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Quantifying links between acute myocardial infarction and depression, anxiety and schizophrenia using case register databases
Journal of Affective Disorders 109 (2008) 177 – 181 www.elsevier.com/locate/jad
Brief report
Quantifying links between acute myocardial infarction and depression, anxiety and schizophrenia using case register databases Anne Helene Jakobsen a,⁎, Leslie Foldager b , Gordon Parker c , Povl Munk-Jørgensen a a
Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Mølleparkvej 10, DK-9000 Aalborg, Denmark b Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, DK-8240 Risskov, Denmark c School of Psychiatry, The University of New South Wales; and Black Dog Institute, The Prince of Wales Hospital, High Street, Randwick NSW 2031, Australia Received 25 April 2007; received in revised form 15 October 2007; accepted 15 October 2007 Available online 28 November 2007
Abstract Aims: To quantify the association between depression and acute myocardial infarction (AMI) in a large sample using case registers, and examine whether any such link is specific to depression or might more reflect mental illness status in general. Methods and results: Accessing the Danish Psychiatric Central Research Register (PCR), patients with a diagnosis of depression were extracted and followed for up to 24 years for episodes of AMI. We used mentally healthy age- and sex-matched controls, and as comparator diagnostic groups, we studied patients with anxiety and schizophrenia. A positive association between depression and AMI was found with an incidence rate ratio (IRR) of 1.16 (CI: 1.10–1.22). The association was not unique for the depressed individuals, but was also found for anxiety patients, where it was even stronger (IRR = 1.56, CI: 1.35–1.79) than for the depressed patients. A negative association (IRR = 0.77, CI: 0.65–0.91) was quantified for schizophrenia, arguing against any link with AMI being determined by psychiatric disorder status per se. Limitations: Being a register study, not all potential confounding variables could be examined. Conclusion: Findings quantify significant associations between depression and AMI as well as between anxiety and AMI, and argue that these two psychiatric disorders should be added to the list of risk factors to coronary artery disease. © 2007 Elsevier B.V. All rights reserved. Keywords: Myocardial infarction; Coronary heart disease; Depression; Anxiety; Schizophrenia
1. Introduction Depression and coronary artery disease are some of the most common diseases in the industrialized world, ⁎ Corresponding author. Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Mølleparkvej 10, DK-9000 Aalborg. E-mail address: [email protected] (A.H. Jakobsen). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.10.012
with ischaemic heart disease and stroke followed by depression as the strongest determinants of disability in industrialized countries (Lepine, 2001). Over the last decade, evidence for an association between depression and acute coronary syndromes has accrued (Dinan, 1999; Glassman and Shapiro, 1998; Lett et al., 2004; Rozanski et al., 1999; Wulsin, 2004; Rugulies, 2002). A recent review article asserts that the presence of depression increases the risk for developing
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A.H. Jakobsen et al. / Journal of Affective Disorders 109 (2008) 177–181
coronary artery disease by a factor ranging from 1.5 to 2.0 (Rugulies, 2002). Despite growing evidence for such an association, depressive disease is not included in the list of important and independent risk factors for cardiovascular disease published by the American Heart Association (Hunt et al., 2005). Furthermore, it is still not common practice for either general practitioners or cardiologists to screen for depression when examining risk factor status for coronary artery disease, or for depressed patients to be screened for risk factors for coronary heart disease. This may reflect insufficient awareness of the associational strength, and the suggested specificity to depressive illness, and argues the need for quantification from large databases as many of the contributing studies have involved relatively small sample sizes. Population and record linkage studies have the capacity to quantify risk more precisely and thus advance awareness. The aims of this study were firstly, to quantify the association between depression and AMI in a large register, and secondly, to examine whether it is depressive disease itself – or a broader variable of being mentally ill as a whole – that may provide increased risk for cardiovascular disease. The latter hypothesis was to be explored by comparing the comparative impact of anxiety and schizophrenia on AMI rates. 2. Methods The study is a longitudinal, historically-designed register study allowing psychiatric patients to be followed for episodes of AMI. Data were extracted from the Danish Psychiatric Central Research Register (PCR). This register contains person-identifiable information about all admissions to psychiatric inpatient facilities in Denmark since 1969 and outpatient facilities since 1995 (Munk-Jorgensen and Mortensen, 1997). Registration is complete for hospitalized patients as there are no private psychiatric hospitals in Denmark. This study also includes information from other national registers. Firstly, from the Central Office of Civil Registration where all citizens are registered by a unique 10-digit number, secondly from the Danish Codes of Death Register, CDR (only deaths proceeding 1998 were completely included in the CDR),and finally from the National Patients Register (NPR), where all somatic admissions are coded. The study cohort included all patients diagnosed and registered in the PCR with an affective disorder of a depressive type from 1 January 1977 to 31 December 2000. In operation, this involved all patients registered with a main diagnosis within the groups: ICD-8 (until
