MCS of students who never smoked was 5.0 points higher than MCS of students who ever smoked. In the sample from Kosovska Mitrovica, students who never smoked outscored ever smokers by 5.6 points in PCS and 7.1 points in MCS. The difference in HRQoL scores of 3 points or higher was shown previously to be clinically significant [33, 34]. Also, similar to previous studies [16, 35], we report a strong association of higher BDI score with lower PCS and MCS. Moreover, longitudinal BELLA study found presence of mental disorders as one of most important risk factors for lower HRQoL in children and adolescents [36].

In line with the previous studies, our results indicated that, in both populations, students who ever smoked had higher BDI score than students who never smoked in their lifetime [37, 38]. Also, in both populations, the association between smoking and HRQoL was lost after adjustment for the BDI score. Coste et al [39] reported that association of smoking with HRQoL was weaker but persisted when the BDI score was added in the regression model, which contrasts our findings. Depression has been reported as a stronger mediator between smoking and HRQoL among women while PCS was observed as an outcome [39]. Differences between our and study by Coste et al. could be possibly explained by differences in population characteristics such as older age of participants, classification of smokers as well additional potential modifiers and covariates accounted for in the current analysis [39].

We found that having more depressive symptoms mediated the association between smoking and poorer HRQoL. Our finding offers additional evidence to appreciate underlying mechanisms of the observed association between smoking and poorer HRQoL. Potential explanation may arise from the effects of nicotine on change in neurotransmitter activity that may lead to development of depression [40, 41]. It has been suggested that numerous chemicals in cigarette smoke interact with high-affinity nicotinic acetylcholine receptors and indirectly stimulate the release of dopamine, enabling, therefore, a sense of reward and positive reinforcement [41, 42]. This effect has also been observed to relieve feelings of depression and positively influence mood swings [41, 42]. Moreover, a study of Boden et al. found an unidirectional causal relationship between smoking and occurrence of depressive symptoms as well as that co-occurrence of smoking and depression cannot be explained by common genes and environment [6].

Impaired mental health is more prevalent in students compared to their peers from the general population and this is probably due to high academic demands [43–45]. The impairment of psychological well-being has been found to progress with the advancing years at school [46]. The study of Grøtan et al. reported a strong association of mental distress with poorer academic self-efficacy as well as with slower study progress [47]. The presence of depression may increase smoking rate in youth indirectly by increasing their vulnerability and acceptance of peer norms [5]. Smoking cessation may help to improve mental health and it is suggested that smoking cessation drugs may also have anti-depressive properties [9, 48]. Continuing stress during higher schooling has been suggested to contribute to the development of mental disorders and substance use disorders [49]. In students, behavioral response to stressors is ranked third, immediately after cognitive and emotional response [50].

In the quantile regression model, BDI score exhibited negative association with PCS and MCS across all quantiles in both student samples. This was especially pronounced among non-smokers who were more likely to have better mental health component of HRQoL, suggesting that non-smokers had better self-perceived mental health features. Thus, students who scored higher on the SF-36 scale tolerated depressive symptoms reasonably well, whereas students who reported poorer HRQoL have endured more depressive symptoms.

Our results provide a more thorough insight in the association between smoking and HRQoL and highlight a strong role of depressive symptoms in this association among university students. These findings suggest that combining the efforts of mental health service and substance abuse specialists could be relevant to enhance the promotion of healthy behavioral patterns and reduce the impact of depression on overall health [49]. Moreover, smoking might be regarded as a symptom of mental health disorders and a marker of increased risk for depression. Previous studies reported that people who have successfully quit smoking have better emotional and mental health stability and score better in the HRQoL measurements [41, 51]. On the other hand, anti-depressive drugs are used for smoking cessation [52]. Thus, our findings can be used to tailor intervention programs and strategies, particularly in populations with high prevalence of smoking and depression. A “Healthy setting” approach, such as Smoke Free Campus within the framework of Health Promoting Campus could combine programs and policies to improve mental health and prevent smoking [53]. As a result, incorporation of smoking cessation in depression treatment programs could yield better clinical outcomes [54]. Assessment of depressive symptoms using BDI could be a good tool to differentiate depression from other mental health conditions and help physicians make prompt and accurate assessment to foster safe and supportive academic environment.

In terms of study limitations, information bias should be considered, because data on smoking, alcohol use and other socio-demographic, behavioral and health factors were self-reported. Smoking status was dichotomized to smoking ever/smoking never and current smoking status, frequency and heaviness of smoking were not considered, therefore we cannot assess dose-response aspect of this association. In addition, cross-sectional study design did not allow for definitive conclusions on causality. Although we attempted to adjust for a number of potential confounders, there are possibly residual factors that were not included in the analysis as well as other unrecognized and unmeasured socio-demographic, behavioral and health factors that can modify effect estimate and introduce residual confounding. On the other hand, the findings were replicated in two populations which differ by time, place and characteristics. Because data from the University of Belgrade were collected in 2009, the study is limited by potential changes in tobacco use over the past decade [55]. Our study examined the association of cigarette smoking on HRQoL. In order to elaborate on this association, further research is warranted on other tobacco products, as well as quantity, frequency and duration of smoking or secondhand smoking.

In conclusion, the association of smoking with impairment of the HRQoL among students in two different settings was mediated by higher levels of depressive symptoms. Findings highlight the need for further research on the interaction between smoking, mental health and quality of life, with implications for prevention, diagnosis and treatment.