Cardiovascular and metabolic risk in outpatients with schizophrenia treated with antipsychotics: Results of the CLAMORS Study

Schizophrenia Research 90 (2007) 162 – 173 www.elsevier.com/locate/schres

Cardiovascular and metabolic risk in outpatients with schizophrenia treated with antipsychotics: Results of the CLAMORS Study Julio Bobes a,⁎, Celso Arango b , Pedro Aranda c , Rafael Carmena d , Margarida Garcia-Garcia e , Javier Rejas f on behalf of the CLAMORS Study Collaborative Group1 a

b

Medicine Department, Psychiatry Area, University of Oviedo, Asturias, Spain Psychiatry Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain c Hypertension Unit, Carlos Haya Hospital, Málaga, Spain d Endocrinology Department, Valencia University Clinic Hospital, Valencia, Spain e Project Management Department, Biometrica CRO, Barcelona, Spain f Health Outcomes Research Department, Medical Unit, Pfizer España, Madrid, Spain

Received 30 May 2006; received in revised form 27 September 2006; accepted 27 September 2006 Available online 21 November 2006

Abstract Aim: To assess the prevalence of Coronary Heart Disease (CHD) and Metabolic Syndrome (MS) in patients treated with antipsychotics. Methods: Retrospective, cross-sectional, multicenter study in which 117 Spanish psychiatrists (the CLAMORS Study Collaborative Group) recruited consecutive outpatients meeting DSM-IV criteria for Schizophrenia, Schizophreniform or Schizoaffective Disorder, receiving antipsychotic treatment for at least 12 weeks. CHD risk was assessed by SCORE (10-year CV ⁎ Corresponding author. Tel./fax: +34 985 10 35 53. E-mail address: [email protected] (J. Bobes). 1 The CLAMORS Study Collaborative Group includes the following investigators: Albaiges L (Barcelona), Alday MO (Barcelona), Alonso M (Cantabria), Álvarez P (Valladolid), Álvarez S (Asturias), Alzate G (Navarra), Anguiano JB (Vizcaya), Antón C (Baleares), Aragues E (Vizcaya), Asensio F (Barcelona), Bardolet C (Baleares), Barragán J (Alicante), Bellido JA (Barcelona), Bordas R (Barcelona), Busto J (Badajoz), Cadevall J (Barcelona), Cañete J (Barcelona), Capllonch I (Baleares), Carmona C (Barcelona), Carrasco E (Murcia), Carrillo A (Madrid), Castillo C (Baleares), Chinea ER (Tenerife), Cleris M (Barcelona), De Dios C (Madrid), De Uña MA (Zaragoza), Díaz N (Barcelona), Doménech JR (Barcelona), Ducaju M (Madrid), Echeveste M (Vizcaya), Fernández A (Madrid), Fernández-Cuevas A (Madrid), Fernández-Villamor R (Sevilla), Figuerido JL (Álava), Fluvia J (Alicante), Franch JI (Valladolid), Galán F (Badajoz), García I (Madrid), García J (Zaragoza), García-Portilla MP (Asturias), Gil P (Vizcaya), Gómez-Trigo J (Madrid), González FA (Santa Cruz de Tenerife), González G (Vizcaya), González P (Lleida), González T (Madrid), González-Quirós M (Asturias), Graizer O (Madrid), Hernández C (Madrid), Hernández JL (Las Palmas de Gran Canaria), Iglesias C (Asturias), Irurita J (Las Palmas de Gran Canaria), Justo MI (Barcelona), Karim M (Álava), Larrazabal LM (Vizcaya), Lizarraga J (Vizcaya), Lojo FM (Murcia), López I (Baleares), López J (Baleares), López L (Murcia), Loro M (Segovia), Martín E (Madrid), Martín F (Burgos), Martínez A (Almería), Martínez de Morentín JJ (Navarra), Martínez JL (Madrid), Martínez JM (Zamora), Martínez M (Málaga), Martínez R (Barcelona), Medina G (Valladolid), Medina JL (Madrid), Megía P (Palencia), Mendezona JI (Vizcaya), Merino MJ (Asturias), Messays M (Barcelona), Misiego JM (Baleares), Mongil JM (Cádiz), Montejo AL (Salamanca), Montes JM (Madrid), More MA (Madrid), Moyano L (Córdoba), Natividad MC (Barcelona), Pacheco L (Vizcaya), Palao DJ (Barcelona), Palomo AL (Barcelona), Parramón G (Barcelona), Pascual G (Zaragoza), Pastor A (Valencia), Pastor FJ (Vizcaya), Peralta E (Almería), Pérez E (Alicante), Prieto N (Salamanca), Rodríguez E (Málaga), Rodríguez JC (Málaga), Roig A (Valencia), Rojano P (Madrid), Rubio T (Zaragoza), Ruiz FC (Palencia), Ruiz JM (Álava), Salesansky A (Las Palmas de Gran Canaria), Salgado MC (Madrid), San Narciso GI (Asturias), Sánchez JM (Cádiz), Sanz J (Vizcaya), Shabiaga P (Barcelona), Silveira JR (A Coruña), Sopelana PA (Madrid), Soto JA (Madrid), Sotomayor E. (Asturias), Teba F (Barcelona), Valdelomar M (Barcelona), Valle JR (Sevilla), Vicente FJ (Madrid), Villagran D (Cádiz), Villamor A (Álava). 0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.09.025

