Evidence-Based Perspective on Metabolic Syndrome and Use of Antipsychotics

Schizophrenia, a devastating mental illness that affects nearly 2.2 million Americans, is associated with high rates of morbidity and mortality.¹ Persons with schizophrenia have a 20% shorter life expectancy than the general population.^1,2 Furthermore, among persons with schizophrenia, there is an increased prevalence of metabolic syndrome characterized by a constellation of risk factors, including insulin resistance, abdominal obesity, dyslipidemia, hyperglycemia, and hypertension,³ all of which contribute to an increased risk of cardiovascular morbidity and mortality.⁴ In fact, more than two-thirds of persons with schizophrenia die of coronary heart disease compared with approximately half in the general population.²

Metabolic syndrome is a global issue. Bobes and colleagues⁵ showed that prevalence of coronary heart disease and metabolic syndrome in Spanish patients with schizophrenia who were treated with antipsychotics was the same as that for persons in the general population who were 10 to 15 years older.⁵ In a study of 231 Turkish patients, Boke and colleagues⁶ found that 32% of persons with schizophrenia met criteria for metabolic syndrome, with a higher prevalence in women (61%) than in men (22.4%). It has been suggested that persons with schizophrenia may have a predisposition toward developing metabolic syndrome that is exacerbated by their generally sedentary lifestyle, poor dietary habits, limited access to care, poor insight, and medication-induced adverse effects.⁷

A number of studies have addressed some of the issues pertaining to the effect of metabolic abnormalities on overall quality of life. Weight gain and obesity increase the risk of impaired physical health and may lead to treatment nonadherence and decrements in subjective well-being.^8-10 Persons with schizophrenia and obesity have been found to have lower scores on measures of health-related quality of life.¹¹ These study findings have highlighted the deleterious effects of weight gain and its consequences on the long-term prognosis and life expectancy and underscore the need to develop methods to prevent and treat weight gain in this population.

In recent years, mental health care providers have been grappling with issues related to metabolic disturbance in schizophrenia as well as the adverse effects of antipsychotic treatments. Recent trials estimate that rates of obesity and diabetes in persons with schizophrenia are nearly twice those of the general population, and dyslipidemias are more common.¹² Prevalence of smoking is 3 times that seen in the general population. Taken together, these factors double the risk of cardiovascular morbidity and mortality compared with that of the general population.¹² A growing body of clinical and translational research evidence has implicated the use of atypical antipsychotics in causing and worsening weight gain, dyslipidemia, and diabetes,¹³ resulting in “an epidemic within an epidemic.”¹⁴

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study compared the incidence of metabolic syndrome in its sample population with an age-matched sample from the general population drawn from the National Health and Nutrition Examination Survey (NHANES).¹⁵ The prevalence of metabolic syndrome at baseline was higher among the CATIE study participants than among the NHANES sample. Among the CATIE study participants, overall prevalence of hypertension was 33.2%. The prevalence of diabetes was 10.4% for the entire cohort, increasing to 10.9% among persons with fasting blood glucose results obtained 8 hours or more after their last meal.

Dyslipidemia, as defined by elevated serum triglyceride levels, was found in 47.3% of fasting patients and, when defined as low serum levels of high-density lipoprotein (HDL) cholesterol, was found in 48.3% of all patients. Rates of non-treatment ranged from 30.2% for diabetes to 62.4% for hypertension and 88% for dyslipidemia.¹⁶ These data reiterate the dilemma confronting practitioners on how best to implement strategies that would change the long-term adverse health consequences of these conditions.

Metabolic Syndrome:
Is There Universal Consensus?
While metabolic syndrome is a growing concern for persons with mental illness, there is no universal agreement on precisely what metabolic syndrome is or how to concisely define it, thus making the diagnosis of metabolic syndrome an ambiguous task. Controversies stem from guidelines with different diagnostic criteria and debate over whether the syndrome represents anything more than the risk associated with these individual abnormalities.¹⁷

Metabolic syndrome is defined as a cluster of clinical and laboratory test result abnormalities that indicate abdominal obesity, insulin resistance, hypertension, low levels of HDL cholesterol, and high levels of triglycerides-all of which can pose a significant risk of cardiovascular morbidity and mortality.⁴ The most recent definitions come from the International Classification of Diseases, Ninth Revision, the International Diabetes Federation (IDF), the World Health Organization (WHO), the American Heart Association, the American Diabetes Association, the NIH, and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). The most commonly applied definitions are from the WHO, the NCEP ATP III, and the IDF, and each includes slightly varying criteria (Table 1).^18-20

