54 - 65: Cardiovascular Disease and Severe Mental Illness

Cardiovascular disease is the leading cause of mortality worldwide, accounting for approximately 30% of all deaths. Similarly, mental illness is also common, affecting 1 in 10 people at any one time. A degree of comorbidity is therefore to be expected but it is clear that mental illness occurs more commonly among people with cardiovascular disease than expected and vice versa [1].

The relationship between cardiovascular disease and mental illness is complex and bi-directional, with mental illness being both a cause and consequence of cardiovascular disease. For example, cross-sectional studies have shown that the prevalence of depression is increased in people with cardiovascular disease with up to 40% of people having either major or minor depression following a myocardial infarction [2]. Furthermore, longitudinal studies indicate that depression increases the risk of myocardial infarction, coronary heart disease, cerebrovascular disease and other cardiovascular diseases by up to 2-fold in both men and women, independent of other risk factors [3,4], and increases mortality following a myocardial infarction [5,6]. Similarly, anxiety is an independent risk factor for incident coronary heart disease and cardiac mortality [7].

This chapter, however, will review the association between severe mental illness (schizophrenia and bipolar disorder) and cardiovascular disease as an example of this complex relationship. It will explore the reasons for the comorbidity and the steps needed to reduce cardiovascular disease in people with severe mental illness. Severe mental illness is associated with a 3-fold increased risk of premature death and shortened life expectancy by approximately 10-20 years [8]. Although suicide accounts for the highest relative risk of mortality, being up to 20-fold more common than the general population, a range of physical illnesses occurs more frequently in people with severe mental illness and which are the cause of approximately three quarters of all deaths, with cardiovascular disease being the most common cause of death [8].

Cardiovascular morbidity and mortality are increased approximately 2- to 3-fold in people with severe mental illness [8]. The relative risk is more markedly increased in younger individuals with severe mental illness, in whom the prevalence of cardiovascular disease is 3.6-fold higher compared with a 2.1-fold increase in people who are older than 50 years [9]. While the morbidity and mortality associated with cardiovascular disease have fallen in the general population over the last 20 years, these benefits have not been shared by people with severe mental illness, which has led to a widening health inequality gap.

There are numerous reasons for the increased rate of cardiovascular disease in people with severe mental illness, including an increased prevalence of modifiable cardiovascular risk factors, such as obesity, smoking, diabetes and dyslipidaemia (table 1), as well as intrinsic biological changes that occur during psychosis [10]. Not only do modifiable cardiovascular risk factors occur more commonly, but they appear at a younger age; in the US Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a quarter of men with schizophrenia, aged 20-29 years, at baseline had metabolic syndrome, a proxy for cardiovascular risk, compared with fewer than 10% in the general US population [11]. The implication of this finding is that healthcare professionals need to pay attention to cardiovascular risk factor management in people with severe mental illness from diagnosis.

The global prevalence of obesity has increased dramatically over the last three decades, driven by changes in diet and physical activity. These demographic changes appear to have affected people with severe mental illness to a greater extent than the general population as studies that pre-date the 1980s did not consistently report higher rates of obesity in those with severe mental illness [12]. By contrast, more recent studies have shown that obesity is approximately 2-fold more common in people with schizophrenia or bipolar disorder. The mean baseline BMI in the CATIE study was 29.7 kg/m², with 37% of men and 73% of women having central obesity as defined by a waist circumference in excess of 102 and 88 cm, respectively.

Obesity occurs early in the natural history of schizophrenia with a significant proportion of people with first-episode psychosis being overweight prior to any treatment. Weight gain frequently occurs rapidly following treatment initiation. Seventeen per cent of people with schizophrenia in the European First Episode Schizophrenia Trial were overweight at baseline prior to treatment and 37-86% had gained more than 7% of their initial body weight during the first year of treatment, depending on medication choice [13].

Body composition is also altered in people with severe mental illness; higher waist-to-hip ratios and increased visceral fat have been found even in people with first episode psychosis; other studies have not replicated these findings, but note marked weight gain and increasing girth during treatment with antipsychotic medication [12].

