General medical illness complicates and shortens the lives of many people with schizophrenia. On average, adults with schizophrenia die 10 years younger than the general population.1 Although a substantial portion of this excess mortality is attributed to factors such as suicide and accidents, most is due to general medical conditions.2
Nearly 50% of people with schizophrenia have a comorbid general medical condition.3 One large survey of people receiving services for schizophrenia found that the most common self-reported lifetime medical problems were with “eyesight, teeth, high blood pressure, and bowels.”4 Studies have noted higher than expected death rates from cardiovascular, pulmonary, endocrine, gastrointestinal, and infectious disorders.5–9
Biological factors that put people at risk for schizophrenia also may put them at risk for some other health difficulties, such as substance use disorders.10 High rates of substance abuse, cigarette smoking, poor diet, and lack of exercise all contribute to general medical complications.11–13 In addition, lack of resources, social skill deficits, and discriminatory treatment from healthcare providers limit access to high-quality healthcare.14 Finally, although second-generation antipsychotics have tolerability advantages over first-generation antipsychotics, evidence is growing that some produce significant metabolic morbidity.15
Psychiatrists, and the systems of care in which they practice, can influence the health outcomes of the people they are serving. This article summarizes the literature on some of the common and important general medical difficulties that affect the lives of people with schizophrenia and outlines current suggestions for screening, treatment, and referral.
Obesity is defined using the body mass index (BMI), an estimate of body fat that is calculated from weight and height measurements. “Overweight” is a BMI above 27 kg/m2, and “obese” is a BMI above 30 kg/m2. Waist circumference, an indirect measurement of intraabdominal fat, is another clinically important obesity-related measurement. Normal waist circumference in men is less than 40 inches and in women is less than 35 inches. A high waist circumference helps identify metabolic syndrome, a prominent cardiovascular risk factor that includes insulin resistance, atherogenic lipid profiles, and hypertension.
Obesity represents an epidemic in the industrialized world and is a potentially life-threatening condition. It is a risk factor for the development of hypertension, type 2 diabetes, hyperlipidemia, heart disease, gallbladder disease, and certain forms of cancer.16 In the United States, 65% of the population is considered overweight and 30% obese.17
While the general population showed significant gain in BMI from 1987 to 1996, people treated for schizophrenia, and especially females, appear to have mean BMIs that are even higher than people without schizophrenia.18 Antipsychotic treatment clearly contributes to this. In 1999, Allison19 performed a meta-analysis to estimate and compare the effects of antipsychotics on weight. The study showed that, at 10 weeks, clozapine and olanzapine were associated with the most weight gain (more than 4 kg), followed by chlorpromazine, sertindole, and risperidone. Weight gain with ziprasidone was negligible (0.04 kg). No data were available on quetiapine, but the subsequent Canadian National Outcomes Measurement Study in Schizophrenia reported a weight gain of more than 7% of baseline in more then half of patients treated with quetiapine.20 Less is known about aripiprazole, but what is known suggests that it may have less effect on weight than most second-generation antipsychotics.15
Factors associated with weight gain include pretreatment BMI, length of treatment, and concomitant treatment with other classes of medications. In people treated with clozapine21 and olanzapine,22,23 higher weight gain was found in previously underweight individuals. Weight gain can start with the initiation of treatment and may not reach a plateau for a year.15 It may be increased by the addition of lithium or valproate.24 However, the addition of fluoxetine did not alter the weight gain observed with olanzapine.25
Several expert forums have made recommendations for monitoring weight. The 2002 Mount Sinai Conference recommended monitoring BMI and waist circumference at every visit for the first 6 months after medication initiation or change; a weight gain of one unit BMI identifies the need for intervention.26 A 2004 consensus panel sponsored by the American Diabetes Association and the American Psychiatric Association recommended monitoring BMI at baseline and at 4, 8, and 12 weeks after initiating or changing second-generation antipsychotic therapy, and quarterly thereafter. If weight gain occurs in excess of 5%, consideration should be given to changing the second generation antipsychotic by cross-titration. The panel also recommended baseline and annual measurement of waist circumference.15
Interventions for obesity include nutrition and physical activity counseling, which should be provided for all people who are overweight. Diet and exercise are the mainstays of obesity treatment in people both with and without schizophrenia. Lifestyle changes in people with schizophrenia are best promoted with structured programs that emphasize skill acquisition, social reinforcements, and incremental approaches to behavioral change.27
Pharmacotherapy may be considered in those with BMI greater than 27 kg/m2. Two drugs, sibutramine and orlistat, are approved by the Federal Drug Administration for the treatment of obesity. In the general population, these medications have shown significant but modest results. Sibutramine, a norepinephrine, serotonin, and dopamine reuptake inhibitor, carries the theoretical concern that it may exacerbate psychotic symptoms and is contraindicated in patients with hypertension and heart disease. Orlistat acts locally to inhibit the pancreatic lipase and blocks the absorption of fat; it can produce gastrointestinal side effects and fat-soluble vitamin deficiencies.
