Phillip J. Tully Bernhard T. Baune

DOI 10.1007/s00127-013-0784-x ORIGINAL PAPER Comorbid anxiety disorders alter the association between cardiovascular diseases and depression: the German National Health Interview and Examination Survey Phillip J. Tully Bernhard T. Baune Received: 2 April 2013 / Accepted: 14 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract Purpose This study aims to examine whether specific anxiety disorder comorbidity alters the purported association between depression and specific cardiovascular diseases (CVDs). Methods In 4,181 representative German participants of the general population, 12-month prevalence of psychiatric disorders was assessed through the Composite International Diagnostic Interview and CVDs by physician verified diagnosis. Adjusting for conventional risk factors logistic regression analyzed the association between CVDs (peripheral vascular disease (PVD), hypertension, cerebrovascular disease and heart disease) and combinations of comorbidity between depression and anxiety disorder types (panic disorder, specific phobia, social phobia and generalized anxiety). Results There were 770 cases of hypertension (18.4 %), 763 cases of cerebrovascular disease (18.2 %), 748 cases of PVD (17.9 %), and 1,087 cases of CVD (26.0 %). In adjusted analyses phobia comorbid with depression was associated with cerebrovascular disease (odds ratio (OR) 1.61; 95 % confidence interval (CI) 1.04 2.50) as was panic disorder (OR 2.89; 95 % CI 1.47 5.69). PVD was significantly associated with panic disorder (adjusted OR 2.97; 95 % CI 1.55 5.69). Panic disorder was associated with CVDs (adjusted OR 2.28; 95 % CI 1.09 4.77) as was phobia (adjusted OR 1.35; 95 % CI 1.04 1.78). P. J. Tully (&) B. T. Baune Discipline of Psychiatry, The University of Adelaide, Adelaide, SA, Australia e-mail: phillip.tully@adelaide.edu.au B. T. Baune Royal Adelaide Hospital, The University of Adelaide, Level 4, Eleanor Harrald Building, Adelaide, SA 5005, Australia Conclusions Classification of anxiety and depression according to comorbidity groups showed discrete effects for panic disorder and specific phobia with CVDs, independent from covariates and depression. Keywords Cardiovascular diseases Vascular diseases Anxiety disorders Depression Comorbidity Introduction Unipolar depression is common in primary care settings, and frequently co-occurs with common cardiovascular diseases (CVDs) such as hypertension [1 3], peripheral vascular disease (PVD) [4] and cerebrovascular disease [5 7]. Etiological research shows that depression is a predisposing risk factor for development of subsequent CVDs, especially coronary heart disease [8 10]. Prognostic research also supports that depression increases risk for mortality, major cardiac events and poor quality of life in patients with pre-existing CVD [11, 12]. Depression intervention trials have produced clinically meaningful, but modest, effect sizes in reducing CVD morbidity [13, 14] raising the possibility that what is understood about the depression-cvd link is incomplete and in the nascent stages. The global disease and morbidity burden attributable to depression and CVDs [15] underscore the necessity to explore alternative epidemiological and biological models to inform our understandings and make appropriate treatment recommendations [16]. Parallel research uncovering an association between CVD and different anxiety disorders questions whether depression is a discrete psychiatric risk factor for CVD [17 23]. Accumulating evidence supports that panic

disorder [24, 25], post-traumatic stress disorder [26], and generalized anxiety disorder [23, 27 29] are associated with CVDs. Few investigations have examined whether specific and social phobias are related to CVDs independent of depression. Collectively, however, large epidemiological studies have tended to focus on affective constructs in isolation (e.g., unipolar depression) or collapse anxiety disorders into a singular any anxiety disorder group, thereby neglecting the clinical reality of psychiatric comorbidity and the unique phenotypic characteristics of the anxiety disorders [30]. As a consequence, the conjoint and independent association between multiple psychiatric disorders and CVDs is largely unknown. Some notable exceptions have examined hypertension in relation to generalized anxiety disorder [23, 27], panic disorder [24], and post-traumatic stress disorder [26]. Studies, however, have typically focused on singular anxiety disorders, and predominantly hypertension, or