Most cultures and countries include alcoholic beverages as part of their usual diet. Alcohol intake is different over world regions regarding the habitual type of beverage and the pattern of consumption (frequency and average intake). In general terms, the consumption of alcoholic beverages is increasing worldwide [1]. Unipolar depression is the most prevalent mental disorder in the world and it is increasing steadily [2].

The simultaneous presence of alcohol-related problems and depression is common [3]. However, problematic intake needs to be distinguished from moderate intake. Problematic alcohol intake may be associated with depression not only because of increased intake of ethanol but also because of other alcohol-related unhealthy lifestyles or because of the social environment surrounding problematic drinkers (job loss, family problems, financial problems or other addictions). Any of these circumstances may be a potential trigger for depression, even in the absence of a specific detrimental role for ethanol.

Unipolar depression and cardiovascular disease are likely to share some common pathophysiological mechanisms. Moderate alcohol intake, especially alcohol from wine, has been repeatedly reported to be inversely associated with the incidence of cardiovascular disease [4–6]. Some of the responsible mechanisms for this inverse association are likely to be involved also in a reduced risk of depression [7, 8]. In the existing literature about non-problematic alcohol use and depression, longitudinal studies are inconsistent [9–20]. However, none of them has investigated the specific role of each beverage. Neither have they used repeated measurements on alcohol intake during follow-up to update the information on exposure to alcohol.

We prospectively evaluated the incidence of depression among light to moderate drinkers from an older Mediterranean cohort at high cardiovascular risk using repeated measurements of intake. An interesting characteristic of this population is that wine was the most frequently consumed alcoholic beverage. We also evaluated specifically the association of wine with incident depression, using repeated measurements of wine consumption.

A total of 443 incident cases of depression were identified during the follow-up period, which accrued 23,655 person-years.

In the repeated-measurement analyses using as exposure the yearly updated information on alcohol intake, we observed a stronger inverse association. We found a statistically significant inverse association for light drinkers (>0 to 5 g/day) with a relative risk (95% CI) of 0.73 (0.57 to 0.95) and also for low-to-moderate drinkers (>5 to 15 g/day) with a relative risk of 0.69 (0.50 to 0.96). We found no effect modification of alcohol intake by sex (P = 0.45). Although the interaction was non-significant, we re-ran the analyses separately for men and women to take into account biological differences between the sexes. The results are available in the supplementary material (Additional file 2).

To account for a non-linear association, we used restricted cubic spline analysis. The U-shaped association found, represented in Figure 1, showed a consistent protection against incident depression for baseline moderate alcohol intake.

Results were also consistent when we investigated the incidence and recovery from depression using fixed-effects models (Additional file 3).

We found that total low-to-moderate alcohol drinking (5 to 15 g/day) was associated with lower risk of depression. A stronger inverse association was found for low-to-moderate wine-drinkers (two to seven glasses/week).

These results seem paradoxical as previous studies found a direct association between alcohol in higher amounts, especially Alcohol Use Disorders (AUD), and depressive symptoms, [11, 17–20, 30]. However, lower amounts of alcohol intake might exert a protection as it has been observed for coronary heart disease (CHD). In fact, it is believed that depression and CHD share common pathophysiological mechanisms [30, 31]. Only one previous cohort, including participants with a high educational level, assessed low-to-moderate levels of intake and found a similar inverse association (HR (95% CI); 0.65 (0.49 to 0.86)) for the same range of exposure 5 to 15 g/day that we have observed [9]. The results of our study and that previous cohort are, therefore, closely consistent. The practical absence of heavy drinkers in our sample and in that cohort, together with the large proportion of participants exposed to low-to-moderate intakes are likely explanations for the diverging results with respect to cohorts including heavy drinkers. The results of those studies have to be carefully interpreted. In several previous cross-sectional studies, a strong positive association was found. Therefore, the definition of a clear temporal sequence is necessary to preclude the possibility of a reverse causation bias [3]. Some longitudinal studies have assessed the reverse direction of this association, that is, the consequences of depression on alcohol intake. They have found direct associations; subjects with depression tend to increase their alcohol intake as a consequence of their mood disorder [2]. Therefore, in some cross-sectional analyses, the positive association found is likely to be the result of the direct effect of depression on alcohol intake, which may overcome the possible inverse association between low-to-moderate alcohol intake and depression risk. They can also capture the detrimental effects of higher amounts of alcohol intake on depression risk. In contrast, in a longitudinal analysis, the temporal sequence is preserved, and reverse causation bias is less likely. In order to minimize the risk of that bias, we assumed an induction period of at least one year and we conducted a sensitivity analysis assuming an alternative induction period of two to three years in the repeated measurement analyses. Early cases may be subclinical cases of depression at the beginning of the interval and may correspond to subjects who changed their alcohol intake before developing overt clinical depression. The fact that the results of these sensitivity analyses are consistent with the main results gives further support to our findings. Moreover, incident cases of depression did not change their alcohol intake differently from those who were not incident cases (P >0.1; data not shown).