Other drugs that have been studied include topiramate and nizatidine. Topiramate was associated with a significant weight loss in healthy obese individuals,28 and case reports note weight loss in clozapine-related weight gain.29 Nizatidine, a histamine-2 blocker, is used in the treatment of gastroduodenal hyperacidity; 300 mg twice daily may have an early transient effect in limiting the weight gain, but this early effect appears to be diminished or eliminated by 16 weeks.30 No weight loss was observed with another histamine blocker, famotidine, when added to a regimen of daily olanzapine.31
Surgical treatment of obesity is recommended for a BMI of greater than 40 kg/m2. It also may be considered with BMI greater than 35 kg/m2 if there are other medical complications.
Based on weight under centrifugation, lipoproteins are divided into the following categories: chylomicrons, very-low density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). The total cholesterol value is obtained from adding serum concentrations of VLDL, LDL, and HDL. The recommended values are represented by a total cholesterol less than 200 mg/dL, HDL greater than 40 mg/dL, and LDL less than 100 to less than 160 mg/dL, depending on the presence of additional risk factors for coronary artery disease in any given individual.32
Hyperlipidemia is a risk factor for heart disease and stroke. HDLs are protective, while LDLs are associated with increased risk. The association of triglyceride level with heart disease is less prominent, although in recent years, treatment of high triglycerides in people with other risk factors for heart disease has been recommended.33 High levels of triglycerides also are associated with the occurrence of acute pancreatitis, which is a severe, acute disease that is potentially fatal. The risk for pancreatitis is moderate when triglycerides are 500 mg/dL and severe at 1,000 mg/dL.34
Although some antipsychotics affect the lipid profile, their dyslipidemic effects differ by class of drug. Among first-generation antipsychotics, the butyrophenones have minimal effects, but the phenotiazines produce moderate increases in triglycerides and LDL with a concomitant decrease in HDL.35 Data are limited for the second-generation antipsychotics, but it appears that substantial effects occur with clozapine, olanzapine, and quetiapine. The lipid abnormalities described are “hyperlipidemia” with clozapine,36 severe triglyceridemia in patients treated with clozapine, olanzapine, and quetiapine,37 increases in the total cholesterol and triglycerides with olanzapine,24 and an increase in fasting cholesterol level with clozapine and olanzapine.38
Risperidone appears to increase the triglyceride level less than olanzapine.24 Ziprasidone has a neutral or small effect; patients cross-tapered from olanzapine, risperidone, or first-generation antipsychotics to ziprasidone have shown a significant decrease in serum cholesterol and triglycerides levels.39 In a retrospective review of the FDA database, acute pancreatitis, sometimes fatal and mostly non–alcohol-related (therefore presumed to be related to increase in triglycerides), has been described in the first 6 months after starting a second-generation antipsychotic,40 most frequently with clozapine, followed by olanzapine and risperidone.
