Meera Narasimhan, MD


 Original release date 8/05. Approved for CME credit through 7/31/06. 

Upon completion of this educational activity, the reader will be familiar with:

The epidemiology of obesity and the metabolic syndrome in patients with mental illness.

The neurobiology and magnitude of metabolic effects associated with antipsychotics.

Evaluating the differential risks associated with atypical antipsychotics.

Implementing treatment strategies and medical monitoring to optimize outcomes while minimizing risks.

Who will benefit from reading this article?

Psychiatrists, primary care physicians, neurologists, nurse practitioners, psychiatric nurses and other mental health care professionals. Continuing medical education credit is available for most specialties. To determine if this article meets the CE requirements for your specialty, please contact your state licensing board.

Dr. Narasimhan is the director of the psychopharmacology program in the department of neuropsychiatry and behavioral sciences at the University of South Carolina School of Medicine and serves as consultant to the Department of Mental Health in Columbia, S.C. Dr. Narasimhan has received grant and research support from Bristol-Myers Squibb and Janssen Pharmaceutica Products, L.P. She has been a consultant for Abbott Laboratories and is a member of the speakers' bureau for Pfizer, Inc.

Dr. Gupta is chairperson of the department of psychiatry at Olean General Hospital in Olean, N.Y. He is clinical professor in the department of psychiatry at the University of Buffalo School of Medicine and Biomedical Sciences and the State University of New York Upstate Medical University. Dr. Gupta has received research grants from Abbott Laboratories; AstraZeneca Pharmaceuticals, L.P.; Eli Lilly and Company; Forest Laboratories, Inc.; GlaxoSmithKline; Johnson & Johnson; Neurochem; and Sanofi-Aventis. He has been a consultant for Eli Lilly; Forest and Shire US, Inc., and a member of the speakers' bureau for Eli Lilly, Forest, GlaxoSmithKline, Shire and Wyeth. He holds stock in Abbott Laboratories and Merck & Company.

Dr. Masand is consulting professor of psychiatry and behavioral sciences at Duke University Medical Center. He has received research and grant support from AstraZeneca Pharmaceuticals, L.P.; Bristol-Myers Squibb; Forest Laboratories, Inc.; GlaxoSmithKline; Janssen Pharmaceutica Products, L.P.; Ortho McNeil Pharmaceuticals; and Wyeth. He is a consultant for Bristol-Myers Squibb; Forest; GlaxoSmithKline; Health Care Technology; Janssen; Jazz Pharmaceuticals; Organon; Pfizer, Inc.; and Wyeth, and is a member of the speakers' bureau for AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, Pfizer and Wyeth. He holds stock in psychCME, Inc.

The prevalence of obesity has reached epidemic proportions in the United States. These numbers are on the rise for all ages and ethnic groups. Being overweight or obese can have detrimental effects on both the physical and emotional well-being of an individual and is an immediate risk factor for cardiovascular disease and metabolic syndrome (Fontaine and Barofsky, 2001; Yancy et al., 2002). Epidemiological studies have shown a strong correlation between psychiatric illness and increased risk for cardiovascular and metabolic disease (Zimmet, 2005). Poor outcomes in the mentally ill may be due to direct biological mechanisms, psychotropic medications, lifestyle (e.g., poor dietary habits, smoking, lack of exercise) or inadequate medical care.

Psychotropics in general--and atypical antipsychotics in particular--have a substantially greater propensity to cause weight gain (Allison and Casey, 2001). Patients on antipsychotics frequently experience a weight gain of 7% to 10% of their usual body weight. Antipsychotic-induced weight gain and metabolic effects have become a growing concern in the psychiatric community (Masand, 1999a). The extent of weight gain varies among atypical antipsychotics, and this could be attributed to their varying receptor binding profiles (Allison et al., 1999).

. A significant weight gain is defined as an increase in body weight ≥7% from baseline (Kawachi, 1999). It is also generally recognized that a body mass index (BMI) >29 kg/m2 is clinically significant. 

 provides a classification of BMI by the National Institutes of Health (1998).

