Cardiovascular and metabolic risk in outpatients with schizoaffective disorder treated with antipsychotics: Results from the CLAMORS study

European Psychiatry 27 (2012) 267–274

Original article

Cardiovascular and metabolic risk in outpatients with schizoaffective disorder treated with antipsychotics: Results from the CLAMORS study J. Bobes a,*, C. Arango b, P. Aranda c, R. Carmena d, M. Garcia-Garcia e, J. Rejas f on behalf of the CLAMORS Study Collaborative Group1 a

Medicine Department, Psychiatry Area, University of Oviedo, Centro de Investigacio´n Biome´dica en Red de Salud Mental CIBERSAM, C/Julia´n Claverı´a, 6, 33006 Oviedo (Asturias), Spain b Psychiatry Department, Hospital General Universitario Gregorio Maran˜o´n and Centro de Investigacio´n Biome´dica en Red de Salud Mental CIBERSAM, Madrid, Spain c Hypertension Unit, Carlos Haya Hospital, Ma´laga, Spain d Department of Endocrinology, Valencia University Clinic Hospital, Valencia, Spain e Operations Department, Biometria Clinica CRO, Barcelona, Spain f Health Outcomes Research Department, Medical Unit, Pfizer Espan˜a, Madrid, Spain

A R T I C L E I N F O

A B S T R A C T

Article history: Received 16 February 2010 Received in revised form 2 September 2010 Accepted 4 September 2010 Available online 30 October 2010

Aim: To assess the coronary heart disease (CHD) risk and prevalence of the metabolic syndrome (MS) in patients with schizoaffective disorder (SD) receiving antipsychotics. Methods: Patients meeting DSM-IV criteria for SD and receiving antipsychotic treatment were recruited in a retrospective, cross-sectional, multicenter study (the CLAMORS study). MS was defined as at least three of the following components: waist circumference greater than 102 cm (men)/greater than 88 cm (women); serum triglycerides greater or equal to 150 mg/dl; HDL cholesterol less than 40 mg/dl (men)/ less than 50 mg/dl (women); blood pressure greater or equal to 130/85 mmHg; fasting blood glucose greater or equal to 110 mg/dl. The 10-year CHD risk was assessed by the Systematic coronary risk evaluation (SCORE) (cardiovascular mortality) and Framingham (any cardiovascular event) functions. Clinical severity was assessed using the PANSS and CGI-S scales. Results: A total of 268 valuable patients with SD (127 men, 48.1%), 41.9  12.3 years (mean  S.D.), were analyzed. The 10-year overall cardiovascular mortality and CV-event risk were 0.8  1.6 (SCORE) and 6.5  6.8 (Framingham), respectively. A high/very high risk of any CV event (Framingham  10%) was associated with severity [CGI-S = 3–4; OR: 4.32 (1.15–16.26), P = 0.03)]. MS was present in 26.5% (95%CI: 21.2–31.8) of subjects, without gender differences, but significantly associated with patient’s impression of severity: CGI = 3–4; OR = 1.90 (0.83–4.36), and CGI = 5–7; OR = 3.13 (1.06–9.24), P = 0 < 0.001, and age [OR = 1.91 (1.09–3.34), P < 0.024)]. Conclusions: CHD risk and MS prevalence were high among patients with SD, being MS prevalence associated with age and severity of disease. ß 2010 Elsevier Masson SAS. All rights reserved.

Keywords: Metabolic syndrome Cardiovascular risk Schizoaffective disorders Outpatients Antipsychotic treatment Mental status

* Corresponding author. Tel.: +34 985 10 35 53; fax: +34 985 10 35 53. E-mail address: [email protected] (J. Bobes). 1 Contributor: The CLAMORS Study Collaborative Group includes the following investigators: Albaiges L. (Barcelona), Alday M.O. (Barcelona), Alonso M. (Cantabria), A´lvarez P. (Valladolid), A´lvarez S. (Asturias), Alzate G. (Navarra), Anguiano J.B. (Vizcaya), Anto´n C. (Baleares), Aragues E. (Vizcaya), Asensio F. (Barcelona), Bardolet C. (Baleares), Barraga´n J. ˜ete J. (Barcelona), Capllonch I. (Baleares), Carmona C. (Barcelona), Carrasco E. (Alicante), Bellido J.A. (Barcelona), Bordas R. (Barcelona), Busto J. (Badajoz), Cadevall J. (Barcelona), Can ˜a M.A. (Zaragoza), Dı´az N. (Barcelona), Dome´nech J.R. (Murcia), Carrillo A. (Madrid), Castillo C. (Baleares), Chinea E.R. (Tenerife), Cleris M. (Barcelona), De Dios C. (Madrid), De Un (Barcelona), Ducaju M. (Madrid), Echeveste M. (Vizcaya), Ferna´ndez A. (Madrid), Ferna´ndez-Cuevas A. (Madrid), Ferna´ndez-Villamor R. (Seville), Figuerido J.L. (A´lava), Fluvia J. (Alicante), Franch J.I. (Valladolid), Gala´n F. (Badajoz), Garcı´a I. (Madrid), Garcı´a J. (Zaragoza), Garcı´a-Portilla M.P. (Asturias), Gil P. (Vizcaya), Go´mez-Trigo J. (Madrid), Gonza´lez F.A. (Santa Cruz de Tenerife), Gonza´lez G. (Vizcaya), Gonza´lez P. (Lleida), Gonza´lez T. (Madrid), Gonza´lez-Quiro´s M. (Asturias), Graizer O. (Madrid), Herna´ndez C. (Madrid), Herna´ndez J.L. (Las Palmas de Gran Canaria), Iglesias C. (Asturias), Irurita J. (Las Palmas de Gran Canaria), Justo M.I. (Barcelona), Karim M. (A´lava), Larrazabal L.M. (Vizcaya), Lizarraga J. (Vizcaya), Lojo F.M. (Murcia), Lo´pez I. (Baleares), Lo´pez J. (Baleares), Lo´pez L. (Murcia), Loro M. (Segovia), Martı´n E. (Madrid), Martı´n F. (Burgos), Martı´nez A. (Almerı´a), Martı´nez de Morentı´n J.J. (Navarra), Martı´nez J.L. (Madrid), Martı´nez J.M. (Zamora), Martı´nez M. (Ma´laga), Martı´nez R. (Barcelona), Medina G. (Valladolid), Medina J.L. (Madrid), Megı´a P. (Palencia), Mendezona J.I. (Vizcaya), Merino M.J. (Asturias), Messays M. (Barcelona), Misiego J.M. (Baleares), Mongil J.M. (Ca´diz), Montejo A.L. (Salamanca), Montes J.M. (Madrid), More M.A. (Madrid), Moyano L. (Co´rdoba), Natividad M.C. (Barcelona), Pacheco L. (Vizcaya), Palao D.J. (Barcelona), Palomo A.L. (Barcelona), Parramo´n G. (Barcelona), Pascual G. (Zaragoza), Pastor A. (Valencia), Pastor F.J. (Vizcaya), Peralta E. (Almerı´a), Pe´rez E. (Alicante), Prieto N. (Salamanca), Rodrı´guez E. (Ma´laga), Rodrı´guez J.C. (Ma´laga), Roig A. (Valencia), Rojano P. (Madrid), Rubio T. (Zaragoza), Ruiz F.C. (Palencia), Ruiz J.M. (A´lava), Salesansky A. (Las Palmas de Gran Canaria), Salgado M.C. (Madrid), San Narciso G.I. ˜a), Sopelana P.A. (Madrid), Soto J.A. (Madrid), Sotomayor E. (Asturias), Teba F. (Asturias), Sa´nchez J.M. (Ca´diz), Sanz J. (Vizcaya), Shabiaga P. (Barcelona), Silveira J.R. (A Corun (Barcelona), Valdelomar M. (Barcelona), Valle J.R. (Seville), Vicente F.J. (Madrid), Villagran D. (Ca´diz), Villamor A. (A´lava). 0924-9338/$ – see front matter ß 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2010.09.001