1993): 296.0, 296.2, 298.0, 300.4, and ICD-10 (from 1994): F31.3, F31.4, F31.5, F32, F33. The registration includes both inpatients, day patients and, from 1995, outpatients. Persons 15 years of age or younger at the time of diagnosis were excluded. Furthermore, we excluded patients receiving a depressive diagnosis who, at any time during the observation period, were also diagnosed with organic psychosis (ICD-8: 290–294, ICD-10: F0), schizophrenia (ICD-8: 295, ICD-10: F20), or anxiety (ICD-8: 300.09, ICD-10: F41). This was to avoid inclusion of organic diseases originally misinterpreted as affective disorders, and furthermore to examine whether any increased occurrence of cardiovascular morbidity was unique to the cohort of depressive patients, or whether it also could be established in patients with anxiety and schizophrenia — the two comparator groups. For this purpose, data for patients diagnosed with schizophrenia or anxiety were analysed in exactly the same way as depressed patients. Study probands were, by means of their personal identification number, checked in the NPR for occurrence of AMI (ICD-8: 410, ICD-10: I21, I22) during the period of follow-up (from 1 January 1977 to 31 December 2001). In order to examine the association between depression and coronary heart disease contrary to progression or aggravation of the latter, we excluded patients diagnosed with AMI prior to the first psychiatric hospitalization. Age and sex-matched controls were extracted from the Central Office of Civil Registration. The controls were characterized by never having been hospitalized in a psychiatric facility. Any control that had experienced an AMI prior to their matched proband's first psychiatric hospitalization was excluded. The date of the proband's first contact with the psychiatric hospital system was used as entry time for both the proband and the corresponding controls. It was then presumed that the proband's index disorder was present at first psychiatric contact. The date of the first episode of AMI was used as failure time, while we censored at
Table 1 The study population: patients with the diagnosis of depression, anxiety or schizophrenia and their matched control groups
Depressed Controls Anxiety Controls Schizophrenic Controls
Male
Female
Total
AMI (% of total)
20,107 92,991 3811 16,807 9743 43,483
38,942 176,309 10,159 45,084 5967 25,964
59,049 269,300 13,970 61,891 15,710 69,447
1895 (3.21%) 8552 (3.18%) 265 (1.90%) 784 (1.27%) 173 (1.10%) 829 (1.19%)
A.H. Jakobsen et al. / Journal of Affective Disorders 109 (2008) 177–181 Table 2 Incidence rate ratio (IRR) and 95% confidence intervals (CI) for AMI among patients with the diagnosis of depression, anxiety or schizophrenia
Depressed Anxiety Schizophrenia
IRR (95% CI)
χ2
P value
1.16 (1.10–1.22) 1.56 (1.35–1.79) 0.77 (0.65–0.91)
32.8 38.7 9.4
b0.0001 b0.0001 0.0021
Adjusted for gender and age.
death, last registration in NPR or PCR, or on the 31 of December 1998 if there was no later registration. Moreover, controls who died between entry and the date of their proband's index diagnosis were excluded to avoid bias from differences in life expectancy. Incidence rate ratios (IRR) and 95% confidence intervals for AMI were calculated separately for the three cohorts of psychiatric patients. Estimates of IRRs were by the Maentel–Haenszel method adjusting for gender and age in the following bands: 15–39, 40–64 and 65+ years. Stata release 8.2 was used for data analysis (Anderson et al., 2001). The study was conducted in accordance with the Declaration of Helsinki, and was approved by the Danish Data Surveillance Agency. According to the Danish Law of Scientific Ethics it needed not, as a register study, to be approved by the Ethical Committee. 3. Results Table 1 reports the numbers of subjects in diagnostic and control groups. In Table 2 the IRRs for AMI among the depressive, anxious and the patients with schizophrenia are presented. Among the depressive patients, the IRR for AMI was elevated significantly, being 1.16 (CI: 1.10–1.22). For subjects with anxiety and AMI, the IRR was also significantly elevated, being 1.56 (CI: 1.35–1.79). For the schizophrenic patients, there was a statistically significant lower risk of AMI, with the IRR being 0.77 (CI: 0.65–0.91). 3. Discussion The present study quantified a significant positive association between depression and acute myocardial infarction with an IRR of 1.16 (CI: 1.10–1.22). As we excluded persons who, prior to their depression had experienced an episode of AMI, the association is truly prospective, and indicates that depressed caseness is associated with an increased risk of myocardial infarct. This supports findings from previous studies (Glassman and Shapiro, 1998; Rugulies, 2002; Fielding, 1991). In a
179