The cause of obesity in people with schizophrenia includes genetic and lifestyle factors as well as illness and treatment effects. Individuals with schizophrenia are more likely to consume a diet that is rich in fat and refined carbohydrates while containing less fibre, fruit and vegetables than the general population [14]. The lower levels of physical activity and social and urban deprivation experienced by those with schizophrenia may contribute further to the increased obesity rates.

It is estimated that between 10 and 15% of people with severe mental illness have diabetes [10]. The onset occurs on average 10 years earlier, with women appearing to have a greater risk of diabetes than men [15]. Type 1 diabetes is not increased and so the 2- to 3-fold excess is explained by an increase in type 2 diabetes. The prevalence of undiagnosed diabetes is also considerably higher in people with schizophrenia than the general population with as many as 70% of cases being undiagnosed. This may reflect a reluctance of people with severe mental illness to volunteer symptoms and the overlap between some symptoms of diabetes and mental illness, leading to less screening in people with severe mental illness.

Like obesity, the rates of diabetes may be increased because of lifestyle factors, but there is also evidence of a genetic link between the two conditions. There is a high prevalence of metabolic abnormalities in the first degree relatives of people with severe mental illness, and between 17 and 50% of people with schizophrenia have a family history of type 2 diabetes [15]. Although these findings may result from shared familial environment, genome-wide association studies have suggested a shared genetic linkage between severe mental illness and diabetes [16].

A meta-analysis including 11 papers on dyslipidaemia showed that the major lipid abnormalities seen in people with severe mental illness are lower levels of HDL cholesterol and hypertriglyceridaemia, although not all studies have shown this [17]. By contrast, total cholesterol was not higher in people with severe mental illness. Overall, dyslipidaemia is reported in 25-69% of people with severe mental illness. The same meta-analysis included 12 papers on hypertension and found a non-significant 11% increase in the prevalence of hypertension (1.11, 95% CI: 0.91-1.35) [17].

Smoking rates are high in people with severe mental illness (50-80%). In the USA, 68% of 689 schizophrenia patients who took part in the CATIE study were smokers compared to 35% of age-matched controls. In the UK general population, 20% of men and 19% of women are current smokers, but the odds of people with schizophrenia being current smokers are 5.3 times higher and the odds are greater for men than women at 7.2 and 3.3, respectively [18]. People with severe mental illness are also heavier smokers both in terms of total number of cigarettes smoked and amount of smoke inhaled.

Severe mental illnesses are associated with a number of biological changes that affect intermediate metabolism and consequently cardiovascular risk [15]. These include hypothalamic-pituitary-adrenal axis dysfunction, manifesting as subclinical hypercortisolism and blunted diurnal cortisol rhythm, altered immune function (e.g. altered cytokine expression) and altered platelet function.

There are concerns that antipsychotics may contribute to cardiovascular risk by inducing weight gain and worsening lipid profile and blood glucose. Weight gain is the most common side effect seen with second-generation antipsychotics, affecting between 15 and 72% of patients [12]. Most weight gain occurs early in treatment, but patients may continue to gain weight for at least 4 years after the initiation of treatment, albeit at a slower rate. There is a hierarchy of weight gain between second-generation antipsychotics, with clozapine and olanzapine being associated with the greatest weight gain, but no agent should be considered as weight neutral. There is an intermediate risk of weight gain with quetiapine and risperidone, while aripiprazole, amisulpride and ziprasidone have little effect on weight. Some first-generation antipsychotics, for example chlorpromazine, and other psychotropic medications, such as certain antidepressants, are also associated with a high risk of weight gain.

Predicting weight gain with treatment is difficult because there is marked inter-individual variation in treatment-induced weight change. Other factors associated with weight gain are younger age, lower initial BMI, family history of obesity, concomitant cannabis use and a tendency to overeat at the time of stress [12]. The best predictor of long-term weight gain is the change in the first 4-6 weeks of treatment, emphasising the need for regular weight measurement during the early phase of treatment.