Risk factors such as abdominal obesity and elevated levels of fasting triglycerides, HDL cholesterol, blood pressure, and fasting blood glucose are among the criteria for diagnosing metabolic syndrome.^18-20 Other important and potentially modifiable risk factors may also warrant consideration, including elevated levels of low-density lipoprotein (LDL) cholesterol, family history of premature coronary heart disease (age 45 years or younger for men and 55 years or younger for women), ethnicity, postmenopausal status, cigarette smoking, diet, alcohol consumption, and exercise or lack of activity either with or without weight changes.¹⁵

While the current definitions seem to imply that the different components of metabolic syndrome are equally important, analyses of the components of metabolic syndrome have shown that the individual components are not necessarily equally associated with elevated risk of coronary heart disease.¹⁵ In fact, most of the risk associated with metabolic syndrome is linked with older age, hypertension, diabetes, and low levels of HDL cholesterol.¹⁵ Therefore, the burden of diagnosis is on the physician, who must closely monitor patients who are taking antipsychotics for signs of metabolic syndrome.

Antipsychotics and Metabolic Syndrome: Pathophysiology
The use of typical antipsychotics, especially low-potency phenothiazines, has been associated with significant weight gain, diabetes, and increased plasma lipid levels.²¹ Dramatic weight gain, diabetes, fatal ketoacidosis, and dyslipidemias following antipsychotic use have raised concerns and demand further scrutiny.^21,22 In most cases, weight gain and central adiposity are major players in the pathophysiology of antipsychotic-induced metabolic syndrome. Increasing visceral/abdominal adiposity (assessed by measuring waist circumference or body mass index [BMI]) is directly linked to insulin resistance, risk of diabetes, and dyslipidemias.

The mechanism of weight gain with antipsychotic drugs is a multifactorial phenomenon that includes appetite-stimulating effects, genetic factors, sedentary lifestyle, and impaired metabolic regulation. The pathophysiology of weight gain is mediated through monoaminergic, cholinergic, and histaminergic neurotransmission.²³ Differential affinities for the serotonin 5-HT_2C and H₁ receptors^24,25 may explain the greater weight gain seen with clozapine and olanzapine.^24,26 Despite its potent 5-HT_2C antagonism, ziprasidone is associated with the least amount of weight gain, which may be attributed to its low H₁ antagonism.²⁷ Aripiprazole is a close second to ziprasidone in associated minimal weight gain. Furthermore, some study findings suggest that persons with a genetic predisposition for aberrant folate metabolism and hyperhomocysteinemia may be at increased risk for antipsychotic-induced metabolic syndrome.²⁸ Additional genetic markers, such as HT_2C receptors, and brain-derived neurotrophic factor levels have also been linked to vulnerability to this adverse effect.^29,30

Antipsychotic-induced weight gain can increase the risk of various comorbidities, including cardiovascular morbidity that can adversely affect the patient’s quality of life.³¹ Obesity is a risk factor for development of insulin resistance, hyperglycemia, and type 2 diabetes.³² Metabolic disturbances associated with the use of atypical antipsychotics may be a direct consequence of the alteration of insulin sensitivity and/or insulin secretion. Antipsychotic-induced weight gain and metabolic liability,³³ along with impaired parasympathetic regulation of B-cell activity mediated by the blockade of histaminergic and muscarinic receptors, may contribute to increased metabolic risk.³⁴ Antipsychotic agents may directly impair glucose transporter function by alterations in the insulin signaling pathway, resulting in elevated circulating glucose levels, compensatory insulin hypersecretion, and reduced insulin sensitivity, and thus lead to development of type 2 diabetes mellitus and metabolic syndrome.³⁵

Antipsychotics, both typical and atypical, affect serum lipid levels to varying degrees. Clozapine and olanzapine can cause greater increases in triglyceride levels than typical antipsychotics and other atypical antipsychotics.³⁶ Several factors play a role in dyslipidemias, including diet, weight gain, mental illness, and antipsychotic use. Elevated fasting plasma triglyceride levels are an important indicator of potential insulin resistance and possible increases in fasting insulin levels.³⁷ This serves as a valuable marker for evaluating a patient’s potential risk of metabolic syndrome and cardiovascular disease. A direct correlation between increased adiposity and increased LDL cholesterol and decreased HDL cholesterol levels has been demonstrated.³⁸ The NCEP ATP III has identified LDL cholesterol as the primary target for reducing the risk of cardiovascular disease.¹⁸