meta-analysis of 11 prospective studies published between 1993 and 2000, a statistically significant total risk of 1.65 for fatal and non-fatal AMI was quantified for currently depressed patients (StataCorp, 2003). Furthermore, a recent review article asserts that the depression increases the risk for developing coronary artery disease by a factor from 1.5 to 2.0 (Lett et al., 2004). Being one of the first register study quantifying depression and coronary heart disease, our study's design and large sample size generates more precise and reliable estimate of the risk. Furthermore the diagnostic validity is high as only admitted patients with clinical diagnoses made by specialist physicians were included, while the diagnosis of AMI was made independently of the psychiatric diagnoses. Finally, because of its historical and prospective design, the period of observation was lengthy, with the probands followed for up to 24 years for episodes of AMI. Many theories have sought to explain the association between depression and coronary heart disease, and evidence points towards both behavioural (Rugulies, 2002; Hoyer et al., 2000; Anderson et al., 2001; Thakore et al., 1997) and more direct biological mechanisms (Pratt et al., 1996; Malhotra et al., 2000). Our study demonstrated that the positive association between depression and AMI was not specific to depression, as it also was demonstrated among patients with anxiety. In fact, we quantified an even stronger association, with the IRR for AMI being 1.56 (CI: 1.35–1.79). A number of studies have examined the effect of anxiety on the prognosis after AMI, but the association between anxiety and the risk for coronary heart disease in initial heart-well individuals has been less commonly investigated. Kubzansky and Kawachi (2000) examined eight prospective studies considering the impact of anxiety on coronary heart disease or sudden death. In four, there was a significant positive association, whereas the remaining four studies – in which three examined anxious patients hospitalized in a psychiatric facility – failed to find an association. A link between anxiety and sudden cardiac death appears supported, whereas any association between anxiety and non-fatal cases of AMI is less clearly established (Haines et al., 1987; Kawachi et al., 1994; Albert et al., 2005). However, in a recent study, Paterniti et al. (2001) found an increased risk for progression of arteriosclerotic changes located at the bifurcation of the carotid arteries (OR = 3.5 (CI: 1.4–8.5)), as well as an increased risk for rupture of the arteriosclerotic plaques, among men with symptoms of anxiety compared to those without such symptoms. As arteriosclerosis of the carotid arteries can be viewed as a marker of generalized arteriosclerosis, including the coronary vessels, this finding supports the
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positive association between anxiety and coronary heart disease demonstrated in this study. In regards to schizophrenia and AMI, we found a significant and negative association, with the IRR being 0.77 (CI: 0.65–0.91), suggesting a protective effect of having schizophrenia when it comes to cardiovascular disease. This goes some way to arguing that it is unlikely to be mental illness per se that provides the increased cardiovascular risk to depressed and anxious patients. Thus, our finding is somewhat counterintuitive and requires clarification in itself as several studies have found an all-over increased somatic morbidity and higher death rates among those with schizophrenia (Joukamaa et al., 2001; Hennekens et al., 2005). Parts of the explanation to our finding could be, though, that schizophrenic patients pay less attention to symptoms of somatic diseases, and that such symptoms are often inclined to be attributed to the psychiatric disorder by both the patients and the doctors (Munk-Jorgensen et al., 2000). Thus, it is possible that the negative association reported here could, to some extent, be a result of an under-diagnosis of somatic diseases among patients with schizophrenia. However, for the purpose of this study, this comparator group argues against mental illness per se providing the increased risk to AMI. 4. Limitations Being register-based our study has some limitations (Byrne et al., 2005; Parker, 2005). Data including diagnoses were reported from daily clinical practice from all treatment facilities in the whole country of Denmark over a 24-year period, and are therefore heterogeneous, mirroring different diagnostic principles as to time and professional tradition. Furthermore, as a register study it was not possible to correct for all potential confounders, which indeed could have influenced the results. Finally, only cases leading to hospitalization was included, suggesting an underestimation of the effect size as many people suffer from depressive symptoms, though not severe enough to meet the case criteria.
Role of funding source Nothing declared. Conflict of interest No conflict declared.
Appendix A. The psychiatric and somatic diagnoses used in this study ICD-8 296.0 Involutional melancholia 296.2 Manic–depressive psychosis, depressed type 298.0 Reactive depressive psychosis 300.4 Depressive neurosis 290 Senile and pre-senile dementia 291 Alcoholic psychosis 292 Psychosis associated with intracranial infection 294 Psychosis associated with other physical condition 295 Schizophrenia 300.0 Anxiety neurosis 410 Acute myocardial infarction ICD-10 F31.3 Bipolar affective disorder, current episode moderate or mild depression F31.4 Bipolar affective disorder, current episode severe depression without psychotic symptoms F31.5 Bipolar affective disorder, current episode severe depression with psychotic symptoms F32 Depressive episode F33 Recurrent depressive disorder F0 Organic, including symptomatic, mental disorder F20 Schizophrenia F41 Other anxiety disorders I21 Acute myocardial infarction I22 Subsequent myocardial infarction References
5. Conclusion This study quantifies positive associations linking both depression and anxiety with an increased risk of AMI. As the association was not demonstrated for those with schizophrenia, our findings argue for some diagnostic specificity. Consequently, both depression and anxiety should be included along with other traditional cardiovascular risk factors in identifying those at risk of coronary heart disease morbidity.