J. Bobes et al. / Schizophrenia Research 90 (2007) 162–173

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death) and Framingham (10-year all CHD events) function. MS was defined by at least 3 of the following components: waist circumference N 102 (men)/N 88 (women) cm; triglycerides ≥150 mg/dl; HDL-cholesterol b40 mg/dl (men)/b50 mg/dl (women); blood pressure ≥ 130/85; fasting glucose ≥ 110 mg/dl. Results: 1452 evaluable patients (863 men, 60.9%), aged 40.7 ± 12.2 years (mean ± SD) were included. MS was present in 24.6% [23.6% (men), 27.2% (women); p = 0.130)]. The overall 10-year risks were 0.9 ± 1.9 (SCORE) and 7.2 ± 7.6 (Framingham). 8% (95%CI: 6.5–9.5) and 22.1% (95%CI: 20.0–24.3) of patients showed a high/very high risk according to SCORE (≥ 3%) and Framingham (≥ 10%) function. Abdominal obesity and low HDL-cholesterol were more prevalent in women: 54.5% (95%CI: 50.2–58.9) versus 34.3% (95%CI: 31.0–37.7), and 46.1% (95%CI: 41.4) versus 28.5 (95%CI: 50.8), p b 0.001 in both cases. Hypertension and hypertriglyceridemia were more prevalent in men: 59.0% (95%CI: 55.7–62.3) versus 46.0% (95%CI: 41.8– 50.2), and 40.7% (95%CI: 37.2–44.2) versus 32.4 (95%CI: 28.3–36.5), p b 0.01 in both cases. Conclusions: CHD risk and MS prevalences among patients with schizophrenia treated with antipsychotics were in the same range as the Spanish general population 10 to 15 years older. © 2006 Elsevier B.V. All rights reserved. Keywords: Cardiovascular risk; Metabolic syndrome; Schizophrenic disorders; Outpatients; Antipsychotic treatment; Mental status

1. Introduction Mortality due to any cause has been shown to be considerably greater among chronic patients with schizophrenia than in the general population in different settings (Brown et al., 2000; Babidge et al., 2001; Hiroeh et al., 2001; Morgan et al., 2003). The reasons for this excess mortality include patients' life style, increased suicidability, premature development of cardiovascular disease, and high prevalences of metabolic syndrome (MS) and carbohydrate and lipid metabolic disorders (Sernyak et al., 2002; Bobes et al., 2003; Wirshing, 2004; Enger et al., 2004; Lamberti et al., 2004; Cohn et al., 2004; Saari et al., 2005; Holt, 2005). Obesity is increasingly prevalent, and has become a serious public health problem in developed countries. In the United States, it has been reported that one-third of the adult population is obese (Centers for Disease Control (CDC), 1997), while in Spain the figure is lower, around 15% (Aranceta et al., 2003). Obesity – particularly abdominal obesity – also appears to be a frequent concomitant condition in schizophrenic patients (Allison et al., 1999; Bobes et al., 2003; Wirshing, 2004). Potential factors associated with the development of obesity include the particular life style of patients with schizophrenia, unbalanced dietary habits and, recently, the effects of psychotropic medication — including both first and second generation antipsychotic drugs (Meyer, 2002; Wirshing and Meyer, 2003; Conley et al., 2005). The importance of these adverse effects is not limited to the fact that they constitute a source of treatment noncompliance (Bernstein, 1987; Fakhoury et al., 2001). Indeed, in the same way as in the general population, they pose an increased risk of developing medical problems related to obesity, such as type 2 diabetes (Lebovitz, 2001; Haupt and Newcomer, 2001) and

particularly the development of MS (Newcomer, 2001, 2005; Heiskanen et al., 2003; Kato et al., 2003; Littrell et al., 2003; Straker et al., 2003; American Diabetes Association et al., 2004; Basu et al., 2004; Cohn et al., 2004; Kato et al., 2004; Marder et al., 2004; McEvoy et al., 2005; Birkenaes et al., 2006; De Hert et al., 2006; Suvisaari et al., 2006). Moreover, these conditions constitute cardiovascular risk factors (Mukherjee et al., 1996; Davidson, 2002; Meltzer et al., 2002; Citrome and Jaffe, 2003; Meyer et al., 2005). However, despite growing interest in this comorbidity in patients receiving antipsychotic treatment, few data are available on its prevalence. In particular, prevalence of diabetes has been reported to be between 9% and 14% (Lindenmayer et al., 2003; Kabinoff et al., 2003), and that of dyslipidemia and arterial hypertension prevalences to be 43% and 30% respectively (Gupta et al., 2003). The CATIE clinical trial, which included patients receiving antipsychotic treatment matched for age, race, and gender with subjects from the NHANES study (McEvoy et al., 2005; Meyer et al., 2005; Goff et al., 2005a, Stroup et al., 2006), 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 males and 6.3% in females (Goff et al., 2005a). These figures are higher than those reported in the general population in the United States, 7.0% in males and 4.2% in females (Plan and Operation of the Third National Health and Nutrition Examination Survey, 1988–94). Moreover, the CATIE trial documented a high prevalence of MS (40.9%) (McEvoy et al., 2005). Few of these studies have provided data on CHD risk according to the Framingham function (Wilson et al., 1988), and on cardiovascular mortality (CVM) risk using the more recent SCORE function (Conroy et al., 2003).