Antipsychotic-induced weight gain and dysregulation of other metabolic parameters may predispose patients with mental illness to an increased risk of cardiovascular morbidity and mortality.³¹ The risk of coronary artery disease is increased in the presence of metabolic syndrome characterized by 3 of the following: insulin resistance (with or without glucose intolerance); atherogenic dyslipidemia (elevated triglyceride levels, low HDL cholesterol levels, and small dense LDL particles); hypertension; abdominal obesity; and prothrombotic and proinflammatory states.¹⁸ The metabolic risks associated with various atypical antipsychotics are outlined in the American Diabetes Association–American Psychiatric Association (ADA-APA) Consensus Guidelines (Table 2).³⁹

The prevalence of metabolic syndrome in the CATIE study was 42.7% at baseline, approximately twice that found in the general population,¹⁴ with lower rates of treatment for the metabolic disturbance. The use of clozapine and olanzapine was associated with the highest risk of metabolic dysfunction. Ziprasidone appeared metabolically neutral. It is not surprising that the use of atypical antipsychotics is associated with an elevated risk of metabolic syndrome, given the body of evidence linking them to weight gain, hyperglycemia, and lipid abnormalities.²²

De Hert and colleagues⁴⁰ compared a historical cohort of first-episode schizophrenia patients treated with typical antipsychotics with a current cohort of patients treated with atypical antipsychotics. They found no difference in baseline prevalence of metabolic syndrome between groups. The atypical group experienced 3 times the rate of metabolic syndrome during a 3-year follow-up; clozapine and olanzapine primarily accounted for the difference. On the other hand, several studies have failed to detect differences in the prevalence of the syndrome between patients taking atypical antipsychotics and those taking typical antipsychotics, raising an important question of whether metabolic syndrome associated with the use of typical antipsychotics may be under-researched and underestimated.^18-27,31,32

Screening and Monitoring During Use of Antipsychotics
It is prudent to evaluate metabolic and cardiovascular risk in persons who have schizophrenia before antipsychotic treatment is started and to closely monitor these factors throughout treatment. A number of authoritative guidelines have been recommended, including the Mount Sinai Conference on medical monitoring and more recently, the ADA-APA Consensus Guidelines developed with the American Association of Clinical Endocrinologists and the North American Association for the Study of Obesity.³⁹ These guidelines are the result of an extensive review of the clinical literature that examined metabolic changes associated with the use of atypical antipsychotic agents, and they provide a wide range of monitoring and management recommendations for assessing physical health needs and reducing morbidity and mortality risks in the mentally ill.

Cohn and Sernyak⁴¹ reviewed the 6 major consensus guidelines published in 2004 and 2005 for metabolic monitoring of patients treated with antipsychotics, including the guidelines published by the Mount Sinai Conference; the ADA-APA; and experts in Australia, Belgium, the United Kingdom, and Canada. They determined that areas of dissent include the frequency of monitoring various signs and symptoms, which patients to monitor, the utility of glucose tolerance testing, and the point at which to consider switching antipsychotics. The authors concluded that there is considerable consensus among the published guidelines, including a systematic assessment of the following:
• Family history.
• Weight and BMI.
• Waist circumference.
• Blood pressure.
• Fasting lipid levels.
• Fasting glucose levels.

According to the ADA-APA Consensus Guidelines, weight should be reassessed at weeks 4, 8, and 12 after initiating or changing an antipsychotic agent, and quarterly thereafter.³⁹ A weight gain of 5% or more of initial body weight warrants a lifestyle modification with diet and exercise and/or therapeutic alternatives, including drug switch strategies. In a study by Tirupati and Chua,⁴² a BMI of more than 28.7 kg/m² correlated well with the presence of metabolic syndrome, which suggests that this measure may be used as a quick marker for metabolic syndrome. Fasting plasma glucose levels, lipid profile, and blood pressure should be assessed every 3 months on initiation of antipsychotic therapy and sooner in persons who are at high risk at baseline.³⁹ Compared with a fasting glucose test, a post-load oral glucose tolerance test is an earlier indicator of failing glucose control.

The implementation of such guidelines can substantially improve the health of persons with schizophrenia, but to adopt them in clinical practice can be quite challenging. The Atypical Antipsychotic Therapy and Metabolic Issues National Survey in 2004⁴³ and, more recently, the nationwide database study by Cuffel and colleagues⁴⁴ showed low rates of monitoring for metabolic risks. Psychiatry needs to acknowledge patient-related, physician-related, and system-related barriers to implementing these guidelines (Table 3).⁴⁵ These barriers highlight an urgent need to transform public mental health care through early intervention, integrated medical and psychiatric care, and customized treatments to enhance subjective wellness and recovery (Table 4).⁴⁵