coronary heart disease. With respect to the latter, the World Mental Health Surveys showed that effect sizes for anxiety disorders are comparable to that observed in depression [31]. Also, a study among 43,093 US civilians reported that the adjusted effect sizes between coronary heart disease and anxiety disorders were strongest for panic disorder, generalized anxiety disorder and specific phobia by comparison to unipolar, bi-polar and dysthymia mood disorders [32]. Though evidence links various anxiety disorders with hypertension and coronary heart disease in particular, the process by which anxiety disorders might have an additive or attenuating effect on the widely reported depression-cvd association is lesser known. Aims of the study In the current study, we used the National Health Interview and Examination Survey that provided physician diagnoses of various CVDs and psychiatric disorders. The aim of this analysis is to (a) estimate the association between various anxiety disorders and CVDs, hypertension, cerebrovascular disease and PVD, and (b) examine the role of comorbidity between anxiety disorders and unipolar depression in their association with CVDs, PVD, cerebrovascular disease and hypertension. Methods Sample The German Health Interview and Examination Survey consisted of a core survey (GHS-CS) and a Mental Health Supplement (GHS-MHS). Data collection was done between October 1997 and March 1999. A full description of the study methodology and sampling can be found elsewhere [33 35]. In brief, a subsample of survey participants aged up to 65 years underwent screening for mental disorders with the Composite International Diagnostic-Screener [34]. Total 4,181 respondents completed the mental health assessment and constituted 100 % of participants who screened-positive for a mental disorder, and 50 % of screening-negative respondents. Data weighting was applied to adjust for age, sex, and regional distribution in Germany and was specified according to national administrative statistics and selection probabilities. The weighting variable also accounted for the oversampling of screening-positive respondents and the differential non-responses among the subgroups. A full description of the weighting method can be found elsewhere [32 34]. Respondents of the core survey older than 65 years were excluded from the GHS-MHS because the psychometric properties of the Composite International Diagnostic Interview (CIDI), applied in the study, have not yet been satisfactorily established for use in older populations [36]. Assessment of CVDs The core survey consisted of (1) a self-report questionnaire on various health-related and social domains; (2) a standardized computer-assisted medical interview; (3) anthropometric and blood pressure measurements and the collection of blood and urine samples, and (4) the abovementioned screening for mental disorders. Medical diagnoses were made by the study physician after medical examination and structured interview; though some diagnoses were revised on the basis of medical reports and of the laboratory test results that became available 2 weeks later. Smoking was assessed by self-report (standardized number of pack years) and obesity was determined by standard international criteria for body mass index (BMI) derived from measured height and weight, BMI C30 kg/m 2 was classified as obese. For this analysis, vascular disorders were restricted to the diagnostic groups of cerebrovascular disease, PVD, hypertension and CVDs. Blood pressure was measured during the examination by means of three consecutive measurements allowing for 3-min intervals between each measure. According to the WHO guidelines, hypertension was defined as having a systolic blood pressure [140 mm Hg and a diastolic blood pressure [90 mm Hg [32]. All three measures had to be above either the diastolic or systolic or both criteria to qualify as hypertensive. Participants with a previous diagnosis of hypertension, but normal blood pressure were considered as hypertensive. Cerebrovascular disease was defined as any previous nonfatal stroke or brain circulation disturbance [33]. PVD was