Factors associated with the magnitude of dyslipidemia induced by antipsychotics include younger age (20 to 34) for clozapine-induced hyperlipidemia36 and the addition of lithium or valproate.24 Although the second-generation antipsychotics associated with the most weight gain have been the ones associated with the most hyperlipidemia, in some studies, weight changes did not correlate with increases in fasting lipids.24
Hyperlipidemia in Patients With Schizophrenia
In light of these data, the Mount Sinai Conference emphasized that people with schizophrenia should be considered at high risk for heart disease, and subsequently, a lipid profile should be checked at least once every 2 years when LDL is normal and every 6 months when LDL is greater than 130 mg/dL.26 The recent American Diabetes Association consensus conference recommended that all patients with schizophrenia should have baseline screening for family and personal history of dyslipidemia, undergo a fasting lipid profile, and be referred for treatment if found to be hyperlipidemic. A fasting lipid profile also should be obtained 3 months after starting an antipsychotic, at 5 year intervals if normal, and more often if clinically indicated.15
The need for pharmacotherapy can be assessed, as in the general population, using laboratory and clinical data to calculate the 10-year risk for cardiovascular disease. This can be done following guideline recommendations of the Third Report of the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).32
Type 2 Diabetes
The diagnosis of type 2 diabetes is defined by any two consecutive abnormal values on the following tests: fasting blood glucose of greater than (or equal to) 126 mg/dL, an abnormal oral glucose tolerance test, or random glucose greater than (or equal to) 200mg/dL in the presence of symptoms. Fasting glucose measurements between 100 and 125 mg/dL define a condition called impaired fasting glucose that may progress to diabetes. Clinical manifestations of diabetes include polyuria, polydipsia, and unexplained weight loss.41
Type 1 diabetes is a disorder of insulin production, whereas type 2 diabetes is characterized by tissue resistance to the action of insulin. Risk factors associated with type 2 diabetes include obesity, age, and sedentary lifestyle. Drugs such as antipsychotics, some mood stabilizers, corticosteroids, and the contraceptive medroxyprogesterone acetate have been involved in the occurrence or worsening of type 2 diabetes.41
People with schizophrenia have high rates of diabetes. The risk appears to be, at least in part, related to antipsychotic treatment. Dixon et al.42 found that the life-time prevalence of diabetes in people with schizophrenia in the US was 14.9%, higher than the 7.8% rate in the general population, even before the widespread use of second-generation antipsychotics.
Awareness of and concern for the risk of diabetes has risen with the introduction of second-generation antipsychotics. The United Kingdom General Practice Research Database revealed an increase in the risk of diabetes among the users of antipsychotics, with a larger association observed with the users of second generation antipsychotics.43 Among the second-generation antipsychotics, clozapine and olanzapine appear to have a stronger association with type 2 diabetes than do risperidone and quetiapine.44,45 Ziprasidone does not show an association.15 Although medication-induced weight gain likely mediates some of the risk, type 2 diabetes has been reported in patients without weight gain.
In case reports, type 2 diabetes sometimes has been temporally linked to medication manipulations. Many have noted that hyperglycemia occurred in an early phase of treatment and resolved on discontinuation of the drug; in some cases, hyperglycemia reoccurred on rechallenge with the drug. Diabetic ketoacidosis, a life-threatening complication of diabetes, has been reported with olanzapine and clozapine, often resolving with drug discontinuation.46,47
Concern about type 2 diabetes has lead to baseline screening and ongoing monitoring recommendations for people prescribed second generation antipsychotics. Recommendations include checking fasting plasma glucose before and 3 months after the initiation of a second-generation antipsychotic, followed by annual checks.15 A glucose level greater than 300 mg/dL or less than 60 mg/dL as well as symptoms of hyperglycemia or hypoglycemia should lead to an immediate referral. Symptoms of diabetic ketoacidosis, such as rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, clouding of sensorium, or coma, constitute an acute emergency.
As with the other conditions produced by the atypical antipsychotics, assessment of the risk–benefit ratio includes assessment of the patient's risk of developing type 2 diabetes based on weight, family history of diabetes, sex, and ethnicity. Consideration should be given, in the presence of risk factors, to choosing one of the antipsychotics that has been less frequently associated with the development of type 2 diabetes, or changing to such an antipsychotic if the monitoring uncovers the development of metabolic side effects.