268

J. Bobes et al. / European Psychiatry 27 (2012) 267–274

1. Introduction In recent years, an important body of evidence has been published in the scientific literature on the increased prevalence of cardiovascular risk and metabolic disorders in psychiatric patients, particularly those diagnosed with schizophrenia spectrum disorders or bipolar disorders [13,17,19,23,28,39,40,47]. The European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC) have recently published a statement with the aim of improving the care of patients suffering from severe mental illness, particularly to initiate cooperation and shared care between the different healthcare professionals and to increase the awareness of psychiatrists and primary care physicians caring for patients with severe mental illness to screen and treat cardiovascular risk factors and diabetes [20]. Different recent reviews also pointed out the need for increasing metabolic and cardiovascular monitoring of psychiatric patients with severe disorders [19,40]. However, little has been explored as it relates to schizoaffective medical conditions, i.e., the combination of metabolic disorders and the associated increase in cardiovascular risk as a consequence of the disease or factors related to the disorder [32,37]. The metabolic syndrome (MS) is a collection of risk factors that are associated with increasing morbidity and mortality due to cardiovascular disease [1]. In a variety of health settings, mortality due to the premature development of cardiovascular disease and high prevalence of MS has been shown to be considerably greater among patients with psychiatric disorders such as chronic schizophrenia [12,14,17,22,28,33,47,49,56] and bipolar disorder [23,24] than in the general population. In particular, several reasons have been postulated as related to the increase of mortality due to premature development of cardiovascular disease, such as poor diet, lack of exercise, cigarette smoking, and stress [21,46]. In addition, schizophrenia patients who are treated with antipsychotics, especially second-generation antipsychotics such as clozapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with MS [34]. In this context, the CATIE clinical trial [25,39,41,50] estimated the mean risk of serious fatal and nonfatal coronary heart disease (CHD) within 10 years, according to the Framingham function, at 9.4% in men and 6.3% in women [25]. These figures are higher than in the general population. Although, the CATIE trial documented a high prevalence of MS (40.9%) in this type of patients [39], few studies have provided data on both CHD risk according to the Framingham function and cardiovascular mortality (CVM) risk using the more recent SCORE function [18]. Schizoaffective disorder was named as a compromise diagnosis in 1933, and remains popular as judged by its place in the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders, its frequent use in clinical practice, and its extensive discussion in the literature. Schizoaffective disorders occupy a position between schizophrenia and pure mood disorders, especially as regard prognosis and premorbid and sociodemographic variables. There is little data on the prevalence of cardiovascular risk of mortality and prevalence of the metabolic syndrome in patients with schizoaffective disorder. The Cardiovascular, Lipid and Metabolic Outcomes Research in Schizophrenia Study – the (CLAMORS) study [13] – was a naturalistic, cross-sectional, retrospective study designed to ascertain the prevalence of cardiovascular risk factors (CVRFs), overall CHD risk and CVM risk, and the prevalence of MS in patients with schizophrenia, schizophreniform or schizoaffective disorders treated with the antipsychotics most commonly used in daily practice. As part of the CLAMORS study, in this manuscript, we describe demographic, lifestyle, and clinical characteristics, and

the degree of cardiovascular risk and prevalence of MS specifically in patients with schizoaffective disorders.