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This present cross-sectional, retrospective study (CLAMORS Study: Cardiovascular, Lipid and Metabolic Outcomes Research in Schizophrenia Study) was conceived with the aim of using appropriate methodology to evaluate 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 disorder receiving treatment with the antipsychotics most commonly used in our setting. 2. Materials and methods

2003), 43% of patients with schizophrenia patients presented dyslipidemia. This factor was chosen to estimate sample size, since it required the largest number of patients. Accordingly, and positing an infinite population size, a sample size of 363 individuals per treatment was estimated to provide ± 5% precision in estimating the proportion of patients with dyslipidemia, with a 95% confidence interval. The final sample size provided ± 2.5% precision for estimating the proportion of patients with total cholesterol ≥ 200 mg/dl (found to be 50.9%), with a 95% confidence interval, the factor requiring the greatest sample size.

2.1. Investigators and patients 2.3. Variables and measurement instruments study design Psychiatrists from all over Spain participated in the study. Selection of the investigators was initially based on quotas reflecting the population sizes in the different regions. The study was carried out between May 2004 and April 2005 in a psychiatry outpatient clinic setting, under the usual medical practice conditions and in accordance with the clinical practice of each investigator. The study enrolled consecutive patients of both sexes, aged 18–74 years, with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder according to the DSM-IV classification, receiving an oral antipsychotic treatment for at least 12 weeks with only one of the following antipsychotic drugs: risperidone, olanzapine, quetiapine, ziprasidone, amisulpride or haloperidol. Patients receiving treatment with two or more antipsychotics at the time of evaluation and/or those admitted to the hospital were excluded. The study complied with the principles of the Declaration of Helsinki regarding medical research in humans (WMA, 2004). An accredited Clinical Research Ethics Committee from 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 protocol for this cross-sectional, retrospective multicenter study, each participating center was to recruit at least the first 12 consecutive patients who meet the selection criteria. Two patients were assigned to receive treatment with each of the most commonly used antipsychotic drugs in our health care setting: risperidone, olanzapine, quetiapine, ziprasidone, amisulpride, and haloperidol. Sample size was established according to the guidelines of the International Conference on Harmonization (ICH) in relation to the established study objectives. According to a study published by Gupta (Gupta et al.,

2.3.1. Prevalence of cardiovascular risk factors The individual prevalence of CVRFs was estimated using the criteria recommended at the time of the study design (SEA, 2003): age ≥40 (males) or ≥45 (females) years, presence of diabetes (diagnosed or receiving treatment with oral antidiabetic drugs or insulin), total cholesterol ≥ 200 mg/dl, HDL-cholesterol b45 mg/dl (males) or b 50 mg/dl (females), systolic blood pressure ≥ 140 mmHg (or ≥130 mmHg in patients with prior cardiovascular disease, renal disease and diabetes), and diastolic blood pressure ≥ 90 mmHg (or ≥80 mmHg in patients with prior cardiovascular disease, renal disease and diabetes). For determination of the analytical risk factors, blood biochemistry testing performed no more than three months before the start of the study was required. Cardiovascular risk was estimated using the SCORE (Systematic Coronary Risk Evaluation) function (Conroy et al., 2003) for CVM risk (including coronary death, sudden death, stroke, aortic aneurism, and heart failure), and the Framingham function (Wilson et al., 1988) 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 multivariant analysis techniques from follow-up studies of individuals in the general population, in which the incidence of a fatal or non-fatal CHD event is related to the individual risk factors of each subject. In the SCORE function, the CVM risk is calculated from the values for age, gender, total cholesterol, HDL cholesterol, systolic arterial pressure, and smoking habit. With the Framingham function, risk is calculated from the same values as SCORE function, but with the addition of the factor of presence of diabetes. In this study, patients were

J. Bobes et al. / Schizophrenia Research 90 (2007) 162–173

classified according to the probability of presenting “very high/high” risk for CVM (SCORE z 3%) and for fatal or non-fatal CHD risk (Framingham function z 10%) within 10 years. 2.3.2. Prevalence of metabolic syndrome MS prevalence was estimated using the criteria of the National Cholesterol Education Program (NCEP) (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001), assessing the presence of three or more of the following components: abdominal obesity (waist circumference N102 cm in males and N 88 cm in females), hypertriglyceridemia (fasting triglyceride concentration ≥ 150 mg/dl under fasting conditions), dyslipidemia (fasting HDL-cholesterol b40 mg/dl in males and b50 mg/dl in females), hypertension (systolic and diastolic blood pressure ≥ 130/85 mmHg), and hyperglycemia (fasting glucose concentration ≥ 110 mg/dl). 2.3.3. Clinical severity Clinical severity was determined using the Schizophrenia Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987; Peralta and Cuesta, 1994), and the Clinical Global Impression-Severity scale (CGI-S; Guy, 1976). 2.3.4. Other measurements In addition to recording the patients' sociodemographic and clinical data, patients answered a series of questions regarding their lifestyle (alcohol and coffee consumption, smoking and eating habits) 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