. Fifty percent of patients who are chronically on an antipsychotic medication gain weight (Baptista, 1999). Weight gain frequently results in noncompliance, relapse and poor quality of life (Kalucy, 1980; Kurzthaler and Fleischhacker, 2001; Perkins, 1999).

A quantitative review of the literature looking at weight changes in patients treated with antipsychotics, both conventional and atypical, revealed that weight gain with most atypical antipsychotics was much greater than with conventional agents. However, the propensity to induce weight gain varied with the individual drug (

The general consensus is that clozapine (Clozaril) and olanzapine (Zyprexa) are associated with the greatest weight gain, and ziprasidone (Geodon) and aripiprazole (Abilify) have the smallest effect on weight gain. In a naturalistic study, Henderson and colleagues (2000) demonstrated that clozapine-induced weight gain was correlated with increases in serum cholesterol and triglyceride concentrations. Atypical antipsychotic agents are associated with long-term weight gain to varying degrees. Mean weight gain in patients treated for a year with an atypical antipsychotic is as follows: aripiprazole=approximately 2.6 kg, olanzapine=6.26 kg and risperidone (Risperdal)=2.3 kg (Csernansky et al., 2002; Jody et al., 2002; Kinon et al., 2001). The manufacturer information showed that patients treated with quetiapine (Seroquel) showed an average weight gain of 1.8 kg and patients treated with ziprasidone showed an average range of -1.3 kg to 1.4 kg.

The mechanism of weight gain with antipsychotic drugs is a poorly understood, multifactoral phenomenon. The pathophysiology of weight gain is a complex interaction between biological mechanisms mediated through the monoaminergic, cholinergic and histaminergic receptors; genes; insulin sensitivity; gonadal steroids and environmental factors (Kishi and Horiguchi, 2003). Genetic factors play a significant role in antipsychotic-induced weight gain. Absence of an allele variant of the 5-HT

 receptor gene in a Chinese cohort predicted a weight gain of >7% of total body weight with chlorpromazine (Thorazine), fluphenazine (Prolixin), risperidone, clozapine and sulpiride (Reynolds et al., 2002). 

(Sulpiride is not approved by the U.S. Food and Drug Administration for use in the United States--Ed.)

Antagonistic effects of atypical antipsychotics at the serotonin 5-HT

 receptor site are thought to play a synergistic role with histaminergic antagonism to increase appetite. Differential affinities for the 5-HT

 receptors (Masand, 1999b; Meyer, 2001) may potentially explain the greatest weight gain with clozapine and olanzapine (Masand, 1999b; Wetterling, 2001). Ziprasidone--despite its potent 5-HT

 antagonism--is associated with the least amount of weight gain, which may be attributed to its low H

 antagonism (Schmidt et al., 2001). Aripiprazole is a close second to ziprasidone with regard to weight gain. It has been shown that pathological eating may be mediated by dopamine deficiency (Wang et al., 2001). Positron emission tomography (PET) studies have demonstrated a reduction in the availability of D

Chronic obesity has been associated with the phenomenon of leptin resistance due to increased serum leptin levels (Kraus et al., 1999). Clozapine and olanzapine have a higher propensity to alter serum leptin levels than other antipsychotics (Melkersson and Hulting, 2001).

Weight gain associated with antipsychotics increases the risk of various medical comorbidities that can adversely impact the patient's quality of life (Masand and Gupta, 2000).

The prevalence of glucose dysregulation, hyperglycemia and type 2 diabetes is two times higher in patients with schizophrenia, bipolar disorder, major depression and Alzheimer's dementia than in the general population (Casey, 2005). There is also a greater risk of drug-induced diabetes mellitus in the mentally ill (Cassidy et al., 1999; Gupta et al., 2003; Ryan et al., 2003). Obesity is a risk factor for insulin resistance, hyperglycemia and type 2 diabetes. Dopamine antagonism in the hypothalamus (Liebzeit et al., 2001) and blockade of serotonin receptor, resulting in a decrease in β-cell function, may partly explain the receptor-mediated effects of atypical antipsychotic-induced diabetes (Henderson, 2001).