2. Patients and methods 2.1. Investigators and patients The methods used in the CLAMORS study have been published in detail elsewhere [13]. Briefly, this multicenter cross-sectional study enrolled consecutive outpatients, aged 18–74 years, with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder according to the DSM-IV classification, receiving oral antipsychotic treatment for at least 12 weeks with only one of the following antipsychotic drugs: risperidone, olanzapine, quetiapine, ziprasidone, amisulpride, or haloperidol. For this paper, we considered only those with schizoaffective disorder. Schizoaffective disorder was defined according to DSM-IV-TR criteria [6]. Patients receiving treatment with two or more antipsychotics at the time of evaluation and/or those admitted to the hospital were excluded. A stratified multistage probability sample without replacement was drawn. The sampling frame was all health regions of the 17 Autonomous Communities of Spain. The first stage consisted of selection of psychiatric clinics within each health region. The number of psychiatric clinics to be selected in each region was proportional to the population of the region. In the second stage, one psychiatrist per clinic, chosen at random from among those with previous experience in clinical and epidemiological research in psychiatry, was invited to participate. The third stage consisted of patient selection with a systematic sampling strategy from the daily list of all patients having an appointment with each of the participating psychiatrists and meeting previously mentioned inclusion and exclusion criteria. The study complied with the principles of the Declaration of Helsinki regarding medical research in humans [57]. An accredited Clinical Research Ethics Committee at one of the participating centers approved the study protocol. Written informed consent was obtained prior to participation in all cases. 2.2. Study design According to the study protocol for this cross-sectional, retrospective multicenter study, each participating center was to recruit at least the first 12 consecutive patients who met the selection criteria. The sample of patients was obtained as a substudy of the previously published CLAMORS study. In the CLAMORS study, sample size was established according to the guidelines of the International Conference on Harmonization (ICH) [29] in relation to established study objectives. 2.3. Variables and measurement instruments 2.3.1. Prevalence of cardiovascular risk factors The individual prevalence of cardiovascular risk factors was estimated using the criteria recommended at the time of the study design [48]: age greater or equal to 40 (men) or greater or equal to 45 (women) years, presence of diabetes (diagnosed or receiving treatment with oral antidiabetic drugs or insulin), total cholesterol greater or equal to 200 mg/dl, HDL cholesterol less than 45 mg/dl (men) or less than 50 mg/dl (women), systolic blood pressure greater or equal to 140 mmHg (or  130 mmHg in patients with prior cardiovascular disease, renal disease, or diabetes), and diastolic blood pressure greater or equal to 90 mmHg (or  80 mmHg in patients with prior cardiovascular disease, renal disease, or diabetes). For determining the analytical risk factors,

J. Bobes et al. / European Psychiatry 27 (2012) 267–274

blood biochemistry testing was required no more than 3 months before the start of the study. Cardiovascular risk was estimated using the Systemic coronary risk evaluation (SCORE) function [18] for cardiovascular risks (including coronary death, sudden death, stroke, aortic aneurism, and heart failure) and the Framingham function [55] to estimate the overall risk of any fatal or nonfatal CHD (including, in addition to the fatal CHD events mentioned above, any type of angina, myocardial infarction, other type of coronary ischemia, congestive heart failure, intermittent claudication, or peripheral arterial ischemia) within 10 years. Both functions are mathematical probability models obtained using multivariate analysis techniques from follow-up studies of individuals in the general population, in which the incidence of a fatal or nonfatal CHD event is related to the individual risk factors of each subject. In the SCORE function, CVM risk is calculated from the values for age, gender, total cholesterol, HDL cholesterol, systolic blood pressure, and smoking. The Framingham function calculates the risk from the same values as the SCORE function, but with the addition of the factor of presence of diabetes. In this study, patients were classified according to the probability of presenting a ‘‘very high/high’’ risk for CVM (SCORE > 3%) and fatal or nonfatal CHD risk (Framingham > 10%) within 10 years. 2.3.2. Prevalence of the metabolic syndrome MS prevalence was estimated using the criteria of the National Cholesterol Education Program (NCEP) [42], assessing the presence of three or more of the following components: abdominal obesity (waist circumference > 102 cm in men and > 88 cm in women), hypertriglyceridemia (fasting triglyceride concentration  150 mg/dl or receiving treatment with fibrates or nicotinic acid), dyslipidemia (fasting HDL cholesterol less than 40 mg/dl in men and less than 50 mg/dl in women), hypertension (systolic blood pressure and diastolic blood pressure  130/ 85 mmHg or undergoing antihypertensive treatment), and hyperglycemia (fasting glucose concentration  110 mg/dl or receiving glucose – lowering treatment or previously diagnosed diabetes mellitus). 2.3.3. Clinical severity Clinical severity was determined using the Schizophrenia Positive and Negative Symptom Scale (PANSS) [31,43] and the Clinical Global Impression-Severity (CGI-S) scale [26]. 2.3.4. Other measurements In addition to recording patients’ sociodemographic and clinical data, patients answered a series of questions regarding to their

269

lifestyle (smoking, eating habits, and physical exercise) and occupational status. 2.4. Statistical analysis A safety-only sample of evaluable patients was used for the analyses, including all patients receiving one of the six aforementioned antipsychotic drugs. The mean, standard deviation, and range were calculated for quantitative variables, and the frequency and percentage of patients were used to estimate the prevalence of the different risk factors and components. The individual prevalence of the cardiovascular risk factors and the prevalence of MS were estimated by the direct method, calculating the corresponding 95% confidence intervals (95% CI). Continuous variables were compared using parametric tests (Student’s t test or ANOVA) or nonparametric tests (Mann-Whitney or Kruskal-Wallis test), according to the distribution of the variables. In addition, a logistic bivariate regression analysis was performed to describe the relationship between qualitative dependent variables (presence of very high/high risk of cardiovascular disease according to SCORE/Framingham or presence of the metabolic syndrome) and independent variables (antipsychotic treatment and doses, duration of disease, CGI score, and total, positive, and negative PANSS score, including also gender and age only for the analysis with presence of the metabolic syndrome). The p values correspond to the statistical significance of two-tailed tests. A p value less or equal to 0.05 was considered statistically significant. The SPSS version 13.0.1 statistical package was used throughout. 3. Results 3.1. Evaluable patients and distribution by groups A total of 314 patients with schizoaffective disorder were recruited in the context of the CLAMORS study, in which 117 psychiatrists from 91 different outpatient centers participated. Of these patients, 46 (14.6%) failed to meet the study selection criteria and were excluded. The main reason for exclusion (42 patients, 13.4%) was current treatment with some antipsychotic for less than 12 weeks (Fig. 1). Two hundred and sixty-eight patients were thus considered evaluable. 3.2. Patients sociodemographic, lifestyle, and clinical characteristics Table 1 shows the principal sociodemographic and general clinical characteristics of the patients as well as their lifestyle and dietary habits. Of the total patients, 48.1% were men and the mean

Recruited patients (n=314)

Excluded patients (n=46*) Reasons for exclusion: - Age > 74 years old (n=1) - Without current antipsychotic treatment or with antipsychotic treatment other than haloperidol, amisulpiride, olanzapine, quetiapine, risperidone and/or ziprasidone (n=6) - Current antipsychotic treatment intravenous (n=4) - Current antipsychotic treatment for less than 12 weeks (n=42) - Current antipsychotic treatment with more than one antipsychotic (n=2) * For each patient, more than one reason for exclusion could be reported simultaneously

Evaluable patients (n=268) Fig. 1. Patient distribution.