The relationship between antipsychotics and diabetes is complex because of the long natural history of diabetes and the potential confounding effects of other diabetes risk factors in people with severe mental illness [19]. The earliest case report linking antipsychotics with diabetes was in 1956 when a man developed haemolytic anaemia and diabetes 2 weeks after stopping chlorpromazine [20]. Since then, cases of diabetes and diabetic ketoacidosis have been seen in people receiving various first- and second-generation antipsychotics [19]. Although these studies provide evidence of causality, particularly when the glucose was measured before treatment initiation and where the diabetes entered remission after treatment discontinuation, the small numbers make it difficult to determine whether these are isolated cases or whether they can be extrapolated to the wider body of people receiving antipsychotic medication.

A large number of pharmaco-epidemiological studies have indicated that people receiving antipsychotics have a higher prevalence of diabetes than the general population and that people receiving second-generation drugs have a slightly increased risk of diabetes compared with those receiving first-generation drugs. One meta-analysis found that the relative risk of diabetes in those prescribed a second-generation antipsychotic was 32% (15-51%) higher than those receiving a first-generation antipsychotic. There was, however, considerable variation between studies [21], and a further systematic review of cohort studies found no consistent difference in diabetes risk between second-generation antipsychotics either as a group when compared with first-generation antipsychotics or between individual drugs [22].

Over the last decade, randomised controlled trials reporting treatment-emergent diabetes have begun to appear in the literature. A systematic review of 22 of these trials found no consistent significant difference in treatment-emergent glucose abnormalities between antipsychotics, either when compared with other antipsychotics or with placebo [23]. However, caution is needed when interpreting this analysis as the primary aim of many of these studies was to assess antipsychotic efficacy rather than metabolic side effects, and as such are underpowered to address this issue. The reporting of metabolic data was inconsistent and duration of many studies was too short to assess diabetes risk. Furthermore, several studies have shown small increases in glucose concentration in people receiving second-generation antipsychotics during the studies, which may translate into meaningful differences in the rate of diabetes over the many years that people with severe mental illness take antipsychotics [24]. A more recent meta-analysis comparing the metabolic side effects of different second-generation antipsychotics found that olanzapine produced a greater increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone, but a similar increase as clozapine [24].

Overall it appears that there is a causative link between antipsychotics and diabetes, but the risk is probably low and the majority of people receiving antipsychotics will not develop diabetes as a result of their medication [19].

Antipsychotic treatment is also associated with increases in LDL cholesterol and triglycerides and decreased HDL cholesterol. In a meta-analysis of 48 studies comparing different second-generation antipsychotics, olanzapine produced a greater increase in total cholesterol than aripiprazole, risperidone and ziprasidone, but no differences with amisulpride, clozapine and quetiapine were seen [24]. These differences may reflect the propensity to weight gain, but there may be other direct mechanisms as hypertriglyceridaemia may occur following treatment despite only modest weight gain.

The effect of antipsychotics on blood pressure is variable; although weight gain may lead to increased blood pressure, this may be offset by adrenergic blockade by the antipsychotics [17].

Overall it appears that many antipsychotics have an adverse effect on cardiovascular risk factors. However, it is important to understand that these are surrogate markers and may not translate into increased cardiovascular events and mortality. Indeed, the opposite is suggested by several large epidemiological studies. A UK study of over 46,000 people found that while exposure to first-generation antipsychotics, particularly high doses, was associated with excess cardiovascular mortality, this increase was not seen in people receiving second-generation antipsychotics [9]. Similarly in a large Finnish study of 66,881 people with schizophrenia, total mortality was lowest in individuals receiving clozapine and olanzapine, with no difference in cardiovascular mortality between drugs [25]. A more recent Finnish study examining the impact of the first- and second-generation antipsychotics on mortality in people with first-onset schizophrenia found that the use of second-generation antipsychotics, especially clozapine, olanzapine and quetiapine, was associated with reduced risk of all-cause mortality in people with schizophrenia [26]. By contrast, first-generation antipsychotics, specifically levomepromazine, thioridazine and clorprothixene, were associated with increased risk of all-cause mortality and levomepromazine with an increased likelihood for cardiovascular death. As these studies are both observational, there may be other explanations or confounders underlying the results [25,26].

