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y 30 (2008) 318–323

General Hospital Psychiatr

Metabolic syndrome in Italian patients with bipolar disorderVirginio Salvi, M.D.a,⁎, Umberto Albert, M.D., Ph.D.a, Alice Chiarle, M.D.a,

Isabella Soreca, M.D.b, Filippo Bogetto, M.D.a, Giuseppe Maina, M.D.aaDepartment of Neuroscience, Psychiatry Clinic, University of Turin, 10126 Turin, Italy

bWestern Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh, PA 15213, USA

Received 22 January 2008; accepted 23 April 2008

Abstract

Objective: This study aimed to evaluate the prevalence of metabolic syndrome (MetS) in Italian patients with bipolar disorder (BD) and todetermine the sociodemographic and clinical correlates of MetS in this patient population.Method: Subjects with BD I and II were included. Sociodemographic and clinical characteristics, lifestyle information (alcohol and smokinghabits and rate of physical exercise) and comorbidity for cardiovascular diseases and diabetes were collected. Patients were assessed for MetSaccording to both National Cholesterol Education Program Adult Treatment Panel III and International Diabetes Federation (IDF) criteria.Results: MetS was evaluated in 99 patients out of 108 who were enrolled. MetS was present in 25.3% of the sample. Abdominal obesity waspresent in 50%, hypertension in 40%, high triglycerides in 34.7%, low HDL-C levels in 32.3% and fasting hyperglycemia in 11% of thesample. Prevalence of MetS was 30% when IDF criteria were employed. Of the investigated variables, age, duration of illness, rate of obesityand cardiovascular disease were higher in patients with MetS. After the regression analysis, only age and obesity were associated to MetS.Conclusions: MetS is highly prevalent in Italian patients with BD. Our 25.3% prevalence rate is consistent with the 21–22% reported inother European studies and lower than that in U.S. studies. Elderly and obese patients with BD are at particularly high risk for MetS.© 2008 Elsevier Inc. All rights reserved.

Keywords: Metabolic syndrome; Cardiovascular risk; Bipolar disorder

1. Introduction

Metabolic syndrome (MetS) is a constellation of meta-bolic abnormalities that include abnormal glucose metabo-lism (type 2 diabetes, impaired glucose tolerance or alteredfasting glycemia), central obesity, atherogenic dyslipidemia,reduced HDL cholesterol and hypertension. When groupedtogether, these conditions are associated with an increasedprevalence of cardiovascular disease [1,2], type 2 diabetes[3,4] and stroke [5].

Bipolar disorder (BD) has often been associated tounhealthy lifestyles, such as excessive caloric and choles-terol intake, cigarette smoking and physical inactivity [6,7],all factors known to increase cardiovascular risk [8,9].Moreover, patients with BD are exposed to lifelong use ofmedications such as antipsychotics or mood stabilizers that

⁎ Corresponding author.E-mail address: v_a_salvi@hotmail.com (V. Salvi).

0163-8343/$ – see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.genhosppsych.2008.04.009

have been associated to weight gain, dyslipidemia anddevelopment of diabetes [10,11]. Finally, the associationbetween BD and polycystic ovary syndrome, whether or notdriven by the use of valproate, is another risk factor formetabolic disturbances [12,13]. Several studies have indeeddemonstrated a higher risk for obesity [14–17] and diabetes[18–20] in patients with BD.

These observations led to the investigation of theprevalence of MetS in bipolar patients. Two studies carriedover 171 and 98 bipolar patients from the United States foundremarkably high rates of MetS of 30% and 49%, respectively[21,22]. However, studies performed in European countrieshave reported much lower rates ofMetS than the U.S. studies.A study conducted in Norway reported the occurrence ofMetS in 21.5% of 110 screened patients with BD [23], andanother recent study conducted on 194 Spanish patients withBD found equivalent rates of MetS of 22.4% [24].