165

the six aforesaid 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 prevalences of the different risk factors and components. The individual prevalences of the cardiovascular risk factors and the prevalence of MS were estimated by the direct method, calculating the corresponding 95% confidence intervals (95%CI). In addition, the patients were classified according to the probability of presenting “very high/ high” CVM risk (SCORE ≥ 3%) and CHD risk in 10 years (Framingham ≥ 10%). The p-values correspond to the statistical significance of two-tailed tests. Statistical significance was considered for p b 0.05. The SPSS version 11.5.1 statistical package was used. 3. Results 3.1. Evaluable patients After increasing the number of patients to be included per investigator, in order to attain the minimum sample size, 1704 patients were recruited by 117 psychiatrists from 91 different centers. Of these, 252 (14.8%) who failed to meet the study evaluability criteria were excluded. The main reason for exclusion (202 patients, 11.9%) was current antipsychotic treatment for less than 12 weeks (Fig. 1). 3.2. Patient characteristics Table 1 shows the patients' main sociodemographic and general clinical characteristics. The diagnosis was of schizophrenia in 1108 patients (77.1%), schizophreniform disorder in 61 patients (4.2%) and schizoaffective disorder in 268 patients (18.6%). The mean duration

Fig. 1. Patient distribution.

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Table 1 Sociodemographic and clinical characteristics of the patients by gender and globally

Gender Male Female Age b25 years 25–34 years 35–44 years 45–54 years 55–64 years ≥ 65 years

Age (years)

Marital status Single Married Divorced/separated Widowed Occupational status Active Unemployed Sick leave Disability pension Others BMI Normal (b25) Overweight (≥25–b30) Obese (≥ 30)

Waist circumference (cm) Disease duration (years) No. hospital admissions d

Healthy lifestyle habits Patients on diet of some kind Patients controlling calorie consumption Patients controlling salt consumption Patients avoiding saturated fat/cholesterol consumption Patients usually consuming high fiber diet a b c d

pa

Males (n = 863)

Females (n = 555)

Total (n = 1452)

nb

%

nb

%

nb

%

– – – 859 67 265 271 154 80 22

– – – 100.0 7.8 30.8 31.5 17.9 9.3 2.6

– – – 554 37 130 162 121 73 31

– – – 100.0 6.7 23.5 29.2 21.8 13.2 5.6

1418 863 555 1437 105 402 436 280 160 54

100.0 60.9 39.1 100.0 7.3 28.0 30.3 19.5 11.1 3.8

– – – b0.001

mb

SD

mb

SD

mb

SD

pc

39.3

11.6

42.5

12.6

40.7

12.2

b0.001

nb

%

nb

%

nb

%

pa

856 653 145 49 9 845 176 155 62 411 41 855 221 385 249

100.0 76.3 16.9 5.7 1.1 100.0 20.8 18.3 7.3 48.6 4.9 100.0 25.8 45.0 29.1

550 288 172 61 29 534 99 79 23 243 90 551 176 195 180

100.0 52.4 31.3 11.1 5.3 100.0 18.5 14.8 4.3 45.5 16.9 100.0 31.9 35.4 32.7

1431 958 324 111 38 1403 278 238 86 666 135 1432 402 589 441

100.0 66.9 22.6 7.8 2.7 100.0 19.8 17.0 6.1 47.5 9.6 100.0 28.1 41.1 30.8

b0.001

mb

SD

mb

SD

mb

SD

p4

98.3 14.7 2.6

16.4 10.4 2.9

90.9 16.6 2.8

18.2 11.3 3.1

95.4 15.5 2.6

17.4 10.8 3.0

b0.001

0.001

b0.001 0.002 0.335

nb

%

nb

%

nb

%

pa

100 122 90 157 177

11.6 14.3 10.5 18.4 20.7

135 176 111 181 193

24.3 31.9 20.1 32.8 35.1

238 302 204 341 374

16.5 21.1 14.3 23.8 26.2

b0.001 b0.001 b0.001 b0.001 b0.001

χ2 test ( p b 0.05). Some patients failed to provide information. Mann–Whitney U-test ( p b 0.05). Due to the psychotic disorder.

