Schizophrenia and coronary artery disease

ABSTRACT: The prevalence of schizophrenia, a chronic and debilitating disease, is increasing nationally. Although suicide and high-risk behaviors contribute to the mortality of people with schizophrenia, the leading cause of death in this vulnerable patient population is coronary artery disease. Unfortunately, schizophrenic patients are not receiving adequate medical treatment to prevent risk factor progression to metabolic syndrome and CAD, and if they do develop CAD they are undertreated and receive poor follow-up care. Initiatives are needed to ensure that the burden of CAD in schizophrenic patients is controlled and does not continue to rise. These initiatives include ongoing monitoring for risk factors, improved communication between psychiatrists and physicians, and community outreach support. A current approach to CAD monitoring in a Canadian inpatient psychiatric ward involves obtaining baseline values for fasting blood glucose and other measurements when a patient is admitted, and then referring the patient to a physician if three of the measurements are outside normal limits.


Risk factors should be monitored to ensure the burden of cardiovascular comorbidities in schizophrenic patients does not continue to rise.


Schizophrenia is a debilitating disease affecting 1% of Canadians,[1] with prevalence rates climbing.[2] Compared with the general population, people with schizophrenia have a risk of premature death that is 2 to 3 times higher.[3,4] Although suicide and high-risk behaviors contribute to mortality, coronary artery disease (CAD) is the leading cause of death[5,6] and accounts for 50% of mortality. While cardiovascular mortality rates are decreasing globally, they are increasing in people with schizophrenia,[5] likely due to underrecognition of cardiovascular-related diseases and risk factors.[7] Recent studies confirm that schizophrenic patients are likely to have risk factors related to CAD and take medications that may increase CAD risk, yet they are consistently undertreated. A current approach to CAD monitoring in a Canadian inpatient psychiatric ward includes screening for risk factors and metabolic syndrome.

Risk factors
Lifestyle factors such as smoking and physical inactivity have long been known to predispose vulnerable patients to the development of CAD. Smoking is associated with increased risk of diabetes mellitus (DM) and CAD,[8] and is significantly more common in people with schizophrenia. Compared with 25% of people in the general population, 75% of people with schizophrenia smoke. Physical inactivity is over 3 times greater in schizophrenics, with poor cardiorespiratory fitness being 2 times higher than in the general population.[9] As well as increasing CAD risk, these poor lifestyle choices increase the risk of developing metabolic syndrome.

Metabolic syndrome includes abdominal obesity, elevated blood pressure, impaired fasting blood glucose levels, elevated cholesterol, and hypertension. Demographic analysis of the CATIE study, the largest US trial evaluating psychopharmacological agents in the schizophrenic population, revealed metabolic syndrome prevalence to be 41% using the Adult Treatment Panel III and 43% using the American Heart Association definitions. Metabolic syndrome prevalence was 36% in schizophrenic males and 52% in schizophrenic females. In comparison, metabolic syndrome prevalence in the general population is 20% in males and 25% in females.[10]

In a Canadian population-based study, Bresee and colleagues found the overall prevalence of CAD to be 27% in the schizophrenia cohort compared with 17% in the general population (OR 1.76, CI = 1.72-1.81).[11] DM has been found to be almost twice as common as in the general population (10% vs 6%), while hypertension and dyslipidemia are also significantly more prevalent in those with schizophrenia. The increased number of risk factors in those with schizophrenia may contribute to the higher prevalence of cardiac disease in this population. Prevalence of acute coronary syndromes, arrhythmia, heart failure, and stroke were greater in those with schizophrenia than those without by values ranging from 1.43 to 2.17.[11]

CAD and metabolic syndrome risk factors are a clear case of “less is more”: studies have shown that the relative risk of CAD increases as the number of metabolic syndrome risk factors increases.[12] The odds ratio (OR) for each of these risk factors ranges from around 1.2 to 2.2. When more than one factor is present the ORs are increased by more than an additive rate so that all five metabolic syndrome risk factors lead to an approximately sevenfold increased risk.