Different lifestyles and ethnicities might account for theobserved lower rate of MetS in European countries. Indeed,it has been stated that the criteria used to define MetS

319V. Salvi et al. / General Hospital Psychiatry 30 (2008) 318–323

populations should slightly differ according to the testedpopulations. The International Diabetes Federation (IDF)stated that obesity, a key factor in determining the occurrenceof the whole syndrome, should be differently assessed inWestern, European and Asian countries, due to a highcardiovascular risk profile in European and Asian subjectseven with a lower threshold for abdominal obesity. On thesepremises, new criteria for the diagnosis of MetS have beenissued [25], although almost all recently published studiesstill employ the National Cholesterol Education ProgramAdult Treatment Panel III (NCEP ATP III) criteria [26].

The aim of our study was to investigate the prevalenceand the sociodemographic and clinical correlates of MetS ina naturalistic Italian sample of inpatients and outpatients withBD utilizing the NCEPATP III criteria. A secondary aim wasto evaluate the prevalence of MetS according to the recentlyissued IDF criteria.

2. Methods

The study had a naturalistic design and involved patientsadmitted to the Psychiatric Inpatient Unit and to the Moodand Anxiety Disorders Outpatient Unit of the University ofTurin (Italy) from April 2006 to September 2007.

2.1. Subjects

All patients consecutively admitted to the inpatient unit ofthe psychiatric clinic of the University of Turin wereconsidered for the present study. Patients with a diagnosisof BD I, II or NOS (DSM-IV) were asked to participate. Theaims of the study as well as study procedures werethoroughly explained to potential participants who gavewritten consent before participation.

Exclusion criteria included age ≤18 years, pregnancy orhaving just gave birth and refusal to give consent prior toparticipating in the study. All subjects were of CaucasianItalian origin.

2.2. Assessments and procedures

All subjects were diagnosed by means of the StructuredClinical Interview for DSM Axis I Disorders [27]. At studyentry, general sociodemographic information was collectedfor each subject.

Lifestyles were also investigated in the study sample:information about exposure to cigarette smoking, duration ofalcohol consumption and physical activity was obtained bydirectly interviewing the patients. A score was assigned tothe intensity of physical activity: absent, mild (b4 h/week),moderate (4 h/week) and intense (N4 h/week, regular) [28].

Comorbidity and family history for diabetes or cardio-vascular diseases and current treatments for hypertension,diabetes or dyslipidemia were assessed by looking at medicalreports and by directly interviewing the patients.

At index visit, weight, height, waist circumference andblood pressure were measured. Weight was measured with

the participant undressed and fasting height was measuredbarefoot. Patients with a BMI≥30 were categorized as obeseaccording to the WHO classification [29,30]. Waist circum-ference, measuring central adiposity, was measured midwaybetween the inferior margin of the ribs and the superior borderof the iliac crest, at minimal respiration. Two blood pressuremeasurements were obtained by using a mercury sphygmo-manometer: the first with the subject in a lying position andthe second with the subject in a seated position at least 2 minafter the first measurement. The mean blood pressure of thetwo measurements was used. All the procedures wereperformed by the attending physician in the hospital setting.

A blood draw for routine blood exam was performedupon hospital admission for inpatients, as part of the clinicalmanagement routine. For outpatients, results of previousblood examinations were considered valid if the last bloodsample was drawn within 2 months before entry in the study;otherwise, patients were scheduled for a blood test within aweek from the study visit. At the time when blood wasdrawn, patients were fasting for the previous 10 h; patientswho did not fast were rescheduled. Blood exams includedassessment of the following: glucose, total cholesterol,triglycerides, LDL and HDL-C. Blood samples were drawnin our clinic and examined in the Laboratorio Analisi Baldi eRiberi, San Giovanni Battista Hospital, Turin, Italy.

