Article Text
Abstract
Mortality from cardiovascular disease is increased in people with mental health disorders in general and schizophrenia in particular. The causes are multifactorial, but it is known that antipsychotic medication can cause cardiac side-effects beyond the traditional coronary risk factors. Schizophrenia itself is a contributor to an increased risk of cardiovascular mortality via cardiac autonomic dysfunction and a higher prevalence of metabolic syndrome, both contributing to a reduced life expectancy. The pro-arrhythmic impact of traditional antipsychotics, especially via the hERG-potassium channel, has been known for several years. Newer antipsychotics have a reduced pro-arrhythmic profile but might contribute to higher cardiac death rates by worsening the metabolic profile. Clozapine-induced cardiomyopathy, which is dose independent, is a further concern and continuous monitoring of these patients is required. Prophylaxis with angiotensin-converting enzyme inhibitors is currently under review. Overall, management of cardiovascular risk within this population group must be multifaceted and nuanced to allow the most effective treatment of serious mental illness to be conducted within acceptable parameters of cardiovascular risk; some practical measures are presented for the clinical cardiologist.
- cardiac risk factors and prevention
- electrophysiology
- metabolic syndrome
- metabolic heart disease
- drug interactions
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- cardiac risk factors and prevention
- electrophysiology
- metabolic syndrome
- metabolic heart disease
- drug interactions
Mental health and cardiovascular disease represent the greatest medical challenges to well-being in the 'developed' world. Of the major psychiatric disorders noted in Section II of the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), the taxonomic and diagnostic tool published by the American Psychiatric Association,1 the focus of this paper is schizophrenia and its spectrum of psychotic illnesses. Other important disorders, particularly severe stress and anxiety, bipolar disorder and severe depression are to be addressed in subsequent papers.
Our approach comprises a review of:
Schizophrenia and the circulation.
The impact of metabolic syndrome in the overall cardiovascular risk in schizophrenia.
The role of autonomic dysfunction.
Biological and genetic links.
Effects of antipsychotic medication on the heart, including arrhythmias and pharmacogenetic considerations.
Clozapine and cardiomyopathy.
Prevention of cardiovascular complications
Schizophrenia and the circulation
Schizophrenia is characterised by disruptions in thought processes, perceptions, emotional responsiveness and social interactions. It is typically persistent and can be both severe and disabling. The prevalence of schizophrenia and related psychotic disorders internationally likely ranges between 0.33% and 0.75%. However, although this is relatively low, schizophrenia is associated with significant health, social and economic concerns and substantially increased risk of premature death.2
Although suicide and high-risk behaviours contribute to mortality, cardiovascular disease (CVD) is the leading cause of death. In a large-scale meta-analysis,3 schizophrenia was significantly associated with CVD, in longitudinal studies (HR=1.95, 95% CI: 1.41 to 2.70, 14 studies), as well as with coronary heart disease (CHD) (HR=1.59, 95% CI: 1.08 to 2.35, 5 studies), cerebrovascular disease (HR=1.57, 95% CI: 1.09 to 2.25, 5 studies) and CVD‐related death (HR=2.45, 95% CI: 1.64 to 3.65, 9 studies). The breakdown of causes of death has been investigated in depth by Lin et al.4 Further, while cardiovascular mortality rates are decreasing globally, they are increasing in people with schizophrenia, likely due to under-recognition of CVD and risk factors. Ample evidence indicates a reduction in life expectancy of about 15–20 years.5 A particular point of concern is that this mortality gap between the general population and schizophrenia patients has increased during the last few decades.6
Metabolic syndrome
A number of lines of evidence indicate possible shared underlying pathophysiological factors between schizophrenia and CVD. The fact that the prevalence of metabolic syndrome is increased in people with schizophrenia—who have a notoriously high risk profile for obesity, poor diet, sedentary lifestyle and smoking and other substance abuse, as well as type 2 diabetes—goes a considerable distance towards explaining the increase in risk for CVD.7 However, studies suggest that severe mental illnesses and the metabolic syndrome might share a number of pathophysiological features, including hypothalamic–pituitary–adrenal and mitochondrial dysfunction, neuro-inflammation, common genetic links and epigenetic interactions.8
Autonomic dysfunction
In addition to putative genetic and metabolic associations, a further link lies in the relationship between cardiac autonomic dysfunction (CADF) and the development of CVD. CADF has been reported in acute and chronic schizophrenia patients irrespective of the received treatment.9
For a long time, psychiatrists attributed increased heart rates in patients with schizophrenia to antipsychotic treatment or as a simple reaction to the symptoms of the disease. However, this can only be partially correct, since profound abnormalities have been described in unmedicated or drug-naïve patients . 10
In a recent study, 32 patients suffering from paranoid schizophrenia and 32 control subjects matched for age, sex, body mass index and lean body mass were investigated to assess whether chronotropic incompetence (CI)—a manifestation of CADF, as well as an established marker of cardiovascular risk—was associated with schizophrenia. Patients taking clozapine or medication influencing heart rate or blood pressure regulation (eg, beta-blockers) were not included. The study reported reduced physical fitness in patients with schizophrenia at submaximal and maximal levels in accordance with previous studies. Second, CI occurs in a substantial number of patients (~45%), and third, a strong correlation exists between reduced physical fitness and decreased heart rate responses in schizophrenia. Low heart rate variability (HRV) with additional heart rate and respiratory regulatory data in schizophrenic patients suggest that their abnormalities of CADF are not simply a reflection of short-lasting stress-induced arousal.