defined as any leg circulation disturbance, artery occlusion, varicose vein or vein thrombosis [33]. The binary CVD variable constituted by any previous ischemic heart disease, myocardial infarction, heart failure, coronary artery occlusion, angina pectoris, hypertension, cerebrovascular disease or PVD [33]. Assessment of mental disorders Psychopathological and diagnostic assessments were based on the CIDI and the psychometric properties constrained the interview to persons aged 18 65 years. The resulting response rate of the age-restricted sample was 87.6 %, yielding a total of 4,181 respondents, aged 18 65 years who completed both the core survey for physical assessment and the German National Health Interview and Examination Survey Mental Health Supplement for mental assessment. The computer-assisted version of the Munich CIDI is a modified version of the World Health Organization CIDI, version 2.1 [37], supplemented by questions to cover Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) and International Classification of Diseases-10. The Munich CIDI is a fully structured interview that allows for the assessment of symptoms, syndromes, as well as 4 week, 12 month and lifetime diagnoses of DSM-IV mental disorders. The CIDI is considered to be a reliable and valid instrument for the diagnosis of affective disorders [38]. Most interviews of the mental health assessment were done within 2 4 weeks after the core survey medical examination at the homes of the respondents. In this analysis we focussed on major depression in combination, or independent from, various anxiety disorders; panic disorder with or without agoraphobia, generalized anxiety disorder, social phobia and specific phobia. Analyses were stratified to create four binary groups; no depression or type of anxiety disorder (reference category), one type of anxiety disorder only, depression only, comorbid depression-type of anxiety disorder. Statistical analysis Statistical analyses were performed with SPSS (version 20.0). Analyses used the 12-month prevalence of medical conditions and 12-month prevalence of mental health disorders. Data were weighted by the standard procedure applied to the National Health Survey according to demographic characteristics (age, gender and geographical location) and selection probabilities (screen-negatives received twice the weight of screen-positives). The strength of association between psychiatric disorders and CVDs/PVD/cerebrovascular disease/hypertension was expressed by odds ratios (OR) and 95 % confidence Table 1 Demographics and characteristics of the sample intervals (95 % CI). To produce estimates generalizable to the population, models were adjusted for age, sex, marital and social status, and sampling weights in each analysis. To control for other confounding factors, the models were adjusted for smoking status and obesity [39], and sensitivity analyses repeated the adjusted regression models removing smoking status and obesity. Ancillary analyses repeated analyses investigating comorbidity between the psychiatric disorders with the strongest associations with CVDs. Social status was described by three strata (low, medium and high social status), assessed with the validated Winkler social index. Information about (1) income, (2) education, and (3) current occupation (scores ranged from 1 to 7 on each of the three single dimensions) yielded a summary score ranging from 3 to 21 points. The three social strata (low, medium, high) derived from this summary score. The Winkler social index is a validated and well-established score applied to several national surveys in Germany [40]. Results N (%) Age (years), M (SD) 43.5 (11.63) Male 1,913 (45.75) Female 2,268 (54.25) Marital status Married, living together 2,617 (62.59) Separated, divorced, widowed 493 (11.79) Single 991 (23.70) Social class Lower 817 (19.54) Middle 2,367 (56.61) Upper 912 (21.81) Body mass index [30 797 (19.06) Smoking 2,240 (53.58) Vascular diseases Cerebrovascular disease 763 (18.25) Peripheral vascular disease 748 (17.89) Hypertension 770 (18.41) Combined cardiovascular disease 1,087 (26.00) 12-month mental health Depression 699 (16.72) Panic disorder ± agoraphobia 121 (2.89) Generalized anxiety disorder (2.89) Social phobia 132 (3.16) Simple phobia 482 (11.53) In total, 4,181 participants aged 18 65 years were assessed for mental health disorders. About half (54.2 %) of the