(standard deviation, SD) of the psychotic disorder was 15.5 years (10.8 years), with a mean 2.6 (3.0) hospital admissions attributable to the psychotic disorder since the onset of the disease. The current treatment had been initiated due to a change in the previous antipsychotic therapy in 727 patients (51.7%), due to an exacerbation

of symptoms in 508 (36.1%) and to deal with a first episode in 171 patients (12.2%). The antipsychotic distribution was as follows: amisulpride (n = 213, 14.7%), haloperidol (n = 202, 13.9%), olanzapine (n = 306, 21.1%), quetiapine (n = 218, 15.0%), risperidone (n = 268, 18.5%), and ziprasidone (n = 240,

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Table 2 Individual prevalence of the main CVRFs, CHD risk (Framingham) and CVM risk (SCORE), in the total sample and by gender

Age ≥ 40 (♂) or ≥45 (♀) years Smoker c Diabetes (type I, type II and glucose ≥126 mg/dl) Hyperglycemia Total cholesterol ≥200 mg/dl c HDL-cholesterol b45 (♂) or b50 (♀) mg/dl c SBP ≥ 140 or ≥ 130 (prior cardiovascular disease, renal disease or diabetes) c DBP ≥90 or ≥80 (prior cardiovascular disease, renal disease or diabetes) c c

pa

Total (n = 1452)

Males (n = 863)

Females (n = 555)

%b

95%CI

%b

95%CI

%b

95%CI

42.9 53.7 6.3 7.9 50.9 43.7 28.5

40.3–45.5 51.1–56.2 5.0–7.5 6.5–9.3 48.2–53.6 40.9–46.6 26.1–30.8

44.4 62.3 5.8 7.5 49.3 43.9 30.9

41.0–47.7 59.1–65.6 4.2–7.4 5.8–9.3 45.8–52.8 40.2–47.6 27.8–34.0

40.6 40.4 6.8 8.5 52.6 46.1 24.8

36.5–44.7 36.3–44.4 4.7–8.9 6.2–10.8 48.2–57.0 41.4–50.8 21.1–28.4

0.165 b0.001 0.422 0.523 0.249 0.472 0.013

22.0

19.9–24.2

22.0

19.2–24.8

21.1

17.6–24.5

0.690

mb

95%CI

mb

95%CI

mb

95%CI

pa

CVM risk in 10 years (SCORE) d

0.9

0.8–1.0

1.1

0.9–1.2

0.5

0.4–0.6

b0.001

CHD risk in 10 years (Framingham) e

6.8

6.5–7.3

8.3

7.9–9.0

4.5

4.1–5.0

b0.001

CVRFs = cardiovascular risk factors; CHD = Coronary Heart Disease (fatal and non-fatal); CVM = cardiovascular mortality. a χ2 and Mann–Whitney U-test. b Prevalence calculated from the total evaluable patients or mean with 95% confidence interval. c Main cardiovascular risk factors according to SEA 2003. d Calculated from the SCORE function (Conroy et al., 2003). e Calculated from the Framingham function (Wilson et al., 1988), considering as diabetic patients those with type I or II diabetes and/or glucose ≥126 mg/dl.

Table 3 Prevalence of metabolic syndrome, and its components, and mean values of its main components, in the total sample and by gender Total (n = 1452) % c

Total patients (%) with metabolic syndrome Components of metabolic syndrome c Abdominal obesity (waist circumference N102 cm (males) or N88 cm (females)] Hypertriglyceridemia (triglycerides ≥ 150 mg/dl) HDL-cholesterolb40 (males) or b50 (females) mg/dl Hypertension (BP ≥130/85) Hyperglycemia (glucose ≥ 110 mg/dl and N126 mg/dl and/or according to CRF) or diabetes (type I or II) or glucose ≥ 126 mg/dl d

Mean values of the main metabolic syndrome components Body mass index (BMI) (kg/m2) Waist circumference (cm) Triglycerides HDL-cholesterol SBP (mmHg) DBP (mmHg) a b c d e

b

Males (n = 863)

95%CI

%

24.6

22.4–26.8

42.4

b

Females (n = 555) b

pa

95%CI

%

95%CI

23.6

20.8–26.5

27.2

23.5–30.9

0.130

39.7–45.1

34.3

31.0–37.7

54.5

50.2–58.9

b0.001

37.3 35.4 54.1 14.2

34.7–40.0 32.6–38.2 51.5–56.7 12.4–16.0

40.7 28.5 59.0 13.3

37.2–44.2 25.1–31.9 55.7–62.3 11.1–15.6

32.4 46.1 46.0 15.3

28.3–36.5 41.4–50.8 41.8–50.2 12.3–18.3

0.003 b0.001 b0.001 0.293

m

SD

m

SD

m

SD

pe

27.9 95.4 145.9 49.9 127.1 77.4

4.9 17.4 89.5 15.9 15.8 10.2

27.8 98.3 154.1 48.0 128.8 78.3

4.3 16.4 93.4 15.4 15.0 9.4

28.0 90.9 134.3 52.7 124.4 75.8

5.6 18.2 83.9 16.4 16.7 11.2

0.725 b0.001 b0.001 b0.001 b0.001 b0.001

χ2 test ( p b 0.05). Percentages calculated from the total evaluable patients. Calculated according to NCEP-ATP III criteria (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults 2001). Also includes patients with diagnosis of diabetes or receiving antidiabetic treatment. Mann–Whitney U-test ( p b 0.05).

