The results of this study confirmed that high tHcy is associated with an increased risk of depression and showed, for the first time, that the use of aspirin is associated a significantly lower risk among older men with high tHcy. These findings suggest that if high tHcy is a true cause of depression in later life,8, 9, 12
then aspirin could attenuate the incidence of depression among high-risk individuals in later life.
This study has several strengths. HIMS originated from a large community-representative sample of older men for whom a wealth of clinical and administrative data are available.20
This enabled us to exclude participants who showed evidence of cognitive impairment (which is associated with both high tHcy and depression), ascertain the use of aspirin, vitamin B and antidepressants, gain access to tHcy, and adjust our analyses for factors known to influence tHcy, such as smoking and medical comorbidities.27
In addition, this investigation was sufficiently large to allow us to investigate interactions between exposures of interest and depression, although we lacked sufficient power to explore the three-way interaction between high tHcy, aspirin and vitamin B use because of the low prevalence of vitamin B consumption in the sample. We acknowledge, however, that the cross-sectional design of the study limits our ability to infer causality between the exposures and depression, and that reverse causality is possible. For example, a large proportion of older men with than without prevalent cardiovascular diseases might be in contact with health services, which would enhance the opportunistic diagnosis of depression and increase antidepressant treatment. Such men may also be more frequent users of aspirin and have high tHcy. Consequently, a lower proportion of men with high tHcy who are using aspirin would be expected to present with clinically significant depressive symptoms (because they are more likely to have health contacts and receive treatment). We have addressed this issue by retrieving Western Australian Data Linkage System data on depression and comorbidity recorded before the assessment for HIMS, and by adjusting our analyses for the use of antidepressants. The adjusted analyses indicate that our findings cannot be easily attributed to reverse causality or confounding due to the use of antidepressants.
We did not have access to information about the use of aspirin after the start of the follow-up period, and it is conceivable that any such changes could have had an effect on depression as an outcome. For example, if non-users with high tHcy initiated consumption of aspirin during follow-up, differences between the study groups would have been attenuated, and this would have biased the results toward the null hypothesis. A similar move toward the null hypothesis would have been associated with status change from user to non-user. Therefore, the ‘antidepressant effect' of aspirin that we observed in this study cannot be easily explained by change in the consumption of aspirin during follow-up.
Our definition of ‘depression' was not based on a structured psychiatric interview or use of accepted diagnostic guidelines, such as ICD-10 and DSM-IV-TR. Previous studies have shown that GDS-15 scores of 7 or greater have good face validity for the diagnosis of a depressive episode according to both the ICD and DSM systems,21
and the additional use of administrative data linkage would have ensured high specificity for cases, although sensitivity might have been suboptimal because people with less severe depressive symptoms might not come into contact with the Western Australian hospital system. The most likely consequence of such a bias would have been loss of power to explore associations with depression, possibly compromising our ability to examine the interaction between high tHcy and B-vitamin use on depression. In addition, we adjusted our analyses for factors known to increase tHcy and the risk of depression (such as smoking and comorbidities), but concede that our adjustments were not exhaustive and that residual confounding might explain some of the observed associations. Finally, we acknowledge that our data are limited to older men and we cannot be certain that similar results would have been found for women or younger adults.
A recent meta-analysis of over 200 genetic epidemiological studies that correlated strokes with tHcy and the methylene tetrahydrofolate reductase C677T polymorphism in 60
000 people found that B-vitamin intake (particularly folate) is unlikely to reduce the risk of subsequent strokes in countries where folate supplementation of wheat is mandatory,28
suggesting that consumption of these vitamins might fail to reduce the health hazards associated with high tHcy if there is no overt vitamin deficiency. Furthermore, any possible cardiovascular benefit of supplementation with B-vitamins might be entirely overridden by the concomitant use of antiplatelet therapy (such as aspirin),19, 29
suggesting that aspirin consumption may be a more helpful way of modifying the cardiovascular risk associated with high tHcy. This might explain our negative findings regarding the use of B-vitamins and risk of depression, even for older men with high tHcy. Indeed, it is possible that current optimistic views about the potential benefits of B-vitamins for the management of depression may lead to its overuse by people who are experiencing relevant symptoms, thus explaining the increased odds of depression that we observed among B-vitamin consumers (that is, prescription bias).
We have previously argued that the use of aspirin could potentially increase the risk of depression in later life because of bleeding and of other medical complications.30
That argument did not take into account the potential interaction between aspirin use and high tHcy, which is a well-established risk factor for both cardiovascular diseases and depression.8, 11
At this point, we can only speculate about the mechanisms by which aspirin modifies the risk of depression in older people with high tHcy. Aspirin might counteract the increased adhesive properties of platelets induced by high tHcy17
or, alternatively, stimulate the release of monoamines that is partly compromised by dysfunction on one-carbon methylation associated with elevated tHcy.31, 32
Regardless the physiological pathway, the results of this study indicate that older men with high tHcy who use aspirin have lower risk of depression, and suggest that antiplatelet therapy may be an effective preventive or management strategy for these cases. Randomized trials are required to confirm the antidepressant effect of aspirin in older persons with high tHcy. Future trials should test the efficacy of aspirin as an adjunctive therapy to standard antidepressants, as treatment with aspirin alone would be ethically questionable. No such concerns would limit the design of a placebo-controlled trial of aspirin to prevent depressive episodes in older people with high tHcy, particularly because homocysteine-lowering treatment with B-vitamins seems to have questionable impact on novel cardiovascular events and future depression.14, 33