J. Bobes et al. / European Psychiatry 27 (2012) 267–274

270

Table 1 Sociodemographic, clinical characteristics, and life style habits of the patients by gender and globally. Men (n = 127) n

a

Women (n = 137) %

– – –

Gender Male Female

n

a

– – –

pc

Total (n = 268) %

– – –

n

a

%

– – –

264 127 137

100.0 48.1 51.9

– – –

Marital status Single Married Divorced/Separated Widowed

127 77 39 9 2

100.0 60.6 30.7 7.1 1.6

135 55 57 17 6

100.0 40.7 42.2 12.6 4.4

265 133 98 26 8

100.0 50.2 37.0 9.8 3.0

0.010

Occupational status Active Unemployed Sick leave Disability pension Others

126 35 12 17 55 7

100.0 27.8 9.5 13.5 43.7 5.6

132 28 18 7 51 28

100.0 21.2 13.6 5.3 38.6 21.2

261 64 30 24 108 35

100.0 24.5 11.5 9.2 41.4 13.4

0.001

BMI Normal (< 25 kg/m2) Overweight (> 25–< 30 kg/m2) Obese (> 30 kg/m2)

127 34 57 36

100.0 26.8 44.9 28.3

136 38 50 48

100.0 27.9 36.8 35.3

267 74 108 85

100.0 27.7 40.4 31.8

0.352

Meana

S.D.

Meana

S.D.

Meana

S.D.

pc

Age (years)

41.3

12.5

42.4

12.1

41.9

12.3

0.443

Disease duration (years)

14.6

10.3

16.3

10.6

15.4

10.4

0.180

3.1

3.6

3.6

3.5

3.4

3.6

0.139

No. Hospital admissions

b

na Smokers Patients Patients Patients Patients

on diet controlling calorie consumption avoiding saturated fat/cholesterol consuming high fiber diet

Physical exercise None Light Mild Intense Highly intense a b c

na

%

%

na

%

79 21 28 30 31

62.2 16.5 22.2 23.8 24.8

64 36 49 44 50

46.7 26.3 36.0 32.4 36.8

144 57 77 74 82

53.7 21.3 28.9 27.8 30.9

126 20 45 37 18 6

15.9 35.7 29.4 14.3 4.8

137 15 46 52 18 6

10.9 33.6 38.0 13.1 4.4

267 35 93 91 36 12

13.1 34.8 34.1 13.5 4.5

pc 0.014 0.055 0.014 0.125 0.037 0.592

Some patients failed to provide information. Due to the psychotic disorder. Chi-squared test or Mann-Whitney U-test (p < 0.05).

age was 41.9  12.3 years, with 63.0% single/divorced/widowed. Few had healthy lifestyle habits. Less than 30% of the patients reported following a diet, controlling calorie intake in general, and avoiding the consumption of saturated fats/cholesterol. In addition, a significantly lower proportion of patients regularly performed moderate to intense physical exercise. In terms of schizoaffective disorder, the average duration of disease was 15.4  10.4 years. PANSS and CGI-S scores are described in Table 2. Antipsychotic drug use data is included in Table 3, along with other psychopharmacologic treatments received by patients concomitantly. The mean duration of antipsychotic treatment was 149.1  238.0 weeks. A small percentage of patients (12.6%) were under treatments other than psychopharmacologic for other diseases (antihypertensives, antihyperlipidemics, antidiabetics, or cardioactive drugs).

higher in women compared with men. High levels of total cholesterol ( 200 mg/dL) or lower levels of HDL cholesterol (< 45 in men/ < 50 mg/dL in women) were shown in 43.3 and 47.4% of the patients, respectively. A moderate percentage of patients had hypertension, and 25.5% and 13.6%, respectively, had high systolic and diastolic blood pressure.

Table 2 CGI-S and PANSS scores of the patients.

CGI-S scores 1–2 3–4 5–6–7

n

%

50 186 28

18.9 70.5 10.6

Meana

S.D.

3.3 64.4 13.1 17.8

1.0 21.4 5.7 7.6

3.3. Individual prevalence of the main cardiovascular risk factors Table 4 shows the individual prevalence of the classical cardiovascular risk factors in the total sample and by gender. Percentage of patients with glucose metabolism disorders was considerable; 8.2% of the patients were diabetics and 8.6% had glucose intolerance. These data were slightly, but not significantly

CGI-S PANSS – Total (30–210) PANSS – Positive (7–49) PANSS – Negative (7–49) a

Some patients failed to provide information.

J. Bobes et al. / European Psychiatry 27 (2012) 267–274 Table 3 Main and concomitant treatments.

Patients with antipsychotics (mean dose  S.D., mg/d) Amisulpride (485.5  226.9) Haloperidol (11.2  10.8) Olanzapine (14.1  6.2) Risperidone (4.2  1.9) Quetiapine (461.7  271.9) Ziprasidone (131.1  45.3)

(BMI). There were no significant differences in BMI according to gender. However, as expected, women had a significantly smaller mean waist circumference than men (92.3% vs 99.3%, P = 0.003).

%a

n 268 38 32 59 34 51 51

14.2 11.9 22.0 12.7 19.0 19.0

Patients with psychopharmacologic treatmentb

230

85.8

Anxiolytics/hypnotics Antidepressants Antiepileptics Lithium Antiparkinson drugs Others

124 116 108 62 31 3

46.3 43.3 40.3 23.1 11.6 1.1

Patients with other than psychopharmacologic treatmentb

41

15.3

Antihypertensives Antihyperlipidemics Antidiabetics Cardioactive drugs Others

11 10 7 6 22

4.1 3.7 2.6 2.2 8.2

271

3.6. Factors associated with cardiovascular risk and the metabolic syndrome

S.D.: standard deviation. a Calculated with respect to the global evaluable patients. b Some patients might have been taken more than one concomitant treatment.