Table 2 Multivariate logistic regression models for the association between cerebrovascular disease and comorbid major depression and panic disorder, generalized anxiety disorder and phobia Cerebrovascular disease No CD CD Unadjusted Adjusted a 12-month disorder N (%) N (%) OR CI lower CI upper OR CI lower CI upper No panic, no depression 2,454 (85.77) 634 (82.98) Reference Reference Panic only 22 (0.76) 20 (2.62) 3.50 1.87 6.56** 2.89 1.47 5.69** Depression only 340 (11.88) 94 (12.30) 1.08 0.85 1.38 1.03 0.79 1.34 Depression and panic 45 (1.57) 16 (2.09) 1.32 0.72 2.44 1.35 0.70 2.62 No GAD, no depression 2,454 (85.77) 645 (84.42) Reference Reference GAD only 22 (0.76) 9 (1.17) 0.90 0.39 2.08 0.94 0.37 2.37 Depression only 330 (11.53) 92 (12.04) 0.95 0.75 1.20 1.05 0.81 1.36 Depression and GAD 56 (1.96) 16 (2.09) 1.50 0.90 2.51 1.27 0.73 2.23 No phobia, no depression 2,262 (79.06) 574 (75.13) Reference Reference Phobia only 214 (7.47) 80 (10.47) 1.43 1.08 1.88** 1.32 0.98 1.79 Depression only 303 (10.59) 70 (9.16) 0.92 0.70 1.21 0.92 0.68 1.24 Depression and phobia 80 (2.80) 39 (5.10) 1.89 1.27 2.82** 1.61 1.04 2.50* No social, no depression 1,861 (85.09) 925 (85.41) Reference Reference Social only 39 (1.78) 13 (1.20) 0.64 0.33 1.22 1.01 0.50 2.06 Depression only 260 (11.89) 125 (11.54) 0.97 0.78 1.22 1.03 0.80 1.34 Depression and social 27 (1.23) 20 (1.85) 1.42 0.78 2.60 1.60 0.83 3.10 CI confidence interval, CD cerebrovascular disease, GAD generalized anxiety disorder, OR odds ratio * p \.05; ** p \.01; *** p \.001 a Adjusted for age, sex, marital and social status, sampling weights, smoking status and obesity sample were women, mean age of all participants was 43.5 years (range 18 65; SD 11.6) (see Table 1). There were 770 cases of hypertension (18.4 %), 763 cases of cerebrovascular disease (18.2 %), 748 cases of PVD (17.9 %), and 1,087 cases of any CVD (26.0 %). The 12-month prevalence of psychiatric disorders was; unipolar major depression (16.7 %), panic disorder ± agoraphobia (2.9 %), generalized anxiety disorder (2.9 %), social phobia (3.2 %) and specific phobia (11.5 %) (Table 1). Cerebrovascular disease The 12-month prevalence of depression and anxiety disorders for participants with cerebrovascular disease is shown in Table 2. Panic disorder had the strongest association with cerebrovascular disease (adjusted OR 2.89; 95 % CI 1.47 5.69). The OR for panic disorder was attenuated when comorbid depression-panic disorder was analyzed (OR 1.35; 95 % CI 0.70 2.62). Phobia, and comorbid depression-phobia were more prevalent in cerebrovascular disease patients though only the latter OR was below conventional significance. There was an additive effect for depression-phobia (OR 1.61; 95 % CI 1.04 2.50) by comparison to phobia only (OR 1.32; 95 % CI 0.98 1.79). There was no association between cerebrovascular disease and depression, GAD or social phobia. Peripheral vascular disease The 12-month prevalence of depression and anxiety disorders for participants with PVD is shown in Table 3. The strongest association was obtained for panic disorder (OR 2.97; 95 % CI 1.55 5.69) and depression appeared to attenuate the association (depression-panic OR 1.47; 0.78 2.78). Depression with specific phobia was more prevalent in persons with PVD (adjusted OR 1.48; 95 % CI 0.97 2.60). There was no association between PVD and depression, GAD or social phobia. Hypertension The 12-month prevalence of depression and anxiety disorders for participants with hypertension is shown in Table 4.These analyses showed that panic disorder alone was associated with hypertension in unadjusted analyses (OR 2.04; 95 % CI 1.13 3.68), and adjustment for covariates attenuated the odds ratios. No other psychiatric disorders were associated with hypertension in unadjusted or adjusted analyses. Cardiovascular diseases The 12-month prevalence of depression and anxiety disorders for participants with PVD is shown in Table 5. The

Table 3 Multivariate logistic regression models for the association between peripheral vascular disease and comorbid major depression and panic disorder, generalized anxiety disorder and phobia PVD No PVD PVD Unadjusted Adjusted a 12-month disorder N (%) N (%) OR CI lower CI upper OR CI lower CI upper No panic, no depression 2,577 (85.58) 616 (82.35) Reference Reference Panic only 25 (0.83) 21 (2.81) 3.48 1.91 6.35*** 2.97 1.55 5.69*** Depression only 364 (12.09) 95 (12.70) 1.09 0.85 1.39 1.00 0.77 1.30 Depression and panic 45 (1.49) 16 (2.14) 1.56 0.81 2.64 1.47 0.78 2.78 No GAD, no depression 2,579 (85.65) 627 (83.82) Reference Reference GAD only 23 (0.76) 10 (1.34) 1.25 0.53 2.92 1.34 0.54 3.29 Depression only 353 (11.72) 95 (12.70) 1.10 0.87 1.40 1.07 0.82 1.39 Depression and GAD 56 (1.86) 16 (2.14) 1.14 0.64 2.03 0.82 0.45 1.52 No phobia, no depression 2,262 (78.78) 574 (75.62) Reference Reference Phobia only 230 (8.01) 75 (9.88) 1.33 1.00 1.76* 1.20 0.89 1.63 Depression only 320 (11.14) 71 (9.35) 0.93 0.71 1.23 0.91 0.67 1.22 Depression and phobia 59 (2.06) 39 (5.13) 1.86 1.26 2.75** 1.48 0.97 2.60 