Discussion
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.
Acknowledgements
We thank the other members of the PREDIMED Group:
University of Navarra, Department of Preventive Medicine and Public Health, Pamplona, Spain: E. Toledo, M. Bes-Rastrollo, A. Sánchez-Tainta, B. Sanjulián, E. Goñi, M. Marques, A. García-Arellano, I. Zazpe, J. Basterra-Gortari, E. H. Martínez-Lapiscina.
University of Navarra, Primary Care Centres, Pamplona, Spain: M. Serrano-Martínez, J. Díez-Espino, N. Ortuño, N. Berrade, V. Extremera-Urabayen, C. Arroyo-Azpa, L García-Pérez, J. Villanueva Tellería, F. Cortés Ugalde, T. Sagredo Arce, Mª D. García de la Noceda Montoy, Mª D. Vigata López, Mª T. Arceiz Campo, A. Urtasun Samper, Mª V. Gueto Rubio and B. Churio Beraza.
University of Navarra, School of Pharmacy, Pamplona, Spain: J. A. Martinez, A. Martí.
Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain: M. Serra, A. Pérez-Heras, C. Viñas, R. Casas, L. de Santamaría, S. Romero, J. M. Baena, M. García, M. Oller, J. Amat, I. Duaso, Y. García, C. Iglesias, C. Simón, Ll. Quinzavos, Ll. Parra, M. Liroz, J. Benavent, J. Clos, I. Pla, M. Amorós, M. T. Bonet, M. T. Martin, M. S. Sánchez, J. Altirruba, E. Manzano, A. Altés, M. Cofán, C. Valls, A. Sala-Vila and M. Doménech.
University Rovira i Virgili, Reus, Spain: M. Bulló, R. González, C. Molina, F. Márquez, N. Babio, M. Sorli, J. García Roselló, F. Martin, R. Tort, A. Isach, B. Costa, J. J. Cabré and J. Fernández-Ballart.
Institute de Recerca Hospital del Mar, Barcelona, Spain: S. Tello, J. Vila, M. Fitó, H. Schröder, R. De la Torre, D. Muñoz-Aguayo, R. Elosúa, J. Marrugat and M. Ferrer.
University of Valencia, Valencia, Spain: P. Carrasco, R. Osma, M. Guillén, P. Guillem-Saiz, O. Portolés, V. Pascual, C. Riera, J. Valderrama, A. Serrano, E. Lázaro, A. Sanmartín, A. Girbés, V. Santamaría, C. Sánchez, Z. Plá, E. Sánchez, C. Ortega-Azorín, J. I. González and C Saiz.
University Hospital of Alava, Vitoria, Spain: I. Salaverría, T. del Hierro, J. Algorta, S. Francisco, A. Alonso, J. San Vicente, E. Sanz, I. Felipe, A. Alonso Gómez and A. Loma-Osorio.
University of Málaga, Málaga, Spain: R. Benítez Pont, M. Bianchi Alba, J. Fernández-Crehuet Navajas, R. Gómez-Huelgas, J. Martínez-González, V. Velasco García, J. de Diego Salas, A. Baca Osorio, J. Gil Zarzosa, J. J. Sánchez Luque and E. Vargas López.
Instituto de la Grasa, Consejo Superior de Investigaciones Científicas, Sevilla, Spain: J. Sánchez Perona, E. Montero Romero, A. Martín Rodríguez and V. Martín Arranz.
Institute of Health Sciences IUNICS, University of Balearic Islands, and Hospital Son Espases, Palma de Mallorca, Spain: M. García-Valdueza, M. Moñino, A. Proenza, R. Prieto, G. Frontera, M. Ginard, F. Fiol, A. Jover and J. García.
Department of Family Medicine, Primary Care Division of Sevilla, Sevilla, Spain: M. Leal, E. Martínez, J. M. Santos, M. Ortega-Calvo, P. Román, F. José García, P. Iglesias, Y. Corchado, E. Mayoral and C. Lama.
School of Pharmacy, University of Barcelona, Barcelona, Spain: M. C. López-Sabater, A. I. Castellote-Bargallo, A. Medina-Remón and A. Tresserra-Rimbau.
University of Las Palmas de Gran Canaria, Las Palmas, Spain: J. Álvarez-Pérez, E. Díez Benítez, I. Bautista Castaño, I. Maldonado Díaz, F. Sarmiendo de la Fe, C. Ruano, M. J. Hernández, B. Macías Gutiérrez, P. Henríquez and I. Castro.
Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain: E. de la Cruz, A. Galera, Y. Soler, F. Trías, I. Sarasa, E. Padres and E. Corbella.
Primary Care Division, Catalan Institute of Health, Barcelona, Spain: C. Cabezas, E. Vinyoles, M. A. Rovira, L. García, G. Flores, J. M. Verdú, P. Baby, A. Ramos, L. Mengual, P. Roura, M. C. Yuste, A. Guarner, A. Rovira, M.I. Santamaría, M. Mata, C. de Juan and A. Brau.
Other investigators of the PREDIMED network: M. T. Mitjavila (University of Barcelona), M. P. Portillo (University of Basque Country), G. Sáez (University of Valencia) and J. Tur (University of Balearic Islands).
AG thanks the Spanish Government for the FPU fellowship received.
Authors’ contributions
AG conducted the literature review, participated in the design of the present study, cleaned the data, conducted the main statistical analyses and prepared the first draft of the manuscript. J-JB participated in the statistical analyses plan and in the design of the present study, and revised the manuscript. RE initiated the collaborative project, designed data collection tools, monitored data collection for the whole trial, revised the manuscript and contributed to the interpretation of findings. AS-V conducted part of the literature review, cleaned and analyzed data, participated in the design of the present study, revised the manuscript and contributed to the interpretation of findings. JS-S implemented the trial in Reus, monitored the data collection and revised the manuscript. PB-C participated in the implementation of the trial in Pamplona, participated in the design of the data collection tools and revised the manuscript. EG-G implemented the trial in Málaga, monitored the data collection and revised the manuscript. M-IC implemented the trial in Barcelona, monitored the data collection and revised the manuscript. DC implemented the trial in Valencia, monitored the data collection, and revised the manuscript. MF implemented the trial in Palma de Mallorca, monitored the data collection and revised the manuscript. FA implemented the trial in Vitoria, monitored the data collection and revised the manuscript. JL implemented the trial in Sevilla, monitored the data collection and revised the manuscript. R-ML-R implemented the trial in Barcelona, monitored the data collection and revised the manuscript. JW participated in the design of the present study, monitored the data collection and revised the manuscript. XP implemented the trial in Barcelona, monitored the data collection and revised the manuscript. LS-M implemented the trial in Las Palmas de Gran Canaria, monitored the data collection and revised the manuscript. M-AM-G initiated the collaborative project, designed data collection tools, monitored data collection for the whole trial, implemented the trial in Pamplona, supervised all the steps in the statistical analyses and preparation of the manuscript, and contributed to the interpretation of findings. He is the guarantor. All authors critically revised the manuscript for important intellectual content and approved the final version to be submitted for publication.