To analyze the factors involved in the increasing prevalence of cardiovascular risk (very high/high risk on the SCORE and Framingham scales) and MS in schizoaffective patients, we performed a logistic regression with cardiovascular risk or MS as dependent variables and duration of disease, antipsychotic treatment, score on the CGI scale and PANSS scores (total, negative, and positive) as independent variables. Compared with the reference group (CGI 1–2), the 10-years cardiovascular risk (Framingham equation) was significantly associated with subjects in the category of 3 to 4 score only [OR = 4.32 (1.15–16.26, P = 0.030)], without a consistent relationship with increasing severity of disease. However, frequency of metabolic syndrome was related with severity of disease. Compared with the reference group (CGI 1–2), subjects scoring 3–4 in CGI showed an OR = 1.90 (0.83–4.36) and patients with a CGI of 5 to 7 showed an OR = 3.13 (1.06–9.24, P = 0 < 0.001). Age was also shown to be a risk factor for frequency of metabolic syndrome with an OR = 1.91 (1.09– 3.34) in men over 40 and women over 45 years of age (P < 0.024). However, it is noteworthy that there was no statistically significant relationship with the PANSS score.

3.4. Prevalence of coronary heart disease risk and cardiovascular mortality risk 4. Discussion Fig. 2 shows the individual prevalence of the CVM risk (SCORE) (panel A) and CHD risk (Framingham) (panel B) within 10 years in the total sample and by gender. The overall CVM risk within 10 years was 1.6% and was significantly higher in men than in women (2.0% vs 0.9%, P < 0.001). The overall risk of CHD in 10 years was 6.5  6.8% and was likewise significantly greater in men than in women (7.8% vs 4.5%, P < 0.001). These differences could be explained, at least in part, by the higher percentage of smokers among men than women (62.2% vs 46.7%, respectively, P < 0.05). 3.5. Prevalence of the metabolic syndrome The overall prevalence of the MS in the study was 26.5% (Table 5). Some individual prevalences of MS components differed statistically between men and women. Specifically, abdominal obesity and lower HDL cholesterol were more prevalent in women (57.9% vs 36.0%, P = 0.001 and 49.5% vs 32.3%, P = 0.011, respectively) and hypertension was more prevalent in men (61.3% vs 43.7%, P = 0.005). Table 5 also shows the individual mean values for MS components and body mass index

This sub-study of the CLAMORS study focused on the prevalence of cardiovascular risk and the metabolic syndrome in patients with schizoaffective disorder. The results of this study show that the prevalence of high/very high cardiovascular mortality risk within 10 years in patients with schizoaffective disorder receiving antipsychotic treatment was 8.4% and 20% based on the SCORE and Framingham functions, respectively. The psychosis population in this study showed higher prevalence of the main cardiovascular risk factors than those reported in the agecomparable general population in our setting. A comparison of our results with published data shows that cardiovascular risk factors such as obesity were much lower for men and women in the general Spanish population than in our subjects with psychotic disorder (13.2% and 17.5% versus 36.0% and 57.9%, respectively, for men and women). Similar findings were observed for smoking (48.1% and 30.2% versus 62.2% and 46.7%, respectively), and in women only for diabetes (2.4% versus 8.0%) and abnormally low HDL cholesterol level (33.1% versus 47.4%) (data from the DORICA study, [7]).

Table 4 Individual prevalence of the main cardiovascular risk factors in the total sample and by gender.

Age  40 (<) or  45 (,) years Smoker Diabetes (type I, type II) or glucose  126 mg/dl Hyperglycemia  110 and < 126 mg/dl Total cholesterol  200 mg/dl HDL cholesterol < 45 (<) or < 50 (,) mg/dl SBP  140 or  130 (prior CVD, renal disease, or diabetes) DBP  90 or  80 (prior CVD, renal disease or, diabetes)

Men (n = 127)

Women (n = 137)

Total (n = 268)

%

CI 95 %

%

CI 95 %

%

CI 95 %

52.0 62.2 7.9 7.1 40.7 46.5 29.0 18.5

43.3–60.7 53.8–70.6 3.2–12.6 2.6–11.5 31.8–49.5 36.6–56.3 21.0–37.0 11.7–25.4

38.0 46.7 8.0 9.5 44.7 49.5 23.0 17.0

29.8–46.1 38.4–55.1 3.5–12.6 4.6–14.4 36.2–53.2 40.2–58.9 15.9–30.1 10.7–23.4

44.7 53.7 8.2 8.6 43.3 47.4 25.5 18.3

41.6–47.8 47.8–59.7 4.9–11.5 5.2–11.9 37.2–49.4 40.7–54.1 20.2–30.7 13.6–22.9

SBP: systolic blood pressure; DBP: diastolic blood pressure; CVD: cardiovascular disease. a Chi-squared test (P < 0.05) and Mann-Whitney U-test (P < 0.05).

pa

0.022 0.012 0.963 0.480 0.521 0.655 0.265 0.751

272

J. Bobes et al. / European Psychiatry 27 (2012) 267–274

Fig. 2. Prevalence of cardiovascular mortality risk (Systematic coronary risk evaluation) (panel A) and any cardiovascular event risk (Framingham) (panel B) within 10 years. The prevalence was calculated with respect to the global evaluable patients with 95% confidence interval. *P < 0.05, ** P < 0.01 versus women.

