Psychiatric Annals

CME Article 

Management of Metabolic Syndrome in Schizophrenia

Pragyan Sharma, MBBS; Hannah E. Brown, MD

Abstract

People with schizophrenia have an increased morbidity and mortality rate compared to the general population. Physical illness, including cardiovascular disease, is a major contributing factor to early mortality. Metabolic syndrome (MetS), an entity of clinical findings consisting of central obesity, dyslipidemia, hyperglycemia, and hypertension, is a major risk factor for the development of cardiovascular disease and diabetes. MetS is prevalent in people with psychiatric disorders, especially those with schizophrenia. Contributing factors for developing MetS among people with schizophrenia include sedentary lifestyle, poor diet, medication side effects, limited access to medical care, and the illness itself. Additionally, screening and monitoring recommendations are less likely to be adhered by people with schizophrenia. To improve overall physical health and decrease the mortality gap for people with schizophrenia, clinicians must implement the appropriate MetS screening, prevention, and treatment measures. [Psychiatr Ann. 2020;50(8):340–345.]

Abstract

People with schizophrenia have an increased morbidity and mortality rate compared to the general population. Physical illness, including cardiovascular disease, is a major contributing factor to early mortality. Metabolic syndrome (MetS), an entity of clinical findings consisting of central obesity, dyslipidemia, hyperglycemia, and hypertension, is a major risk factor for the development of cardiovascular disease and diabetes. MetS is prevalent in people with psychiatric disorders, especially those with schizophrenia. Contributing factors for developing MetS among people with schizophrenia include sedentary lifestyle, poor diet, medication side effects, limited access to medical care, and the illness itself. Additionally, screening and monitoring recommendations are less likely to be adhered by people with schizophrenia. To improve overall physical health and decrease the mortality gap for people with schizophrenia, clinicians must implement the appropriate MetS screening, prevention, and treatment measures. [Psychiatr Ann. 2020;50(8):340–345.]

Metabolic syndrome (MetS) is a significant risk factor for cardiovascular disease and diabetes. MetS is more prevalent in people with schizophrenia compared to the general population. Risk factors for developing MetS include poor nutrition, sedentary behavior, cigarette smoking, and treatment with antipsychotic medications.1 This article reviews MetS in people with schizophrenia, focusing on causes of MetS, appropriate monitoring, prevention, and treatment.

Definition of Metabolic Syndrome

MetS is a group of clinical findings that increase a person's risk for cardiovascular disease and type 2 diabetes. Criteria for MetS include central obesity, elevated blood pressure, elevated triglycerides, hyperglycemia, and low high-density lipoprotein. There is slight variation between the expert consensus guidelines criteria for MetS, with the International Diabetes Federation (IDF) including abdominal obesity as necessary criteria. However, a subsequent unifying criteria has been proposed by the IDF and the American Heart Association/National Heart, Lung, and Blood Institute2 (Table 1). Under this definition, the presence of 3 of the 5 risk factors is consistent with a definition of MetS.

Criteria for Defining Metabolic Syndrome

Table 1.

Criteria for Defining Metabolic Syndrome

Morbidity and Mortality

People with schizophrenia have a 10- to 25-year reduction in life expectancy compared to the general population.3 Physical diseases, including cardiovascular disease, account for most of the increased mortality rate.4 MetS, which imparts increased risk for cardiovascular disease, is prevalent among people with schizophrenia, and it is estimated that the prevalence of MetS in people with schizophrenia is approximately 33%, and the relative risk is 1.87 times higher than in the general population.5 Further, people with schizophrenia often have limited access to medical care, contributing to elevated morbidity and mortality rates.6

Risk Factors and Mechanisms

Weight gain, specifically abdominal obesity, is one of the earliest risk factors for developing MetS. Among people with schizophrenia, treatment with antipsychotic medications can cause significant weight gain. Potential mechanisms for antipsychotic medication-induced weight gain include dysregulation of the hypothalamic-targeting hormones leptin and ghrelin, 5-hydroxytryptamine receptor 2c receptor antagonism affecting satiety signaling, and histamine H1 receptor antagonism increasing energy intake and inappetite.7,8 Both first-generation and second-generation antipsychotic medications have been associated with weight gain, although mean weight gain varies substantially between antipsychotic drugs. A recent network meta-analysis of 32 antipsychotic medications showed not only olanzapine and clozapine, but also quetiapine, risperidone, iloperidone, and risperidone caused significant weight gain when compared to placebo. Antipsychotic medications including ziprasidone, aripiprazole, and haloperidol cause minimal weight gain.9Table 2 demonstrates the extent of weight gain for many antipsychotic medications.9,10

Weight Gain Caused by Antipsychotic Medication

Table 2.

