Evidence-Based Perspective on Metabolic Syndrome and Use of Antipsychotics

April 16, 2010

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

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-HT2C and H1 receptors24,25 may explain the greater weight gain seen with clozapine and olanzapine.24,26 Despite its potent 5-HT2C 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 HT2C 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.


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