European Psychiatry 25 (2010) S6-S11
Physical health in schizophrenia: a challenge for antipsychotic therapy A. Heald Ward 7 Office, Leighton Hospital, Middlewich Road, Crewe, Cheshire CW1 4QJ, UK
Abstract In the management of schizophrenia, mental health outcomes are the principal focus of treatment. The objective is to control the psychotic symptoms while minimising negative features of the illness, to achieve an overall improvement in the societal functioning of patients. Physical health is also important because if it is compromised, many of the benefits of improved mental health will be offset. Compared with the general population, schizophrenia patients are at increased risk of weight gain, abdominal obesity, diabetes, metabolic syndrome, and cardiovascular disease. These physical health problems can contribute to the decreased quality of life, lowered self-esteem and reduced life expectancy commonly reported in schizophrenia. For these reasons there is a pressing need to improve both the monitoring and the management of physical health in patients with schizophrenia as a part of their overall care. A consensus for metabolic monitoring of patients receiving treatment with antipsychotic drugs is available. However, the practicing clinician requires guidance about management of physical health in routine clinical practice. This should include recommendations for measurements that have strong predictive value about physical health risks yet are easy to make, and about the use of medications that have the least effect on physical health parameters. This article will review the gravity of the physical health risks facing schizophrenia patients. Keywords: Schizophrenia; Physical health; Antipsychotic therapy; Health assessment; Diabetes; Cardiovascular risk.
1. Background The main aim of the treatment of schizophrenia is to control psychotic symptoms and enable patients to function as normally as possible. To achieve this, patients must be compliant with treatment because sub-optimal adherence to antipsychotic medication greatly increases the risk of relapse and rehospitalisation. Reported adherence rates vary greatly according the patient population and method of assessment. Adherence rates in terms of prescription filling are typically around 50-75%, and appear to be similar for psychiatric and non-psychiatric drugs [11,41]. Adherence in terms of treatment actually taken is presumably lower than these values suggest. A recent study reported an association between poor adherence and increased risks of suicide and death . In addition, the effects of the illness and its treatment on physical health must be managed to obtain an optimal outcome. Diabetes, obesity, cardiovascular abnormalities and metabolic syndrome are highly prevalent in schizophrenia patients and can impose a major physical health burden. Medications used to treat psychiatric symptoms should be Correspondence. Tel.: +44 (0)1270 612353. E-mail address: [email protected]
© 2010 Elsevier Masson SAS. All rights reserved.
selected with consideration of their impact on physical as well as mental health . This article will consider these and other physical health risks as high priority targets in the routine management of schizophrenia patients. 2. Diabetes and obesity as drivers of physical health impairment in schizophrenia In the general population, diabetes is associated with an increased risk for a number of serious complications, including cardiovascular, renal and nervous system conditions, blindness, dental disease and sexual dysfunction. Diabetes is also associated with significantly increased all-cause mortality  and mortality from coronary heart disease  that may occur within 2 years of onset . Diabetes is more common in schizophrenia patients than in the general population across all age groups. The excess prevalence of diabetes between schizophrenia patients and the general population increases from around 2% in the 15-25 age group to almost 20% in the 55-65 age group  (Fig. 1). The reasons for this difference may include an inherent increased risk of diabetes associated with the illness itself  and an
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Fig. 1. Prevalence of diabetes by age in people with schizophrenia compared with the general population .
increased prevalence of obesity in schizophrenia patients  (Fig. 2), often attributed to antipsychotic treatment [29,31]. One study reported impaired glucose tolerance in 30.9% of patients . Two important factors that contribute to the development of diabetes are insulin resistance and obesity. The link between obesity and diabetes is well established. A 10-year follow-up study in the general population has shown that people with a body mass index (BMI) of ≥35 are approximately 20 times more likely to develop diabetes than ageand gender-matched subjects with a BMI of <25. Risks for coronary heart and cerebrovascular diseases are also greater in obese subjects . Abdominal obesity, measured as the
waist-to-hip ratio, impairs glucose disposal  and more than doubles the relative risk of myocardial infarction . The higher prevalence of obesity and diabetes may explain why approximately 25% of all deaths in patients with schizophrenia result from cardiovascular or cerebrovascular disease . 3. Metabolic syndrome in schizophrenia patients The expression ‘metabolic syndrome’ is used to describe the observation that risk factors for cardiovascular disease tend to co-exist in the same individual to a greater extent
Fig. 2. Increased prevalence of obesity in patients with schizophrenia . Reproduced with permission from the Journal of Clinical Psychiatry (Copyright 1999). American Society for Clinical Psychopharmacology.