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16.5%). The mean duration of antipsychotic treatment was 136.4 weeks (SD = 210.1). Most of the patients included in the study did not present healthy lifestyle habits (Table 1).

of smokers and subjects with systolic hypertension among males than in females: 62.3% versus 40.4%, p b 0.001, and 30.9% versus 24.8%, p = 0.013 respectively (Table 2). The risk of CHD and CVM in 10 years increased with age in both sexes (Table 4).

3.3. Individual prevalence of CVRFs and CHD risk according to the Framingham function and CVM risk according to the SCORE function

3.4. Prevalence of metabolic syndrome and its components

Table 2 shows the individual prevalence of the main CVRFs in the total sample and by gender, as well as CVM risk (SCORE) and CHD risk (Framingham function) within 10 years. The overall CVM risk within 10 years was 0.9% (1.9), and was significantly higher in males than in females: 1.1% versus 0.5%, p b 0.001. The overall risk of CHD in 10 years was 6.8% (6.9), and was likewise significantly greater in males than in females: 8.3 versus 4.5, p b 0.001. These differences could be explained by the higher presence

The overall prevalence of MS (3 or more components) was 24.6% (Table 3), and was higher in females (27.2%) than in males (23.6%), — although the difference was not statistically significant ( p = 0.130). Two or more MS components were found in 49.9% of the sample presented: 54.8% in females versus 47.6% in males — the difference being significant ( p = 0.009). The individual prevalences of each MS component differed significantly between males and females, with the exception of hyperglycemia, abdominal obesity,

Table 4 Prevalence of CVM (SCORE) and CHD (Framingham) risk in 10 years and metabolic syndrome, according to age group and overall, in the total sample and by gender Total (n = 1452) %

b

Males (n = 863) 95%CI

%

b

Females (n = 555) b

pa

95%CI

%

0.0–6.2 0.0–1.6 0.1–2.3 5.4–15.9 47.0–70.1 77.3–99.2 7.8–12.0

0.0 0.0 0.0 0.0 9.4 71.4 5.2

0.0–10.7 0.0–3.1 0.0–2.6 0.0–3.3 2.2–16.5 54.7–88.2 3.3–7.2

NP NP 1.000 b0.001 b0.001 0.059 0.003

% of patients with high/very high 10 years risk of developing CHD (Framingham) b25 years 0.0 0.0–3.6 0.0 0.0–5.4 25–34 years 1.8 0.5–3.1 2.6 0.7–4.6 35–44 years 14.1 10.8–17.4 21.0 16.2–25.9 45–54 years 36.0 30.3–41.7 50.0 42.1–57.9 55–64 years 63.4 55.8–71.0 86.3 78.7–93.8 N65 years 56.6 43.3–69.9 86.4 66.7–95.3 Overall 20.7 18.6–22.8 26.5 23.6–29.5

0.0 0.0 2.5 18.2 38.4 35.5 11.7

0.0–9.4 0.0–2.9 0.1–4.9 11.3–25.1 27.2–49.5 18.6–52.3 9.0–14.4

NP 0.101 b0.001 b0.001 b0.001 b0.001 b0.001

% of patients with MS c b25 years 12.4 25–34 years 16.7 35–44 years 26.6 45–54 years 32.9 55–64 years 30.6 N65 years 35.2 Overall 24.6

10.8 20.0 27.8 33.9 28.8 45.2 27.2

0.8–20.8 13.1–26.9 20.9–34.7 25.5–42.3 18.4–39.2 27.6–62.7 23.5–30.9

0.768 0.260 0.720 0.804 0.507 0.093 0.130

% of patients with high/very high 10 years risk of CHD death (SCORE) b25 years 0.0 0.0–3.6 0.0 25–34 years 0.0 0.0–1.0 0.0 35–44 years 0.3 0.2–1.3 0.4 45–54 years 5.8 2.5–7.7 10.6 55–64 years 35.1 23.4–38.0 58.6 N65 years 81.6 63.9–87.1 95.2 Overall 8.0 6.5–9.5 9.9

6.1–18.7 13.0–20.3 22.5–30.8 27.4–38.4 23.5–37.8 22.4–47.9 22.4–26.8

13.4 15.5 26.2 32.5 33.8 22.7 23.6

5.3–21.6 11.1–19.8 21.0–31.4 25.1–39.9 23.4–44.1 5.2–40.2 20.8–26.5

95%CI

CHD = Coronary Heart Disease (fatal and non-fatal); MS = Metabolic Syndrome. NP: statistical significance could not be calculated because all patients belong to the same patients risk group. a χ2 test between males and females. b Prevalence calculated with respect to the global evaluable patients with 95% confidence interval. c Calculated according to NCEP-ATP III criteria (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults 2001).