Integration of Psychiatric and General Medical Care
Treatment with atypical antipsychotics imposes new standards for patient education, informed consent, and risk-benefit analysis in the selection of pharmacotherapy. The NCEP ATP III treatment guidelines recommend a lifestyle modification, including reduced intake of saturated fats and cholesterol, increased fiber intake, weight reduction, and increased physical activity as the first-line therapeutic approach to reduce the risk of cardiovascular disease.¹⁸ Monitoring guidelines suggest the consideration of switching to an atypical antipsychotic with less weight gain liability if a person with schizophrenia gains more than 5% of his or her baseline weight or if dyslipidemia or hyperglycemia worsens. Behavioral approaches that use educational, motivational, and pragmatic techniques to achieve weight loss in patients with schizophrenia have had variable success. Guidelines for weight reduction are outlined in Table 5.⁴⁶

The NCEP ATP III guidelines suggest that weight loss lowers LDL cholesterol and triglyceride levels, increases HDL cholesterol levels, lowers blood pressure, and reduces insulin resistance.¹⁸ When clinically indicated, LDL-lowering drugs, including HMG-CoA reductase inhibitors (statins), nicotinic acid, bile acid sequestrants, and fibric acids, are necessary to achieve target LDL cholesterol levels. Statin therapy has been shown to significantly decrease triglyceride, total cholesterol, LDL cholesterol, and non-HDL cholesterol levels without changing HDL cholesterol levels, BMI, waist circumference, or glucose homeostasis.⁴⁷

The use of metformin and the thiazolidinedione class of drugs reduces insulin resistance and risk of new-onset coronary heart disease in obese persons with diabetes and prevents or delays type 2 diabetes mellitus in persons with impaired glucose tolerance.³² Persons with hypertension who are taking atypical antipsychotics and meet criteria for metabolic syndrome should be treated with therapeutic lifestyle changes and medications in accordance with hypertension guidelines.³² The use of low-dose aspirin may be helpful in reducing the prothrombotic state in patients with metabolic syndrome and an elevated risk of coronary heart disease.³² Recently, alpha-lipoic acid has shown possible beneficial effects on metabolic adverse effects of antipsychotics in a small study.⁴⁸

Switching Strategies
Study findings have suggested that switching to a medication with a lower weight gain liability may produce significant reductions in body weight if therapeutic lifestyle modification strategies fail. The ADA-APA Consensus Guidelines suggest that clozapine and olanzapine have the greatest propensity for weight gain, risperidone and quetiapine have an intermediate risk, and ziprasidone and aripiprazole have minimal effects on weight (Table 2).⁴⁹

Studies have shown that patients had an average weight increase of 6.8 to 11.8 kg with olanzapine, 5.3 to 6.3 kg with clozapine, 2.8 to 5.6 kg with quetiapine, and 2 to 2.3 kg with risperidone after the first year of therapy, and after 6 months of therapy, patients had an increase of 0.23 kg with ziprasidone on average.^50,51 Other studies have shown that patients treated for 1 year gained an average of 2.6 kg with aripiprazole, 6.26 kg with olanzapine, and 2.3 kg with risperidone.^52-54 The CATIE study found that patients being treated with olanzapine gained an average of 2 lb (0.9 kg) per month, whereas patients being treated with risperidone and quetiapine gained an average of 0.4 lb and 0.5 lb (0.18 kg and 0.23 kg) per month, respectively. Patients who were being treated with ziprasidone lost an average of 0.3 lb (0.14 kg) per month; however, most of the patients were taking another antipsychotic before switching to ziprasidone, which may account for the weight loss.⁵⁵

Weiden and colleagues⁵⁶ demonstrated that patients who had switched from olanzapine or risperidone to ziprasidone lost an average of 1.8 kg and 0.9 kg, respectively, during 6 weeks. In addition, Casey and colleagues⁵⁷ showed that patients who had switched from olanzapine or risperidone to aripiprazole lost an average of 2 kg and 0.7 kg, respectively. Simpson and colleagues⁵⁸ showed that patients who continued to take ziprasidone after switching from olanzapine lost an average of 10 kg during 58 weeks, whereas patients who took ziprasidone after switching from risperidone lost an average of 6.8 kg during 58 weeks. Weight loss has occurred with a switch to ziprasidone or aripiprazole from medications that have a greater propensity to induce weight gain; otherwise, when patients switch from agents with similar weight profiles, there are no weight loss benefits. Therefore, a switch to ziprasidone or aripiprazole is effective for reversing weight gain that is induced by other atypical antipsychotic agents.

