1. Introduction
Patients with psychiatric disorders have a shorter life expectancy, with cardiovascular disease being the major contributor to these premature deaths [Reference Colton and Manderscheid1, Reference Viron and Stern2]. However, the epidemiological evidence informing the management of cardiovascular risk (CVR) in these patients is still too limited in order to inform effective clinical interventions. This contributes to a poor control of CVR factors and poor cardiovascular outcomes [Reference Osborn, Wright, Levy, King, Deo and Nazareth3]. Patients with psychiatric disorders often have an unhealthy lifestyle, which is associated with and increased CVR [Reference Stubbs, Williams, Gaughran and Craig4, Reference De Leon and Diaz5]. While the prevalence of some cardiovascular risk factors, such as hypertension and diabetes, have been studied recently in a number of systematic reviews for patients with specific diseases, i.e. depression or schizophrenia, the evidence is weaker for patients with other conditions such as anxiety or personality disorders [Reference Meng, Chen, Yang, Zheng and Hui6–Reference Vancampfort, Mitchell, De Hert, Sienaert, Probst and Buys10]. These reviews highlight limitations in the some of the available evidence, including non-prospective study design, small sample size, and inadequate data on demographic and lifestyle factors. An association between antidepressants or antipsychotics, and a higher prevalence of CVR factors such as diabetes has been identified [Reference Vancampfort, Stubbs, Mitchell, De Hert, Wampers and Ward7,Reference Correll, Detraux, De Lepeleire and De Hert11–Reference Galling, Roldán, Nielsen, Nielsen, Gerhard and Carbon14]. Social deprivation is strongly associated with psychiatric conditions and with higher CVR as well [Reference Addo, Ayerbe, Mohan, Crichton, Sheldenkar and Chen15–Reference Patel, Lund, Hatherill, Plagerson, Corrigall, Funk, Blas and Kurup17]. However, the extent to which antidepressants, antipsychotics, and social deprivation contribute to the development of CVR factors among patients with different psychiatric disorders is unclear [Reference Osborn, Wright, Levy, King, Deo and Nazareth3]. Many symptoms of psychiatric conditions, including cognitive impairment, together with other factors, such as the stigmatization of these patients, make difficult their access to health care [Reference Viron and Stern2]. This may result in later diagnoses and less effective management of CVR factors.
The first objective of this study is to estimate the risk of developing incident type 2 diabetes, hypertension, hyperlipidemia, active smoking, obesity, and physical inactivity, over a ten year period, for patients previously diagnosed with schizophrenia, bipolar disorder, depression, anxiety or personality disorders. The second objective is to investigate the potential explanatory role of antidepressants, antipsychotics and deprivation in the association between each psychiatric condition and each CVR factor. The third objective is to compare the age at the time of diagnosis of each CVR factor, in patients with and without psychiatric disorders.
2. Methods
The study conformed to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) study design recommendations [Reference Gallo, Egger, McCormack, Farmer, Ioannidis and Kirsch-Volders18].
2.1. Study population
Data from the 524,952 patients living in three inner boroughs of east London (UK), registered with the local primary care surgeries, were used. Anonymized demographic and clinical data recorded in primary care electronic health records were extracted using EMIS web software from 140 of the 144 surgeries in the boroughs (four surgeries used a different computer system and were not included) for all patients aged 30 years and over in March 2015. Patients from that age category were selected because most cardiovascular events occur in patients over 30 and clinical guidelines suggest periodic screening for CVR factors in patients from the age of 40 [Reference Perk, De Backer, Gohlke, Graham, Reiner and Verschuren19, 20].