Unfortunately, people with schizophrenia are more likely to have multiple risk factors and a higher chance of developing three or more. The ORs for having one, two, or three cardiovascular risk factors are 1.23, 1.14, and 1.43, respectively, while the OR for having less than one is 0.78.[11]

Role of medications
Integral to the discussion of risk factors in schizophrenia is the role of medications used for treatment. Mitchell and colleagues studied the causal effect of antipsychotics (as a group including first- and second-generation agents) to risk factor development. They found that in early schizophrenia (unmedicated and first episode) all risk factors and metabolic abnormalities were significantly less common. After finding an overall rate of metabolic syndrome of 9.8% in unmedicated schizophrenic patients and 9.9% in first-episode patients, they saw the rate of metabolic syndrome rise drastically to 53.5% in chronically medicated patients.[13] Multi-episode, chronically treated schizophrenics were at highest risk for developing multiple CAD risk factors, including obesity (OR 4.43), diabetes (OR 1.99), dyslipidemia (OR 2.73), low high-density-lipoprotein cholesterol (OR 2.35), and hypertension (OR 1.36).

Recent publications from Canada,[14] the US,[15] and Denmark[16] have noted greater incidence and prevalence of CAD morbidity and mortality with the increased popularity of second-generation atypical antipsychotics (SGA). Atypical antipsychotics have gained favor in the medical community because of their lower risk for causing extrapyramidal motor control disabilities, such as parkinsonian-type disorders, rigidity, dystonia, and involuntary tremors.[17] In a Canadian population-based study, SGA drugs were used in the treatment of 80% of diagnosed schizophrenics in 2006 compared with only 50% in 2002.[18] Compared with first-generation antipsychotics, SGAs are associated with a 3 times higher incidence of developing metabolic syndrome.[19]

The question of which antipsychotic drug should be preferred for treatment of schizophrenia is controversial. Newcomer showed that among the SGAs, clozapine and olanzapine are associated with the highest risk of substantial weight gain (a risk similar to that of low-potency first-generation antipsychotics such as thioridazine or chlorpromazine), and an increased risk of diabetes and dyslipidemia.[20] Patel and colleagues showed that risperidone was associated with the smallest elevations in triglyceride and total cholesterol levels.[21] Importantly, patients receiving antipsychotic polytherapy rather than monotherapy have even higher rates of metabolic syndrome and lipid markers of insulin resistance.[22] Studies show that comparing typical and atypical antipysychotics for risk of metabolic syndrome oversimplifies[23] the problem and that clinical judgment and informed patient preference are of utmost importance.

Along with medications, genetics may play a part. In 2013, Andreassen and colleagues identified 10 overlapping single nucleotide polymorphisms associated with schizophrenia and increased BMI, increased waist-to-hip ratio, increased systolic blood pressure, and abnormal lipids, which implies plausible causal genetics and shared mechanisms between schizophrenia and CAD risk factors. The majority of the identified loci were involved in lipid pathways, suggesting a strong relationship between schizophrenia and lipid levels.[24]

Barriers to care
Despite data regarding CAD risk, patients with schizophrenia are consistently undertreated. In one study, schizophrenic patients were 40% less likely to receive treatment for their comorbidities.[25] Undiagnosed comorbidities had nontreatment rates of 30% for DM, 62% for hypertension, and 88% for hyperlipidemia.[26] Even with an established CAD diagnosis, the revascularization rate was 47% less than in the general population. In a British schizophrenic population, 82% were prescribed beta-blockers, 51% given a statin,[27] and only 53% received follow-up with a cardiologist within 30 days of discharge. Not surprisingly, the risk of death within 30 days following discharge from hospital after admission for an acute coronary syndrome was 1.56 times higher in the schizophrenic population.[28] In the late 1990s, a Canadian database study found that patients with dyslipidemia and chronic psychiatric disease had poorer control of lipid levels than patients who did not have psychiatric disease.[25] Kurdyak and colleagues found recently that Canadian schizophrenic patients were more likely to die after an acute myocardial infarction, possibly due to less invasive management and inadequate follow-up with a cardiologist.[28]