Diabetes is a significant risk factor for cardiovascular disease and microvascular complications such as retinopathy, nephropathy and neuropathy (American Diabetes Association [ADA], 2002). The increased risk of weight gain and type 2 diabetes with atypical antipsychotics warrants careful monitoring.

Patients with chronic psychiatric disorders have a higher prevalence of hyperlipidemia (Casey, 2005). Antipsychotics, both conventional and atypical, affect serum lipids to varying degrees. Both clozapine and olanzapine can cause greater increases in triglycerides than conventional antipsychotics and other atypical antipsychotics (Meyer, 2002). Several factors play a role in dyslipidemias, including diet, weight gain, presence of a mental illness and antipsychotics. Counseling on proper diet, exercise and healthy lifestyle and close monitoring of lipid profile for patients taking antipsychotics is recommended.

Weight gain increases the risk for hypertension, diabetes and dyslipidemia, all of which independently increase the risk for coronary heart disease. There is an increased prevalence of hypertension in the chronically mentally ill (Casey, 2005). Studies have clearly demonstrated that weight gain is associated with increases in blood pressure (Huang et al., 1998; Kannel et al., 1967).

The risk of coronary artery disease is increased in the presence of metabolic syndrome characterized by three of the following: insulin resistance (with or without glucose intolerance), atherogenic dyslipidemia (elevated triglyceride, low high-density lipoprotein [HDL] cholesterol and small dense low-density lipoprotein [LDL] particles), hypertension, abdominal obesity, and prothrombotic and proinflammatory states (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001). Antipsychotic-induced weight gain and dysregulation of other metabolic parameters may predispose patients with mental illness to cardiovascular morbidity and mortality (Masand and Gupta, 2003). The metabolic risks associated with various atypical antipsychotics are outlined by the Consensus Guidelines Panel (ADA et al., 2004) (

). Mental illness severely limits the ability of a patient to communicate and socially interact due to impaired cognition, making them less likely to understand and seek assistance for their medical problems.

Even though psychotropic drug-induced weight gain is a particularly distressing adverse effect (Buis, 1992), very few studies have evaluated weight gain as an adverse effect that influences compliance. Obese individuals with a chronic mental illness are 13 times more likely to discontinue their medication because of weight gain than nonobese individuals (Weiden et al., 2000). Weight gain is one of the most common side effects of antipsychotic treatment that has negative consequences on the quality of life (Angermeyer and Matschinger, 2000).

Combination therapy commonly prescribed for psychiatric patients, such as an antipsychotic plus a mood stabilizer, is notorious for inducing weight gain due to the additive effects of the medications (Bowden, 2005). Weight gain is a common adverse effect reported by patients taking divalproex (Depakote) and lithium (Eskalith, Lithobid), whereas lamotrigine (Lamictal) appears to be weight-neutral, and topiramate (Topamax) and zonasimide (Zonegran) can result in weight loss (Masand, 2000; Masand et al., in press).

. Given the health risks associated with weight gain, prevention and management strategies need to be implemented. Identifying high-risk individuals who are likely to gain weight prior to initiating the antipsychotic is recommended. Patients should be screened for risk factors including diabetes, cardiovascular disease, family history, race, age, level of physical activity, gender, baseline BMI, psychiatric diagnoses, blood pressure, lipid profile and fasting blood sugars (

). Being on olanzapine or clozapine alone or in combination with a mood stabilizer markedly increases the risk of weight gain. It is extremely important to do a good risk-benefit assessment prior to starting an antipsychotic. The risk factors for antipsychotic-induced weight gain are listed in 

. Health care providers should commence treatment by providing patients with education, explaining the risks and benefits associated with psychotropics. Complications of weight gain in patients on antipsychotics may be prevented by choosing an agent that is efficacious with a lower incidence of weight gain. Counseling patients regarding proper diet and exercise needs to be an integral part of their treatment plan. Referrals to treatment programs that emphasize a healthy diet, exercise and lifestyle modification in order to lose weight need to be strongly recommended to overweight and obese patients.

