**4. The metabolic syndrome**

Much attention has been focused on the metabolic syndrome which brings together a series of abnormal clinical and metabolic findings which are predictive of cardiovascular risk. The most commonly used definition for the metabolic syndrome are the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP), (Jama, 2001) and the adapted ATP-III-A proposed by the American to Heart Association following the American Diabetes Association lowering of the threshold for impaired fasting glucose 100mg/dl. (Quindy et al, 2005 ; Alberti et al, 2006).

Another recent definition, by the International Diabetes Federation (Alberti et al, 2006; Sarafidis &, Nilsson, 2006) stressed the importance of waist circumference, using ethnic/race specific criteria (Table 3).


\*or treated with antihypertensive medication

\*\*or treated with insulin or hypoglycemic medication

Table 3. Definitions of metabolic syndrome: The metabolic syndrome has been shown to be an important risk factor for the development of both type 2 diabetes and cardiovascular disease.

Dyslipidemia and Mental Illness 355

Antipsychotic Weight Risk for diabetes Worsening lipid

Clozapine +++ + + Olanzapine +++ + + Risperidone ++ D D Quetiapine ++ D D Ziprasidone +/- - - Aripiprazole +/- - -

Metabolic disturbances related to atypical antipsychotics may result from a direct alteration of insulin sensitivity and/or insulin secretion. Antipsychotic affinity at both histamine and muscarinie acetylcholine receptors correlates with weight gain and metabolic liability (Matsui-Sakata, 2005) and impaired parasympathic regulation of β all activity may contribute to metabolic risk (Silvestre &-Prous, 2005). Certain antipsychotic agents may directly impair glucose transporter function. Direct attenuation of glucose transporter function by antipsychotic agents would result in elevations in circulating glucose and a compensatory hypersecretion of insulin, which overtime may further reduce insulin sensitivity, triggering the cascade of events leading to metabolic syndrome and type 2

Some antipsychotic drugs increase appetite and this leads to adiposity. Affinity of the antipsychotic drugs for histamine-1 (H1) receptors closely correlates with weight-gaining potential and appears to involve H1 receptor-linked activation of hypothalamic AMPkinase. Also, 5-HT2C receptor antagonism may contribute to weight gain. The H1 and 5HT2C blocking effects of antipsychotic medications may interfere with leptin-mediated

Adiposity alone does not explain the potential side effects of atypical antipsychotic medications. Animal and human studies describe the adverse effect of clozapine and olanzapine on insulin and glucose metabolism (Hasnain & Vieweg, 2008). Significant insulin resistance has also been documented in non-obese patients receiving clozapine or olanzapine versus those receiving risperidone (Henderson et al, 2006). Diminished or inefficient insulin release from pancreatic beta cells as well peripheral insulin resistance may underlie the diabetogenic effect of some antipsychotic medications. Blocking muscarinic type 3 and 5-HT1A receptors may be a factor to diminished pancreatic beta-cells responsiveness and blocking 5HT2A receptor may suppress glucose uptake in muscle (Nasrallah, 2008). Some antipsychotic medications may impair and/or alter the action of insulin on adipocytes leading to progressive lipid accumulation (Vestri et al, 2007). The impaired effect of insulin on adipocytes may explain weight gain independent dyslipidemia

Another study examine whether patients taking selective serotonin reuptake inhibitors (SSRIs) are more likely to have elements of the metabolic syndrome compared with those

aAdapted with the permission from the American Diabetes Association Abbreviation:

Table 4. Atypical antipsychotic drugs and metabolic disturbancesa

appetite suppression (Reynolds,2006; Matsui-Sakata et al,2005).

D = discrepant results

Symbols: + = increased effect, - = no effect

diabetes (Dwyer & Donohoe, 2003).

(De leon et al, 2007, Birkenaes et al, 2008).

proli B

In the study, the clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), one third of patients met the NCEP criteria for metabolic syndrome at baseline (Mc Eoy et al, 2005 ; Meyer et al, 2005).

And from this study, 88% of patients with dyslipidemia were not receiving treatment, as were 62% of the hypertensive patients and 38% those with diabetes (Nasrallah et al, 2006). The presence of the metabolic syndrome increases the risk for the distribution of fat within the body is a key factor. Abdominal fat distribution, particularly visceral adiposity, increases the risk of dyslipidemia, glucose intolerance, and cardiovascular disease. Multiple organ systems are affected, including adipose, muscle, hepatic, nervous, and adrenal tissues, and the most important site of impact is the vasculature. The concept of insulin resistance is central to the metabolic syndrome. Insulin resistance is a major contributor to glucose intolerance, and the lipoprotein abnormalities seen in the metabolic syndrome are also predictable, at least in part, from the known effects of insulin to inhibit lipolysis in adipocytes. With resistance to insulin, unchecked lipolysis leads to increased delivery of free fatty acids to the liver for triglyceride synthesis and packaging into very low-density lipoprotein (VLDL) particles. Higher VLDL levels contribute to lower HDL levels because of the reciprocal exchanges between these lipoproteins mediated by cholesterol ester transfer protein. Is has been shown that blood pressure is related to insulin resistance independent of differences in age, gender, and degree of obesity(Zavaroni et al,1992). Visceral obesity is the primary determinant of insulin resistance and, as such, represents the fundamental pathophysiologic change leading to the metabolic syndrome. The risk of insulin resistance increases with adiposity, particularly the amount of visceral adiposity. Insulin resistance is associated with impaired glucose control, increase plasma triglycerides, reduced highdensity lipoprotein (HDL) cholesterol, increased blood pressure, increased risk of blood clotting, and increases in markers of inflammation, all which are associated with an increase risk for cardiovascular disease. Thus, markers of insulin resistance, such as elevated fasting plasma Triglycerides, can be a key point for monitoring and evaluating a patient's risk.