Weight Gain Caused by Antipsychotic Medication

Impaired glucose tolerance and development of diabetes are also associated with treatment with antipsychotic medications. Underlying causes for impaired glucose tolerance may differ between antipsychotic medications. For example, olanzapine and clozapine have direct effect on both insulin secretion from pancreatic beta cells and on glucose transport, whereas haloperidol may not affect glucose transport.7 Other potential mechanisms for antipsychotic-induced insulin resistance include inhibition of glucose uptake through the glucose transporter, decreased insulin sensitivity of glucose transporters, and promotion of basal insulin release, leptin resistance, and impaired glucose metabolism.7,11 Further, people with schizophrenia who do not take antipsychotic medication demonstrate insulin resistance, suggesting psychotic illness itself confers a direct risk of impaired glucose regulation and diabetes.12

Dyslipidemia is another risk factor for cardiovascular disease. Antipsychotic medications can increase triglyceride and low-density lipoprotein cholesterol levels and decrease high-density lipoprotein cholesterol levels.13 Triglyceride level change differs between antipsychotic medications; for example, olanzapine, clozapine, and quetiapine significantly elevate triglyceride levels, whereas ziprasidone does not.14,15 Antipsychotic medication-induced lipid dysregulation may be caused by a disruption in adipose tissue function through disruption in lipogenesis and lipolysis, as well as impairment of cholesterol biosynthesis.7

In addition to the effects of antipsychotic medications, people with schizophrenia are exposed to environmental factors that contribute to the development of MetS. Those with schizophrenia have a more sedentary lifestyle, which can lead to weight gain and central obesity. The sedentary lifestyle is attributable to unhealthy diet and poor nutrition, as well as illness-specific causes including negative symptoms, disorganization, or depressive symptoms.16 Additionally, people with schizophrenia have an increased rate of cigarette smoking, contributing to decreased physical activity and increased risk of MetS. Finally, people with schizophrenia frequently receive poor medical care, including fewer preventive primary care visits and less frequent screening for and treatment of cardiovascular disease compared to the general population.17

Monitoring Guidelines and Treatment

Treatment of schizophrenia is often focused only on treating the psychiatric symptoms, with limited attention to prevention, screening, and monitoring for MetS.18 Preventing MetS should be prioritized when caring for patients with schizophrenia. Lifestyle interventions including minimizing sedentary behaviors and encouraging exercise, as well as monitoring and modifying diet, are considered initial strategies for decreasing risk for MetS.19 Nutrition education and a structured exercise program can help reduce risk factors for MetS, including decreasing triglyceride levels, decreasing fasting glucose levels, and decreasing waist circumference.20 Nutrition education should focus on healthy eating choices including limited intake of saturated fat (with goal of predominately unsaturated fat intake), trans fat, cholesterol, and sugar. Target exercise goals should include at least 30 minutes of continuous physical activity (aerobic exercise) 5 days per week.21 Working with patients to find an enjoyable, satisfying, and practical exercise regimen is key for exercise adherence.

There are both screening and monitoring guidelines for cardiometabolic risk, including factors contributing to MetS, that should be addressed in clinical practice. Practice guidelines vary, and most guidelines indicate that the frequency of monitoring depends on existing cardiometabolic risk factors. In the United States, four national associations, including the American Psychiatric Association and the American Diabetes Association, developed consensus monitoring guidelines in 2004 for people taking second-generation antipsychotic medications.22 These monitoring guidelines include baseline monitoring (when initiating treatment with antipsychotic medication) including a personal and family history of cardiovascular and diabetes risk factors, weight and height, waist circumference, blood pressure, fasting plasma glucose, and lipids. They recommend follow-up monitoring at designated intervals including quarterly for body mass index, annually for blood pressure, fasting glucose, and waist circumference, and every 5 years for fasting lipids (or earlier if clinically indicated). Of note, these guidelines have not been updated recently, and others have suggested more current monitoring practices for cardiometabolic risk in people with serious mental illness, including regular lifestyle modification advice.23

People with schizophrenia who develop MetS should continue to receive support implementing lifestyle modifications. Antipsychotic medication treatment plans should be frequently assessed. An antipsychotic medication dose decrease or switch to an antipsychotic medication with less cardiometabolic risk such as aripiprazole or ziprasidone should be considered.24 A risk/benefit analysis (eg, symptom control and MetS risk) and discussion with the patient should precede any medication change. Smoking cessation should also be a goal of treatment to reduce cardiovascular disease risk. In addition to nicotine replacement therapy, pharmacologic treatment with bupropion or varenicline plus behavioral therapy can be effective for smoking cessation.25,26 Initial case reports and post-marketing data suggested an association between treatment with varenicline and bupropion and neuropsychiatric symptoms, including suicidal and aggressive behaviors. However, subsequent randomized control trials, including a large multinational trial that included participants with psychiatric disorders with stable symptoms, showed treatment with varenicline and buproprion is likely to cause only minimal increased risk of neuropsychiatric symptoms.27