The mechanisms by which the vagal activity is suppressed in schizophrenia are obscure, but disturbances in cortico-subcortical circuits modulating autonomic nervous activity have been suggested. The effects of medication make the situation less clear, although some workers have clearly found a decrease in the high-frequency spectral component of HRV, independent of medication.8 The altered sympatho-vagal balance may also reflect underlying neurophysiological differences; a number of studies have suggested that the right hemisphere predominantly modulates sympathetic activity, whereas the left hemisphere predominantly modulates parasympathetic activity.11
Biological and genetic links
Possible biological and genetic links between CVD and schizophrenia have been suggested on the basis of genome-wide association studies and data based on genetic pleiotropy. The group confirmed 9 single nucleotide polymorphisms linked to schizophrenia in prior studies, but also identified 16 new loci—some of which are also associated with CVD. Among these were shared risk factors—triglyceride and lipoprotein levels, waist–hip ratio, systolic blood pressure and body mass index. The findings suggest that shared biological and genetic mechanisms might help explain why schizophrenia patients have a greater risk of CVD12 (figure 1) although this position is controversial.13
Antipsychotic medications and the heart
Antipsychotic medication, whether typical antipsychotics (eg, chlorpromazine, haloperidol, droperidol, thioridazine or pimozide) or the newer, so-called 'atypical' agents (such as clozapine, olanzapine, risperidone, aripiprazole, ziprasidone and quetiapine), have transformed the lives of countless patients. The predominant antipsychotic mechanism is considered to involve antagonism of central dopamine D2 receptors.14
From the introduction of these drugs, ECG abnormalities (ie, widening of QRS complexes, prolongation of the QTc interval, depression of ST segments and abnormal T morphology or large U waves) were a relatively common finding, with a prevalence of up to 25%.15 Reilly et al 16 found a point prevalence of 8% for QT prolongation (QTc >456 ms), the prevalence rising with the dose of drug, increasing age and concomitant use of tricyclic antidepressants. In contrast, antipsychotic treatment was not associated with abnormal QT dispersion or other T-wave abnormalities.
Concerns emerged over safety with respect to cardiovascular events. The Royal College of Psychiatrists17 reported in 1997 on the association between antipsychotic drugs and sudden death.
Similar problems, both with respect to QT prolongation and sudden cardiac death (SCD), arose with some of the newerantipsychotic drugs such as sertindole, ziprasidone and pimozide, none of which are now in use.18 Sulpiride has been implicated in SCD, as has risperidone and clozapine. Although quetiapine and olanzapine have occasionally produced a measure of QT prolongation, to date, they have never been associated with SCD (table 1 19–28).
A review by Kahl et al 29 highlighted the importance of antipsychotic polypharmacy, especially in the elderly who are treated with antipsychotics for multiple additional causes such as delirium, agitation or affective disorders. The combined drug potency with an additional second antipsychotic increases the risk of arrhythmias via QTc prolongation, because QTc prolongation is dose-dependent.30
Mechanisms of arrhythmia
From early comparisons of thioridazine and quinidine, it was clear that antipsychotic drugs had analogous effects on cardiac conduction to class 1a anti-arrhythmic drugs, including sodium channel blockade, decreasing the rate of rise of phase 0 of the action potential and decrease in slope of phase 4 spontaneous depolarisation. Elegant molecular studies established that a likely structural basis for drug-induced QT prolongation is that of inhibition of the IKr subtype of the delayed rectifier potassium channel (human ether-a-go-go-related gene (hERG)-encoded K+ channel).31 Overall, both depolarisation and repolarisation are prolonged and appear as prolongation of QRS duration and of the QT interval.
