**Cardiovascular Risk in Tunisian Patients with Bipolar I Disorder**

Asma Ezzaher1,2, Dhouha Haj Mouhamed1,2, Anwar Mechri2, Fadoua Neffati1, Wahiba Douki1,2, Lotfi Gaha2 and Mohamed Fadhel Najjar1 *1Laboratory of Biochemistry-Toxicology,* 

*²Research Laboratory "Vulnerability to Psychotic Disorders LR 05 ES 10", Department of Psychiatry/Monastir University Hospital, Tunisia* 

#### **1. Introduction**

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Bipolar disorder (previously also labeled manic-depressive illness) is typically referred to as an episodic, yet lifelong and clinically severe affective (or mood) disorder, affecting approximately 3.5% of the population (Marmol, 2008; Simon, 2003; Wittchen et al., 2003; Woods, 2000). The term bipolar disorder, however, encompasses several phenotypes of mood disorders, i.e. mania, hypomania or cyclothymia that may present with a puzzling variety of other symptoms and disorders. According to the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 2004), the diagnostic classificatory system used in most epidemiological studies, bipolar disorder is defined by a set of specific symptom criteria. Bipolar type I requires the presence or the history of at least one manic or mixed episode. Although, typically, patients with a manic episode also experience major depressive episodes, bipolar disorder can be diagnosed even if only one manic episode and no past major depressive episodes are present. Bipolar disorder type II differs from type I only by presence of hypomanic but no manic episodes. Hypomanic episodes differ from mania by a shorter duration (at least 4 days instead of 1 week), and less severe impairment (not severe enough to cause marked impairment in social or occupational functioning, psychiatric hospitalization, or psychotic features). The DSM-IV also includes "cyclothymia" as a bipolar spectrum disorder with hypomanic as well as depressive episodes that do not meet criteria for major depression (American Psychiatric Association, 2004).

Bipolar disorder is a chronic disease that is associated with a potentially devastating impact on patients' wellbeing and social, occupational, and general functioning (Revicki et al., 2005). The disorder ranks as the sixth leading cause of disability in the world, with an economic burden that in the US alone that was estimated more than a decade ago at \$7 billion in direct medical costs and \$38 billion (1991 values) in indirect costs (Wyatt et al., 1991).

A number of reviews and studies have shown that people with severe mental illness, including bipolar disorder, have an excess mortality, being two or three times as high as that

Cardiovascular Risk in Tunisian Patients with Bipolar I Disorder 323

years). All subjects were questioned about their age, gender, previous treatments and

The clinical and socio-demographic characteristics are shown in table 1. Differences between patients and controls for body mass index (BMI) (p < 0.001) and smoking status (p =0.025) were noted. Therefore, these variables were considered as potential confounder factors for

> **Patients (n = 130)**

*Gender*: Men/Women (ratio) 85/45 (1.89) 102/73 (1.39) 0.143 *Age* (years) (mean ± SD) 37.9 ± 12.1 40.1 ± 14.0 0.840 *BMI* (kg/m²) (M ± ET) 27.1 ± 4.6 25.3 ± 4.1 **< 0.001** 

[25-30[ 40 30.7 72 41.1 **< 0.001** 

Yes 68 52.3 69 39.4 **0.025** No 62 47.7 106 60.6

Yes 17 13.1 12 6.9 0.067 No 113 86,9 163 93.1

Depressive 21 16.2 - - - Euthymic 73 56.1 - - - Manic 36 27.7 - - -

Valproic acid 64 49.3 - - - Lithium 12 9.2 - - - Carbamazepine 10 7.7 - - - Valproic acid and lithium 6 4.6 - - - Antipsychotics 38 29.2 - - - Antipsychotics: Haloperidol, Risperidone, Chlorpromazine, Olanzapine; BMI: body mass index Table 1. Sociodemographic and therapeutic characteristics of studied population.

After a 12 h overnight fasting, venous blood for each patient was drawn in tubes containing lithium heparinate and immediately centrifuged. The plasma samples were stored at -20°C

The methods of dosage and the normal values of the different biological parameters are

< 25 47 36.2 89 50.9

≥ 30 43 33.1 14 8

**Controls** 

**Nombre % Nombre % p** 

**(n = 175) <sup>p</sup>**

cigarette and alcohol consumption habits.

this analysis.

*BMI* (kg/m²)

*Cigarette smoking*

*Alcoholic beverages*

*Illness episode*

*Treatment*

**2.2 Samples** 

until the biochemical analysis.

**2.3 Biochemical analysis** 

shown in table 2.

in the general population. This mortality gap, which translates to a 13-30 year shortened life expectancy in severe mental illness patients, has widened in recent decades, even in countries where the quality of the health care system is generally acknowledged to be good. About 60% of this excess mortality is due to physical illness especially cardiovascular disease. Additionally, several studies have found that after suicide and accidents, cardiovascular and all vascular diseases are the main leading causes of death in these patients (De Hert et al., 2011; Garcia-Portilla et al., 2009).

Patients with bipolar disorder, especially type I, are known to suffer a considerable number of associated pathologies that may manifest at earlier ages and with higher frequency than in the general population. The most recent studies have explored cardiovascular risk and the association with metabolic and endocrine disorders fundamentally, obesity and metabolic syndrome which are clearly associated with the development of cardiovascular disease (Angst et al., 2002; Sicras et al., 2008).

Cardiovascular disease, i.e. coronary heart disease, stroke, and peripheral vascular disease, are potentially preventable diseases. Thanks to epidemiological, experimental and clinical studies, the primary determinants of cardiovascular disease have been identified, as well as the efficacy of specific interventions. The prevalence of cardiovascular disease is increasing in less urbanized, developed populations across the world, as their lifestyles change to a so called "western style", with increasing consumption of dietary saturated fat, cholesterol and salt, cigarette smoking, decreased physical activity and the rise in cardiovascular risk factors including obesity and diabetes. Other known factors that contribute to cardiovascular disease risk are stress and high alcohol intake. Among all these factors, hypercholesterolemia is the leading cause of death from cardiovascular disease. As a result, public health agencies have attempted to reduce the prevalence of hypercholesterolemia through screening and by increasing public awareness and strategies for reducing it (Muntoni et al., 2009).

The exact mechanisms increasing the incidence of cardiovascular risk in bipolar patients remain to be clarified, but they possibly include industrialisation, stress, lack of exercise, dietary lipids (that is, omega-3 fatty acid deficiency) and increasing incidence of smoking and alcohol consumption and other factors (Ezzaher et al., 2010).

This study aims to investigate the principal factors predisposing to the cardiovascular risk in Tunisian bipolar I patients (cigarette smoking, hypertension, diabetes, obesity, lipid profile, hyperhomocysteinemia and metabolic syndrome) and to determine the association between these factors and the clinical and therapeutic characteristics of bipolar I disorder.