Albert, C.M., Chae, C.U., Rexrode, K.M., Manson, J.E., Kawachi, I., 2005. Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 111, 480–487. Anderson, R.J., Freedland, K.E., Clouse, R.E., Lustman, P.J., 2001. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 24, 1069–1078. Byrne, N., Regan, C., Howard, L., 2005. Administrative registers in psychiatric research: a systematic review of validity studies. Acta Psychiatr. Scand. 112, 409–414. Dinan, T.G., 1999. The physical consequences of depressive illness. BMJ 318, 826.
A.H. Jakobsen et al. / Journal of Affective Disorders 109 (2008) 177–181 Fielding, R., 1991. Depression and acute myocardial infarction: a review and reinterpretation. Soc. Sci. Med. 32, 1017–1028. Glassman, A.H., Shapiro, P.A., 1998. Depression and the course of coronary artery disease. Am. J. Psychiatry 155, 4–11. Haines, A.P., Imeson, J.D., Meade, T.W., 1987. Phobic anxiety and ischaemic heart disease. Br. Med. J. (Clin. Res. Ed.) 295, 297–299. Hennekens, C.H., Hennekens, A.R., Hollar, D., Casey, D.E., 2005. Schizophrenic and increased risk of cardiovascular disease. Am. Heart J. 150, 1115–1121. Hoyer, E.H., Mortensen, P.B., Olesen, A.V., 2000. Mortality and causes of death in a total national sample of patients with affective disorders admitted for the first time between 1973 and 1993. Br. J. Psychiatry 176, 76–82. Hunt, S.A., Abraham, W.T., Chin, M.H., Feldman, A.M., Francis, G.S., Ganiats, T.G., Jessup, M., Konstam, M.A., Mancini, D.M., Michl, K., Oates, J.A., Rahko, P.S., Silver, M.A., Stevenson, L.W., Yancy, C.W., Antman, E.M., Smith, S.C., Adams, C.D., Anderson, J.L., Faxon, D.P., Fuster, V., Halperin, J.L., Hiratzka, L.F., Jacobs, A.K., Nishimura, R., Ornato, J.P., Page, R.L., Riegel, B., 2005. ACC/ AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Circulation 112, e154–e235. Joukamaa, M., Heliovaara, M., Knekt, P., Aromaa, A., Raitasalo, R., Lehtinen, V., 2001. Mental disorders and cause-specific mortality. Brit. J. Psychiatr. 179, 498–502. Kawachi, I., Sparrow, D., Vokonas, P.S., Weiss, S.T., 1994. Symptoms of anxiety and risk of coronary heart disease. The Normative Aging Study. Circulation 90, 2225–2229. Kubzansky, L.D., Kawachi, I., 2000. Going to the heart of the matter: do negative emotions cause coronary heart disease? J. Psychosom. Res. 48, 323–337. Lepine, J.P., 2001. Epidemiology, burden, and disability in depression and anxiety. J. Clin. Psychiatry 62, 4–10 Suppl 13. Lett, H.S., Blumenthal, J.A., Babyak, M.A., Sherwood, A., Strauman, T., Robins, C., Newman, M.F., 2004. Depression as a risk factor for
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coronary artery disease: evidence, mechanisms, and treatment. Psychosom. Med. 66, 305–315. Malhotra, S., Tesar, G.E., Franco, K., 2000. The relationship between depression and cardiovascular disorders. Curr. Psychiatry Rep. 2, 241–246. Munk-Jorgensen, P., Mortensen, P.B., 1997. The Danish Psychiatric Central Register. Dan. Med. Bull. 44, 82–84. Munk-Jorgensen, P., Mors, O., Mortensen, P.B., Ewald, H., 2000. The schizophrenic patient in the somatic hospital. Acta Psychiatr. Scand. 102, 96 (Suppl. 102 Issue p407). Parker, G., 2005. Register now: validity later. Acta Psychiatr. Scand. 112, 407–408. Paterniti, S., Zureik, M., Ducimetiere, P., Touboul, P.J., Feve, J.M., Alperovitch, A., 2001. Sustained anxiety and 4-year progression of carotid atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 21, 136–141. Pratt, L.A., Ford, D.E., Crum, R.M., Armenian, H.K., Gallo, J.J., Eaton, W.W., 1996. Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up. Circulation 94, 3123–3129. Rozanski, A., Blumenthal, J.A., Kaplan, J., 1999. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99, 2192–2217. Rugulies, R., 2002. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am. J. Prev. Med. 23, 51–61. StataCorp, 2003. Stata Statistical Software: Release 8. TX: Stata Corporation, College Station. Thakore, J.H., Richards, P.J., Reznek, R.H., Martin, A., Dinan, T.G., 1997. Increased intra-abdominal fat deposition in patients with major depressive illness as measured by computed tomography. Biol. Psychiatry 41, 1140–1142. Wulsin, L.R., 2004. Is depression a major risk factor for coronary disease? A systematic review of the epidemiologic evidence. Harv. Rev. Psychiatry 12, 79–93.