No social, no depression 2,549 (84.97) 624 (83.65) Reference Reference Social only 45 (1.50) 12 (1.60) 0.99 0.51 1.94 1.57 0.76 3.23 Depression only 363 (12.10) 93 (12.47) 1.03 0.80 1.32 1.00 0.76 1.30 Depression and social 43 (1.43) 17 (2.28) 1.51 0.84 2.72 1.43 0.75 2.72 CI confidence interval, GAD generalized anxiety disorder, OR odds ratio, PVD peripheral disease * p \.05; ** p \.01; *** p \.001 a Adjusted for age, sex, marital and social status, sampling weights, smoking status and obesity Table 4 Multivariate logistic regression models for the association between hypertension and comorbid major depression and panic disorder, generalized anxiety disorder and phobia Hypertension No HTN HTN Unadjusted Adjusted a 12-month disorder N (%) N (%) OR CI lower CI upper OR CI lower CI upper No panic, no depression 2,647 (87.91) 645 (83.77) Reference Reference Panic only 36 (1.20) 17 (2.21) 2.04 1.13 3.68* 1.69 0.88 3.28 Depression only 275 (9.13) 97 (12.60) 1.06 0.83 1.34 1.20 0.92 1.57 Depression and panic 53 (1.76) 11 (1.43) 0.90 0.47 1.74 1.02 0.49 2.10 No GAD, no depression 2,651 (85.21) 656 (85.19) Reference Reference GAD only 32 (1.03) 6 (0.78) 0.67 0.26 1.73 0.69 0.24 1.89 Depression only 368 (11.83) 89 (11.56) 0.97 0.76 1.24 1.12 0.85 1.48 Depression and GAD 60 (1.93) 19 (2.47) 1.34 0.79 2.27 1.39 0.78 2.47 No phobia, no Depression 1,746 (76.01) 835 (79.37) Reference Reference Phobia only 241 (10.49) 71 (6.75) 1.21 0.92 1.61 1.21 0.88 1.66 Depression only 230 (10.01) 107 (10.17) 0.99 0.76 1.28 1.16 0.87 1.55 Depression and phobia 80 (3.48) 39 (3.70) 1.23 0.80 1.88 1.29 0.80 2.08 No social, no depression 2,617 (84.41) 651 (84.89) Reference Reference Social only 60 (1.93) 8 (1.04) 0.47 0.22 1.04 0.66 0.28 1.55 Depression only 379 (12.22) 96 (12.52) 1.01 0.80 1.29 1.17 0.89 1.53 Depression and social 44 (1.42) 12 (1.56) 1.12 0.58 2.13 1.24 0.60 2.56 CI confidence interval, GAD generalized anxiety disorder, HTN hypertension, OR odds ratio * p \.05; ** p \.01; *** p \.001 a Adjusted for age, sex, marital and social status, sampling weights, smoking status and obesity

Table 5 Multivariate logistic regression models for the association between any cardiovascular disease and comorbid major depression and panic disorder, generalized anxiety disorder and phobia Any cardiovascular disease No CVD CVD Unadjusted Adjusted a 12-month disorder N (%) N (%) OR CI lower CI upper OR CI lower CI upper No panic, no depression 1,890 (86.07) 919 (84.54) Reference Reference Panic only 16 (0.73) 22 (2.02) 2.88 1.48 5.61*** 2.28 1.09 4.77** Depression only 257 (11.70) 126 (11.59) 1.01 0.80 1.27 1.06 0.82 1.37 Depression and panic 33 (1.50) 20 (1.84) 1.26 0.71 2.24 1.38 0.72 2.64 No GAD, no depression 1,888 (85.97) 930 (85.56) Reference Reference GAD only 18 (0.82) 11 (1.01) 0.90 0.39 2.08 0.94 0.37 2.37 Depression only 253 (11.52) 119 (10.95) 0.95 0.75 1.20 1.05 0.81 1.36 Depression and GAD 37 (1.68) 27 (2.48) 1.50 0.90 2.51 1.27 0.73 2.30 No phobia, no depression 1,746 (79.51) 835 (76.8) Reference Reference Phobia only 160 (7.29) 106 (9.8) 1.22 0.91 1.64 1.35 1.04 1.78* Depression only 231 (10.52) 107 (9.8) 1.05 0.80 1.38 0.97 0.76 1.24 Depression and phobia 59 (2.69) 39 (3.6) 1.32 0.83 2.09 1.37 0.90 2.08 No social, no depression 1,861 (85.09) 925 (85.41) Reference Reference Social only 39 (1.78) 13 (1.20) 0.64 0.33 1.22 1.02 0.50 2.06 Depression only 260 (11.89) 125 (11.54) 0.97 0.78 1.22 1.03 0.80 1.34 Depression and social 27 (1.23) 20 (1.85) 1.42 0.78 2.56 1.60 0.83 3.10 CI confidence interval, CVD cardiovascular disease, GAD generalized anxiety disorder, OR odds ratio * p \.05; ** p \.01; *** p \.001 a Adjusted for age, sex, marital and social status, sampling weights, smoking status and obesity strongest association was again obtained for panic disorder (OR 2.28; 95 % CI 1.09 4.779) and depression appeared to attenuate the association (depression-panic OR 1.38; 0.72 2.64). There was no association between CVDs and depression, GAD or social phobia. Sensitivity analysis: omitting obesity Sensitivity analyses removing obesity from the abovementioned adjusted models provided generally similar results to that reported above. It was found that the association between PVD and the depression-phobia comorbidity was strengthened (OR 1.52; 95 % CI 1.00 2.32). The odds ratios were attenuated for the association between panic disorder and cerebrovascular disease (OR 2.01; 95 % CI 1.02 4.30), and also with PVD (OR 2.84; 95 % CI 1.50 5.40). Sensitivity analysis: omitting smoking Sensitivity analyses removing