J. Bobes et al. / Schizophrenia Research 90 (2007) 162–173

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Table 5 Comparative table of the prevalence of metabolic syndrome in different populations: patients with schizophrenia and Spanish population without schizophrenia Study (author and year)

Country

Patients

n

Mean age (years) or range (SD)

All subjects (%)

Male (%)

Female (%)

MS in schizophrenic patients: CLAMORS

Spain

1452

40.7 (12.2)

24.6

23.6

27.2

RICAVA (Cañas et al., 2006)

Spain

733

38.0 (11.3)

19

NA

NA

(Correll et al., 2006)

USA

367

42.9 (15.3)

37.3

37.9

36.7

(De Hert et al., 2006)

USA

430

36.5 (11.8)

28.4

28

29.1

(Meyer et al., 2006)

USA

80

49.0 (NA)

51.2 a

NA

NA

CATIE (McEvoy et al., 2005)

USA

1460

40.6 (11.1)

40.9

51.6

36.0

Saari et al. (2005)

Finland

31

NA

19

NA

NA

Kato et al. (2004)

USA

48

NA

63

NA

NA

Heiskanen et al. (2003)

Finland

Schizophrenics, outpatients Schizophrenics, from acute units Schizophrenics, inpatients Schizophrenics, outpatients Schizophrenics, outpatients Schizophrenics, outpatients Schizophrenics, outpatients Schizophrenics, outpatients Schizophrenics, outpatients

35

45.0 (10.4)

37

47.3

25

MS in general population in Spain: MESYAS (Alegría et al., 2005) b Oviedo (Álvarez-Cosmea et al., 2005)

Spain Spain

7256 358

45.4 (9.8) 56.5 (10.4)

10.2 23.5

NA NA

NA NA

Madrid (Coca et al., 2005) Segovia (Martínez-Larrad et al., 2005) DESIRE (Ascaso et al., 2004)

Spain Spain Spain

259 809 4232

54.8 (18.1) 54.0 (11.5) N45

28.6 18.9 22.6

NA 16.8 NA

NA 20.7 NA

ENCA (Álvarez et al., 2003) VIVA (Lorenzo et al., 2003)

Spain Spain

578 2947

N45 49.3 (13.1)

24.4 25.9

24.5 20.8

24.3 30.9

Working population Primary Care outpatients Primary Care outpatients General population Primary Care outpatients General population General population

NA: not available. a Age-adjusted metabolic syndrome prevalence. b Prevalence of metabolic syndrome calculated from modified NCEP criteria (body mass index ≥ 28.8 kg/m2 as criterion for abdominal obesity in substitution of waist circumference).

and hypercholesterolemia (more prevalent among females) and hypertriglyceridemia and hypertension (more prevalent among males) (Table 3). Arterial hypertension (54.1%) and abdominal obesity (42.4%) were the most prevalent components in the total sample. The prevalence of MS increased significantly with age in both sexes (Table 4). Table 3 also shows the individual mean values of the MS components and body mass index (BMI). There were no significant differences in BMI according to gender. Though, as expected, females had a significantly smaller mean waist circumference than males, and mean male value for waist circumference was below the threshold for abdominal obesity, whereas female mean value exceeded it — this situation coinciding with the greater prevalence of abdominal obesity in females:

54.5% versus 34.3% in males, p b 0.001 (Table 3). These data coincide with the significantly greater prevalence of obesity (BMI ≥ 30 kg/m2) in women than in men ( p b 0.001) (Table 1). 4. Discussion The CLAMORS study corroborates the results of earlier studies published in the literature. Table 5 shows a comparison of the prevalence of MS in the CLAMORS study and in previous studies of patients with schizophrenia in various health settings, and in populations without schizophrenia in Spain. In general, with the exception of the study by Saari et al. (2005) the prevalence of MS was found to be lower in the population with schizophrenia in Spain than in other

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countries. However, the prevalence of MS in Spanish patients with schizophrenia was in the range of that recorded in populations without schizophrenia aged 10 to 15 years older (Álvarez-Cosmea et al., 2005; Coca et al., 2005; Martínez-Larrad et al., 2005). Interestingly, this study found a high prevalence of obesity and abdominal adiposity, particularly among females, coinciding with the findings of the CATIE study (McEvoy et al., 2005, Stroup et al., 2006). Likewise, the prevalence of hypertension was above N 50%, and was particularly high in males — a finding clearly at odds with those of the CATIE study. Nevertheless, prevalence of MS in the Spanish population with schizophrenia was considerably lower than those reported in countries such as the United States, Finland, and Canada (Correll et al., 2006; De Hert et al., 2006; Meyer et al., 2006; McEvoy et al., 2005; Cohn et al., 2004; Kato et al., 2004; Heiskanen et al., 2003) — with the exception of the study published by Saari et al. (Saari et al., 2005), whose results were similar to those recorded in the present study. The prevalences of MS found in this study for males and females (23.6% and 27.2% respectively), were much lower than those reported in the CATIE study (36.0% and 51.6% respectively) in a population with schizophrenia of similar age (Goff et al., 2005a). The limited sample size in most of these studies should be borne in mind when interpreting the results. Mean age, one of the factors significantly associated with MS prevalence, does not appear to be responsible for the discrepancy, considering the similarity between the mean ages recorded in the various studies (with the exception of the US studies by Correll et al. (2006) and Meyer et al. (2006) and the Scandinavian study published by Heiskanen et al. (2003) with mean ages 2, 8, and 4 years older respectively). Therefore, the differences can be attributed to the fact that the present study records considerably lower individual prevalences of dyslipidemia (hypertriglyceridemia and low HDL-cholesterol) in both males and females. In the general population this phenomenon has previously been attributed to the possible effect of the dietary habits of Mediterranean populations (Bautista and Engler, 2005; Kokkinos et al., 2005; Serrano-Martínez et al., 2005; Gómez et al., 2005). The psychotic population of this study showed higher prevalences of main CVRF than those reported in the age-comparable general population in our setting (Aranceta et al., 2004). In the DORICA study by Aranceta et al. (2004) obesity rates were much lower for males and females in the general Spanish population than in our subjects with psychotic disorder: 13.2% and 17.5% versus 29.1% and 32.7% respectively for men and women. Similar findings were observed for