Brief report
Quantifying links between acute myocardial infarction and depression, anxiety and schizophrenia using case register databases Anne Helene Jakobsen a,⁎, Leslie Foldager b , Gordon Parker c , Povl Munk-Jørgensen a a
Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Mølleparkvej 10, DK-9000 Aalborg, Denmark b Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, DK-8240 Risskov, Denmark c School of Psychiatry, The University of New South Wales; and Black Dog Institute, The Prince of Wales Hospital, High Street, Randwick NSW 2031, Australia Received 25 April 2007; received in revised form 15 October 2007; accepted 15 October 2007 Available online 28 November 2007
Abstract Aims: To quantify the association between depression and acute myocardial infarction (AMI) in a large sample using case registers, and examine whether any such link is specific to depression or might more reflect mental illness status in general. Methods and results: Accessing the Danish Psychiatric Central Research Register (PCR), patients with a diagnosis of depression were extracted and followed for up to 24 years for episodes of AMI. We used mentally healthy age- and sex-matched controls, and as comparator diagnostic groups, we studied patients with anxiety and schizophrenia. A positive association between depression and AMI was found with an incidence rate ratio (IRR) of 1.16 (CI: 1.10–1.22). The association was not unique for the depressed individuals, but was also found for anxiety patients, where it was even stronger (IRR = 1.56, CI: 1.35–1.79) than for the depressed patients. A negative association (IRR = 0.77, CI: 0.65–0.91) was quantified for schizophrenia, arguing against any link with AMI being determined by psychiatric disorder status per se. Limitations: Being a register study, not all potential confounding variables could be examined. Conclusion: Findings quantify significant associations between depression and AMI as well as between anxiety and AMI, and argue that these two psychiatric disorders should be added to the list of risk factors to coronary artery disease. © 2007 Elsevier B.V. All rights reserved. Keywords: Myocardial infarction; Coronary heart disease; Depression; Anxiety; Schizophrenia
1. Introduction Depression and coronary artery disease are some of the most common diseases in the industrialized world, ⁎ Corresponding author. Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Mølleparkvej 10, DK-9000 Aalborg. E-mail address: [email protected] (A.H. Jakobsen). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.10.012
with ischaemic heart disease and stroke followed by depression as the strongest determinants of disability in industrialized countries (Lepine, 2001). Over the last decade, evidence for an association between depression and acute coronary syndromes has accrued (Dinan, 1999; Glassman and Shapiro, 1998; Lett et al., 2004; Rozanski et al., 1999; Wulsin, 2004; Rugulies, 2002). A recent review article asserts that the presence of depression increases the risk for developing
178
A.H. Jakobsen et al. / Journal of Affective Disorders 109 (2008) 177–181
coronary artery disease by a factor ranging from 1.5 to 2.0 (Rugulies, 2002). Despite growing evidence for such an association, depressive disease is not included in the list of important and independent risk factors for cardiovascular disease published by the American Heart Association (Hunt et al., 2005). Furthermore, it is still not common practice for either general practitioners or cardiologists to screen for depression when examining risk factor status for coronary artery disease, or for depressed patients to be screened for risk factors for coronary heart disease. This may reflect insufficient awareness of the associational strength, and the suggested specificity to depressive illness, and argues the need for quantification from large databases as many of the contributing studies have involved relatively small sample sizes. Population and record linkage studies have the capacity to quantify risk more precisely and thus advance awareness. The aims of this study were firstly, to quantify the association between depression and AMI in a large register, and secondly, to examine whether it is depressive disease itself – or a broader variable of being mentally ill as a whole – that may provide increased risk for cardiovascular disease. The latter hypothesis was to be explored by comparing the comparative impact of anxiety and schizophrenia on AMI rates. 2. Methods The study is a longitudinal, historically-designed register study allowing psychiatric patients to be followed for episodes of AMI. Data were extracted from the Danish Psychiatric Central Research Register (PCR). This register contains person-identifiable information about all admissions to psychiatric inpatient facilities in Denmark since 1969 and outpatient facilities since 1995 (Munk-Jorgensen and Mortensen, 1997). Registration is complete for hospitalized patients as there are no private psychiatric hospitals in Denmark. This study also includes information from other national registers. Firstly, from the Central Office of Civil Registration where all citizens are registered by a unique 10-digit number, secondly from the Danish Codes of Death Register, CDR (only deaths proceeding 1998 were completely included in the CDR),and finally from the National Patients Register (NPR), where all somatic admissions are coded. The study cohort included all patients diagnosed and registered in the PCR with an affective disorder of a depressive type from 1 January 1977 to 31 December 2000. In operation, this involved all patients registered with a main diagnosis within the groups: ICD-8 (until
