CARDIOVASCULAR COMORBIDITY ASSOCIATED WITH SCHIZOPHRENIA SPECTRUM DISORDERS

Schizophrenia spectrum disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder) is associated with numerous health problems. Patients with these conditions are prone to poverty, institutionalization and social isolation. They have great difficulty in taking care of themselves, they have inappropriate lifestyle because of sedentary, inadequate nutrition, smoking and excessive consumption of alcohol or other substances. There is also a social- professional degradation while the disease advances. Most of the patients live in poverty, are socially isolated, are unemployed or provides work below the level of their parents, are married or divorced, have limited social contacts outside the family, fail to achieve educational goals. Often, there might occur a significant cognitive impairment that persists during periods of remission of psychotic symptoms and has a significant influence on the ability of self-care and daily functioning.

The mortality rate of people with schizophrenia spectrum disorders is described as excessive and premature (1). It is considered that the death of these patients may occur with 10-25 years earlier, compared to the general population(2). Men with schizophrenia or related disorders die with 20 years earlier, women with 15 years earlier, compared with those without major psychiatric disorders. Suicide can be a major cause for premature death, the remaining causes of death being due to cardiovascular disorders, diabetes, pulmonary disease as a result of excessive smoking (approximately 70% of patients diagnosed with psychotic disorders smoke) (3).
Patients with these conditions have an increased risk of obesity (1.5-2 times higher), diabetes mellitus (2 times higher), dyslipidemia (5 times higher), smoking (by 2-3 times more) compared to people who do not suffer from these conditions (4).
Most antipsychotic drugs increase the risk of comorbidities, leading to weight gain, elevated blood sugar, cholestatic liver diseases (5).
It is thought that at least 10% of the people who take antipsychotic drugs for a long time, shall develop type 2 diabetes mellitus, two times more than the general population. Also, it is thought that there is a common genetic vulnerability, between psychosis and the risk of diabetes.
An observational study conducted by Smith DJ, et al, on a sample representing about a third of the population of Scotland, tried to identify the most common comorbidities associated with schizophrenia and related psychotic disorders. The highest prevalence was obtained for viral hepatitis, constipation or Parkinson’s disease. Other somatic diseases with high prevalence in patients with disorders like schizophrenia compared with the population undiagnosed with major psychiatric disorders were diabetes, COPD, chronic pain, epilepsy, irritable bowel syndrome. Surprisingly, cardiovascular disease, high blood pressure, atrial fibrillation, coronary disease and cancer had a lower prevalence in those with schizophrenia compared with those without psychiatric disorders, although many other studies see these as some of the causes of premature death in this population (3). According to the author, this may be due to the fact that patients with major psychiatric disorders either do not see the general practitioner of the cardiologist due to a low acknowledgement of the cardiovascular symptoms or their wrong interpretation, either because, despite the frequent contacts with medical specialists, are less investigated, monitored and they are not treated with the same attention and consideration as the patients without related psychotic disorders (3).
The authors of this study believe that the low prevalence of high blood pressure is also due to the hypotensive effect of psychotropic medication. Also based on the adverse effects of antipsychotics may explain the greater percentage of patients with constipation or Parkinson’s disease (anticholinergic effects, namely neuroleptization effect, parkinsonian syndrome).
In the general population, QTc interval prolongation is associated with increased cardiovascular mortality with sudden death, especially in patients who have had a history of diabetes mellitus and cardiovascular diseases. In patients with psychiatric disorders, the QTc interval prolongation is a consequence of antipsychotic treatment, although schizophrenia is associated with prolongation of the OTC interval even in the absence of psychotropic medication. To this is added the presence of metabolic syndrome and diabetes mellitus, frequently encountered in patients with schizophrenia spectrum d i s o r d e r s a n d f u r t h e r c o n t r i b u t e t o i n c r e a s e d cardiovascular mortality within this population. Alcohol consumption, physical inactivity, poor adherence to treatment plan required for those with cardiovascular disease, the presence of other comorbidities determines an additional negative influence. A comparative meta- analysis performed by AJ Mitchell and Lawrence D, published in 2011, points out that after an acute cardiovascular event, patients with a major psychiatric disorder experience a 14% lower rate of invasive coronary interventions (47% in those with schizophrenia) and have an 11 percentage of mortality (6).