Monitoring the patient's weight and vital signs at the beginning of treatment and at subsequent follow-up visits is recommended. This would provide the physician with an opportunity to act early to prevent or reverse weight gain. Switch strategies are suggested for rapid increases of 5 lb in four weeks or a total ≥5.0 kg (11 lb) (Masand, 1999a; Russell and Mackell, 2001). Switch studies with ziprasidone and aripiprazole have demonstrated a reduction in body weight and other metabolic effects in addition to symptom improvement (Casey et al., 2003; Weiden et al., 2003). Ziprasidone and aripiprazole may offer a beneficial effect in terms of weight gain and metabolic effects. Switching to quetiapine is not as beneficial in reducing weight or improving metabolic parameters (Gupta et al., 2004).

The amount of weight loss with switch strategies far exceeds that with use of adjunctive medications. Switching can reverse the metabolic effects induced by certain antipsychotics. Prior to switching antipsychotics, patients need to be informed of the potential risk of relapse. A gradual cross-taper over several weeks is suggested. Fasting serum lipid and glucose concentrations for patients on psychotropic medications need to be routinely monitored. Measurements of abdominal girth that is reflective of central adiposity and metabolic parameters can be used as a predictor of insulin resistance and metabolic syndrome. However, if weight gain occurs despite these measures, several weight loss agents have been suggested. These include metformin (Glucophage) (Baptista et al., 2001; Morrison et al., 2002), amantadine (Symmetrel) (Floris et al., 2001), topiramate (Gupta et al., 2000), nizatidine (Axid) (Breier et al., 2002; Sacchetti et al., 2000), sibutramine (Meridia) and orlistat (Xenical) (Meyer, 2001). Current evidence does not support the general use of pharmacological interventions for patients with antipsychotic-related weight gain, though individual patients may benefit from it (Werneke et al., 2002).

Currently available antipsychotic medications are not free of side effects such as weight gain, metabolic disturbance or extrapyramidal symptoms. Some antipsychotics have less of a side-effect burden than others, and pharmacotherapy needs to be tailored to individual patients based on their risk-benefit ratio.

Below, two clinical cases with medication-induced weight gain and strategies that successfully minimized the risk are described. Both of these case vignettes involved chronically ill patients, attending a continuing day treatment program.

"Ms. A" is a 52-year-old female with a diagnosis of chronic undifferentiated schizophrenia. She had a baseline weight of 200 lb. She had been on olanzapine 40 mg once a day since January 2001. Her other medications included escitalopram (Lexapro) 20 mg/day and bupropion SR (Wellbutrin sustained-release) 200 mg twice daily. Her medical history was significant for type 2 diabetes mellitus, obesity, hypertension and dyslipidemia, suggesting a metabolic syndrome. While on olanzapine she weighed 242 lb. She was started on the topiramate in April 2003 and an 1800-calorie ADA diet in July 2004. Her most recent weight was 209 lb while still continuing on olanzapine. Her abdominal girth declined from 47 to 46 in. Along with the pharmacological strategies, this patient was successful in making lifestyle modifications such as reduced portion size, substituting water for soda and walking on a daily basis.

 diagnosis of chronic paranoid schizophrenia. She weighed 164.8 lb in January 2003 while being treated with aripiprazole 20 mg/day, fluoxetine (Prozac) 60 mg/day and hydroxyzine (Atarax) 50 mg at bedtime. In February 2003, an exacerbation of her psychotic symptoms resulted in a psychiatric hospitalization. She was switched to olanzapine 40 mg/day and divalproex 1500 mg/day in divided doses. She appeared stable on this regimen, but in June 2004, her weight started creeping up to 249.6 lb. This patient had a subsequent exacerbation of psychotic symptoms and aripiprazole 20 mg was added to her medication regimen in July 2004. When she was rehospitalized in August 2004, she was taken off of the olanzapine and divalproex and treated with a combination of aripiprazole 20 mg/day and ziprasidone 80 mg twice daily (weight prior to hospitalization was 247.6 lb; abdominal girth 51 in). In September 2004 her weight declined to 229.2 lb and her abdominal girth was 40 in. The aripiprazole was subsequently tapered off and ziprasidone was gradually increased to 120 mg in the morning and 80 mg at bedtime with continued weight decline to 193 lb in October 2004 with an abdominal girth of 48 in. She was continued the entire time on fluoxetine 60 mg/day. This patient was unable to carry out the simplest of dietary interventions or other lifestyle changes. This case outlines the success of switching from a combination of olanzapine and divalproex to ziprasidone in maintaining symptom control as well as weight reduction.