1993): 296.0, 296.2, 298.0, 300.4, and ICD-10 (from 1994): F31.3, F31.4, F31.5, F32, F33. The registration includes both inpatients, day patients and, from 1995, outpatients. Persons 15 years of age or younger at the time of diagnosis were excluded. Furthermore, we excluded patients receiving a depressive diagnosis who, at any time during the observation period, were also diagnosed with organic psychosis (ICD-8: 290–294, ICD-10: F0), schizophrenia (ICD-8: 295, ICD-10: F20), or anxiety (ICD-8: 300.09, ICD-10: F41). This was to avoid inclusion of organic diseases originally misinterpreted as affective disorders, and furthermore to examine whether any increased occurrence of cardiovascular morbidity was unique to the cohort of depressive patients, or whether it also could be established in patients with anxiety and schizophrenia — the two comparator groups. For this purpose, data for patients diagnosed with schizophrenia or anxiety were analysed in exactly the same way as depressed patients. Study probands were, by means of their personal identification number, checked in the NPR for occurrence of AMI (ICD-8: 410, ICD-10: I21, I22) during the period of follow-up (from 1 January 1977 to 31 December 2001). In order to examine the association between depression and coronary heart disease contrary to progression or aggravation of the latter, we excluded patients diagnosed with AMI prior to the first psychiatric hospitalization. Age and sex-matched controls were extracted from the Central Office of Civil Registration. The controls were characterized by never having been hospitalized in a psychiatric facility. Any control that had experienced an AMI prior to their matched proband's first psychiatric hospitalization was excluded. The date of the proband's first contact with the psychiatric hospital system was used as entry time for both the proband and the corresponding controls. It was then presumed that the proband's index disorder was present at first psychiatric contact. The date of the first episode of AMI was used as failure time, while we censored at
Table 1 The study population: patients with the diagnosis of depression, anxiety or schizophrenia and their matched control groups
Depressed Controls Anxiety Controls Schizophrenic Controls
Male
Female
Total
AMI (% of total)
20,107 92,991 3811 16,807 9743 43,483
38,942 176,309 10,159 45,084 5967 25,964
59,049 269,300 13,970 61,891 15,710 69,447
1895 (3.21%) 8552 (3.18%) 265 (1.90%) 784 (1.27%) 173 (1.10%) 829 (1.19%)
A.H. Jakobsen et al. / Journal of Affective Disorders 109 (2008) 177–181 Table 2 Incidence rate ratio (IRR) and 95% confidence intervals (CI) for AMI among patients with the diagnosis of depression, anxiety or schizophrenia
Depressed Anxiety Schizophrenia
IRR (95% CI)
χ2
P value
1.16 (1.10–1.22) 1.56 (1.35–1.79) 0.77 (0.65–0.91)
32.8 38.7 9.4
b0.0001 b0.0001 0.0021
Adjusted for gender and age.
death, last registration in NPR or PCR, or on the 31 of December 1998 if there was no later registration. Moreover, controls who died between entry and the date of their proband's index diagnosis were excluded to avoid bias from differences in life expectancy. Incidence rate ratios (IRR) and 95% confidence intervals for AMI were calculated separately for the three cohorts of psychiatric patients. Estimates of IRRs were by the Maentel–Haenszel method adjusting for gender and age in the following bands: 15–39, 40–64 and 65+ years. Stata release 8.2 was used for data analysis (Anderson et al., 2001). The study was conducted in accordance with the Declaration of Helsinki, and was approved by the Danish Data Surveillance Agency. According to the Danish Law of Scientific Ethics it needed not, as a register study, to be approved by the Ethical Committee. 3. Results Table 1 reports the numbers of subjects in diagnostic and control groups. In Table 2 the IRRs for AMI among the depressive, anxious and the patients with schizophrenia are presented. Among the depressive patients, the IRR for AMI was elevated significantly, being 1.16 (CI: 1.10–1.22). For subjects with anxiety and AMI, the IRR was also significantly elevated, being 1.56 (CI: 1.35–1.79). For the schizophrenic patients, there was a statistically significant lower risk of AMI, with the IRR being 0.77 (CI: 0.65–0.91). 3. Discussion The present study quantified a significant positive association between depression and acute myocardial infarction with an IRR of 1.16 (CI: 1.10–1.22). As we excluded persons who, prior to their depression had experienced an episode of AMI, the association is truly prospective, and indicates that depressed caseness is associated with an increased risk of myocardial infarct. This supports findings from previous studies (Glassman and Shapiro, 1998; Rugulies, 2002; Fielding, 1991). In a
