Among women with suspected myocardial ischemia followed for a median 5.9 years, the joint use of anxiety and depression symptoms predicted incident CVD events and death above and beyond each symptom cluster. Using questionnaires to assess anxiety and depression symptom severity, the two mood dimension scores interacted such that a significant main effect relationship between depression and CVD death and events was found to vary across levels of anxiety. Specifically, the association between depression and CVD outcomes became progressively weaker across low, moderate, and high levels of anxiety symptoms. This result suggested that assessing depression and anxiety together more accurately predicted CVD outcomes than assessing either condition alone. Rates of elevated depression and anxiety were high in this sample, based on standards of either questionnaire scores or psychotropic use. However, these rates appeared appropriate given the symptomatic nature of the participants, along with the well-documented gender differences in rates of depression and anxiety documented in women (35
). Depression and anxiety symptoms likewise overlapped substantially in this sample, with the inter-scale correlation approaching r=.70.
Anxiety and depressive disorders are common in the U.S. (35
). The symptom overlap between these two mood conditions in cardiac populations is well-known (36
), and many studies have examined both mood dimensions as predictors of cardiovascular outcomes (e.g., 2
). Nevertheless, depression rather than anxiety continues to garner the lion's share of attention in behavioral cardiology research. However, growing evidence suggests that anxiety warrants a greater focus in cardiac populations, particularly among women (40
). Reports from cardiac samples, for example, have shown rates of anxiety disorders ranging from 25-36%, with rates twice as high among women compared to men (41
). Prevalence statistics also show that rates of specific anxiety disorders such as agoraphobia, panic disorder, and generalized anxiety disorder are at least twice more common among women than men in medical and healthy samples (43
). These findings parallel gender difference statistics for depression (43
), and support the need for research addressing joint anxiety and depression effects in women.
Few studies have directly examined combined versus independent anxiety and depression symptoms as predictors of health outcomes in cardiovascular populations. Watkins (23
) used questionnaire measures of depression (BDI) and phobic anxiety (Crown-Crisp index), with their results indicating that each symptom class was a predictor of ventricular arrhythmias alone, but when modeled together neither variable was significant. The latter effect was speculated to be a result of the high degree of overlap between the anxiety and depression scores. A composite (a sum of the standardized questionnaire scores) anxiety-depression score also predicted events in this study to a non-significantly greater degree than the separate anxiety and depression scores; however, no formal interaction between these measures was tested.
In patients with established coronary artery disease, Frasure-Smith and Lesperance (22
) also assessed anxiety and depression comorbidity in the prediction of cardiac events using a combination of interview-based diagnoses and questionnaire scores (BDI-II and the anxiety subscale from the Hospital Anxiety and Depression Scale [HADS]). Interview-based diagnoses of generalized anxiety disorder and major depressive disorder were stronger predictors than questionnaire scores, but the combined presence of elevated anxiety and depression detected through diagnostic methods did not predict cardiovascular events more effectively than separate mood conditions. Interestingly, however, in a breakdown of questionnaire-derived depression effects across different levels of anxiety symptoms, these authors observed relatively stronger effects of depression when combined with low levels of anxiety. Although no specific test for an interaction effect was performed with the questionnaire scores, the latter pattern resembles the simple effect breakdown we have described here.
Our assessment of the joint effects of anxiety and depression indicated that higher anxiety levels attenuated (or, protected against, as the reader may prefer) the relationship between BDI scores and incident CVD death and events. BDI scores were significant predictors of CVD outcomes among women with moderate and low STAI scores, defined as those scoring at the scale mean and one standard deviation below the mean. However, among those with higher STAI scores, the BDI-CVD outcomes relationship was not significant. This effect is not due to confounding: to be a confounding relationship the confounding variable (in this case anxiety) must be statistically associated with both the predictor and the outcome (45
), but anxiety was not significantly related to CVD outcomes in our analyses. Likewise, this effect cannot be explained by multicollinearity, as our diagnostic tests ruled out this possibility. Lacking evidence of a statistical artifact, the speculation that high levels of anxiety may in some way affect the accuracy or reliability of depression symptom reporting becomes more tenable. This effect may occur through the similarity in symptoms between these conditions (e.g., potentially artificially elevating depression scores through an overlap in somatic symptoms), via shared pathophysiological mechanisms (e.g., impaired heart rate variability or increased sympathetic nervous system activation), or behavioral correlates (e.g., anxious-depressed patients may more actively pursue healthcare, which might buffer the risk associated with depression). In regards to the latter speculation, depression was recently shown to predict increased healthcare usage in WISE participants (46
). Finally, the fact that WISE participants were enrolled specifically because they had clinical symptoms serious enough to warrant coronary angiographic testing may also have influenced the anxiety-depression relationship, as depression and anxiety symptoms are known to correlate with cardiac symptom reporting (e.g., 6-7). Clearly, these topics will require further investigation to resolve.