Cardiac Disease and Sudden Death
Cardiovascular disease (CVD) is the leading cause of death and disability in most Western industrialized countries, including the US. By age 85, 53% of deaths are CVD-related. Cardiac risk factors explain most CVD48 and are represented by hypertension, hypercholesterolemia, cigarette smoking, type 2 diabetes, obesity, and sedentary lifestyle.49 The main pathological process responsible for CVD is atherosclerosis, which is a lifelong process that results in thickened arterial vessel intima that ultimately restricts blood flow. Atherosclerosis manifests as myocardial infarction, stroke, congestive heart failure, and peripheral vascular disease. Atherosclerosis is the major etiologic factor of sudden death, which represents as many as 50% of all cardiac deaths. Other factors, such as proarrhythmic drugs, autonomic dysregulation, or electrolyte imbalances, can further increase the risk of sudden death.
Patients with schizophrenia have higher cardiovascular mortality than the general population.50,51 In a large retrospective cohort study of Medicaid enrollees, the risk of sudden cardiac death among users of moderate doses of first-generation antipsychotics was higher than nonusers.52,53 Necroptic evidence indicates that people with schizophrenia have no structural heart changes in the absence of known atherosclerotic heart disease,54 a finding consistent with the hypothesis that no specific genetic predisposition for cardiovascular disease is associated with schizophrenia. Rather, the high rate of cardiac disease in these patients appears to be caused by a high prevalence of the standard cardiac risk factors, the use of antipsychotic medications, and lack of access to general medical care.
As noted above, people with schizophrenia tend to have high rates of obesity, metabolic syndrome, type 2 diabetes, and hyperlipidemia. They also are less likely than the general population to eat healthy diets, exercise regularly, and avoid smoking.13 In addition, gaining access to good general healthcare is a particular challenge for people with schizophrenia. One study showed that patients with mental health illness enrolled in a Veteran Administration psychiatric clinic received less primary care.55 In regard to cardiovascular care, the Cooperative Cardiovascular Care project reported that patients with schizophrenia hospitalized for a myocardial infarction had an underuse of revascularization procedures.56
In addition to increasing the risk for atherosclerosis, some antipsychotics contribute to sudden death through autonomic dysregulation or QT prolongation. The autonomic dysregulation effect, such as the orthostatic hypotension, is more pronounced with lowpotency phenothiazines and clozapine.57 The QT interval prolongation is associated with “torsades de pointes,” a ventricular arrhythmia that can precipitate ventricular fibrillation and sudden death. Additional risk factors include older age, female gender, concomitant proarrhythmic drugs such as tricyclic antidepressants, and electrolyte abnormalities, particularly hypokalemia and hypomagnesemia. Several antipsychotic medications appear to carry this risk; thioridazine, mezoridazine, pimozide and droperidol all can increase the QT interval, leading to the recommendation of using thioridazine and mezoridazine as second-line agents. In addition, ziprasidone has been shown to increase the QT interval, although the amount of prolongation is generally modest and does not usually reach a QT interval of 500 milliseconds, the length associated with increased risk for arrhythmias.58
Management of cardiac risk in people with schizophrenia is based on addressing the risk factors. The American College of Cardiology consensus conference recommended the strategy of reducing the cardiovascular morbidity and mortality in the general population by reducing blood pressure, lowering cholesterol, promoting smoking cessation, treating diabetes, encouraging weight loss, and increasing physical activity.49 The same recommendations should be used when serving with people with schizophrenia. Mental healthcare providers can play an important role in promoting the benefits of healthy diet, exercise, and smoking cessation. Good partnerships with primary care doctors and cardiologists can help assure access to appropriate care over time.