smoking from the fully adjusted models for cerebrovascular disease provided similar results for PVD, hypertension and CVD as reported above. The two findings that were notable include the attenuated strength of association between panic alone and cerebrovascular disease (OR 2.32; 95 % CI 1.11 4.83), while the association between panic and PVD strengthened (OR 3.05; 95 % CI 1.06 5.82). Ancillary analysis: adjusted Ancillary analyses focussed on panic disorder and simple phobia for their association with CVDs. Analyses were stratified to create four binary groups; panic disorder only, specific phobia only, comorbid panic disorder with specific phobia, and no anxiety disorder (as reference category, data not shown). The findings showed that PVD was associated with panic alone (OR 2.20 (95 % CI 1.18 4.12) p =.01), and panic comorbid with phobia (OR 2.01 (95 % CI 1.06 3.81) p =.03). There was also a trend association between panic alone and CVD (OR 1.87; 95 % CI 0.96 3.64) p =.07). There was no significant association between panic or phobia with hypertension. Discussion This study was one of few studies to examine whether anxiety disorder comorbidity alters the association between depression and specific CVDs [23, 27, 28]. The current data suggest that the strongest associations were evident for panic disorder independent of depression, though no

association was evident with hypertension. By contrast, it was found that though simple phobia was also significantly associated with CVD, there was an additive effect found for simple phobia-depression comorbidity upon cerebrovascular disease and PVD, but not CVD. The absence of association with CVD according to depression alone, social phobia or GAD suggests a differential association between the anxiety disorders and CVDs. A strength of this study was structured diagnostic interview for mental disorders and also use of physician verified CVDs according to predetermined study criteria as opposed to other studies that utilized self-reported medical disorders [31, 32, 41] or medical claims data [24]. Use of physician verified medical disorders may be particularly important in context of anxiety disorder-cvd associations to limit bias from selfreport and health anxieties [32]. The results here corroborate that a broader approach to psychiatric presentation may be valuable for studying CVDs rather than pure depression. Consistent with findings here a Taiwanese study matching 3,672 panic patients with 18,360 controls reported significant associations between panic disorder and coronary heart disease (OR 7.69; 95 % CI 7.69 8.71), cerebrovascular disease (OR 3.61; 95 % CI 3.00 4.35) and hypertension (OR 3.31; 95 % CI 2.99 3.67) [24]. Scherrer et al. [20] showed in longitudinal follow-up of initially heart disease free patients that effect sizes for incident myocardial infarction were greater for panic disorder than patients with comorbid depression and panic disorder. By contrast Gomez-Caminero et al. [25] showed that depression had an additive effect upon the association between panic disorder and coronary heart disease. However, the association between panic disorder and CVDs is not supported by all literatures [42] and inverse associations between panic and coronary artery disease have been documented [43]. The differential findings could also be interpreted according to hierarchical taxonomic structures [30] that characterize disorders according to distinct phenotypes [44]. That is, panic disorder, along with simple phobia, social phobia and agoraphobia was shown to correlate within a visceral-fear cluster [30]. By comparison, depression, GAD and dysthymia, were correlated within a distinct anxious-misery cluster [30]. When reporting strong relationships between anxiety disorders and self-reported CVDs, Goodwin and colleagues [32] indicated that potentially important relationships would be obscured when not examining anxiety and depression contemporaneously. Previous research collapsing anxiety disorders into an any anxiety disorder category has shown higher prevalence in persons with CVDs and other somatic diseases [22] likely due to the greater statistical power afforded by broader mental disorder categories. This contrasts with the smaller cell sizes here when stratified by depression-anxiety comorbidity and CVDs. Nevertheless, the findings here with respect to panic, phobia and GAD corroborate that the effects upon CVD are disorder-specific, rather than generalizable across all of the anxiety disorders. For example, by contrast