The increased prevalence of cardiovascular disease and its modifiable risk factors in people with severe mental illness provides a strong rationale to screen for cardiovascular risk factors. Screening should begin prior to the onset of treatment or as soon as is reasonably possible, 2-3 months later to assess the acute metabolic effects of the antipsychotics, and thereafter on an annual basis unless significant treatment changes are contemplated (table 2).

Cardiovascular risk assessment should include a detailed medical history to assess risk factors, physical examination to include weight and blood pressure, a blood test to assess lipids and glycaemia, and an electrocardiogram [10]. It is known that waist circumference is more closely associated with cardiovascular disease than BMI, but in some settings, such as within the UK primary care, there has been reluctance to undertake this measurement. The close correlation between weight and waist circumference for most of the population would suggest that while additional information may be obtained from a waist measurement, weight is a pragmatic and practical alternative.

A fasting blood sample is required to interpret a full lipid profile, but a non-fasting sample is acceptable where logistical difficulties prevent the patient from attending in a fasting state. The sensitivity and specificity for diabetes, particularly if the glucose measurement is combined with glycated haemoglobin, does not differ greatly and most 10-year cardiovascular risk engines use the total and HDL cholesterol, which are largely unaffected by eating. Although it may be easier to obtain a non-fasting sample, clinicians should not assume that patients with severe mental illness are unable to attend fasted as several studies have shown that this is feasible [27].

Despite clear guidance from both national and international bodies [10,28,29,30], it is clear that many people with severe mental illness are not being screened for cardiovascular risk factors. In an audit of 50 in-patients and 50 out-patients with severe mental illness in Hampshire, UK, documented evidence that blood pressure had been measured was found in only 32% of case notes, and glucose (16%), lipids (9%) and weight (2%) were assessed even less frequently [31]. This was despite a high prevalence of metabolic syndrome in these patients and a significant number at high risk of cardiovascular disease.

The effectiveness of national guidelines and campaigns has been questioned by a study of US psychiatrists which showed that US Food and Drug Administration guidelines and a joint position statement of the American Psychiatric Association, American Diabetes Association and North American Association for the Study of Obesity had no effect on screening rates for diabetes [32]. There is a lack of clarity among mental healthcare professionals about whose responsibility physical health screening is [33]. In some countries, such as the UK, the responsibility for screening is placed within primary care [28]. This may be appropriate because many people with mental illness have frequent contact with their primary care doctor and primary care doctors have all the skills and training to address this issue. However, some people with severe mental illness only see their mental health team and under this circumstance it is important the screening occurs in this setting. It is clear that good communication is needed between primary care and mental health teams to ensure that the patient does not fall between the two settings. Mental healthcare professionals have also expressed concern about their lack of understanding about what should be measured and when and how to interpret the results [33]. Lack of access to necessary equipment may be a further barrier.

It is well recognised that people with severe mental illness are less likely to take advantage of health screening [34] and health services. Since to a large extent care is not offered unless requested, people with severe mental illness may be disadvantaged. The Disability Rights Commission has highlighted that instead of receiving holistic care, many people with mental illness describe how their physical illnesses are overshadowed by the mental illness, with healthcare professionals concentrating on the latter to the detriment of the former [35].

Cardiovascular risk is usually assessed by the use of locally relevant risk engines. These have not been validated in people with severe mental illness who are typically younger, have higher blood pressure and are more likely to smoke than the populations used to derive cardiovascular disease risk scoring systems, such as Framingham and QRISK. As traditional risk factors only partially explain the excess cardiovascular disease seen in people with severe mental illness, it is possible that these traditional risk engines may underestimate cardiovascular risk in people with severe mental illness. However, pending further research, they provide a guide for the initiation of primary preventative measures.