The use of proarrhythmic drugs should prompt EKG follow-up of the QT interval, with values above 500 milliseconds or increases of more than 60 milliseconds during treatment requiring intervention.59 As for ziprasidone, in 2002, the Mount Sinai Conference on the Pharmacotherapy of Schizophrenia recommended baseline and annual EKG for patients treated with ziprasidone only if additional risk factors are present, such as a family history of syncope or sudden death or congenital long QT syndrome.26
Blood-Borne Viral Infectious Diseases
Hepatitis B, hepatitis C, and HIV are all potentially fatal illnesses and major public health concerns. Hepatitis C transmission is predominantly blood-borne, while hepatitis B and HIV are transmitted through sexual activity as well as blood (especially intravenous drug use), and often from a carrier mother to child. Certain risky behaviors (eg, abusing intravenous drugs, sharing needles, having unprotected sex) are associated with infection.60
Five percent of cases of acute hepatitis B, 80% of cases of hepatitis C infections, and virtually 100% of HIV infections become chronic. The morbidity associated with these infectious diseases is significant. Chronic hepatitis B and chronic hepatitis C can lead to cirrhosis and, rarely, to hepatocellular carcinoma.61 Cirrhosis and liver failure are irreversible conditions that require a liver transplant for cure. The risk for these complications increases with the presence of co-infection of hepatitis B and C and with alcohol abuse. HIV morbidity is well-known: decreased quality of life, decreased survival, and complications affecting multiple systems, including the central nervous system.
People with severe mental illness have increased prevalence of hepatitis B, hepatitis C, and HIV infection. In a multicenter study, Rosenberg62 tested adults with severe mental illness — 45% with schizophrenia, 20% with schizoaffective disorder, and 35% with severe affective disorders. The study identified a prevalence of hepatitis B exposure five times the rate of the general population in the US (23.4%), hepatitis C infection 11 times the rate of the general population (19.6%), and HIV eight times the rate of the general population (3.1%). Reviews have indicated that people with schizophrenia have higher rates than the general population for activities that put them at risk for contracting these infectious diseases.63,64
Management involves recognition of the risk and appropriate testing, counseling, and referral for treatment.65 Recognizing that people with mental illness are at increased risk should prompt inquiry about risk factors or behaviors and testing. Each infection has specific screening tests (Table, see page 79). Counseling goals vary according to the risk behaviors identified and infection status. People not already infected should be counseled to stop high-risk practices such as intravenous drug use. People infected with hepatitis C should also be told about the additional toxic impact of alcohol on the liver.65
Screening and Diagnosis of Blood-borne Viral Diseases
As with people with schizophrenia who have other medical conditions, people with infectious diseases need referral, advocacy, and support for medical evaluation and treatment. Brunette and colleagues66 have developed and tested service models for efficiently screening and serving people with severe mental illness. The process begins with service systems recognizing the high risk for these infectious diseases and redesigning their systems to identify and refer people needing counseling and treatment. Because it is difficult for individual psychiatrists to keep up with the evolving field, specialized accessible resources are very helpful.
Treatment for these viral diseases is aimed at stopping or suppressing the viral replication. Treatments available for hepatitis B are associated with poor responses. Recently, it was shown that response of a group treated with pegylated (PEG) interferon alfa was better compared to a group treated either with lamivudine or with the combination PEG interferon alfa and lamivudine.67 Patients with hepatitis C have been treated with a combination of interferon alfa and ribavirin and, more recently, with PEG interferon alfa and ribavirin combination. The combination of PEG interferon alfa and ribavirin has a 40% to 80% response rate, depending on the hepatitis C genotype.68 The treatment is of long duration and often includes significant side effects, increasing the challenge of adherence to treatment.
Treatment of HIV infection with two reverse-transcriptase inhibitors and one protease inhibitor results, in a majority of patients, in suppression of HIV replication. HIV treatment requires strict compliance to avert significant morbidity.