2.2. Variable definition
Sociodemographic variables included age, gender, and self-reported ethnic group. The Townsend score for social deprivation was also recorded [Reference Jarman, Townsend and Carstairs21]. Ethnicity was grouped into four categories: white, south Asian, black African/Caribbean and other. Individuals of mixed ethnicity were grouped with the relevant ethnic minority group. Clinical data included routinely recorded diagnoses of schizophrenia, bipolar disorder, depression, anxiety, personality disorders, type 2 diabetes, hypertension, hyperlipidemia, obesity, and self-reported smoking status and physical inactivity. Given the large number of exposures and outcomes analysed, all clinical data were coded as binary variables. A systematic approach to accurately identify each psychiatric condition and CVR factor from patient records was used. Lists of terms (Read codes) used by primary care physicians were compiled for each psychiatric condition and CVR factor using the UK National Health Service Clinical Terminology Browser version 2 10-01-2013 (Appendix A). Data was also extracted on prescriptions of antidepressants and antipsychotic drugs according to their classification in the British National Formulary [22] (Appendix B). Obesity was defined by the record of body mass index > 30. The medical records included terms reporting whether patients were smokers or non-smokers. There were also terms reporting different frequency for physical activity, and patients were categorized accordingly: ≥ 3 sessions of exercise a week active, and < 3 inactive [Reference Eckel, Jakicic, Ard, de Jesus, Houston Miller and Hubbard23]. There were only terms reporting the presence, but not the absence, of other CVR factors such as diabetes, psychiatric conditions, or prescribed drugs, and patients without these terms in their records were considered not to have them.
2.3. Statistical analysis
The risk of being diagnosed with type 2 diabetes, hypertension, hyperlipidemia, being a current smoker, obese, or physically inactive, between March 2005 and March 2015, was compared for patients with and without a diagnosis of schizophrenia, bipolar disorder, depression, anxiety, or personality disorder, at the beginning of that period. Patients with diagnosis of a CVR factor before the March 2005 were not included in the analysis for that specific outcome. When a CVR factor (i.e. obesity) had been recorded more than once during the follow up, only the first record in clinical notes was included in the analysis.
Cox regression models adjusted for potential confounders (age, gender, and ethnicity) were first used to estimate the associations of each psychiatric condition with each CVR factor. In a second step potential explanatory factors for the associations (prescription of antidepressants and antipsychotics before the 19th March 2005, and Townsend deprivation score), were included in the models. The age at the time of having each CVR factor recorded in patients with and without schizophrenia or other psychiatric disorder was compared using linear regression models adjusted for gender and ethnicity. The whole sample was treated as a single cohort, as patients were all living in the same area of London, where there is free access to health care for everyone, health care is standardized, and all patients were treated as independent within the cohort.
2.4. Ethical approval
All data were anonymised and managed according to the UK National Health Service information governance requirements. Ethical approval was not required for the use of routinely collected anonymised data in this observational study.
3. Results
A total of 524,952 patients, with mean age 45.9 (SD: 13.9), were included in the study. The sociodemographic description of the cohort, the medications prescribed, and the CVR risk factors diagnosed in patients with each psychiatric condition, are presented in Tables 1 and 2.
Table 1 Characteristics of participants in the study.
Table 2 Cardiovascular risk factors identified during study period among participants with different psychiatric disorders at study entry.
3.1. Association between psychiatric disorders and cardiovascular risk factors
The risk for CVR factors in patients with each psychiatric disorder is presented in Table 3.
Table 3 Risk of developing CV Risk factors in patients with psychiatric conditions.
Patients with all psychiatric disorders had an increased risk of having an incident diagnosis of type 2 diabetes, with Hazard Ratios (HRs) ranging from 1.31 (1.25–1.37) for those with anxiety disorders to 2.42 (2.20–2.67) P < 0.001 for those with schizophrenia. The risk of hyperlipidaemia was also increased for all patients with psychiatric disorders, with HRs ranging from 1.25 (1.23–1.28), for those with anxiety disorders, to 1.78 (1.60–1.97) P < 0.001 for those with bipolar disorder. Obesity was also associated with all psychiatric conditions, with HR ranging from 1.09 (1.06–1.12), for those with anxiety disorders, to 1.90 (1.67–2.15) P < 0.001 for those with bipolar disorders. Patients with schizophrenia, depression and anxiety had an increased risk of hypertension.