Satoh et al 32 have reported a study of beagles subjected to high-dose haloperidol. Ventricular repolarisation phase (VRP) and effective refractory period (ERP) were both prolonged, but the former more than the latter, indicating an increase in electrical vulnerability. The haemodynamic effects of haloperidol were a reduction in heart rate and blood pressure. Of interest, the addition of high-dose intravenous MgSO4 led to a decreased heart rate and BP and increased left ventricular (LV) preload; the atrioventricular (AV) and intraventricular conduction were delayed and the ERP and VRP were both prolonged. Unlike the situation with haloperidol alone, the prolongation of ERP and VRP was equivalent so there was no effect on duration of the vulnerable period.
Pharmacogenetic considerations
Adrenergic activation can be extreme in acute psychotic states. In a particular context, that is, with antipsychotic medication and/or an unfavourable genetic profile, the combination can be lethal. Abnormalities of single cardiac ion channel coding genes that underlie several cardiac disorders, such as the hereditary long-QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia and idiopathic atrial fibrillation, will convey a particular risk in patients who require antipsychotic medication 12 ,33
Salvo and colleagues conducted a meta-analysis of observational studies in 2015 to assess the mortality rate of nine individual antipsychotics. Higher potency of hERG blockade resulted in a higher mortality risk, likely attributable to its QT-prolonging properties. The incidence rate per 1000 person-years was 1.0 for quetiapine, 1.5 for olanzapine, 2.8 for haloperidol, 2.9 for risperidone, 3.8 for clozapine and 5.1 for thioridazine. They concluded that a heterogenic risk exists for different antipsychotics and these could be attributable to the potency of hERG blockade of the drug 34
Newer antipsychotic agents and coronary risk
A further important observation has been that of the antipsychotic agents changing the metabolic profile through weight gain, dyslipidaemia and development of diabetes(table 2) .35 36
A very interesting approach has been chosen for the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study. This randomised controlled trial (RCT) followed 1125 patients who were treated with antipsychotics for 18 months and extrapolated the attributable 10-year cardiovascular risk (CHD) from the collected data. Patients with schizophrenia are known to have a higher cardiac risk profile with a higher rate of smoking, high BMI and dyslipidaemia. But there was an additional coronary risk burden caused by olanzapine, quetiapine, risperidone or perphenazine beyond the traditional risk factors using the Framingham heart study formula. In contrast, the overall 10-year CHD risk decreased with perphenazine, risperidone and ziprasidone. Whereas the continuous treatment did not affect smoking rates, diabetes profiles or hypertension treatment, it did show a cholesterol lowering effect although one that did not translate into a risk reduction.37
Rummel-Kluge's and colleagues35 designed a meta-analysis of 48 RCTs in 2010 investigating the metabolic side effects of newer antipsychotics. Olanzapine and clozapine exhibited similar increases in BMI, cholesterol and glucose intolerance, but both showed higher rates than amisulpride (by 2 kg), aripiprazole(4 kg) and risperidone (3 kg). Olanzapine and risperidone showed the highest rates of cholesterol rise, followed by quetiapine, in comparison to aripiprazole and risperidone. The highest glucose level increase was seen by olanzapine and clozapine, but the authors could not establish if all samples were fasting glucose samples, which rather negated the outcome. Overall, olanzapine and clozapine contribute negatively to a long-term cardiovascular risk profile.
It has been shown that newer antipsychotics have a lower risk of pro-arrhythmic events and a reduced incidence of SCD. But they show inter-drug variability, which might be attributable to interpersonal hERG differences and therefore individual increased mortality risk from QTc-related arrhythmias. In addition, they carry an increased cardiovascular risk profile. A closer follow-up of these patients is required with more emphasis on primary prevention and cardiac rehabilitation. Patients who have had a recent CV event are more susceptible to arrhythmias and show an increased mortality if treated with antipsychotics during this vulnerable time frame when they are at higher risk of idioventricular tachycardias.