Weight loss and reversal of metabolic effects with switch strategies far exceed those with the use of adjunctive medications. However, if weigh

t gain occurs despite these measures, several weight loss agents, including metformin,^59,60 amantadine,⁶¹ topiramate,⁶² nizatidine,⁶³ sibutramine, and orlistat,²⁵ have been suggested. Current evidence does not support the general use of pharmacological interventions for patients who have antipsychotic-related weight gain, although some patients may benefit from it.⁶⁴

Medications associated with significant increases in total cholesterol levels and triglyceride levels include clozapine, olanzapine, quetiapine, and risperidone, whereas aripiprazole and ziprasidone cause decreases in total cholesterol levels. The CATIE study showed that olanzapine and quetiapine are associated with increases in total cholesterol levels of 9.4 mg/dL and 6.6 mg/dL, respectively; it showed also that they are associated with increases in triglyceride levels of 40.5 mg/dL and 21.2 mg/dL, respectively.⁵⁵ Risperidone and ziprasidone are associated with decreases in cholesterol levels of 1.3 mg/dL and 8.2 mg/dL and decreases in triglyceride levels of 2.4 mg/dL and 16.5 mg/dL, respectively.⁵⁵

A literature review by Newcomer²² found that clozapine and olanzapine cause sustained elevations in lipid levels, but there is limited if any increased risk of treatment-induced dyslipidemia with risperidone or quetiapine. Newcomer also reported a lack of evidence indicating that aripiprazole and ziprasidone cause dyslipidemia. In a 58-week study, Weiden and colleagues⁶⁵ showed that switching from olanzapine to ziprasidone resulted in an average decrease of 20 mg/dL in cholesterol levels and an average decrease of 17 mg/dL in triglyceride levels, and switching from risperidone to ziprasidone resulted in an average decrease of 13 mg/dL in cholesterol levels. In a study by Litman and colleagues,⁶⁶ switching from olanzapine to aripiprazole decreased total cholesterol levels by an average of 39.1 mg/dL and decreased LDL cholesterol levels by an average of 28.9 mg/dL during 12 weeks.

In addition to weight gain and lipid abnormalities, patients who received clozapine and olanzapine were shown to have significant elevations in glucose levels and reductions in insulin sensitivity compared with healthy controls. Aripiprazole and ziprasidone, on the other hand, are associated with an overall improvement of metabolic components.

In a retrospective study using a cutoff of 126 mg/dL for fasting blood glucose levels, clinically significant elevations were seen in 44% of patients treated with clozapine, 27% treated with olanzapine, 36% treated with risperidone, and 13% treated with quetiapine.⁶⁷ When a cutoff of 200 mg/dL for random blood glucose levels is used, clinically significant elevations were seen in 4% of patients treated with clozapine, 5% treated with olanzapine, 8% treated with risperidone, and 0% treated with quetiapine. In addition, clinically significant elevations in total cholesterol levels (to 200 mg/dL) were seen in 48% of patients receiving clozapine, 25% of those receiving olanzapine, 21% of those receiving risperidone, and 25% of patients receiving quetiapine.⁶⁷

Implementing the Switch
A clinician should choose to switch a patient’s therapy to a new antipsychotic on the basis of the reason behind the decision to change medications and of the metabolic adverse-effect profiles of each drug (current and new) as described in the literature. A clinician must also consider the differential efficacies of the antipsychotics, particularly if a patient has a good therapeutic response to the current medication. Other considerations are the potential to maintain long-term efficacy and the risk of developing tolerance to a new medication. Therefore, the clinician must determine whether a switch in antipsychotics for metabolic concerns is realistic for the patient’s overall treatment goals.

Before switching antipsychotics, patients need to be informed of the potential risk of relapse. A gradual cross-taper over several weeks is suggested.^49,68,69 Medication changes and adjustments need to be tailored to patients on the basis of their risk to benefit ratio.

Data from the CATIE study, using the number needed to treat (NNT) and the number needed to harm (NNH) in assessing efficacy tolerability and the risk of weight gain associated with antipsychotic use, showed an advantage for olanzapine for all-cause discontinuation, with a NNT of 6 for olanzapine versus quetiapine, 11 for olanzapine versus risperidone, and 7 for olanzapine versus ziprasidone.⁷⁰ While an efficacy advantage was shown for olanzapine in every 8 to 11 patients, a tolerability disadvantage was determined for every 12 to 31 patients. While NNT and NNH are predictors of events, either adverse or desired, there are no guarantees of weight changes, drug efficacy, or changes in other metabolic parameters, thus indicating that the decision to switch or to continue taking a particular antipsychotic must be individualized.⁷⁰

Correll⁷¹ described 8 distinct switch strategies and discussed situations in which the various strategies could be best used when changing from one antipsychotic to another.⁷² An individualized approach to switching antipsychotics was acknowledged as reasonable when considering the adverse effects leading to the medication switch and the adverse effects that may occur secondary to the medication change.⁷¹ Correll noted that when patients switch to the metabolically neutral antipsychotics ziprasidone and aripiprazole, an overlapping switch strategy may be more effective to avoid withdrawal and/or rebound from the antihistaminic and anticholinergics blockades that may cause “activating” adverse effects.⁷¹ However, further research is needed to develop treatment guidelines for safely and effectively switching antipsychotics.

