This is, to our knowledge, the first population-based study to examine the relationship between a clinical diagnosis of depression and mortality due to CVD and IHD in a cohort of young adults. In addition, it is the first study to examine a history of suicide attempts along with depression as a marker for future CVD and IHD mortality. Because previous studies have included middle-aged and older populations, the dramatic impact of depression and suicidality (as measured by attempted suicide) on IHD mortality in younger individuals has gone unrecognized. Our results are supported by other studies that show increased cardiac susceptibility to psychosocial stress in younger vs older populations5,6,27
and further underscore the importance of stress reduction in young adults. Young women may also be at particular risk given that 5 of 7 IHD deaths (as opposed to 4 of 21 in young men) involved depression and/or attempted suicide.
Although several studies have examined the relationship between depression and CVD mortality,1
our study differs in many substantial ways. First, we examined a clinical diagnosis of unipolar or bipolar depression, which may be a more robust risk indicator for IHD mortality compared with depressive symptom scales, which were the focus of most previous population studies.28
Second, we examined young individuals, whereas much of the previous data come from older populations with comorbidities and a larger burden of IHD risk factors.1
Because our young sample is considerably healthier than the older populations included in previous studies, the potential for unaccounted confounding factors is less, adding validity to our findings. Third, along with depression, we considered a history of attempted suicide, a related factor that may help capture mood and personality disturbances in young individuals at a population level that may have been missed by the Diagnostic Interview Schedule and that was never examined before with respect to cardiovascular risk.29
Although we did not find significant sex interaction with regard to CVD and IHD mortality, we did find significant sex differences in non-CVD mortality that were in the opposite direction. Specifically, women with depression/attempted suicide were at higher risk for CVD and IHD mortality but not for non-CVD mortality, whereas men showed more consistent associations across types of mortality. Although the reasons for this are not clear, it implies that the increased risk associated with depression/attempted suicide in women is specific to IHD, whereas in men it reflects a more general mortality risk. Our findings are consistent with previous studies that, albeit in different populations, have noted higher risks associated with depression among women than men,30,31
although such sex differences are also subject to debate.32
We found that a history of attempted suicide was at least as predictive of CVD/IHD mortality as depression. Although suicidality is a symptom of depression, people with a history of attempted suicide may be affected by other psychiatric disorders in addition to depression, which may also increase CVD risk.29
Patients with increased suicidality exhibit changes in the brain that are consistent with a state of severe, enduring stress, including increased serotonin binding sites in the brain in those who completed suicide.33
It is possible that a history of attempted suicide is a marker of severe depression and hopelessness or is an index of multiple adverse psychological risk factors that synergistically increase CVD risk. In addition, the increased suicide rate found in patients with MI by Larsen et al8
may, in part, be owing to increased prevalence of antecedent suicidality in patients with MI. A history of attempted suicide, therefore, is likely a very important and underrecognized risk factor for IHD in addition to depression.
Depression is thought to increase the risk of IHD through several stress-related physiological mechanisms that may also occur in people with a history of attempted suicide. For example, heart rate variability, an indicator of poor autonomic function and a risk factor for IHD,34
is lower in persons with depression compared with those without depression.35
Depression is also associated with increased cortisol secretion,36
which has potential adverse cardiovascular effects, including decreased glucose intolerance and increased visceral adiposity.37
Lifestyle factors may also play a role in mediating the relationship between depression and IHD,38
although our study showed a significant risk of depression and a history of attempted suicide even after thorough adjustment for health behaviors. Therefore, direct physiological effects of depression may play a greater role than lifestyle factors in this young population.
Although we did not use sample weights, we attempted to minimize this limitation by controlling for the sampling factors of race/ethnicity in our analysis. Each risk factor was measured only at inception of the cohort and is subject to change over time; therefore, this may increase random error. However, this problem would only bias the estimates toward the null. The utility of a history of attempted suicide as a preventable risk factor is limited by the understanding of its underlying cause, although 2 primary causes, hopelessness and impulsivity (even without an intent to die), are amenable to psychotherapy.39
A history of attempted suicide may be misclassified because it was ascertained from a single question and subject to recall bias. Questions regarding the use of cocaine, alcohol, and tobacco may be subject to recall bias as well. The cause of death was ascertained by death certificate data and may also be subject to misclassification owing to missing information. However, such misclassification more frequently occurs in elderly individuals.40
Also, it is likely that these causes of misclassification are equally distributed in exposed and unexposed individuals, again biasing the study estimates toward the null.
Possibly the most important limitation of this study is the low event rate given the young age of our population. This limited the power of our analysis and caused wide CIs. As a result, the sex interaction was not statistically significant, and despite large numerical differences in HRs, we cannot make definite conclusions about sex differences. Although bias is possible in multivariate models because of few outcomes, a ratio of 5 outcomes per predictor has been shown to suffice for accurate (<10% bias) estimation of relative risk.22
The number of covariates was also minimized in our analysis by using the FRS rather than individual CVD risk factors. In addition, we performed a series of sensitivity analyses, including a diverse array of adjustment factors, and our results remained robust. Because of this, we believe that our analyses are unbiased and our results are valid; nonetheless, further study is necessary. We believe that the identification of risk factors for CVD in younger adults is so important for prevention that this area should not be neglected on the basis of low event rates alone. This practice may especially limit our understanding of preventable risk factors for women, who notoriously have lower event rates than men until elderly age. On the other hand, women remain a group for whom more knowledge about CVD risk factors and pathophysiologic mechanisms is needed.
In conclusion, our study uncovers a profound role of psychological factors on premature CVD deaths in young individuals. Although young men and women with depression or a history of attempted suicide are at increased risk of CVD, women with these risk factors may be especially susceptible to death from IHD. Given the high impact of premature death on families and the workforce, more research and more preventive and therapeutic efforts are warranted to uncover the causes and mitigate the consequences of these adverse effects. Our data also suggest that more research should take a life-course approach to identify risk factors for IHD early in life.