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meta-analysis of 11 prospective studies published between 1993 and 2000, a statistically significant total risk of 1.65 for fatal and non-fatal AMI was quantified for currently depressed patients (StataCorp, 2003). Furthermore, a recent review article asserts that the depression increases the risk for developing coronary artery disease by a factor from 1.5 to 2.0 (Lett et al., 2004). Being one of the first register study quantifying depression and coronary heart disease, our study's design and large sample size generates more precise and reliable estimate of the risk. Furthermore the diagnostic validity is high as only admitted patients with clinical diagnoses made by specialist physicians were included, while the diagnosis of AMI was made independently of the psychiatric diagnoses. Finally, because of its historical and prospective design, the period of observation was lengthy, with the probands followed for up to 24 years for episodes of AMI. Many theories have sought to explain the association between depression and coronary heart disease, and evidence points towards both behavioural (Rugulies, 2002; Hoyer et al., 2000; Anderson et al., 2001; Thakore et al., 1997) and more direct biological mechanisms (Pratt et al., 1996; Malhotra et al., 2000). Our study demonstrated that the positive association between depression and AMI was not specific to depression, as it also was demonstrated among patients with anxiety. In fact, we quantified an even stronger association, with the IRR for AMI being 1.56 (CI: 1.35–1.79). A number of studies have examined the effect of anxiety on the prognosis after AMI, but the association between anxiety and the risk for coronary heart disease in initial heart-well individuals has been less commonly investigated. Kubzansky and Kawachi (2000) examined eight prospective studies considering the impact of anxiety on coronary heart disease or sudden death. In four, there was a significant positive association, whereas the remaining four studies – in which three examined anxious patients hospitalized in a psychiatric facility – failed to find an association. A link between anxiety and sudden cardiac death appears supported, whereas any association between anxiety and non-fatal cases of AMI is less clearly established (Haines et al., 1987; Kawachi et al., 1994; Albert et al., 2005). However, in a recent study, Paterniti et al. (2001) found an increased risk for progression of arteriosclerotic changes located at the bifurcation of the carotid arteries (OR = 3.5 (CI: 1.4–8.5)), as well as an increased risk for rupture of the arteriosclerotic plaques, among men with symptoms of anxiety compared to those without such symptoms. As arteriosclerosis of the carotid arteries can be viewed as a marker of generalized arteriosclerosis, including the coronary vessels, this finding supports the
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positive association between anxiety and coronary heart disease demonstrated in this study. In regards to schizophrenia and AMI, we found a significant and negative association, with the IRR being 0.77 (CI: 0.65–0.91), suggesting a protective effect of having schizophrenia when it comes to cardiovascular disease. This goes some way to arguing that it is unlikely to be mental illness per se that provides the increased cardiovascular risk to depressed and anxious patients. Thus, our finding is somewhat counterintuitive and requires clarification in itself as several studies have found an all-over increased somatic morbidity and higher death rates among those with schizophrenia (Joukamaa et al., 2001; Hennekens et al., 2005). Parts of the explanation to our finding could be, though, that schizophrenic patients pay less attention to symptoms of somatic diseases, and that such symptoms are often inclined to be attributed to the psychiatric disorder by both the patients and the doctors (Munk-Jorgensen et al., 2000). Thus, it is possible that the negative association reported here could, to some extent, be a result of an under-diagnosis of somatic diseases among patients with schizophrenia. However, for the purpose of this study, this comparator group argues against mental illness per se providing the increased risk to AMI. 4. Limitations Being register-based our study has some limitations (Byrne et al., 2005; Parker, 2005). Data including diagnoses were reported from daily clinical practice from all treatment facilities in the whole country of Denmark over a 24-year period, and are therefore heterogeneous, mirroring different diagnostic principles as to time and professional tradition. Furthermore, as a register study it was not possible to correct for all potential confounders, which indeed could have influenced the results. Finally, only cases leading to hospitalization was included, suggesting an underestimation of the effect size as many people suffer from depressive symptoms, though not severe enough to meet the case criteria.
Role of funding source Nothing declared. Conflict of interest No conflict declared.
Appendix A. The psychiatric and somatic diagnoses used in this study ICD-8 296.0 Involutional melancholia 296.2 Manic–depressive psychosis, depressed type 298.0 Reactive depressive psychosis 300.4 Depressive neurosis 290 Senile and pre-senile dementia 291 Alcoholic psychosis 292 Psychosis associated with intracranial infection 294 Psychosis associated with other physical condition 295 Schizophrenia 300.0 Anxiety neurosis 410 Acute myocardial infarction ICD-10 F31.3 Bipolar affective disorder, current episode moderate or mild depression F31.4 Bipolar affective disorder, current episode severe depression without psychotic symptoms F31.5 Bipolar affective disorder, current episode severe depression with psychotic symptoms F32 Depressive episode F33 Recurrent depressive disorder F0 Organic, including symptomatic, mental disorder F20 Schizophrenia F41 Other anxiety disorders I21 Acute myocardial infarction I22 Subsequent myocardial infarction References
5. Conclusion This study quantifies positive associations linking both depression and anxiety with an increased risk of AMI. As the association was not demonstrated for those with schizophrenia, our findings argue for some diagnostic specificity. Consequently, both depression and anxiety should be included along with other traditional cardiovascular risk factors in identifying those at risk of coronary heart disease morbidity.