The differences between our results and those of previous studies could also be explained by the different average alcohol intake between populations, the different pattern of consumption and especially because the predominant type of beverage consumed is different, wine being the preferential beverage in our cohort. The PREDIMED trial includes an older, traditional Spanish Mediterranean population, that consumed chiefly wine, and mainly in a context of socialization with family or friends. Subjects with problematic use of alcohol (≥2 positive answers in the CAGE questionnaire) [21] were explicitly excluded from this trial because this was one of the exclusion criteria. Moreover, they were in a trial where an intervention with a Mediterranean diet was done, including the advice to consume wine moderately only for those who were already wine drinkers at inception. However, the intervention designed for this trial did not attain any significant change in average levels of alcohol intake (−1.4 g/day, −1.4 g/day, and −0.9 g/day in the Mediterranean diet + virgin olive oil, Mediterranean diet + nuts and control groups, respectively) without any between-group significant difference. In addition, the Mediterranean diet has also been associated with lower incidence of depression [32]. Therefore, dummy variables for the two active intervention groups were included in the multiple-adjusted model as potential confounders.

The relationship between alcohol intake and depression is biologically different among men and women [20, 33, 34]. For instance, alcohol bioavailability is different between sexes [35], and women seem to be more likely to develop depression [36]. Therefore, we presented the analyses stratified by sex despite there being no evidence of statistical interaction by sex.

Besides the sensitivity analysis mentioned above, we conducted eight other sensitivity analyses to explore further potential sources of bias. The reference category in the main analysis was the abstainers’ group. This group may include former drinkers. Therefore, we excluded from the abstainers’ group all participants who reported drinking alcohol ever in her/his past life, and the results remained similar. However, the results became non-significant after the exclusion of prevalent diabetics at baseline. This fact may be explained by a loss of statistical power because almost 50% of our participants were diabetics. Alternatively, it might be attributed to a better disease classification among diabetic than among non-diabetic participants. Diabetics usually are more likely to have more frequent medical visits due to their diabetes; therefore, they have more opportunities to receive a medical diagnosis of depression than non-diabetic patients.

To our knowledge, with the exception of the recent results of the University of Navarra follow-up Study (“Seguimiento Universidad de Navarra” (SUN cohort)), no other large prospective cohort study has previously reported conclusive results about the relationship between specific alcoholic beverages and incident depression. Non-alcoholic components of wine can account for the inverse association found in our study. For instance, trans-resveratrol has been postulated as a neuroprotective substance [37–40]. Previous investigations suggest that the hippocampal complex may play a role in the development of major depression [41]. This neuroprotection applied to the hippocampus may prevent moderate wine drinkers from developing depression.

An alternative potential explanation for this association can be that wine-drinkers or moderate drinkers might be healthier in other aspects than non-wine drinkers or non-moderate drinkers, as it has been suggested for other outcomes [42]. In order to account for confounding by these factors, several lifestyle variables, including quality of the diet and several indicators of an overall healthy lifestyle and health consciousness, had been included in the multiple-adjusted model.

Some important strengths of the present study are its prospective design, the use of repeated measurements of alcohol intake during follow-up, the large sample size of a very homogeneous population and the good adjustment for potential confounders. In addition, the high prevalence of low-to-moderate average alcohol intake with almost null prevalence of excessive drinking together with the preference for wine consumption offered a unique opportunity to investigate the influence of these two particular factors (light-to-moderate drinking and wine consumption), while it limited our power to detect associations between heavy drinking and depression.

Inherent to nutritional epidemiology methods, we have to point out the possibility of some degree of misclassification in the dietary assessment methods. However, we used a FFQ extensively validated in Spain for the dietary assessment [26, 43, 44]. In addition, the correlation coefficient in the validation study was higher for alcohol than for most other nutrients. Moreover, if there is some misclassification it will be more likely non-differential and, therefore, the association would probably be driven towards the null value. Another limitation in our study is that we are not exclusively using a clinical diagnosis of depression. Probably we are achieving a high specificity at the expense of losing sensitivity. Moreover, there is a possibility that patterns of alcohol consumption may be associated with decisions to seek care. If heavy drinkers were less likely to seek medical care, this could result in the rates of depression being under-estimated among heavy drinkers.

In conclusion, low-to-moderate total alcohol intake and specifically wine consumption may reduce incident depression, while heavy drinkers seem to be at higher risk. Further cohort studies are needed to confirm these results.