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than would be expected by chance alone. Several definitions of the metabolic syndrome have been proposed. Most are based on three of more of: abdominal obesity, hypertension, elevated triglycerides and hyperglycaemia (or, in some definitions, insulin resistance)1. Metabolic syndrome is strongly associated with increased mortality. In a study of 3606 general population subjects over a median follow-up of 6.9 years, the presence of the syndrome was associated with significantly higher all-cause mortality (18.0% versus 4.6%; p < 0.001) and cardiovascular mortality (12.0% versus 2.2%; p < 0.001) . An increased waist circumference is closely correlated with the presence of the metabolic syndrome in patients with schizophrenia . Measurement of waist circumference is simple, and should be routine practice. Furthermore lower waist circumference has been shown predict better self-reported quality of life in individuals with schizophrenia . Metabolic syndrome is present in approximately 1 in 6 patients with schizophrenia at the time of the first episode, rising to approximately 1 in 2 after >20 years (Fig. 3) . At the start of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, metabolic syndrome was present in 51.6% of female patients and 36.0% of male patients, compared with 25.1% and 19.7% respectively in an age- and sex-matched population (p < 0.001 for each gender) . The estimated 10-year CHD risk was also increased in both sexes . An important recent finding is that rates of metabolic syndrome at the first episode of schizophrenia today are no different from those of patients 15 to 20 years ago. Metabolic syndrome increased over time in both current and historical cohorts, but patients started on second generation antipsychotics had a three times higher incidence rate of metabolic syndrome than those patients treated in the past with first generation antipsychotics . A reduction in the prevalence of metabolic syndrome is an important target to improve the physical health of patients with schizophrenia.
Some authorities have questioned the relevance of the metabolic syndrome, arguing that it does not predict CV risk any more accurately than individual components [23,24,30,36]. However it can help to identify individuals with multiple CV risk factors who should receive intensive management including lifestyle interventions and pharmacological treatment if indicated [1,17]. 4. Cardiovascular risk factors and schizophrenia Risk factors for cardiovascular morbidity and mortality in the general population include those that are inherently non-modifiable (gender, age, family history) and those, as highlighted in the Framingham study , that are modifiable through behavioural changes and improved care (smoking, obesity, diabetes, hypertension and dyslipidaemia). The high prevalence of modifiable risk factors in schizophrenia patients  (Table 1) is consistent with their increased cardiovascular morbidity and mortality. The presence of multiple risk factors (e.g. as in the metabolic syndrome) is particularly ominous because it results in a much higher risk of CVD than would be expected by adding the individual risks together . Cardiovascular illness may partly explain why patients with schizophrenia die at least 10 years earlier than the general population . The risk of cardiovascular death is more than twice that in the general population in males (Standardised Mortality Ratio [SMR] 2.3) and females (SMR 2.1)  and they have not shared the decline in death rates from CVD seen in the general population in recent decades . A recent cohort study of primary care patients in the UK has confirmed the increased prevalence of CVD associated with severe mental illness . It is an accepted priority to identify and minimise cardiovascular risk factors in the general population. This is an even greater priority in schizophrenia patients. 5. Other physical health issues in schizophrenia patients
1 The International Diabetes Federation (IDF) defines metabolic syndrome as central obesity (waist circumference [WC] ≥94 cm in Europid males and ≥80 cm in Europid females, with different values for other ethnic groups) in the presence of any two of raised blood pressure (BP) (≥130/85 mmHg), elevated triglyceride (TG) levels (≥150 mg/dL or ≥1.7 mmol/L), HDL-cholesterol levels <40 mg/dL (<1.03 mmol/L) in males and <50 mg/dL (<1.29 mmol/L) in females, and/or a fasting plasma glucose level >100 mg/dL (≥5.6 mmol/L), taking into account ethnicity, current treatment with antihypertensive or blood lipid modifying medications, and the presence of treated type 2 diabetes, respectively. A more recent joint definition from the IDF and several other medical societies defines the syndrome as three or more of: elevated WC by country- or population-specific definitions; BP ≥130/85 mmHg; TG ≥150 mg/dL (≥1.7 mmol/L); HDL-cholesterol <40 mg/dL (<1.0 mmol/L) in males and <50 mg/dL (<1.3 mmol/L) in females; fasting plasma glucose >100 mg/dL (≥5.6 mmol/L) . Drug treatment of BP, HDL-cholesterol, TG or elevated glucose are acceptable alternative criteria.