Albert, C.M., Chae, C.U., Rexrode, K.M., Manson, J.E., Kawachi, I., 2005. Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 111, 480–487. Anderson, R.J., Freedland, K.E., Clouse, R.E., Lustman, P.J., 2001. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 24, 1069–1078. Byrne, N., Regan, C., Howard, L., 2005. Administrative registers in psychiatric research: a systematic review of validity studies. Acta Psychiatr. Scand. 112, 409–414. Dinan, T.G., 1999. The physical consequences of depressive illness. BMJ 318, 826.
A.H. Jakobsen et al. / Journal of Affective Disorders 109 (2008) 177–181 Fielding, R., 1991. Depression and acute myocardial infarction: a review and reinterpretation. Soc. Sci. Med. 32, 1017–1028. Glassman, A.H., Shapiro, P.A., 1998. Depression and the course of coronary artery disease. Am. J. Psychiatry 155, 4–11. Haines, A.P., Imeson, J.D., Meade, T.W., 1987. Phobic anxiety and ischaemic heart disease. Br. Med. J. (Clin. Res. Ed.) 295, 297–299. Hennekens, C.H., Hennekens, A.R., Hollar, D., Casey, D.E., 2005. Schizophrenic and increased risk of cardiovascular disease. Am. Heart J. 150, 1115–1121. Hoyer, E.H., Mortensen, P.B., Olesen, A.V., 2000. Mortality and causes of death in a total national sample of patients with affective disorders admitted for the first time between 1973 and 1993. Br. J. Psychiatry 176, 76–82. Hunt, S.A., Abraham, W.T., Chin, M.H., Feldman, A.M., Francis, G.S., Ganiats, T.G., Jessup, M., Konstam, M.A., Mancini, D.M., Michl, K., Oates, J.A., Rahko, P.S., Silver, M.A., Stevenson, L.W., Yancy, C.W., Antman, E.M., Smith, S.C., Adams, C.D., Anderson, J.L., Faxon, D.P., Fuster, V., Halperin, J.L., Hiratzka, L.F., Jacobs, A.K., Nishimura, R., Ornato, J.P., Page, R.L., Riegel, B., 2005. ACC/ AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Circulation 112, e154–e235. Joukamaa, M., Heliovaara, M., Knekt, P., Aromaa, A., Raitasalo, R., Lehtinen, V., 2001. Mental disorders and cause-specific mortality. Brit. J. Psychiatr. 179, 498–502. Kawachi, I., Sparrow, D., Vokonas, P.S., Weiss, S.T., 1994. Symptoms of anxiety and risk of coronary heart disease. The Normative Aging Study. Circulation 90, 2225–2229. Kubzansky, L.D., Kawachi, I., 2000. Going to the heart of the matter: do negative emotions cause coronary heart disease? J. Psychosom. Res. 48, 323–337. Lepine, J.P., 2001. Epidemiology, burden, and disability in depression and anxiety. J. Clin. Psychiatry 62, 4–10 Suppl 13. Lett, H.S., Blumenthal, J.A., Babyak, M.A., Sherwood, A., Strauman, T., Robins, C., Newman, M.F., 2004. Depression as a risk factor for
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coronary artery disease: evidence, mechanisms, and treatment. Psychosom. Med. 66, 305–315. Malhotra, S., Tesar, G.E., Franco, K., 2000. The relationship between depression and cardiovascular disorders. Curr. Psychiatry Rep. 2, 241–246. Munk-Jorgensen, P., Mortensen, P.B., 1997. The Danish Psychiatric Central Register. Dan. Med. Bull. 44, 82–84. Munk-Jorgensen, P., Mors, O., Mortensen, P.B., Ewald, H., 2000. The schizophrenic patient in the somatic hospital. Acta Psychiatr. Scand. 102, 96 (Suppl. 102 Issue p407). Parker, G., 2005. Register now: validity later. Acta Psychiatr. Scand. 112, 407–408. Paterniti, S., Zureik, M., Ducimetiere, P., Touboul, P.J., Feve, J.M., Alperovitch, A., 2001. Sustained anxiety and 4-year progression of carotid atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 21, 136–141. Pratt, L.A., Ford, D.E., Crum, R.M., Armenian, H.K., Gallo, J.J., Eaton, W.W., 1996. Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up. Circulation 94, 3123–3129. Rozanski, A., Blumenthal, J.A., Kaplan, J., 1999. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99, 2192–2217. Rugulies, R., 2002. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am. J. Prev. Med. 23, 51–61. StataCorp, 2003. Stata Statistical Software: Release 8. TX: Stata Corporation, College Station. Thakore, J.H., Richards, P.J., Reznek, R.H., Martin, A., Dinan, T.G., 1997. Increased intra-abdominal fat deposition in patients with major depressive illness as measured by computed tomography. Biol. Psychiatry 41, 1140–1142. Wulsin, L.R., 2004. Is depression a major risk factor for coronary disease? A systematic review of the epidemiologic evidence. Harv. Rev. Psychiatry 12, 79–93.