Patients were stated to have MetS if they endorsed at leastthree out of the following five criteria, according to NCEPATP III:

• Abdominal obesity: waist circumference N102 cm inmen and N88 cm in women

• Hypertriglyceridemia: ≥150 mg/dl or on lipid-low-ering medication

• Low HDL-C: b40 mg/dl in men and b50 mg/dl inwomen

• High blood pressure: systolic pressure ≥130 mmHgand diastolic pressure ≥85 mmHg or on antihyperten-sive medication

• High fasting glucose: ≥110 mg/dl or on glucose-lowering medication

We also assessed the prevalence of MetS according to theIDF criteria. Abdominal obesity, defined by a waistcircumference ≥94 cm in men and ≥80 cm in women, andmeeting two of the following criteria were required to arriveat a diagnosis of MetS:

• Raised triglycerides: ≥150 mg/dl or specific treatmentfor this lipid abnormality

• Reduced HDL cholesterol: b40 mg/dl in men andb50 mg/dl in women or specific treatment for this lipidabnormality

• Raised blood pressure: systolic blood pressure ≥130mmHg and/or diastolic blood pressure ≥85 mmHg ortreatment of previously diagnosed hypertension

• Raised fasting plasma glucose: fasting plasma glucose≥100 mg/dl or previously diagnosed type 2 diabetes

able 2revalence of MetS (NCEP ATP III) and its components

riteria n (%)

bdominal obesity: N102 cm (men) and N88 cm (women) 51 (50)ypertriglyceridemia: ≥150 mg/dl or being onlipid-lowering medication

35 (34.7)

ow HDL-C: b40 mg/dl (men) or b50 mg/dl (women) 31 (32.3)igh blood pressure: ≥130/85 mmHg or beingon antihypertensive medication

42 (40)

igh fasting glucose: ≥110 mg/dl or being onglucose-lowering medication

11 (11)

etS (three or more criteria) 25 (25.3)

320 V. Salvi et al. / General Hospital Psychiatry 30 (2008) 318–323

2.3. Statistical analysis

Subjects' characteristics were summarized as mean and S.D. for continuous variables and frequency and percentage forcategorical variables. We examined demographic andclinical correlates of MetS by way of chi-square in the caseof categorical variables, performing the Yates correction inthe case of a 2×2 table and independent-samples t tests in thecase of continuous variables. In order to control forconfounding factors, we entered the significant independentvariables in a stepwise logistic regression analysis with MetSas the dependent variable.

All data were analyzed using SPSS version 14.0 (SPSSInc., Chicago).

3. Results

One hundred eight patients with BD were recruited in thestudy. The mean (±S.D.) age of the sample was 51.7±13.9years; 59.3% of the patients were females; 64.8% had bipolarII disorder; the mean (±S.D.) duration of illness was 19.2±12.6 years. Patients were on a mean (±S.D.) of 2.6±1.2medications for BD; 84.9% were receiving at least one moodstabilizer, 37.7% were receiving at least one antipsychoticand 60.4% were treated with at least an antidepressant. Themean (±S.D.) BMI was 26.9±5.2 kg/m2. All sociodemo-graphic and clinical characteristics are displayed in Table 1.

Of the 108 patients in the study, 99 had completelaboratory and clinical data: the subsequent analyses werecomputed on these patients. MetS was present in 25.3% ofthe sample when the NCEP ATP III criteria were used.Abdominal obesity was the most frequently endorsedcriterion, present in 50% of the subjects. Hypertension wasthe second most frequent metabolic abnormality, affecting40% of participants. High triglycerides, low HDL-C levelsand fasting hyperglycemia were observed in 34.7%, 32.3%

Table 1Sociodemographic and clinical characteristics of the sample

Characteristics Value

Females, n (%) 64 (59.3)Age (years), mean±S.D. 51.7±13.9Education years, mean±S.D. 12.1±7.9Occupational status, n (%)White collar 42 (38.9)Blue collar 19 (17.6)Housewife 18 (16.7)Student 3 (2.8)Retired 16 (14.8)Unemployed 10 (9.3)

Bipolar I, n (%) 38 (35.2)Duration of illness, mean±S.D. 19.2±12.6Number of medications for BD, mean±S.D. 2.6±1.2Mood stabilizers, n (%) 90 (84.9)Antipsychotics, n (%) 40 (37.7)Antidepressants, n (%) 64 (60.4)BMI, mean±S.D. 26.9±5.2

TP

C

AH

LH

H

M

and 11% of the sample, respectively (Table 2). When IDFcriteria were employed, prevalence of MetS was 30%.