3.2. Role of antidepressants, antipsychotics and social deprivation
The associations between psychiatric disorders and CVR factors remained significant after adjustment for antidepressants, antipsychotics and deprivation score (Table 3). Patients with schizophrenia, bipolar disorder, and depression had a higher risk of smoking only in the models adjusted for age, gender, ethnicity, antidepressants, antipsychotics and deprivation. Those with depression, bipolar, and personality disorders had an increased risk of physical inactivity only after adjustment for age, gender ethnicity, antidepressants, antipsychotics and deprivation (Table 3).
An independent association was observed between the prescription of antidepressants and an increased risk of type 2 diabetes, with HRs ranging from 1.28 (1.23–1.33) to 1.35 (1.04–1.15), hypertension, with HRs ranging from 1.09 (1.05–1.12) to 1.11 (1.07–1.14), and hyperlipidemia, with HRs ranging from 1.05 (1.03–1.07) to 1.12 (1.10–1.14). However, the risk of smoking, obesity and physical inactivity was significantly lower among those who had been prescribed antidepressants. Patients who had been prescribed antipsychotics had an increased risk of type 2 diabetes but lower risk of hypertension, hyperlipidemia, smoking, obesity and physical inactivity (Table 4).
Table 4 Risk of developing cardiovascular risk factors in patients taking antidepressants and antipsychotics.
Models adjusted for each psychiatric disease, age gender ethnicity, Townsend, antipsychotics and antidepressants.
3.3. Age at detection of CVR factors for those with and without psychiatric disorders
Smoking was diagnosed at a later age for all patients with psychiatric disorders, with age at detection 36.7 (36.7–36.8) for those without schizophrenia and 45.0 (44.2–45.8) P < 0.001 for those with schizophrenia (Table 5). Similarly, physical inactivity was diagnosed at a later age among all patients with psychiatric disorders, with age at detection 44.0 (43.9–44.1) for those without schizophrenia and 45.4 (44.6–46.2) for those with schizophrenia P < 0.001, age 49.6 (48.8–50.4) P < 0.001 for those with personality disorder and age 42.1 (42.1–42.2) for those with no personality disorder. Obesity was also diagnosed later in patients with schizophrenia and other psychiatric conditions except in bipolar disorder. Finally, hyperlipidemia was diagnosed at a later age for patients with depression, anxiety and personality disorders (Table 5).
Table 5 Age at the time of recording of each CV Risk factor in patients with and without psychiatric disorder. P-values for the differences observed in multivariate analysis.
Y: yes; N: no.
4. Discussion
4.1. Summary of findings
Patients with psychiatric disorders were found to have an increased risk of having a new diagnosis of CVR factors, especially diabetes, hyperlipidemia, and obesity. The excess is risk of the majority of CVR facts amongst patients with psychiatric conditions could not be fully explained by antidepressants, antipsychotics and social deprivation. Exceptions included smoking and physical inactivity, where these variables had an important explanatory role. Antidepressant use was independently associated with higher risk of diabetes, hypertension, and hyperlipidemia, and antipsychotic use were independently associated with a higher risk of diabetes, but both groups of drugs were associated with lower risk of other CVR factors. Patients with psychiatric conditions were found to have a later detection of CVR factors, particularly smoking and obesity.