While there are additional challenges in ensuring that the person with severe mental illness understands the aims and rationale for treatment, cardiovascular risk factor management is essentially along similar lines to the general population.

Healthcare professionals should provide smokers with information about the risks of smoking and encourage them to quit. Interventions for smoking cessation range from basic advice to pharmacotherapy coupled with either individual or group psychological support. Smokers with schizophrenia are less likely to quit than the general population, with one meta-analysis reporting the smoking cessation rate for people with schizophrenia to be 9% compared with 14-49% in the general population (OR 0.19, 95% CI: 0.14-0.24) [18]. This lower rate is partly attributable to an increased severity of nicotine dependence, fewer attempts to stop smoking, lower motivation to quit and less access to interventions [36,37]. However, the rates of smoking cessation in people with schizophrenia can be increased with appropriate support [38].

The three main pharmacotherapies are nicotine replacement therapy, the antidepressant bupropion and the nicotinic receptor partial agonist varenicline. Of these, bupropion is both safe and effective in increasing the rates of abstinence in people with schizophrenia. A meta-analysis showed that those taking bupropion with co-interventions (group therapy alone or in combination with nicotine replacement therapy) for up to 12 weeks were 3 times more likely to be abstinent 6 months after starting treatment, compared with those taking a placebo [39]. Bupropion, however, is contraindicated in people with bipolar disorder. Varenicline may also improve smoking cessation rates in people with schizophrenia, but there have been reports of suicidal ideation and behaviours from people on varenicline.

The pessimism surrounding treatment of obesity in people with severe mental illness has been challenged by a number of recent observational studies and randomised controlled trials of lifestyle and pharmacological interventions. A recently published meta-analysis of non-pharmacological interventions in people with schizophrenia has shown that these led to a mean reduction in weight of 3.12 kg over a period of 8-24 weeks [40]. In addition, there were commensurate reductions in waist circumference and improvements in other cardiovascular risk factors. The benefits of these programmes were seen irrespective of the duration of mental illness treatment, whether the intervention was delivered to an individual or in a group setting, whether the intervention was based on cognitive behavioural therapy or a nutritional intervention, or whether it was designed to promote weight loss or prevent weight gain. Out-patient interventions appeared more effective than in-patient settings. The meta-analysis acknowledges a number of limitations of the trials, including the small numbers of participants and the lack of long-term follow-up. Most studies do not extend beyond 12 weeks and hence their applicability to the long-term nature of schizophrenia remains uncertain. The few studies reporting long-term effects suggest that these may be persistent after the end of the programme for up to 1 year, but others suggest that long-term behaviour change is difficult to achieve [41].

There are several longer-term observational studies of the effects of weight management programmes. Menza et al. [42] showed that a 52-week multimodal weight control programme led to significant improvements in weight, BMI, glycated haemoglobin, blood pressure, levels of exercise and nutritional knowledge in 20 of the 31 participants who completed the programme. Another study of 33 people with schizophrenia in Taiwan demonstrated a mean 3.7 and 2.7 kg reduction in body weight after 6 months and 1 year, respectively, following a 10-week multimodal weight control program [43]. A long-term (8 years) observational study of a group intervention demonstrated that further weight loss is achievable with ongoing support [44]. In this study of well-motivated patients, there was a progressive statistically significant reduction in mean weight and BMI throughout the follow-up with no suggestion of a plateau. The mean weight loss was approximately 10% at 1 year (approx. 10 kg), with 61% achieving a 7% weight loss. By the end of the programme, 92% (n = 130) had lost some weight. The only predictor of weight loss was the number of sessions attended; gender, age, diagnosis and treatment were not related to weight loss. This suggests that an intervention of greater intensity or stronger focus may be needed in people with severe mental illness compared with the general population. Although previous studies have suggested that lifestyle interventions are hard to maintain in people with schizophrenia without support [41], there may be other factors that contributed to the achieved weight loss in this clinic. The model of care offered a multimodal programme that incorporated nutrition, exercise and some degree of behavioural interventions on the premise that weight management should not be viewed in isolation and is best combined with a holistic approach to lifestyle management. The clinic first utilised a group approach as a pragmatic low cost way forward, but the group setting and peer support was also appreciated by many participants. Lifestyle changes were not imposed on patients by healthcare professionals, but were chosen by the participants themselves. Furthermore, many of the initial health behaviours, such as high intake of sugary carbonated beverages, were readily amenable to change. The stepwise change made the process simple, achievable and sustainable.