Some of the challenges and complexities involved in addressing weight gain and metabolic syndrome in a patient receiving antipsychotic therapy are illustrated in the Case Study, “Managing Metabolic Effects.”

Toward a Comprehensive Model of Care
The debate about whether metabolic effects induced by atypical antipsychotics are a class effect or a differential effect continues to spark a great deal of interest, although the phenomenon is poorly understood. Despite evidence suggesting that the risk of diabetes and metabolic syndrome associated with use of the various atypical antipsychotics is strongly correlated with weight gain,^22-27,31-39 there is a paucity of evidence about whether atypical antipsychotics that are weight-neutral or have minimal effects on weight gain have a propensity to cause diabetes and metabolic syndrome. Patients with chronic mental illness generally represent a high-risk group, and the ADA-APA Consensus Guidelines recommend metabolic monitoring and clinical vigilance for all persons taking atypical antipsychotics.³⁹

Before treatment with an antipsychotic is started, identifying high-risk persons who are likely to gain weight is considered prudent practice. Health care providers should educate their patients about the risks and benefits associated with the use of psychotropics, allowing for a shared decision, which is the first step toward treatment adherence. Counseling patients on proper diet and exercise needs to be an integral part of the treatment plan. Participation in treatment programs that emphasize a healthy diet, exercise, and lifestyle modification to lose weight needs to be strongly recommended to overweight and obese patients.

Psychiatry lacks clear-cut, definitive guidelines to aid clinicians in switching antipsychotics. When switching from one antipsychotic to another is clinically warranted because of intolerable adverse effects, the clinician should be aware of a number of potential risks associated with this strategy. Open communication with patients concerning these risks can help the clinician manage problems that may occur during the switch process.

Many persons with schizophrenia receive little or no medical care for physical ailments. Often, individuals with serious mental illness have had inadequate evaluation and treatment of medical illnesses. Several provocative questions continue to remain unanswered:
• How does the increasing prevalence of metabolic syndrome shape the practice of medicine?
• What does this mean for mental health care providers?
• How do we begin to move toward creating collaborative models that would address some of these issues that clearly have implications for increasing the life expectancy of persons with schizophrenia?

The field of psychiatry has seen a flurry of guidelines that have raised awareness of the magnitude of this problem and the need to stringently monitor this vulnerable patient population. But, given the issues pertaining to treatment adherence, affordability of care, resources, and financial constraints, translating these management guidelines into clinical practice is quite challenging. Although this is discouraging, it also presents the unique public health opportunity for health care providers to strive to increase awareness of the physical health of persons with serious mental illness. This, in turn, may lead to the establishment of a comprehensive model of care that integrates medical and psychiatric management to improve the overall health of persons who have schizophrenia.

References:

References
1. Osby U, Correia N, Brandt L, et al. Mortality and causes of death in schizophrenia in Stockholm County, Sweden. Schizophr Res. 2000;45:21-28.
2. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005;150:1115-1121.
3. Heiskanen T, Niskanen L, Lyytikäinen R, et al. Metabolic syndrome in patients with schizophrenia. J Clin Psychiatry. 2003;64:575-579.
4. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716.
5. Bobes J, Arango C, Aranda P, et al; CLAMORS Study Collaborative Group. Cardiovascular and metabolic risk in outpatients with schizophre-nia treated with antipsychotics: results of the CLAMORS Study. Schizophr Res. 2007;90:162-173.
6. Boke O, Aker S, Sarisoy G, et al. Prevalence of metabolic syndrome among inpatients with schizophrenia. Int J Psychiatry Med. 2008;38:103-112.
7. Brown S, Inskip H, Barraclough B. Causes of the excess mortality of schizophrenia. Br J Psychiatry. 2000;177:212-217.
8. Allison DB, Mackell JA, McDonnell DD. The impact of weight gain on quality of life among persons with schizophrenia. Psychiatr Serv. 2003; 54:565-567.
9. Fontaine KR, Bartlett SJ, Barofsky I. Health- related quality of life among obese persons seeking and not currently seeking treatment. Int J Eat Disord. 2000;27:101-105.
10. Perkins DO. Adherence to antipsychotic medications. J Clin Psychiatry. 1999;60(suppl 21):25-30.
11. Kolotkin RL, Corey-Lisle PK, Crosby RD, et al. Impact of obesity on health-related quality of life in schizophrenia and bipolar disorder. Obesity (Silver Spring). 2008;16:749-754.
12. Cohn T, Prud’homme D, Streiner D, et al. Characterizing coronary heart disease risk in chronic schizophrenia: high prevalence of the metabolic syndrome. Can J Psychiatry. 2004;49:753-760.
13. De Hert M, van Winkel R, Van Eyck D, et al. Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study. Clin Pract Epidemol Ment Health. 2006;27:14.
14. Fenton WS, Chavez MR. Medication-induced weight gain and dyslipidemia in patients with schizophrenia. Am J Psychiatry. 2006;163:1697-1704.
15. McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res. 2005;80:19-32.
16. Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res. 2006;86:15-22.
17. Sarafidis PA, Nilsson PM. The metabolic syndrome: a glance at its history. J Hypertens. 2006; 24:621-626.
18. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285: 2486-2497.
19. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15:539-553.
20. International Diabetes Federation. The IDF Consensus Worldwide Definition of the Metabolic Syndrome. http://www.idf.org/ebdata/docs/ IDF_Meta_def_final.pdf. Accessed April 24, 2009.
21. Haupt DW, Newcomer JW. Abnormalities in glucose regulation associated with mental illness and treatment. J Psychosom Res. 2002;53:925-933.
22. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19(suppl 1):1-93.
23. Bray GA. Drug insight: appetite suppressants. Nat Clin Pract Gastroenterol Hepatol. 2005;2:89-95.
24. Masand PS. Relative weight gain among antipsychotics. J Clin Psychiatry. 1999;60:706-708.
25. Meyer JM. Effects of atypical antipsychotics on weight and serum lipid levels. J Clin Psychiatry. 2001;62(suppl 27):27-34.
26. Wetterling T. Body weight gain with atypical antipsychotics: a comparative review. Drug Saf. 2001;24:59-73.
27. Schmidt AW, Lebel LA, Howard HR Jr, Zorn SH. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol. 2001;425:197-201.
28. Ellingrod VL, Miller DD, Taylor SF, et al. Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants. Schizophr Res. 2008;98:47-54.
29. Mulder H, Franke B, van der-Beek van der AA, et al. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. J Clin Psychopharmacol. 2007;27:338-343
30. Zhang XY, Zhou DF, Wu GY, et al. BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology. 2008; 33:2200-2205.
31. Masand PS, Gupta S. Long-term adverse effects of novel antipsychotics. J Psychiatr Pract. 2000;6: 299-309.
32. Grundy SM, Brewer HB Jr, Cleeman JI, et al; American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-438.
33. Matsui-Sakata A, Ohtani H, Sawada Y. Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. Drug Metab Pharmacokinet. 2005;20:368-378. 34. Silvestre JS, Prous J. Research on adverse drug events, I: muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes. Methods Find Exp Clin Pharmacol. 2005;27:289-304.
35. Dwyer DS, Donohoe D. Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol Biochem Behav. 2003;75:255-260.
36. Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry. 2002;63:425-433.
37. Metzler W, Fücker K, Schwanebeck U, et al. Significance of triglycerides for other metabolic parameters in the familial metabolic syndrome [in German]. Dtsch Med Wochenschr. 2003;128: 1941-1946.
38. Walton C, Lees B, Crook D, et al. Body fat distribution, rather than overall adiposity, influences serum lipids and lipoproteins in healthy men independently of age. Am J Med. 1995;99:459-464.
39. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004; 65:267-272.
40. De Hert M, Schreurs V, Sweers K, et al. Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: a retrospective chart review. Schizophr Res. 2008;101:295-303.