Other physical health issues relevant in schizophrenia patients include prolactin elevation and its potential consequences. Elevated prolactin appears to be treatment-related rather than illness-related in schizophrenia as it is seen more with some antipsychotic medications than others [27,39]. The short-term effects of prolactin elevation may include menstrual irregularities, galactorrhoea in women, sexual dysfunction, and depression. Longer-term risks may include decreased bone mineral density to a greater extent than would be expected with normal ageing, and osteoporosis . However, not all patients with raised prolactin levels show these clinical signs, and some of them can be associated with other causes (e.g. sexual dysfunction as consequence of diabetes, or depression as part of the psychotic syndrome).
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Fig. 3. Prevalence of metabolic syndrome by age and duration of schizophrenia (IDF criteria) . (Findings were similar when the analysis was conducted using the Adult Treatment Panel III (ATP-III) criteria ).
Table 1 Prevalence of modifiable cardiovascular risk factors in schizophrenia. Risk factor Measured as Smoking Mean >20 cigarettes per day Obesity Body mass index >30 kg/m2 Diabetes Dyslipidaemia
Fasting serum glucose >126 mg/dL Use of hypoglycaemic medication/insulin Serum high-density lipioprotein cholesterol Men <40 mg/dL; women <50 mg/dL Fasting serum triglycerides >200 mg/dL Total cholesterol >240 mg/dL Use of medication for hyperlipidaemia Systolic blood pressure >140 mmHg Diastolic blood pressure >90 mmHg Use of antihypertensive medication
Moreover, prolactin levels are not routinely measured in all schizophrenia patients. The clinical significance of prolactin elevation therefore remains unclear. Nevertheless, sexual dysfunction (expressed as reduced libido, erectile dysfunction, and orgasm and ejaculation problems) is widespread among schizophrenia patients receiving antipsychotic medication . Discussion of sexual function with patients may detect a potential cause of long-term adverse health effects as well as of non-adherence to antipsychotic therapy . Further physical health issues associated with antipsychotic drugs include sedation, hypotension, extrapyramidal symptoms and anticholinergic effects. Each of these can also impact on patient satisfaction, treatment adherence, self-esteem and ultimately optimal treatment outcomes, and are therefore targets for attention when considering physical health outcomes during the routine management of schizophrenia patients.
Prevalence (%) 64.1 Men ≈18 Women ≈ 26 10.9
6. Implications for action The maintenance of physical health is an important factor in the successful global management of schizophrenia patients. The high prevalence of diabetes, obesity, metabolic syndrome, and sexual dysfunction in these patients can significantly affect their life expectancy, quality of life and medication adherence. The potential contribution of antipsychotic medications to these conditions cannot be ignored . The evidence highlights the need for regular metabolic screening in patients with schizophrenia throughout the chronic course of the illness. Even though a consensus for metabolic monitoring of patients receiving antipsychotic medication is available  there is still a long way to go to mimimise physical health disorders for all patients. A physical health monitoring and management plan that is easy to use in the clinic could help to achieve this goal. A protocol to
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identify which cardiovascular risk factor demands the most urgent attention in each patient might help to reduce the burden of cardiovascular disease without greatly increasing workload. Individual hospitals and units, including some in the UK, have recently introduced guidance for physical health checks prior to the introduction of antipsychotics and during treatment. Protocols for annual physical health checks, including cardiovascular risk factors, have also been developed. A notable feature of these new protocols is that physical health management is shared between specialist services and primary care. Attention to one risk factor at a time should be coupled with the selection of antipsychotic drugs with a good metabolic profile, and recommendations to patients and carers about appropriate lifestyle changes. Continued monitoring and treatment of physical health should be adopted as part of a long term management strategy to improve global outcomes in schizophrenia.
7. Conflicts of interest A. Heald: Consultant or speaker (sanofi-aventis, Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline and Takeda); Unrestricted research funding from sanofi-aventis and Bristol-Myers Squibb.
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