Several pharmacological agents have been tried to reverse or prevent antipsychotic-induced weight gain [45]. No drug has been found to be particularly effective, but a recent systematic review showed that there was preliminary evidence that metformin may attenuate weight gain in both adult and adolescent patients taking second generation antipsychotics [46]. The review included 14 articles, 8 of which were double-blind, placebo-controlled studies. The studies lasted 8-16 weeks and used doses ranging from 500 to 2,550 mg daily. Most of these studies showed a modest reduction in weight with metformin (approx. 1 kg), while those treated with placebo gained weight. Where it was measured, insulin resistance appeared to improve in those treated with metformin. The review concluded that although there was no clear substantial evidence that metformin, as an adjuvant to second generation antipsychotic use, will decrease weight gain and improve metabolic effects, the results are encouraging and additional studies of longer duration were recommended.

Although target levels of total cholesterol and LDL cholesterol are the same as the general population (<5.0 and <3.0 mmol/l, respectively), tighter goals of <4.0 and <2.0 mmol/l may be appropriate for individuals with established cardiovascular disease or diabetes. No cardiovascular disease outcome trials with statins have been performed specifically in people with severe mental illness, but these drugs are as effective in lowering total and LDL cholesterol as the general population [47]. Furthermore, there is no evidence that lipid-lowering medication is associated with suicide or traumatic deaths in people with severe mental illness.

The treatment of diabetes in people with severe mental illness should follow currently available treatment algorithms, although oral antidiabetes agents that induce less weight gain may have advantages given the high prevalence of obesity in people with severe mental illness [48]. The additional challenges of managing comorbid diabetes and mental illness, however, require close collaboration between mental and diabetes services. As hyperglycaemia is associated with an increased risk of diabetes complications, neuropathy, retinopathy and nephropathy, glycaemic targets should be determined for each individual with diabetes. The precise target is dependent on a number of factors including disease duration, risk of hypoglycaemia, life expectancy and comorbidities including macrovascular disease as well as patient attitude and resources; however, glycated haemoglobin targets between 6.5 and 7.5% (48-58 mmol/mol) would be usual [48].

Prevention of diabetes is also an important consideration as lifestyle intervention programmes involving dietary modification, weight loss and increased physical activity have been shown to reduce the incidence of type 2 diabetes [49]. As these programmes share many features with lifestyle weight loss programmes used in people with severe mental illness, it is hoped that the programmes may also lead to diabetes prevention, although this has not been formally assessed. Metformin may also be considered [10].

The management of hypertension in severe mental illness should follow the same treatment algorithms as the general population, with recommended target blood pressure levels of <140/90 mm Hg. Patients should be advised to reduce smoking and salt intake. European and UK guidelines emphasise the need to choose antihypertensive agents best suited to the individual patient's needs as the achieved blood pressure is more important than the agent used to achieve this.

The increased rates of cardiovascular disease in people with severe mental illness provide a clinical imperative to screen and manage cardiovascular risk factors with a systematic approach. In the past, the physical health needs of people with severe mental illness have largely been ignored, creating significant heath inequalities. Contrary to expectation, individuals with severe mental illness are as motivated about their physical health as the rest of the population, but often lack awareness and fail to prioritise physical well-being [50]. Providing a supportive environment in which cardiovascular risk factors can be managed systematically is likely to have a significant impact on cardiovascular morbidity and mortality in people with severe mental illness.

Professor Holt has lectured on cardiovascular risk in people with severe mental illness for Sanofi-Aventis, Eli Lilly, Otsuka, Lundbeck and Bristol-Myers Squibb.