**5. Effects of antipsychotics treatment**

Antipsychotic treatment is associated with metabolic side effects that include various degrees of weight gain, dyslipidemia and susceptibility to type 2 diabetes (Newcomer, 2005).

Elevated blood lipids, particularly triglycerides, are associated with some typical antipsychotic agents. Shortly after their introduction, phenothiazines were found to elevate serum triglyceride and total cholesterol levels. Then much was written on the effects of specific atypical drugs on lipid profiles. Both clozapine and olanzapine have been shown to cause significant hypertriglyceridemia compared with typicals. Studies have also reported a significant association between weight gain and triglyceride change for patients under atypical antipsychotic therapy (Meyer, 2001).

The atypical antipsychotics vary in their propensity to induce weight gain (Table 4): clozapine and olanzapine produce the most weight gain, quetiapine and risperidone produce intermediate weight gain, and ziprasidone and aripiprazole produce the least weight gain (Allison et al, 1999; American Diabetes Association [ADA], 2004). The differences in weight gain associated with these agents reflect their order of risk for insulin resistance, glucoregulatory dysfunction, and dyslipidemia (Haupt & Newcomer 2002; ADA, 2004).

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,

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.

Antipsychotic treatment is associated with metabolic side effects that include various degrees of weight gain, dyslipidemia and susceptibility to type 2 diabetes (Newcomer,

Elevated blood lipids, particularly triglycerides, are associated with some typical antipsychotic agents. Shortly after their introduction, phenothiazines were found to elevate serum triglyceride and total cholesterol levels. Then much was written on the effects of specific atypical drugs on lipid profiles. Both clozapine and olanzapine have been shown to cause significant hypertriglyceridemia compared with typicals. Studies have also reported a significant association between weight gain and triglyceride change for patients under

The atypical antipsychotics vary in their propensity to induce weight gain (Table 4): clozapine and olanzapine produce the most weight gain, quetiapine and risperidone produce intermediate weight gain, and ziprasidone and aripiprazole produce the least weight gain (Allison et al, 1999; American Diabetes Association [ADA], 2004). The differences in weight gain associated with these agents reflect their order of risk for insulin resistance, glucoregulatory dysfunction, and dyslipidemia (Haupt & Newcomer 2002; ADA,

2005 ; Meyer et al, 2005).

**5. Effects of antipsychotics treatment** 

atypical antipsychotic therapy (Meyer, 2001).

2005).

2004).


aAdapted with the permission from the American Diabetes Association Abbreviation:

D = discrepant results

Symbols: + = increased effect, - = no effect

Table 4. Atypical antipsychotic drugs and metabolic disturbancesa

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 diabetes (Dwyer & Donohoe, 2003).

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

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

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

Dyslipidemia and Mental Illness 357

In the general population, lipid screening with a fasting lipid profile (total chol, LDL, HDL and triglyceride) is recommended for all adults aged 20 years and older, repeteated every 5 years in asymptomatic individuals (Expert Panel on Detection, Evaluation and Treatment, of High Blood Cholesterol in Adults, 2001). Adequate fasting, about 10 to 12 hours is necessary to obtain valid LDL and triglyceride levels-Target LDL levels are determined by a Framingham assessment based on age, sex, chol, HDL, systolic blood pressure, and smoking status (Wilson et al, 1998). Patients on antipsychotic treatment frequently have a metabolic dyslipidemia with elevations of triglyceride and reduced HDL (Cohn et al, 2004), along with associated features of the metabolic syndrome. Some SSRIs induced metabolic disturbance

Treatment of metabolic dyslipidemia is a secondary goal for intervention following achievement of LDL targets. Clinical trials show that LDL-lowering therapy reduces risk for coronary heart disease (CHD). For these reasons, ATP III continues to identify elevated LDL cholesterol as the primary goal of cholesterol-lowering therapy. Those with diabetes or established cardiovascular disease are considered high risk and are treated to the most stringent LDL targets. Risk determinants in addition to LDL cholesterol include the presence or absence of CHD, other clinical forms of atherosclerotic disease , and the major risk factors other than LDL. Other major risk factors are cigarette smoking, hypertension, low HDL cholesterol, family history of premature CHD, diabetes and age. These major risks are

A variety of medical conditions and drugs can exacerbate hyperlipidemias. Elevations of the serum LDL cholesterol level can occur in response to hypothyroidism and nephrotic syndrome. Hypertriglyceridemia and decreased HDL levels are commonly seen with insulin resistance, diabetes, and the metabolic syndrome. This fact is usually seen in patients with mental illness. Individuals are characterized by their coronary risk profile according to the National Cholesterol Education Program Adult Treatment Panel III guidelines, as shown in

> Optimal Near optimal Borderline high High

> Desired Borderline high High

> > Low High

Lipoprotein and serum concentration Status

Table 5. ATP III Classification of LDL, Total, and HDL Cholesterol (mg/dL)

**6.1 Screening** 

Table 5.

particularly hypercholesterolemia.

commonly observed in patients with mental illness.

Low-density lipoprotein (LDL) cholesterol) (primary target of therapy) <100 mg/dl 100-129mg/dl 130-159 mg/dl ≥160 mg/dl

> Total cholesterol <200 mg/dl 200-239 mg/dl ≥ 240 mg/dl

> HDL cholesterol <40 ≥60

taking no psychotropic drugs. Patients taking SSRIs had a significantly increased prevalence of obesity, abdominal fat, and hypercholesterolemia. The associations with this factors were significant after adjustment for age, gender , and several covariates. The individuals SSRIs might display differences in their side effect profile, the study performed analysis of the various SSRIs. Paroxetine was strongly associated with general and abdominal obesity but not with hypercholesterolemia, whereas citalopram was associated with neither obesity nor dyslipidemia. Patients taking sertraline, fluoxetine, or fluvoxamine, SSRIs treatment was significantly associated with abdominal obesity and with hypercholesterolemia. SSRIs induce transcriptional activation of cholesterol and fatty acid biosynthesis. The lipogenic effect could represent a common mechanism for explaining in part the lipid disturbances (Reader et al, 2006).

Weight gain is a major side effect of the main mood stabilizers. Chronic treatment with lithium is associated with increased weight, reaching more than 10kg in 20% of patients (Garland et al, 1998).Valproic acid leads to unequivocal weight gain. Lamotrigene, another anticonvulsant that acts as a mood stabilizer, is not associated with significant weight gain (Zimmermann et al, 2003).

With regard to mood stabilizers, additional factors could be involved. An insulin-like action cause by lithium at the treatment stage could increase fat deposition. In addition, edema secondary to sodium retention and subclinical hypothyroidism also contribute to weight gain (Garland et al, 1998). The mechanism by which the valproic acid causes weight gain is still little explored; an action in the sense of inhibiting oxidation of fatty acids might be involved (Isojärvi et al, 1998).

Studies are not in accordance. A controlled study, with children undergoing anticonvulsant treatment, did not find significant changes in HDL and triglycerides levels associated with use of carbamazepine or valproic acid. But, in the group taking carbamazepine, there were was significant increase in total cholesterol levels (Fanzoni et al, 1992).

Another study assessed 101 patients undergoing anticonvulsant therapy for at least 3 months. Compared with controls paired for gender and age, patients taking valproic acid presented significantly lower total cholesterol and LDL levels; patients taking carbamazepine presented significantly increased HDL and apolipoprotein A levels (Calandre et al, 1991).