Pharmacological interventions to prevent weight gain are considered a next step for treatment when behavioral methods or switching antipsychotic medications is unsuccessful. Metformin has been the most widely studied adjunctive treatment of weight gain in people with serious mental illness. Although the trials for adjunctive metformin treatment are relatively short in duration (most are 12–14 weeks long with a dose range of 500–2,000 mg/day), there is evidence that metformin treatment results in weight loss, particularly early in the course of illness.28 Topiramate is another pharmacologic intervention for treatment of weight gain in patients with schizophrenia, although there are fewer studies and with shorter duration than compared to metformin. Available evidence suggests topiramate at a dose range of 50 to 200 mg/day can be effective for weight reduction.28 In general, randomized control trials demonstrate tolerability of metformin and topiramate in people with schizophrenia. The main side effects of metformin treatment include gastrointestinal symptoms such as nausea and diarrhea, and topiramate treatment is associated with parathesias and cognitive side effects.29 Finally, adjunct treatment with aripiprazole (5–15 mg/day) can also help reduce antipsychotic-induced weight gain.30

If hypertension or dyslipidemia persists despite a switch of antipsychotic medication or behavioral interventions, or the risk of switching medication outweighs the benefit, treatment with antihypertensive agents or statins can be initiated, often in collaboration with a patient's primary care physician (PCP). Treatment with omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) can reduce triglyceride levels and increase high-density lipoprotein levels; however, there is little evidence that omega-3 fatty acid treatment actually reduces cardiovascular disease risk.31 Medication for glycemic control, such as metformin, should also be considered in consultation with the PCP. Care of patients with schizophrenia has historically been fractured between medical and psychiatric teams; coordination between health care teams, including sharing of medical records, is crucial for decreasing risk of MetS in this vulnerable and often marginalized population. Collaborative care should focus on primary, secondary, and tertiary prevention strategies.32

Conclusion

People with schizophrenia have a significant reduction in life expectancy compared to the general population, in part due to increased rate of cardiovascular disease. People with schizophrenia have an elevated rate of MetS, imparting an increased risk for the development of cardiovascular disease and diabetes. Further, patients with schizophrenia often receive suboptimal preventive care and regular health maintenance. Clinicians must adhere to indicated screening and monitoring guidelines to decrease cardiometabolic risk, and they should discuss risks and benefits of treatment of specific antipsychotic medications. Lifestyle interventions and smoking cessation strategies should be implemented early in treatment. Referral for further treatment of illnesses such as hypertension and diabetes should be done in a timely manner, with integration of care teams. MetS poses a significant health risk, to which people with schizophrenia are particularly vulnerable. It is the responsibility of the psychiatric provider to be aware of cardiometabolic risk factors and take appropriate measures to prevent and treat.

References

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Criteria for Defining Metabolic Syndrome

Requirements for Diagnosis NCEP ATP III IDF AHA/NHLBI
Criteria 3 of 5 criteria Waist circumference plus 2 criteria 3 of 5 criteria
Waist circumference Male >101 cm Female >89 cm Male 94 cm Female 80 cm Male 102 cm Female 88 cm
Blood pressure (mm Hg) 130/85 130/85 or pharmacologic treatment 130/85 or pharmacologic treatment
HDL (mg/dL) Male <40 Female <50 or pharmacologic treatment Male <40 Female <50 or pharmacologic treatment Male <40 Female <50 or pharmacologic treatment
Triglycerides (mg/dL) 150 or pharmacologic treatment 150 or pharmacologic treatment 150 or pharmacologic treatment
Fasting glucose (mg/dL) 100 or pharmacologic treatment 100 100 or pharmacologic treatment

Weight Gain Caused by Antipsychotic Medication

Severe weight gain Moderate weight gain Minimal weight gain
Clozapine Lurasidone Ziprasidone
Olanzapine Brexpiprazole Aripiprazole
Chlorpromazine
Haloperidol
Iloperidone
Caripiprazole
Quetiapine
Asenapine
Paliperidone
Loxapine
Risperidone

Authors

Pragyan Sharma, MBBS, is an Assistant Professor of Psychiatry, The University of New Mexico School of Medicine. Hannah E. Brown, MD, is the Director, Wellness and Recovery after Psychosis Program, Department of Psychiatry, Boston Medical Center; and an Assistant Professor of Psychiatry, Boston University School of Medicine.

Address correspondence to Hannah E. Brown, MD, Boston Medical Center, Doctor's Office Building, Suite 1150, 720 Harrison Avenue, Boston, MA 02118; email: Hannah.brown2@bmc.org.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20200702-01

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