Once developed the cardiovascular disorder, patients with schizophrenia have a reduced capacity to adhere to secondary prevention programs, such as exercise, weight control through proper diet, even weight loss. A study published by Kurdyak P et al in 2012 had as main objective to compare mortality upon 30 days of hospital discharge after acute myocardial infarction among patients with schizophrenia and those without. A secondary objective has been to follow the process of patient care (visits to the cardiologist and procedures performed in the first 30 days after myocardial percutaneous transluminal coronary or revascularization intervention by coronary bypass). 71668 subjects were included in the research, including 862 diagnosed with schizophrenia. The study showed an increase in mortality in patients with schizophrenia and myocardial infarction within 30 days of discharge after the latter. With 56% higher than for subjects with infarction, but undiagnosed with schizophrenia. People with schizophrenia received 50% less adequate cardiac procedures or care compared with people without this psychiatric disorder. Fewer than 1 in 4 patients with schizophrenia received interventional cardiology procedure and only 12 of 100 had cardiac check-ups within 30 days of discharge after an acute myocardial infarction (7).
An observational study coordinated by the Finnish Suvisaari J investigated the prevalence of coronary heart disease and myocardial infarction in people over 30 years, 71 diagnosed with psychotic disorders in a sample of over 8,000 persons, considered representative of the population of Finland, monitoring EKG changes, mainly the prolongation of the OTc interval, physical examination data and meaningful information from patient observation charts. Only 71.2% of people with psychotic disorders and coronary heart disease reported having been diagnosed with heart disease and were able to report if they followed cardiology treatment, compared with only 88.5% of patients with coronary artery disease. The main conclusion of this study is that patients with schizophrenia are associated with more severe forms of coronary artery disease, the presence of Q infarction waves on the ECG and believes that monitoring the signs and symptoms of coronary artery disease should be more active in people with psychotic disorders , in particular schizophrenia (8).
Two studies conducted by Curkendall SM and McDermott S, respectively, indicated an incidence, prevalence and an increased risk of congestive heart failure but did not reveal a statistically significant increase in the risk, prevalence or incidence of coronary disease in patients with schizophrenia (9, 10).
CATIE study showed that after 10 years the risk of developing coronary heart disease is increased in patients with schizophrenia, compared with the general population (11).
A study published by Jin et al in 2011 in Schizophrenia Research, using the Framingham 10-year coronary heart disease predictions (uses as predictors the age of 30-74 years, diabetes, smoking, blood pressure, total cholesterol and LDL cholesterol) suggests that middle-aged patients with psychotic symptoms have the Framingham 10 years prediction score of coronary heart disease significantly increased, especially among those with schizophrenia (12).
Type 2 diabetes is increased in prevalence in individuals with major psychiatric disorders. This is probably due both to antipsychotics that cause weight gain, hyperglycaemia and dyslipidemia, as well as to the improper lifestyle, lack of exercise, inadequate diet (13). Type 2 diabetes increases the risk of cardiac disease for 2 to 4 times and it is considered to provide an equivalent risk of a coronary event as the one induced by pre-existing cerebrovascular disease. American Diabetes Association recommended statins as the first-line therapy for the treatment of hyperlipidaemia (inhibitors of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase), and for those with diabetes and high blood pressure or kidney disease, the same association recommends inhibitors of the angiotensin converting enzyme and angiotensin receptor antagonists. They are designed to improve cardiovascular parameters and progression of diabetic nephropathy where it exists. A study published in 2008 by Kreyenbuhl J et al (14) showed that individuals who frequently resort to mental health services have a lower likelihood of being prescribed above mentioned treatments to prevent cardiovascular risk in patients with diabetes and dyslipidemia or high blood pressure or diabetes and diabetic nephropathy (14).
Another study published this year, sought to identify the most common causes of sudden death in patients with schizophrenia, based on autopsy reports. From a sample of 7189 patients with schizophrenia, admitted to a psychiatric hospital for 25 years, 57 have died suddenly. The cause of death was myocardial infarction 52.9%, followed by respiratory diseases (pneumonia 11.8%, obstructed airways 7.8%), myocarditis 5.9%, in other cases the sudden death was due, in equal measure of about 2 %, to pulmonary embolism, dilated cardiomyopathy, haemorrhagic cerebral accidents, haemopericardium and brain tumours (15).