The substantial overlap we observed between anxiety and depressive symptoms appears characteristic of cardiac samples. For example, Denollet and colleagues (36
) reported that a mixed mood profile comprised of anxiety and depressive symptoms, rather than depression alone, was the most common presentation in post-MI patients (37
). At least 90% of their post-MI patients meeting criteria for depression showed evidence of mixed anxiety-depression, leading the authors to conclude that anxiety is a common element of post-MI depression. The Frasure-Smith sample (22
) experienced similar symptom overlap, from which 77.3% of patients with high BDI-II scores also had elevated HADS anxiety scores. Combined with our present findings, these collective results suggest that investigations reporting on depression alone in association with CVD outcomes are greatly underestimating the degree of comorbidity with anxiety symptoms. Whether this symptom overlap is more accurately conceptualized using composite scores (23
), categorical breakdowns of anxiety and depression scores (22
), factor analyses to create a mood meta-factor (17
), or interaction terms as used in the current study, remains an empirical question.
In practice, one of the most difficult challenges facing a clinician is to accurately interpret the frequent overlap of depression, anxiety, and CVD symptoms. Are mental health symptoms a cause, consequence, or exacerbating agent in the patient's medical presentation? Alternatively, could both the mental health and CVD symptoms be the result of a common factor, such as inflammation? To add even more complexity, the role of mental health symptoms may change at different stages of the CVD process in a given patient, and the various roles are not exclusive. An example of this complexity is apparent in the interpretation of results by Walters and colleagues (47
), who reported that newly diagnosed panic attacks or panic disorder were associated with an increased risk of MI or heart disease diagnosis in a sample of nearly 400,000 adults. Although panic symptoms were more strongly associated with cardiovascular outcomes in younger participants (<50 years of age), even in this higher risk group the authors point out that it cannot be clearly inferred whether panic symptoms represent a risk factor for cardiac outcomes or whether early stages of CVD were simply misdiagnosed as an anxiety condition.
How clinicians conceptualize this symptom overlap will go far in determining their diagnoses, treatment plans, and possible referrals for additional testing and services. At present, unfortunately, no foolproof guidelines for navigating this decision process exist, but evidence of errors and biases in current practices is abundant. Numerous studies, for example, indicate that women presenting with cardiac symptoms are less aggressively diagnosed and treated (e.g., 48-49), despite women having overall higher CVD death rates (50
), suggesting that cardiologists are more likely to interpret women's symptoms as originating from non-cardiac or mental health sources.
This study offers some novel methodological features compared to previous research, including: (1
) examining independent versus interacting anxiety-depression relationships with CVD events in the largest female cohort to date; (2
) tracking CVD outcomes over nearly six years, roughly twice the length of previous efforts; (3
) objectively quantifying the degree of CAD severity for use as a covariate, and; (4
) examining trait anxiety rather than specific anxiety disorder subsets such as generalized anxiety disorder and phobic anxiety, which may create a different pattern of associations. However, several important limitations deserve acknowledgement. Our results addressed cardiovascular outcomes in a sample comprised exclusively of clinically symptomatic women, among whom obstructive CAD was present in approximately 40% (28
), which differs substantially from the two previous investigations reported on this topic that included only participants with known CVD. The recruitment methods followed for WISE were intended to reflect the usual clinical circumstances of symptomatic women undergoing assessment for the presence of CAD; however, this study characteristic limits our ability to generalize findings to women with known CAD and asymptomatic samples. A substantial number of WISE participants did not complete the BDI and STAI questionnaires due to the absence of these measures from the baseline protocol during the initial months of the study. Psychological questionnaires were administered only at baseline, and no psychiatric interviews were included to document mental disorders. Although we found no evidence of bias between the groups completing versus not completing the mood questionnaires, we cannot rule out the possibility that the later cohort differed on unmeasured variables. Lastly, our results document a statistical interaction between depression and anxiety symptoms, which should not be confused with a biological interaction described in some epidemiological research. In contrast to biological interactions, which describe an effect emerging from the combination of two or more causal factors, statistical interactions carry the limitations of a non-causal interpretation and the effects being dependent on the choice of measurement scale (51
Among patients with CVD, both anxiety and depression are common and these symptom dimensions overlap substantially. However, the cardiovascular research literature to date has largely examined these mood dimensions as separate predictors despite their known congruence. In a sample of women undergoing coronary angiography for the assessment of suspected myocardial ischemia, we specifically addressed the combination of anxiety and depression symptoms, observing that the interaction between anxiety and depression measures was superior in the prediction of CVD death and events compared to separate use of the mood measures. Perhaps our most provocative finding was that elevated anxiety appeared to diminish the effectiveness of depression as a predictor. The high rate of anxiety and depression co-occurrence documented both in this study and in previous research, combined with the value observed here for the joint value of these emotional dimensions as CVD event predictors, presents a compelling argument for moving beyond single construct research in behavioral cardiology and more towards theoretical models that incorporate multiple dimensions of negative affect.