In this large prospective cohort of older women free from clinical depression or severe depressive symptoms at baseline, risk of depression decreased in a dose-dependent manner with increasing consumption of caffeinated coffee. Consumption of decaffeinated coffee was not associated with reduced risk of depression. Most previous studies that investigated the relationship between caffeine or coffee consumption and depression were cross-sectional20–28
and thus unable to determine whether coffee consumption affects depression or vice-versa
. The only previous prospective study was conducted in Finland in a population-based cohort of 2,232 men; 49 cases of depression were identified after 17.5-year follow-up through the national hospital discharge register.3
In this cohort, the multivariate-adjusted relative risks of depression was 0.28 (95% CI, 0.08 to 0.96) for light coffee drinker (<375 ml/d), 0.45 (95% CI, 0.16 to 1.29) for moderate coffee drinker (375–813 ml/d) and 0.23 (95% CI, 0.06 to 0.83) for heavy coffee drinkers (>813 ml/d), compared to non-drinkers. Although no associations were observed for quartiles of caffeine consumption, an inverse association could have been obfuscated by the high caffeine consumption of the lowest quartile (up to 425 mg/d) and small sample size. In 2 U.S.4, 5
cohort studies, a lower risk of suicide has been reported with a higher coffee consumption. However, a J-shape association was noted for coffee and suicide risk in a cohort study from Finland. The risk of suicide decreased progressively until coffee consumption reached 6–7 cups/d, but increased with consumption of 8–9 and ≥10 cups/d.6
It is possible that persons with more severe forms of depression used very high doses of coffee as a form of self-medication that was, nevertheless, insufficient to elevate their mood. We observed an inverse dose-response relation between caffeine or caffeinated coffee consumption and depression risk, but we were unable address the effects of very high consumption because only 0.52% of our participants drank ≥6 cups/d of caffeineated coffee. We were also unable to see a relationship between caffeine from non-coffee sources and depression risk, perhaps due to insufficient power particularly after consumers of one or more cups of caffeinated coffee daily were excluded.
In North-America as well as many European countries, coffee and tea are the primary dietary sources of caffeine for adults.2
According to the U.S. Department of Agriculture surveys data (1994–96, 1998), 90% of the US adult population consumed caffeine, and mean consumption ranged from 166 to 336 mg/d.2
Coffee accounts for about 81% of the total daily caffeine consumed by adults older than 36 years.2
Elimination half-life of caffeine can be influenced by many factors including sex, use of oral contraceptives or other exogenous estrogens (approximately twice among users), and smoking (reduced by 30–50%).19
At dose lower than 10 mg/kg caffeine half-life range between 2.5 and 4.5h.19
The significant interaction that we noted between caffeinated coffee and current smoking was unexpected, and may be due to chance. Alternatively, caffeine may antagonize the adverse effects of smoking on depression through still unknown mechanisms, or may interact with genetic factors that predispose to smoking and depression.29
Chronic caffeine consumption has several biological effects that should be taken into account when considering the plausibility of its potential to reduce depression risk. At low to moderate doses, caffeine has well-known psychostimulant effects such as improved psychomotor performance, increased vigilance, elevated arousal (lesser somnolence and greater activation), and increased sensations of well-being and energy.30, 31
The known effects of caffeine are dose-dependent, but typically biphasic, i.e. low doses are perceived as pleasant and stimulating whereas a reverse effect is observed with higher doses.32
Most individuals seem to adapt their caffeine consumption to their own tolerance, so that the habitual is within the range between reinforcing and aversive effects.32
Caffeine affects brain function mainly by its antagonist action on the adenosine A2a receptor and, therefore, plays a role in the modulation of dopaminergic transmission.30, 33
The antagonist effect of caffeine on adenosine might also imply non-dopaminergic mechanisms, such as modulation of the release of acetylcholine and serotonin.30
The major strengths of this study include its large sample size, prospective design, and repeated measures of caffeine, caffeinated beverages and other covariates, which relied on the use of validated food-frequency questionnaires administered 7 times over a period of 22 years. This study also has limitations and the results should thus be interpreted with caution. First and foremost, because of its observational design, this study cannot prove that caffeine or caffeinated coffee reduce the risk of depression, but only suggest the possibility of such protective effect. Reverse causation is another concern in most epidemiological studies. To minimize this bias, we excluded at baseline 10,280 women with severe depressive symptoms, and we computed the cumulative average of caffeinated and not-caffeinated beverages with at least 2-year latency; yet, we cannot exclude the possibility that mild depressive symptoms were the common reason for low caffeine/coffee consumption and incident depression. Furthermore, we confirmed the robustness of our results in sensitivity analyses using at least 8-year lag of exposure.
In individuals with a particular genetic background34
or otherwise sensitive, caffeine might induce sleep disturbances and insomnia35
or anxiogenic effects.20, 36, 37
It is possible that sleep-sensitive or anxious women are aware of the stimulatory effects of caffeine and lower their consumption accordingly. A similar behavior among depressed women or women predisposed to depression in our cohort might thus explain our results, because the majority of late-life depressions occur among women who already had previous episodes,38
and lacking a lifetime history of depression we cannot exclude this possibility. Biased relative risk estimates may also result from error in assessing caffeine consumption. Dietary validation studies, however, have indicated that the frequency of coffee consumption reported on a food-frequency questionnaire is highly reproducible (r=0.78) and agrees well with assessments using diet records.13
Although between-person variation in cup size and strength of the coffee brew have probably contributed to some random misclassification with regard to the exposure, this would be more likely to weaken rather than strengthen observed associations between coffee consumption and depression risk. Finally, some outcome misclassification bias is inevitable because of a combination of errors in reporting depression and antidepressants use, low recognition of depression by physicians,39
under-treatment of depression,40
and use of antidepressant medication for indications other than depression.41–43
We tried to maximize the specificity of case definition, accepting as incident cases of depression only women who reported both a diagnosis of depression and the use of antidepressants. This definition excludes women with untreated depression, as well as women who used antidepressants for short period of time and were not regular users at the time of completing one of the biennial questionnaires. However, to the extent that the probability of correctly classifying women with an incident case of depression is independent from their dietary habits (non-differential misclassification of outcome), the low sensitivity of this strict case definition should not bias RR estimates.44
Over 10 years of follow-up, we noted an incident rate of clinical depression of 5.6 per 1,000 person-years. This incidence is not directly comparable to that observed in unselected populations because to minimize reverse causation we excluded women with severe depressive symptoms at baseline, thus eliminating a group of women at higher risk of depression.
In conclusion, our results support a possible protective effect of caffeine, mainly from coffee consumption, on risk of depression. These findings are consistent with earlier observations that suicide risk is lower among persons with higher consumption of coffee. Further investigations are needed to confirm this finding and to determine whether usual caffeinated coffee consumption may contribute to prevention or treatment of depression.