On the other hand, prevalence of the metabolic syndrome in schizoaffective patients was 26.5% in the total study population, and slightly, but not significantly more prevalent in men than in women. Comparing these data with the prevalence of the metabolic syndrome in the general Spanish population, the prevalence of MS in patients with schizoaffective disorder was similar to that found in the general population 10 to 15 years older. Thus, other studies in the literature showed a prevalence of MS ranging from 10.2 to 28.6% in the general population in Spain with a mean age ranging from 45.5 to 56.5 years [2,3,4,9,16,36,38]. In those studies, the age of the patients ranged from 54.8 to 56.5 years, whereas the mean age in our study was 41.9  12.3 years. Previous studies have also reported the prevalence of MS in patients with schizoaffective disorders, with a range of prevalence from similar to our study population [11,19,40,45,52] to almost twice as showed by van Winkel and colleagues [8]. Interestingly, this study found a high prevalence of abdominal obesity among patients with schizoaffective disorder. The prevalence of abdominal obesity was 47.5% in the total population, and was specifically high in women (57.9%). This value corroborates the data from the CATIE study [39]. This high, significant rate of abdominal obesity observed in schizoaffective patients was far

higher than the rate of obesity found in the general reference population in Spain (13% to 17%) [53]. Despite the fact that some antipsychotic drugs may contribute to increased abdominal obesity, unhealthy lifestyle habits may also have contributed. As shown in Table 1, less than 30% of the patients reported following a diet, controlling calorie intake in general, and avoiding the consumption of saturated fats/cholesterol. In addition, a significantly lower proportion of patients regularly performed moderate to intense physical exercise. Abdominal obesity has gained importance in the last years since it has been postulated that some inflammatory cytokines, such as TNF-alpha or IL-6, might be released into the circulation by adipose tissue, stimulating hepatic C-reactive protein production, leading to a pro-inflammatory state, frequently associated with cardiovascular disorders [51]. Also, patients with schizophrenia tend to have reduced levels of adiponectin [17], which has been associated with increased cardiovascular risk, particularly when associated with weight gain after taking antipsychotics [10,27]. Another important risk factor that contributes to both cardiovascular risk and MS is hypertension. Unlike the CATIE study, we found the prevalence of hypertension to be quite high in patients with schizoaffective disorder. The prevalence of hyper-

S.D.

0.282 0.003 0.063 0.018 0.001 0.013 27.9 95.5 139.0 50.1 126.0 76.3 5.3 19.3 80.2 14.9 15.6 10.7

Mean S.D.

SBP: systolic blood pressure, DBP: diastolic blood pressure, CRF: case report form. a Calculated according to the NCEP-ATP III criteria. b Chi-squared test (P < 0.05) and Mann-Whitney U-test (P < 0.05).

4.7 18.7 87.2 16.5 16.5 8.9 Mean values of the main metabolic syndrome components Body mass index (BMI) (kg/m2) 27.6 Waist circumference (cm) 99.3 Triglycerides (mg/dL) 148.5 HDL cholesterol (mg/dL) 48.1 SBP (mmHg) 129.5 DBP (mmHg) 77.7

28.2 92.3 131.0 51.7 123.1 75.1

S.D.

36.0 38.1 32.3 61.3 15.0

Mean

26.8

Components of the metabolic syndromea Abdominal obesity (waist circumference > 102 cm (men) or > 88 cm (women) Hypertriglyceridemia (triglycerides  150 mg/dL) HDL cholesterol < 40 (men) or < 50 (women) mg/dL Hypertension (BP  130/85) Hyperglycemia (glucose  110 and < 126 mg/dL and/or according to CRF) or diabetes (type I or II) or glucose  126 mg/dL

Mean

27.2–44.8 29.4–46.9 23.1–41.5 52.7–69.9 8.8–21.2

57.9 30.5 49.5 43.7 17.5

49.3–66.6 22.6–38.4 40.2–58.9 35.3–52.1 11.2–23.9

47.5 34.0 41.4 51.3 16.8

5.0 19.2 83.5 15.8 16.2 9.9

pb

0.001 0.207 0.011 0.005 0.574 41.2–53.8 28.2–39.8 34.8–48.1 45.3–57.4 12.3–21.3

21.2–31.8 26.5 19.6–34.4 27.0

%

19.1–34.5

%

Women (n = 137)

%

Total patients (%) with the metabolic syndromea

Table 5 Prevalence of the metabolic syndrome and its components in the total sample and by gender.

CI 95 % Men (n = 127)

CI 95%

Total (n = 268)

CI 95%

pb

0.966

J. Bobes et al. / European Psychiatry 27 (2012) 267–274

273

tension was 51.3% in the total study population, and was higher in men (61.3%). These values are considerably high compared to the general population in Spain, which shows values ranging for 25– 40% [15,44,54]. Another remarkable finding of our study was that schizoaffective patients had a higher prevalence of the metabolic syndrome compared with previous data in patients with schizophrenia (CLAMORS study, [13]) and a prevalence in the same range as bipolar disorder in our setting [24]. The total prevalence of MS was 24.6% in schizophrenia patients vs 25.6% in schizoaffective patients. Considering that the characteristics of the schizophrenia and schizoaffective patients were closely related, a plausible explanation for the increasing prevalence of MS in schizoaffective patients might be that the concomitant treatments were different in two types of patients. In particular, 43.3% of the schizoaffective patients were receiving antidepressant treatment, compared with 25.2% of the schizophrenia patients. In fact, it has been postulated that certain selective serotonin reuptake inhibitors induce clinical and biochemical manifestations of the metabolic syndrome by an as-yet unknown mechanism [35]. On the other hand, controversies arise when addressing the factor(s) involved in the increasing prevalence of the metabolic syndrome in schizophrenia/schizoaffective patients. In the present sub-study, logistic regression results showed a progressive increase in prevalence of the MS with the severity of the disease (OR = 1 with CGI scale of 1–2 and OR = 3.13 with CGI scale of 5–6–7), but not with the symptoms of the disease, measured by the PANSS score. This was consistent with the CATIE study, where no association was found between the presence of the MS and psychopathological severity as scored on the PANSS, either in raw terms or after adjusting for age, sex, race, and ethnic group – with the exception of PANSS item G1, relating to somatic concern. One general limitation of this study is the fact that, due to the patient sampling system used, despite of our efforts to balance the different antipsychotics included in the study, we cannot guarantee that the true prevalence of the MS and cardiovascular risk may not in fact be somewhat different in routine clinical practice, where the distribution of antipsychotics will probably vary (with increased use of olanzapine, risperidone, or haloperidol) and/or use of two or more antipsychotics. This may constitute a source of bias, due to the effects on body weight and carbohydrate and lipid metabolism of some of these second-generation antipsychotics (American Diabetes Association, [5,30]). Another additional limitation of this study was that institutionalized patients were not included in our sample. Finally, we did not search for other potential factors related to metabolic disorders, such as prothrombotic and inflammatory markers (i.e., C-reactive protein, labile fraction of glycosylated hemoglobin a1, blood leptin level, etc.). In conclusion, the results of this comparative sub-analysis of schizoaffective patients show that cardiovascular risk and MS prevalence were high among patients with schizoaffective disorder. Age and severity of disease were associated with an increase of MS prevalence. Improving our understanding of the metabolomic aspects associated with cardiovascular risk in this vulnerable population may help to establish preventive and therapeutic programs in higher risk groups. Contributors Funding: This study has been funded by an unrestricted grant of Pfizer Spain.