Physicians should practice evidence-based medicine, taking into account patient factors, and select an antipsychotic with long-term efficacy and a favorable side-effect profile after a thorough risk-benefit assessment. Patients and their families should be a part of the decision-making process. Informed consent regarding side effects including weight gain, diabetes mellitus and lipid abnormalities should be documented.

Health care providers should provide counseling on proper diet and exercise for all patients. Patients taking antipsychotics should be monitored for weight gain with a fasting lipid profile (includes HDL, LDL, very low density lipoprotein, cholesterol and triglycerides) and fasting blood sugar at intervals recommended by the Consensus Guideline Panel (ADA et al., 2004). The ADA criteria for diagnosing diabetes include a fasting plasma glucose ≥126 mg/dL, a random plasma glucose level ≥200 mg/dL or a two-hour plasma glucose level of greater than or equal to 200 mg/dL during an oral glucose tolerance test (ADA, 2005). These findings are contingent upon confirmation on a different day.

Detection of abnormal laboratory results warrants referral to a primary care physician. Patients who have normal laboratory values should be screened at least every six months while those with significant abnormalities should be in treatment and screened at least every three months. Patients with risk factors for metabolic syndrome may need more frequent monitoring. Adherence to medication needs to be adequately monitored and efficacy and side effects evaluated at every follow-up visit.

The Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes recommended the following monitoring guidelines for atypical antipsychotics (ADA et al., 2004).

. This should include personal and family history of obesity, diabetes, dyslipidemias, hypertension or cardiovascular disease and measurement of BMI, waist circumference, blood pressure, fasting plasma glucose, and lipids.

. After initiating treatment, weight should be reassessed at four, eight and 12 weeks-then quarterly and annually. Weight gain ≥5% of baseline weight warrants switching to another agent with a favorable safety profile. Fasting blood glucose, lipids and blood pressure need to be assessed three months after treatment initiation and then annually or more frequently if risk factors are present. If there is worsening of glycemia, diabetic ketoacidosis or dyslipidemia, consider consulting a primary care physician and switching to another atypical with minimal metabolic effects.

The panel recommended nutrition and physical activity counseling be provided to all patients who are overweight or obese. Referral to a health care professional or program with expertise in weight management is recommended. It is good clinical practice to monitor patients on atypical antipsychotics for all potential side effects. (See <

. Effective weight management strategies should include lifestyle and medication counseling, regular check-ups, discussion of medication efficacy and tolerability issues, and behavioral and pharmacological interventions when clinically indicated. Weight gain can be prevented by prescribing an antipsychotic agent with low weight gain liability. Switching to another antipsychotic that has minimal effects on metabolic parameters is an option.

Weight management should include physical exercise, dietary habits and smoking cessation. Behavioral interventions may include cognitive-behavioral therapy; consumer weight reduction programs; focusing on nutrition and exercise; and the use of lipid-lowering agents, antidiabetic agents and/or insulin therapy in consultation with a primary care physician or endocrinologist, if clinically indicated (ADA et al., 2004).

There are no standardized pharmacological treatments for antipsychotic-induced weight gain. Studies have assessed antiobesity drugs (sibutramine, orlistat), antiviral agents (amantidine), H

 blockers (cimetidine [Tagamet] and nizatidine), anticonvulsants (topiramate) and hypoglycemic agents (metformin) in antipsychotic-induced weight gain. Antiobesity drugs if considered need to be used as an adjunct to lifestyle changes, diet and exercise modification.

Customize treatment plans for individual patients, taking into account their diagnosis, comorbidities, medication effectiveness, patient preference, prior response to treatment, safety, cost and ease of use (

), while working closely with their primary care providers when clinically indicated. Education and careful monitoring of adverse events improves effectiveness and quality of life, minimizes noncompliance, and decreases morbidity and mortality in our patient population.

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Casey DE, Carson WH, Saha AR et al. (2003), Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology (Berl) 166(4):391-399.

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