41. Cohn TA, Sernyak MJ. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry. 2006;51:492-501.
42. Tirupati S, Chua LE. Body mass index as a screening test for metabolic syndrome in schizophrenia and schizoaffective disorders. Australas Psychiatry. 2007;15:470-473.
43. Newcomer JW, Nasrallah HA, Loebel AD. The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists. J Clin Psychopharmacol. 2004;24(5 suppl 1):S1-S6.
44. Cuffel B, Martin J, Joyce AT, et al. Lipid and glucose monitoring during atypical antipsychotic treatment: effects of the 2004 ADA/APA consensus statement. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto.
45. Sernyak MJ. Implementation of monitoring and management guidelines for second-generation antipsychotics. J Clin Psychiatry. 2007;68(suppl 4):14-18.
46. Brar JS, Ganguli R, Pandina G, et al. Effects of behavioral therapy on weight loss in overweight and obese patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2005; 66:205-212.
47. Hanssens L, De Hert M, Kalnicka D, et al. Pharmacological treatment of severe dyslipidaemia in patients with schizophrenia. Int Clin Psychopharmacol. 2007;22:43-49.
48. Kim E, Park DW, Choi SH, et al. A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J Clin Psychopharmacol. 2008;28:138-146.
49. Weiden PJ, Buckley PF. Reducing the burden of side effects during long-term antipsychotic therapy: the role of “switching” medications. J Clin Psychiatry. 2007;68(suppl 6):14-23.
50. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of North American trials. J Clin Psychiatry. 1997;58:538-546.
51. Csernansky J, Okamoto A. Risperidone versus haloperidol for prevention of relapse in schizophrenia. Presented at: 10th Annual Meeting of the Biennial Winter Workshop on Schizophrenia; February 2000; Davos, Switzerland.
52. Kinon BJ, Basson BR, Gilmore JA, Tollefson GD. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry. 2001;62:92-100.
53. Csernansky JG, Mahmoud R, Brenner R; Risperidone-USA-79 Study Group. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia [published correction appears in N Engl J Med. 2002;346:1424]. N Engl J Med. 2002;346:16-22.
54. Jody D, Saha AR, Iwamoto T, et al. Meta-analysis of weight effects with aripiprazole. Int J Neuropsychopharmacol. 2002;5:S186.
55. Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.
56. Weiden PJ, Simpson GM, Potkin SG, O’Sullivan RL. Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. J Clin Psychiatry. 2003;64:580-588.
57. Casey DE, Carson WH, Saha AR, et al; Aripiprazole Study Group. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology (Berl). 2003;166:391-399.
58. Simpson GM, Weiden PJ, Loebel A, et al. Long-term improvements of symptoms in an extension study of ziprasidone. Presented at: 157th Annual Meeting of the American Psychiatric Association; May 1-6, 2004; New York.
59. Baptista T, Hernàndez L, Prieto LA, et al. Metformin in obesity associated with antipsychotic drug administration: a pilot study. J Clin Psychiatry. 2001;62:653-655.
60. Morrison JA, Cottingham EM, Barton BA. Metformin for weight loss in pediatric patients taking psychotropic drugs. Am J Psychiatry. 2002; 159:655-657.
61. Floris M, Lejeune J, Deberdt W. Effect of amantadine on weight gain during olanzapine treatment. Eur Neuropsychopharmacol. 2001;11:181-182.
62. Gupta S, Masand PS, Frank BL, et al. Topiramate in bipolar and schizoaffective disorders: weight loss and efficacy. Prim Care Companion J Clin Psychiatry. 2000;2:96-100.
63. Sacchetti E, Guarneri L, Bravi D. H(2) antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients. Biol Psychiatry. 2000;48:167-168.
64. Werneke U, Taylor D, Sanders TA. Options for pharmacological management of obesity in patients treated with atypical antipsychotics. Int Clin Psychopharmacol. 2002;17:145-160.
65. Weiden PJ, Loebel A, Yang R, Lebovitz H. Course of weight and metabolic benefits 1 year after switching to ziprasidone. Presented at: 157th Annual Meeting of the American Psychiatric Association; May 2004; New York.
66. Litman R, Maiorca M, Courage E, et al. Body mass indices, lipid and glucose metabolism in olanzapine-treated schizophrenia patients before and after switching to aripiprazole. Presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 2003; San Juan, Puerto Rico.
67. Wirshing DA, Boyd JA, Meng LR, et al. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002;63:856-865. 68. Burns T, Chabannes JP, Demyttenaere K. Switching antipsychotic medications: general recommendations and switching to amisulpride. Curr Med Res Opin. 2002;18:201-208.
69. Edlinger M, Baumgartner S, Eltanaihi-Furtmüller N, et al. Switching between second-generation antipsychotics: why and how? CNS Drugs. 2005;19:27-42.
70. Citrome L. The effectiveness criterion: balancing efficacy against the risks of weight gain. J Clin Psychiatry. 2007;68(suppl 12):12-17.
71. Correll CU. Real-life switching strategies with second-generation antipsychotics. J Clin Psychiatry. 2006;67:160-161.
72. American Diabetes Association. Standards of medical care in diabetes [published correction appears in Diabetes Care. 2005;28:990]. Diabetes Care. 2005;28(suppl 1): S4-S36.