Antipsychotic medication causes a number of cardiovascular complications: orthostatic hypotension, high blood pressure, arrhythmia, myocarditis. Orthostatic hypotension is due to blocking of adrenergic α1 or anticholinergic effects of antipsychotic medication. A persistent hypotensive effect was associated with significant side effects, such as stroke and myocardial infarction, in severe cases (16).
Torsades de pointes, a polymorphic ventricular tachycardia associated with QTc interval prolongation (17). Although often resolves itself, torsade de pointes may cause sustained ventricular fibrillation and sudden death (16). Several atypical antipsychotics can cause QT interval prolongation. Myocarditis, inflammation of the heart muscle is a rare side effect, caused by clozapine (18).
Patients with psychiatric disorders from the schizophrenia spectrum can associate a number of cardiovascular diseases during evolution. These are due to the major psychiatric disorders, side effects of psychotropic medication and inadequate living style. Perhaps an essential feature of these patients is the neglect of health in general. Compared to the general population, may provide much less information about related comorbidities, specific treatments recommended and are certainly much less adherent to therapeutic indications, especially those involving lifestyle changes through proper nutrition, exercise, giving up unhealthy habits, such as smoking or excessive alcohol consumption. Although, paradoxically, they have some more contact with health systems than the general population, quality of care received is lower. This may be due to the fact that experts consider a sign of „mental instability” frequent contacts of patients with psychiatric services, which could mean a weak capacity of understanding and compliance with therapeutic recommendations. However, this only renders vulnerable, once more, this special category of patients with significantly impaired quality of life.

REFERENCES
1. Mayer JM, Nasrallah HA. Medical illness and schizophrenia. Second edition. England: London, 2009, 17. ISBN 978-1-58562-346-4
2. Hennekens CH. Schizophrenia and increased risks of cardiovascular disease. American Heart Journal 2005: 115-121.
3. Smith DJ. Schizophrenia is associated with excess multiple physical health comorbidities but low levels of recorded cardiovascular disease in primary care: cross- sectional study. BMJ Open 2013: 3.
4. Lambert T, Newcomer JW. Are the cardiometabolic complications of schizophrenia still neglected? Barriers to care. Medical Journal 2009;190(4 Suppl): S39-42.
5. Levenson JL. Textbook of psychosomatic medicine. Psychiatric care of the medically ill. Second edition. The American Psychiatric Publishing, 2011. ISBN 978-1- 58562-379-2
6. Mitchell AJ. Revascularisation and mortality rates following acute coronary syndromes in people with severe mental illness: comparative meta-analysis. The British Journal of Psychiatry 2011;198: 434-441.
7. Kurdyak P. High mortality and low access to care following incident acute myocardial infarction in individuals with schizophrenia. Schizophrenia Research
2012;142: 52-57.
8. Suvisaari J. Coronary heart disease and cardiac conduction abnormalities in patients in persons with psychotic disorder in a general population. Psychiatry Research 2010;175: 126-132.
9. Curkendall SM. Cardiovascular disease in patients with schizophrenia in Saskatchewan, Canada. Journal of Clinical Psychiatry 2004;65: 715-720.
10. McDermott S. Heart disease schizophrenia and affective psychoses: epidemiology of risk in primary care. Community Mental Health Journal 2005;41: 747-745.
11. Goff DC et al. A compare study of ten-year cardiac risk estimates in schizophrenia patients from the Catie study and matched controls. Schizophrenia Research 2005;80(1): 45-53.
12. Jin H et al. Increased Framingham 10-year risk of coronary heart disease in middle-age and older patients with psychotic symptoms. Schizophrenia Research 2011;125: 295-299.
13. Newcomer JV. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005;19(supp 1): 1-93.
14. Kreyenbuhl J. Use of medications to reduce cardiovascular risk among individuals with psychotic disorders and type 2 diabetes. Schizophrenia Research
2008; 256-265.
15. Ifteni P. Sudden unexpected death in schizophrenia: Autopsy findings in psychiatric inpatients. Schizophrenia Research 2014;155: 72-76.
16. Khasawneh F. Minimizing cardiovascular adverse effects of atypical antipsychotic drugs in patient with schizophrenia. Cardiology Research and Practice 2014. doi:10.1155/2014/273060
17. Justo D. Torsade de pointes induced by psychotropic drugs and the prevalence of its risk factors. Acta Psychiatr Scand 2005;111(3): 171-6.
18. Haas SJ. Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003. Drug Safety 2007: 47-57.
***