Overcoming barriers
Obstacles to adequate treatment of CAD-related comorbidities in schizophrenia may include patient noncompliance and unwillingness to seek help, physician discomfort when treating patients with mental illness, and difficult-to-access health networks. At the very least, a schizophrenia diagnosis and treatment with second-generation antipsychotics should signal the need for attentive assessment of cardiovascular risk factors by way of metabolic monitoring.[29] Studies have shown that education can prevent the development and sequelae of metabolic syndrome even in the schizophrenic population. DM education in patients with schizophrenia, especially when it incorporates diet and exercise advice, can have a positive impact on weight reduction and a significant decrease in blood glucose levels.[30]

The Department of Psychiatry at St. Paul’s Hospital has developed a screening program for CAD risk factors and metabolic syndrome. Upon admission, all new psychiatry patients undergo laboratory testing to obtain baseline values (fasting blood glucose, LDL-C, HDL-C, triglycerides), and nursing staff obtain blood pressure and waist circumference measurements. If three or more of the measurements obtained fall outside normal limits, a referral is made to the consulting family practice physician, who then determines how best to address these risk factors.

Summary
Schizophrenia is a chronic and debilitating disease that predisposes patients to coronary artery disease. The natural progression of schizophrenia, genetics, and the sequelae of treatment all increase the development of CAD risk factors. Unfortunately, schizophrenic patients are not receiving adequate medical treatment to prevent risk factor progression to metabolic syndrome and CAD, and if they do develop CAD they are undertreated and receive poor follow-up care. CAD is the leading cause of death in this vulnerable patient population.

Initiatives are needed to ensure that the burden of CAD in schizophrenic patients is controlled and does not continue to rise. These initiatives include ongoing monitoring for CAD risk factors, improved communication between psychiatrists and consulting or family physicians, and community outreach support. As well, further research is needed to identify the cardiometabolic effects of various antipsychotic medications.

Primary care practitioners and assertive community treatment teams are particularly well placed to ensure that CAD risk factors and CAD treatment are not overlooked. Clinicians should consider prescribing antipsychotics associated with a lower risk of metabolic side effects. They should also consider routine monitoring of metabolic parameters and begin patient education and behavioral and pharmacological interventions early. Weight gain begins soon after patients start antipsychotic therapy, so BMI should be included in a baseline risk profile. CAD risk in this vulnerable group of mentally ill patients needs to be taken seriously by patients and physicians alike.

Competing interests
None declared.


This article has been peer reviewed.