smoking (48.1% and 30.2% versus 62.3% and 40.4% respectively), and in women only for diabetes (2.4% versus 6.8%) and abnormally low HDL cholesterol level (33.1% versus 46.1%). The risk of CHD reported in this study is similar to that observed in the CATIE study at a comparable age: 9.4% for males and 6.3% and females (Goff et al., 2005a), and also similar to the results of Correll et al. (2006) and Cohn et al. (2004). However, the CLAMORS study found a non-negligible risk of CV mortality when using the SCORE function; 8% of the patients (9.9% in males and 5.2% in females) were at high or very high risk of CVM within 10 years, in a population with a mean age below 41 years. Like in earlier studies (Conley et al., 2005), the results of the present study also suggest that efforts to prevent cardiovascular diseases and cardiovascular risk in patients with schizophrenia should go beyond body weight control and should also be aimed to the control of different risk factors such as smoking, dyslipidemia, and the cardiovascular side effects of antipsychotic treatments, using following appropriate monitoring and management guidelines. The present study has several limitations. Though designed as a prevalence study, it assessed outpatient prevalence in mental health centers among patients with schizophrenia presenting for review of their health problem. No other population groups were included, such as children and adolescents, patients over 74 years of age, institutionalized subjects, patients not controlled by the Spanish National Health Care System, patients taking another antipsychotic treatment, or those not taking antipsychotic medication. Likewise, the study did not include a control group and did not have the opportunity to extract patients from public health surveys, as was the case in the NHANES III survey in the CATIE study (McEvoy et al., 2005, Stroup et al., 2006) and in the Canadian health survey (Cohn et al., 2004). Nevertheless, this limitation was partially offset by a sufficient number of Spanish publications presenting information that allows comparison (albeit indirect) of the prevalences studied. Furthermore, due to the patient sampling system, although we sought an equivalent presence of the different antipsychotics included in the study, it cannot be ruled out that the true prevalence of metabolic syndrome and cardiovascular risk may be somewhat different in routine clinical practice, where the distribution of antipsychotics is different (with an increased use of olanzapine, risperidone or haloperidol) — given the known effects that some of these drugs have on body weight and carbohydrate and lipid metabolism.

J. Bobes et al. / Schizophrenia Research 90 (2007) 162–173

The results of the CLAMORS study, together with the previously published data, suggest that clinicians treating patients with schizophrenia with antipsychotics should appropriately monitor the CVRFs discussed here – including the components of MS – and should be ready to intervene as required (Goff et al., 2005a). In particular, our study highlights the need for intervention programs targeted to reduce smoking (Goff et al., 2005a) and to improve diet, including efforts to combat general and abdominal obesity (Goff et al., 2005b), in these patients, and also the need to consider the CVRFs mentioned here, in order to ensure the best possible choice of antipsychotic treatment and general management in all cases. In conclusion, the CLAMORS study has shown that the prevalence of MS in Spanish patients with schizophrenic, schizophreniform and schizoaffective disorders receiving antipsychotic therapy, while lower than in North America or Scandinavia, seems considerably higher than in the reference general and clinical populations, presenting values that these latter populations reach only when 10 to 15 years older. This situation in an already excessively stigmatized patient population group should be a source of concern for public health care and society as a whole. Acknowledgement Pfizer España provided an unrestricted grant for this multicenter, cross-sectional study. Pfizer España contributed to and approved the study design and the final draft of the manuscript. A CRO was engaged by Pfizer España to conduct the study, including logistics, monitoring, data management, and statistical analysis. Pfizer España oversaw the entire process of the study. Conflict of interest: Drs. Bobes, Arango, Aranda and Carmena have been consultants for Pfizer España. Ms Garcia-Garcia is an employee of Biometrica, a CRO contracted by Pfizer España. D. Rejas is an employee of Pfizer España. Contributors: All authors contributed to and have approved the design and the protocol of the study, the literature searches and analyses, and the first and final draft of the manuscript. All of them contributed substantially to all parts of the manuscript, including references and tables. References Alegría, E., Cordero, A., Laclaustra, M., Grima, A., León, M., Casasnovas, J.A., Luengo, E., del Río, A., Ferreira, I., en representación de los investigadores del registro MESYAS, 2005. Prevalencia del síndrome metabólico en población laboral española: registro MESYAS. Rev. Esp. Cardiol. 58, 797–806.

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