Conflict of interest statement Javier Rejas is an employee of Pfizer Spain. The others authors have no conflict of interest.

274

J. Bobes et al. / European Psychiatry 27 (2012) 267–274

References [1] Alberti KG, Zimmet P, Shaw J, IDF Epidemiology task Force Consensus Group. The metabolic syndrome – a new worldwide definition. Lancet 2005;366:1059–62. [2] Alegrı´a E, Cordero A, Laclaustra M, Grima A, Leo´n M, Casasnovas JA, et al. En representacio´n de los investigadores del registro MESYAS. Prevalencia del ˜ ola: registro MESYAS. Rev Esp sı´ndrome metabo´lico en poblacio´n laboral espan Cardiol 2005;58:797–806. [3] A´lvarez EE, Ribas L, Serra L. Prevalence of the metabolic syndrome in the population of Canary Islands, Spain. Med Clin (Barc) 2003;120:172–4. [4] A´lvarez-Cosmea A, Lo´pez V, Sua´rez S, Arias T, Prieto MA, Dı´az L. Diferencias en la prevalencia del sı´ndrome metabo´lico segu´n las definiciones del ATP-III y la OMS. Med Clin (Barc) 2005;124:368–70. [5] American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596–601. [6] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th text rev. ed, Washington, DC: Author; 2000. [7] Aranceta J, Perez C, Serra L, Ribas L, Quiles J, Vioque J, et al. Prevalence of obesity in Spain: results of the SEEDO 2000 study. Med Clin (Barc) 2003;120:608–12. [8] Aranceta J, Pe´rez-Rodrigo C, Foz-Saal M, Mantilla T, Serra Ll, Moreno B, et al. ˜ ola. Tablas de evaluacio´n del riesgo coronario adaptadas a la poblacio´n espan Estudio DORICA. Med Clin (Barc) 2004;123:686–91. [9] Ascaso JF, Gabriel R, Franch J, Godoy A, Ferna´ndez de Bobadilla J, Ortega R, et al. Grado de concordancia de los distintos criterios que definen el sı´ndrome metabo´lico en el estudio DESIRE [abstract]. Av Diabetologia 2004;20:23. [10] Bai YM, Chen TT, Yang WS, Chi YC, Lin CC, Liou YJ, et al. Association of adiponectin and metabolic syndrome among patients taking atypical antipsychotics for schizophrenia: a cohort study. Schizophr Res 2009;111:1–8. [11] Basu R, Brar JS, Chengappa R, John V, Parepally H, Gershon S, et al. The prevalence of the metabolic syndrome in patients with schizoaffective disorder – bipolar subtype. Bipolar Disord 2004;6:314–8. [12] Bobes J, Rejas J, Garcia-Garcia M, Rico-Villademoros F, Garcı´a-Portilla MP, Ferna´ndez I, et al. Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiapine or haloperidol: results of the EIRE study. Schizophr Res 2003;62:77–88. [13] Bobes J, Arango C, Aranda P, Carmena R, Garcia-Garcia M, Rejas J. Cardiovascular and metabolic risk in outpatients with schizophrenia treated with antipsychotics: results of the CLAMORS Study. Schizophr Res 2007;90:162–73. [14] Brown S, Inskip H, Barraclough B. Causes of the excess mortality of schizophrenia. Br J Psychiatry 2000;177:212–7. [15] Cabrera de Leo´n A, Rodriguez-Perez MC, del Castillo-Rodriguez JC, Brito-Diaz B, Perez-Mendez LI, Muros de Fuentes M, et al. Coronary risk in the population of the Canary Islands, Spain, using the Framingham function. Med Clin 2006;126:535–6. [16] Coca MM, Hernanz P, Vega M, Sua´rez C. Prevalencia de sı´ndrome metabo´lico en la poblacio´n de un centro de atencio´n primaria urbano. Aten Primaria 2005;35:436–7. [17] Cohn T, Remington G, Zipursky RB, Azad A, Connolly P, Wolever T. Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: a preliminary report. Can J Psychiatry 2006;51:382–6. [18] Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987–1003. [19] De Hert M, Schreurs V, Vancampfort D, Van Winkel R. Metabolic syndrome in people with schizophrenia: a review. World Psychiatry 2009;8:15–22. [20] De Hert M, Dekker JM, Wood D, Kahl KG, Holt RI, Mo¨ller HJ. Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry 2009;24:412–24. [21] Dixon L, Weiden P, Delahanty J, Goldberg R, Postrado K, Lucksted A, et al. Prevalence and correlates of diabetes in national schizophrenia samples. Schizophr Bull 2000;26:903–12. [22] Enger C, Weatherby L, Reynolds RF, Glasser DB, Walker AM. Serious cardiovascular events and mortality among patients with schizophrenia. J Nerv Ment Dis 2004;192:19–27. [23] Fagiolini A, Frank E, Scott JA, Turkin S, Kupfer DJ. Metabolic syndrome in bipolar disorder: findings from the Bipolar Disorder Center for Pennsylvanians. Bipolar Disord 2005;7:424–30. [24] Garcia-Portilla MP, Saiz PA, Benabarre A, Sierra P, Perez J, Rodriguez A, et al. The prevalence of metabolic syndrome in patients with bipolar disorder. J Affect Disord 2008;106:197–201. [25] Goff DC, Sullivan LM, McEvoy JP, Meyer JM, Nasrallah HA, Daumit GL, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 2005;80:45–53. [26] Guy W. Early Clinical Drug Evaluation (ECDEU). Assessment Manual. Rockville. Nat Inst Ment Health 1976;218–22. [27] Hanssens L, van Winkel R, Wampers M, Van Eyck D, Scheen A, Reginster JY, et al. A cross-sectional evaluation of adiponectin plasma levels in patients with schizophrenia and schizoaffective disorder. Schizophr Res 2008;106:308–14. [28] Holt RI. Diagnosis, epidemiology and pathogenesis of diabetes mellitus: an update for psychiatrists. Br J Psychiatry 2005;(Suppl. 47):S55–63. [29] International Conference on Harmonization (ICH): E9 Statistical Principles for Clinical Trials. Rockville (USA). Food Drug Adm;1998.