References

1.    Canadian Psychiatric Association. Canadian clinical practice guidelines for the treatment of schizophrenia. Can J Psychiatry 1998;43(Suppl2):255-405.
2.    Dealberto MJ. Are the rates of schizophrenia unusually high in Canada? A comparison of Canadian and international data. Psychiatry Res 2013;209:259-265. 
3.    Brown S, Inskip H, Barraclough B. Causes of the excess mortality of schizophrenia. Br J Psychiatry 2000;177:212-217.
4.    Casadebaig F, Philippe A. Mortality in schizophrenia patients. 3 years follow-up of a cohort. Encephale 1999;25:329-337.
5.    Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry 1998;173:11-53.
6.    Brown S, Kim M, Mitchell C, et al. Twenty-five year mortality of a community cohort with schizophrenia. Br J Psychiatry 2010;196:116-121.
7.    Crump C, Winkelby MA, Sundquist K, et al. Comorbidities and mortality in persons with schizophrenia: A Swedish national cohort study. Am J Psychiatry 2013;170:324-333.
8.    Willi C, Bodenmann P, Ghali WA, et al. Active smoking and the risk of type 2 diabetes: A systematic review and meta-analysis. JAMA 2007;29:2654-2664.
9.    Koivukangas J, Tammelin T, Kaakinen M, et al. Physical activity and fitness in adolescents at risk for psychosis within the Northern Finland 1986 Birth Cohort. Schizophr Res 2010;116:152-158.
10.    McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: Baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005;80:19-32.
11.    Bresee LC, Majumdar SR, Patten SB, et al. Prevalence of cardiovascular risk factors and disease in people with schizophrenia: A population-based study. Schizophr Res 2010;117:75-82.
12.    Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108:414-419.
13.    Mitchell AJ, Vancampfort D, De Herdt A, et al. Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizophr Bull 2013;39:295-305.
14.    Callaghan RC, Boire MD, Lazo RG, et al. Schizophrenia and incidence of cardiovascular morbidity: A population-based longitudinal study in Ontario, Canada. Schizophr Res 2009;115:325-332. 
15.    Weber NS, Cowan DN, Millikan AM, et al. Psychiatric and general medical conditions comorbid with schizophrenia in the National Hospital Discharge Survey. Psychiatr Serv 2009;60:1059-1067.
16.    Laursen TM, Munk-Olsen T, Agerbo E, et al. Somatic hospital contacts, invasive cardiac procedures, and mortality from heart disease in patients with severe mental disorder. Arch Gen Psychiatry 2009;66:713-720. 
17.    Leucht S, Corves C, Arbter D. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet 2009;373(9657):31-41.
18.    Alessi-Severini S, Biscontri RG, Collins DM, et al. Utilization and costs of antipsychotic agents: A Canadian population-based study, 1996–2006. Psychiatr Serv 2008;59:547-553.
19.    De Hert M, Schreurs V, Sweers K, et al. Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: A retrospective chart review. Schizophr Res 2008;101:295-303.
20.    Newcomer J. Antipsychotic medications: Metabolic and cardiovascular risk. J Clin Psychiatry 2007;68:8-13.
21.    Patel J, Buckley P, Woolson S, et al. Metabolic profiles of second-generation antipsychotics in early psychosis: Findings from the CAFE study. Schziphr Res 2009;111:9-16.
22.    Correll C, Frederickson A, Kane J, et al. Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res 2007;89:91-100.
23.    Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet 2013;382(9896):951-962.
24.    Andreassen OA, Djurovic S, Thompson WK, et al. Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am J Hum Genet 2013;92:197-209.
25.    Redelmeier DA, Tan SH, Booth GL. The treatment of unrelated disorders in patients with chronic medical diseases. N Engl J Med 1998;338:1516-1520.
26.    Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: Data from the CATIE schizophrenia trial sample at baseline. Schizophr Res 2006;86:15-22.
27.    Kisely S, Campbell LA, Wang Y. Treatment of ischaemic heart disease and stroke in individuals with psychosis under universal healthcare. Br J Psychiatry 2009;195:545-550.
28.    Kurdyak P, Vigod S, Calzavara A, et al. High mortality and low access to care following incident acute myocardial infarction in individuals with schizophrenia. Schizophr Res 2012;142:52-57.
29.    Morden NE, Mistler LA, Weeks W, et al. Health care for patients with serious mental illness: Family medicine’s role. J Am Board Fam Med 2009;22:187-195.
30.    Cimo A, Stergiopoulos E, Cheng C, et al. Effective lifestyle interventions to improve type II diabetes self-management for those with schizophrenia or schizoaffective disorder: A systematic review. BMC Psychiatry 2012;12:24.


Dr Ignaszewski is a PGY-1 psychiatry resident in the Department of Psychiatry at Tufts University-Baystate Medical Center who became aware of this topic as a final-year medical student with the St. Paul’s Hospital Family Doctor on Consultation service on the psychiatric wards. She is affiliated with the St. Paul’s Healthy Heart Program in the Department of Cardiology through prior clinical work and research. Dr Yip is a senior resident in the Department of Cardiology at the University of British Columbia. Dr Fitzpatrick is a clinical professor in the Department of Psychiatry at UBC. He is also assistant head of the Department of Psychiatry for Providence Health Care, where he works as a consultation-liaison psychiatrist.

Martha J. Ignaszewski,, A. Yip, MD,, S. Fitzpatrick, MD, FRCPC,. Schizophrenia and coronary artery disease. BCMJ, Vol. 57, No. 4, May, 2015, Page(s) 154-157 - Clinical Articles.



Above is the information needed to cite this article in your paper or presentation. The International Committee of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.

About the ICMJE and citation styles

The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.

An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.

BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:

  • Only the first three authors are listed, followed by "et al."
  • There is no period after the journal name.
  • Page numbers are not abbreviated.


For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit www.icmje.org

BCMJ Guidelines for Authors

Leave a Reply