to panic disorder, depression had an additive effect on the simple phobia association with CVDs. Previously, Goodwin and colleagues [32] also showed a modest, but significant association between specific phobias and heart disease (OR 1.37; 95 % CI 1.13 1.67). The findings of our study differ from previous studies who have reported that GAD increases risk for CVDs independent of major depression in either initially disease free samples [27], prognostic studies with known CHD [21, 45], or crosssectional studies [23, 32]. Multifaceted collaborative care intervention that conjointly targeted depression and somatic diseases reported improvements in depression, glycated hemoglobin, blood pressure, cholesterol, satisfaction with care and quality of life [46]. Though depression treatments in CVD have clinically important effects on depression symptoms [14], few interventions focussed specifically on the anxiety disorders in CVD. Shemesh and colleagues [47] conducted a safety and feasibility study with post-traumatic stress disorder and showed that imaginal exposures did not increase blood pressure, arterial pressure or heart rate. Other psychological interventions in CVDs typically target nonspecific self-reported anxiety rather than particular psychiatric disorders [48], perhaps as the safety of anxiety exposure therapies is not established in CVDs [28]. Other authors have highlighted that detection of psychiatric disorders in cardiology settings is poor [49] though the necessity for treatment of relatively mild anxiety disorders such as simple phobia is overemphasised [22]. The pathophysiological mechanisms through which anxiety and depression may predispose psychologically distressed people to cardiopathogenesis and cardiac events are complex. The biological mechanisms hypothesized to increase the risk of cardiopathogenesis are similar across depression and anxiety (e.g., enhanced platelet aggregability, reduced heart rate variability, dysregulation of the hypothalamic pituitary adrenal axis) though contrasting findings have been reported [50 52]. Likewise behavioral mechanisms such as non-adherence to medications and rehabilitation, sedentary lifestyle and smoking are also reported among persons with anxiety [28, 52]. Several limitations need to be recognized when interpreting the findings of this study including the cross-sectional study design. The use of German sampling sites may temper the generalizability of the results and the data were weighted based on specific sampling probabilities. Moreover, the CIDI component of the DEGS study did not assess respondents older than 65 years. Though it would be expected that older patients would have higher

probabilities for CVDs and somatic diseases, exclusion of 65-year-old patients might provide more robust results by assessing only early onset CVDs. The study included null findings for hypertension itself a risk factor for other CVDs and thus the results possibly reflect only more severe CVDs. Further investigation of depression ± anxiety comorbidity among the second DEGS, and other international population databases, could confirm these findings while assessing potential changes in CVD prevalence over time. That said, it is evident that rates of CVDs have largely remained stable over the past two decades within Germany [53 55]. The study was underpowered to analyze obsessive compulsive disorder and no psychiatric data were obtained regarding post-traumatic stress disorder. It was possible that the diagnostic phenotypes characteristic of each psychiatric disorder confounded these results. For example, panic disorder patients overreport medical symptoms leading to more investigations [32]; conversely social phobia patients show patterns of avoidance [56], whereas worrisome GAD patients may engage in more preventative health behaviors [28]. Also, this study did not focus on specific phobia subtypes (e.g., blood-injury) that may work via discrepant pathophysiological mechanisms as has been reported for various depression sub-types [57]. In conclusion, this study has demonstrated that panic disorder was consistently associated with CVDs independent of depression. Also, phobic anxiety exhibited a cumulative effect increasing the strength of association with CVDs evident for depression. The data corroborate discrete associations between mental disorders and CVDs and suggest that classification of anxiety-depression comorbidity is important for understanding the relationship with CVDs. 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