Interferon is particularly relevant to psychiatrists because its neuropsychiatric side effects have traditionally precluded “psychiatric” patients from receiving the treatment. The side effects of interferon treatment include depression, suicidal anxiety, mania, and cognitive impairment.69,70 Depression occurring during the treatment can contribute to poor treatment adherence. The predictors of depression include baseline pretreatment depressive symptoms and low social support.71,72 Therefore, depression screening and monitoring during interferon treatment are strongly recommended. Furthermore, pretreatment with an antidepressant such as paroxetine starting 2 weeks before the interferon therapy can reduce depression induced by interferon alfa.73
Mental health providers need to support patients with schizophrenia in receiving treatment with interferon. Interdisciplinary care can provide good results, as shown in one study in which patients with psychiatric disorders had good compliance and results when adequate monitoring and psychiatric treatment was available.74
Other Medical Conditions
The evidence for co-occurrence of other general medical conditions with schizophrenia is less strong. Gupta et al.75 reported increased incidence of irritable bowel syndrome in patients with schizophrenia and concluded that patients should be asked specifically about the presence of gastrointestinal symptoms, because they rarely complain. Takahashi et al.76 reported increased incidence of sleep-related respiratory disorders.
Data about an association of schizophrenia with cancer are controversial. Increased risk of cancer related to lifestyle risk factors (pharyngeal, lung),77 decreased gastrointestinal cancers,78 decreased prostate cancer linked to cumulative use of high dose phenotiazines,79 and overall decreased risk of cancer in patients with schizophrenia80 or their relatives77 have all been reported.
Promoting General Health in Mental Health Care Settings
Patients with schizophrenia are at increased risk for many serious medical conditions. Mental healthcare professionals can influence the health outcomes of the people they serve by building general health recommendations into routine mental health care. It takes focused effort over time, however, to address general health consistently while providing other services.
The literature on healthcare change suggests reading a journal article such as this one is unlikely to change clinical practice or improve consumer outcomes.81,82 The system of care must be redesigned so the appropriate health interventions are easy to offer and reinforced within the clinical work environment. Psychiatrists serving people with schizophrenia tend to be very busy. During a given clinical interaction, general health issues often compete with other compelling dimensions of life that also require attention. These other important issues can include addressing symptoms of psychosis and depression, assessing suicidality, diagnosing and treating co-occurring substance use disorders, identifying and decreasing the impact of trauma, reducing homelessness, facilitating educational and vocational aspirations, supporting families and other loved ones, and promoting hope and self-sufficience. With these competing foci for attention, health promotion must be built into the system of care so that it is reinforced by the flow of daily work.
Redesigning a system of care to address general health issues requires interventions that range in complexity. Relatively simple changes include assuring that psychiatrists have the tools they need in their offices, such as scales, tape measures, blood pressure cuffs, and lab slips. Redesigning paperwork to include flow sheets for weight and waist circumference can support and reinforce health monitoring. More complex potential interventions include hiring and training case managers to facilitate and even attend (when appropriate) visits to primary care doctors or infectious disease specialists. These case managers can facilitate communication and provide health advocacy.83
General health is supported even more when primary care resources are available and woven into services at mental health facilities. Ultimately, creating optimal care may require county or state mental health authority action and support. For example, the model for infectious disease care designed and tested by Brunette and colleagues84 involves a team of clinicians who rotate through numerous community mental health centers screening, testing, and referring this high-risk population. Pilot studies show that this method of providing service is more practical than building the resources into individual sites.
In the 2001 book entitled Crossing the Quality Chasm: A New Health System for the 21st Century, the Institute of Medicine asserts that “the ultimate test of the quality of a health care system is whether it helps the people it intends to help.”85 Given the serious nature of the general health risks in people with schizophrenia, meeting this test involves redesigning and improving our systems of care to include a careful focus on promoting general health. We would want no less from our care were we in need of treatment for schizophrenia.
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Screening and Diagnosis of Blood-borne Viral Diseases
|First screening test||Confirmatory test|
|Hepatitis B||Hepatitis B surface antigen (HBsAg)||HBV DNA. Additional testing to assess for replicative phase: HBeAg, HBeAb, HBcAg, HBcAb.|
|Hepatitis C||Hepatitis C antibody (ELISA)||HCV qualitative RNA. Additional testing to assess viral replication (HCV quantitative RNA) and HCV genotype.|
|HIV||HIV antibody (ELISA)||HIV antibodies (Western Blot). Additional testing: HIV RNA quantitative levels, CD4 count.|