4.2. Strengths and weaknesses
The data are derived from an almost complete population residing in a single contiguous geographical area, and not from selected individuals or organisations, which provides the least biased sampling frame. All patients were registered in the surgeries when the dataset was defined in March 2015, with all historic clinically relevant information available, which allowed for the accurate identification of prevalent and incident diagnoses and prescriptions. However, no data were available from patients who died, or left the surgeries between 2005 and 2015. By contrast with many previous articles, this study has a large number of cases and long follow up period, which improved statistical power and allowed for the observation of different CVR factors developing over ten years [Reference Osborn, Wright, Levy, King, Deo and Nazareth3]. While some degree of residual confounding is probably affecting these results, it was possible to model a range of explanatory variables simultaneously, allowing the independent explanatory role of multiple factors to be assessed. The analysis of a high number of factors increases the possibility that some of the observed finding may not be true associations and the result of chance. However, it should be noted that most associations were consistent in the analyses for different psychiatric problems and the adjustment of different confounders. This study included data on prescription of antidepressants and/or antipsychotics but no data was available on medication compliance and dosage, specific drug type, or continuity of prescribing. Furthermore, all exposures and outcomes were coded as binary variables, even those that have a natural continuous distribution such as smoking or physical activity; this is a limitation of this paper. Future studies may address the risk developing different degrees of each CVR in patients with psychiatric disorders. The lower screening rates for these CVR factor in patients with psychiatric disorders, together with the overdiagnosis of some psychiatric problems, especially depression, may have resulted in an underestimation of the associations investigated [Reference Stubbs, Vancampfort, De Hert and Mitchell9,Reference Mitchell, Vaze and Rao24,Reference Osborn, Baio, Walters, Petersen, Limburg and Raine25]. Nonetheless, the use of structured data entry templates, and clinical facilitation in the east London practices studied, enabled routine entry of high quality data using agreed code sets for recording CVR factors. The diagnoses of different psychiatric conditions, CVR factors, and the medication prescribed is routinely reviewed by local clinicians as part of their national Quality and Outcome Framework audit returns which provides further validation of data quality [26].
4.3. Interpretation of results in relation to previous literature
The increased risk of some CVR factors, such as smoking, in patients with selected psychiatric conditions has been reported before [Reference De Leon and Diaz5–Reference Vancampfort, Mitchell, De Hert, Sienaert, Probst and Buys10,Reference Chaiton, Cohen, O’Loughlin and Rehm27–Reference Luppino, de Wit, Bouvy, Stijnen, Cuijpers and Penninx29]. However, the comprehensive approach to the distribution of different major CVR factors among patients with a wide range of specific psychiatric conditions had only been presented by a small number of studies of limited quality [Reference Osborn, Wright, Levy, King, Deo and Nazareth3].
The potential for weight gain observed in patients taking antidepressants and antipsychotics may explain the increased risk of diabetes [Reference Correll, Detraux, De Lepeleire and De Hert11, Reference Andersohn, Schade, Suissa and Garbe12]. Some antipsychotics, such as clozapine and olanzapine, are associated with high metabolic risk [Reference Stahl30]. Antipsychotics work on the cerebral centers responsible of appetite and satiety. They disrupt the anorexigen signal to the hypothalamus and they can cause obesity by blocking dopaminergic receptors that affect eating behavior. Other central effects of antipsychotics that can result in weight gain include the increase of prolactin secretion, and sedation, which may affect weight via physical inactivity. At a peripheral level, antipsychotics also block the muscarinic receptors localized in the beta-cells of the pancreas, decreasing plasma levels of insulin [Reference Miron, Baroană, Popescu and Ionică31]. These mechanisms can lead to obesity, insulin resistance, and dyslipidemia during prolonged treatments [Reference Stahl30].
Many patients, who developed the CVR factors of interest prior to the study period, and potentially prior to the psychiatric diagnosis, were not eligible for inclusion into the study. This may explain the inconsistent association between different psychiatric disorders and a first ever detection of smoking, and also the lower risk for some CVR factors, including obesity, smoking and lack of physical activity, among those who had taken antipsychotics and antidepressants. The positive effect of antidepressants and antipsychotics in the mental health of these patients may also result in some patients adopting a healthier lifestyle, having better access to health services, and subsequently experiencing better control of some CVR factors. This could also explain the association between psychiatric disorders and smoking which is only significant once the models are adjusted for use of antidepressants and antipsychotics. This study may also be observing the unintentional but positive effect of antidepressants on smoking behaviour [Reference Hughes, Stead, Hartmann-Boyce, Cahill and Lancaster32], or an unreported long-term effects of these antidepressants and antipsychotics. It has been observed that studies reporting high prevalence of CVR factors among patients with psychiatric disorders are cited more often than those reporting a low prevalence [Reference Chapman, Ragg and McGeechan33]. The self-reporting of CVR factors, such as physical activity or smoking, may be poorer for patients with psychiatric conditions [Reference Stubbs, Williams, Gaughran and Craig4, Reference Soundy, Roskell, Stubbs and Vancampfort34]. The different approach of clinicians to patients with psychiatric conditions may also have resulted in the unequal recording of CVR factors [Reference Mitchell, Vancampfort, De Hert and Stubbs35]. These differences could explain the observed association between antipsychotics and higher rates of physical activity or lower rates of smoking, which may not be real. The delayed detection of some CVR factors in patients with mental health conditions may have been affected by the financial incentives offered to some UK based general practitioners for the recording of CVR factors for patients with and without psychiatric conditions [26]. The later identification of CVR factors in patients with mental health conditions is also in line with a study that showed that these patients are less likely than the general population to receive annual CVR screening [Reference Osborn, Baio, Walters, Petersen, Limburg and Raine25]. This study assumed that the date that each psychiatric condition and CVR was entered into the medical records was the true date of diagnosis. In UK primary care doctors tend to enter diagnostic data during or immediately after consultation. Therefore, it was considered that the date of record and the date of actual diagnosis would not have differed substantially. The heterogeneity between the different psychiatric conditions observed in this study should be acknowledged, as clinical relevance of each of them can be very different.