Clozapine-induced myocarditis and cardiomyopathy
Clozapine is more effective than standard drugs in some patients with refractory schizophrenia, certainly with respect to ‘positive’ symptoms, but also probably for ‘negative’ symptoms as well. The improved efficacy is also associated with a far lower incidence of extrapyramidal and related adverse effects.38 However, clozapine-induced cardiomyopathy is a concern, with an incidence ranging from 0.02% to 0.1% in Australia.39 This figure is based on reports to regulatory agencies and is thus almost certainly an under-reporting of actual cases. An analysis of the French Pharmaco-Vigilance Database reported an OR of 11.5 for developing cardiomyopathy with clozapine, and an Italian study suggested that a >5% decrease in LV ejection fraction occurred at 1 year in one-third of patients started on clozapine.40
Dose and duration of treatment
Clozapine-induced cardiomyopathy does not appear to be dose-dependent. The time to onset of clozapine-induced cardiomyopathy can vary between 3 weeks and 4 years, but most cases of cardiomyopathy appear within 6–9 months of initiation,41 while symptoms of myocarditis tend to occur within the first 2 months.
Mechanisms of clozapine cardiotoxicity
Clozapine causes tachycardia at rest, perhaps due to decreased parasympathetic tone and increased adrenergic drive. Persistent inappropriate tachycardia causes impairment of LV function both in animal models and in humans. Furthermore, clozapine induces a rise in plasma catecholamines that correlates with the degree of myocardial inflammation.42 Other potential mechanisms include cytochrome P450 1A2/1A3 enzyme deficiencies, blockade of calcium-dependent ion channels, increased production of inflammatory cytokines and low serum selenium levels43 (figure 2).
Identification and screening
Tachycardia occurs in around 25% of clozapine users, especially during dose titration early in treatment. When heart failure develops, 60% of patients present with breathlessness, 36% with palpitations and 4% with fatigue.44
Cardiac biomarkers, including creatine kinase, troponin and B-type natriuretic peptide (BNP), are routinely measured in patients with clozapine-induced cardiac dysfunction, although validation studies for BNP testing are awaited. Echocardiography is essential for pre-screening, initial diagnosis and serial assessment, often done 6-monthly.
Prevention: CVD in general
The Raise-ETP study has considered the prevalence of CV risk factors in patients treated for schizophrenia prior to and after treatment to establish the influence of antipsychotics on CV risk factors. Although smoking rates, pre-diabetes, pre-hypertension were higher in comparison to the general US population, other CV risk factors such as obesity and dyslipidaemia were comparable. BMI and waist circumference, as well as smoking, correlated with the duration of psychiatric disease, while dyslipidaemia was related to treatment with antipsychotics and increased after treatment. However, even brief antipsychotic exposure was associated with a significant effect of antipsychotic treatment duration in disturbing lipid metabolism and lipid-based proxy measures of early insulin resistance, but not on body composition or carbohydrate metabolism indices.45
In this context, the European Psychiatric Association has produced an extremely helpful guideline emphasising the role of physical exercise in addition to conventional risk factor management.46
Prevention: clozapine cardiomyopathy
Careful observation, monitoring for early adverse effects and early diagnosis are the mainstays of management in clozapine cardiotoxicity. Several protocols for monitoring and treatment have been suggested, including an Australian 4-week protocol47 that relies predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness but defines a threshold for cessation. There has been one study in animals, which suggested that captopril protected against clozapine-induced myocarditis,48 with a decrease in the histological hallmarks and biochemical markers of myocarditis in a dose-dependent manner. Larger, human studies are awaited to establish whether angiotensin-converting enzyme inhibitors should be given as prophylaxis in patients who need clozapine.
Treatment of established cases
Early cessation of clozapine improves clinical outcomes. LV dysfunction caused by clozapine treatment is broadly reversible, provided clozapine therapy is discontinued.49 Some patients present with fulminant myocarditis and may need management in intensive care.
Conclusion
In the context of a burgeoning mental health burden, we have presented a review of the effects of schizophrenia on the circulation, possible commonalities in the risk factor profile between these two major illness groups and some guidance on the safety of antipsychotic medication use. The overriding objective remains to reduce the burden of both diseases, and where both co-exist, to optimise the treatment, but ideally not at the expense of either (table 3).50
References
Footnotes
Contributors All the four authors contributed to this manuscript in terms of researching the material, drafting sections and creating the figures and table. The senior author (SDR) additionally brought together the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.