[30] Kane JM, Barrett EJ, Casey DE, Correll CU, Gelenberg AJ, Klein S, et al. Metabolic effects of treatment with atypical antipsychotics. J Clin Psychiatry 2004;65:1447–55. [31] Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–76. [32] Kilbourne AM, Brar JS, Drayer RA, Xu X, Post EP. Cardiovascular disease and metabolic risk factors in male patients with schizophrenia, schizoaffective disorder, and bipolar disorder. Psychosomatics 2007;48:412–7. [33] Lamberti JS, Crilly JF, Maharaj K, Olson D, Wiener K, Dvorin S, et al. Prevalence of diabetes mellitus among outpatients with severe mental disorders receiving atypical antipsychotic drugs. J Clin Psychiatry 2004;65:702–6. [34] Lamberti JS, Olson D, Crilly JF, Olivares T, Williams GC, Tu X, et al. Prevalence of the Metabolic Syndrome among patients receiving clozapine. Am J Psychiatry 2006;163:1273–6. [35] Levkovitz Y, Ben-Shushan G, Hershkovitz A, Isaac R, Gil-Ad I, Shvartsman D, et al. Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases. Mol Cell Neurosci 2007;36:305–12. [36] Lorenzo C, Serrano-Rı´os M, Martı´nez-Larrad MT, Gabriel R, Williams K, Go´mezGerique JA, et al. Central adiposity determines prevalence differences of the metabolic syndrome. Obes Res 2003;11:1480–7. [37] Mackin P, Bishop D, Watkinson H, Gallagher P, Ferrier IN. Metabolic disease and cardiovascular risk in people treated with antipsychotics in the community. Br J Psychiatry 2007;191:23–9. [38] Martı´nez-Larrad MT, Ferna´ndez-Pe´rez C, Gonza´lez-Sa´nchez JL, Lo´pez A, Ferna´ndez-A´lvarez J, Riviriego J, et al. Prevalence of the metabolic syndrome (ATPIII criteria). Population-based study of rural and urban areas in the Spanish province of Segovia. Med Clin (Barc) 2005;125:481–6. [39] McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005;80:19–32. [40] Meyer JM, Stahl SM. The metabolic syndrome and schizophrenia. Acta Psychiatr Scand 2009;119:4–14. [41] Meyer JM, Nasrallah HA, McEvoy JP, Goff DC, Davis SM, Chakos M, et al. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome. Schizophr Res 2005;80:9–18. [42] National Institutes of Health. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) Final Report. Circulation 2002;106:3143–421. [43] Peralta V, Cuesta M. Validation of positive and negative symptom scale (PANSS) in a sample of Spanish schizophrenia patients. Actas Luso Esp Neurol Psiquiatr Cienc Afines 1994;22:171–7. ˜ o AF, Cadarso-Sua´rez C, Botana MA, Tome MA, [44] Pe´rez-Ferna´ndez R, Marin Solache I, et al. Prevalence, awareness, treatment and control of hypertension in Galicia (Spain) and association with related diseases. J Hum Hypertens 2007;21:366–73. [45] Ribeiro PJ, Lopes F. The prevalence of metabolic syndrome among psychiatric inpatients in Brazil. Rev Bras Psiquiatr 2007;29:330–6. [46] Ryan MC, Collins P, Thakore JH. Impaired fasting glucose tolerance in firstepisode, drug-naive patients with schizophrenia. Am J Psychiatry 2003;160:284–9. [47] Saari KM, Lindeman SM, Viilo KM, Isohanni MK, Ja¨rvelin MR, Laure´n LH, et al. A 4-fold risk of metabolic syndrome in patients with schizophrenia: the Northern Finland 1966 Birth Cohort study. J Clin Psychiatry 2005;66:559–63. [48] SEA. Obesidad y riesgo cardiovascular. Documento consenso. Sociedad Espa˜ ola de Arterioesclerosis; 2003. n [49] Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561–6. [50] Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006;163:611–22. [51] Sutherland JP, McKinley B, Eckel RH. The metabolic syndrome and inflammation. Metab Syndr Relat Disord 2004;2:82–104. [52] Suvisaari JM, Saarni SI, Perala J, Suvisaari JV, Harkanen T, Lonnqvist J, et al. Metabolic Syndrome among persons with schizophrenia and other psychotic disorders in a general population survey. J Clin Psychiatry 2007;68:1045–55. [53] van Winkel R, van Os J, Celic I, Van Eyck D, Wampers M, Scheen A, et al. Psychiatric diagnosis as an independent risk factor for metabolic disturbances: results from a comprehensive, naturalistic screening program. J Clin Psychiatry 2008;69:1319–27. ˜ oz Cacho P, Sanz de Castro S. Arterial hipertensio´n [54] Vara-Gonza´lez L, Mun prevalence, detection, treatment and control in Cantabria, Spain, 2002. Rev Esp Salud Publica 2007;81:211–9. [55] Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837–47. [56] Wirshing DA. Schizophrenia and obesity: impact of antipsychotic medications. J Clin Psychiatry 2004;65:13–26. [57] WMA. Policy. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects; 2004. http:// www.wma.net/e/policy/b3.htm.