4.4. Clinical implications
Clinicians should consider frequent and long-term monitoring of CVR factors for patients with mental health conditions. Patients with psychiatric disorders receive fragmented care and guidelines in different countries are not consistent when stating whether CVR should be approached by primary care or psychiatry services [Reference Foguet i Boreu36]. It appears essential that clinicians in both services agree on who should deliver this care, and work co-ordinately. Clinical guidelines mention that CVR is especially high for those with either serious mental health problems [20], or for those with anxiety and depression [Reference Perk, De Backer, Gohlke, Graham, Reiner and Verschuren19]. However, our findings would support the enhanced management of CVR for patients with a wide variety of psychiatric disorders. The European guidelines for prevention of cardiovascular disease recommend checking for CVR factors male patients over the age of 40 and women over the age of 50 [Reference Perk, De Backer, Gohlke, Graham, Reiner and Verschuren19]. Our results also show that after adjustment for gender, many patients with psychiatric conditions developed CVR factors from the age of 40. This would support screening for CVR in patients, both men and women, with psychiatric conditions from the age of 40. Future studies may address whether these CVR factors can be detected and effectively treated also in patients under 40. Monitoring CVR alone is insufficient for improving health outcomes. Studies show that the interventions for reducing CVR in patients with psychiatric conditions can be effective, for example via smoking cessation, exercise, and lifestyle change [Reference Fernández-San-Martín, Martín-López, Masa-Font, Olona-Tabueña, Roman and Martin-Royo37–Reference Bennett, Wilson, Genderson and Saperstein39]. Exercise is associated with maximum benefit from interventions that include 90 minutes of moderately intense aerobic exercise a week. In order to minimise CVR these interventions may need to be delivered shortly after the diagnosis.
Special attention should be given to patients treated with antidepressants who were found to have a higher risk of diabetes, hypertension, and hyperlipidemia, and those on antipsychotics, who were found to have an increased risk of diabetes. Many factors contribute to the later detection and poor control of CVR factors in these patients, which ultimately can lead to poorer health outcomes [Reference Viron and Stern2]. Therefore, patients with psychiatric conditions require an especially proactive clinical approach, with clinicians from primary and secondary care working closely in conjunction with one another. The evidence base for clinical practice is primarily drawn from clinical trials, which in most cases have less than one year of follow up [Reference Kennedy, Kumar and Datta40–Reference Essali and Ali45]. Further studies examining the long-term effects on CVR factors of antidepressants and antipsychotics are required.
Funding
Salma Ayis was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Luis Ayerbe is funded by an NIHR Clinical Lectureship. This article therefore presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. This project was conducted with no direct involvement from funders.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgement
This study depended on the work and cooperation of general practitioners, practice staff and administrators in Newham, City and Hackney and Tower Hamlets Clinical Commissioning Groups and the Clinical Effectiveness Group who support the east London electronic health database.
Appendices. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.eurpsy.2016.02.004.
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