Table 3 describes clinical and sociodemographic corre-lates of MetS. Subjects with MetS were significantly older(58.2±14.3 years) than those without the syndrome (50.1±13.7 years, t=−2.51, df=97, P=.014). Prevalence of MetSwas not significantly different with regard to gender, years ofeducation and occupational status.

Patients with MetS had a significantly longer duration ofillness (24.3 years vs. 17.6 years) than patients without MetS(t=−2.26, df=96, P=.026). Other clinical variables were notsignificantly associated to the presence of MetS.

Smoking status, alcohol consumption and physicalactivity were not different between patients with and thosewithout MetS.

MetS was strongly associated with diabetes and cardio-vascular disease: 60% of patients with MetS had a diagnosisof either cardiovascular disease or diabetes, versus 20.3% ofthose without MetS (χ2=13.966, df=1, Pb.001). MetS wasalso significantly more prevalent in patients with obesity:52% of patients with MetS had BMI ≥30 versus 12.7% ofthose without MetS (χ2=16.186, df=1, Pb.001).

We then performed a logistic stepwise regression analysiswith MetS as the dependent variable and age, duration ofillness and obesity as covariates. We decided not to includecomorbidity for cardiovascular disease, even though it issignificantly associated with MetS, because it appears to bemore an outcome than a predictor of MetS.

After performing the regression analysis, only age andobesity were still significantly associated to MetS.

4. Discussion

This is the first study to examine the prevalence andcorrelates of MetS in Italian patients with BD. Our cross-sectional observation confirms that MetS is highly prevalentin patients with BD, across different ethnical and culturalbackgrounds. We found a prevalence of MetS of 25.3%among patients with BD, which is definitely higher thanthose reported in the Italian general population: severalstudies conducted in northern and central Italy employingNCEP ATP III criteria have reported highly homogeneous

Table 3Characteristics of patients with or without MetS (NCEP ATP III)

MetS No MetS Statistics

t/χ2 df P

Gender, % females 56 63.5 0.446 1 .504Age, mean±S.D. 58.2±14.3 50.1±13.7 −2.508 97 .014Education years, mean±S.D. 10.2±4.3 12.8±8.9 1.372 96 .173Type of BD, % BD I 36 33.8 0.041 1 .840Age at onset, mean±S.D. 33.5±14.5 32.5±12.9 −0.338 96 .736Duration of illness, mean±S.D. 24.3±13.6 17.6±12.3 −2.255 96 .026Number of manic episodes, mean±S.D. 4.0±6.0 2.9±2.2 −0.870 23.933 .393Number of depressive episodes, mean±S.D. 6.4±6.1 4.4±3.1 −1.568 25.694 .129Current psychiatric comorbidity 66.7 60.3 0.313 1 .576Lifetime psychiatric comorbidity 50 51.4 0.013 1 .908Number of medications for BD, mean±S.D. 2.6±1.3 2.7±1.2 0.350 96 .727Psychiatric family history, % 36 48.6 1.206 1 .272Years of cigarette smoking, mean±S.D. 35.3±10.4 29.1±12.9 −1.263 40 .214Years of alcohol consumption, mean±S.D. 29.5±11.3 31.6±12.3 0.417 26 .680Physical activity, % 4.286 3 .232Absent 64 50.7Mild 24 21.9Moderate 4 21.9Intense 8 5.5Obesity, % 52 12.7 16.186 1 b.001Cardiovascular/diabetes comorbidity, % 60 20.3 13.966 1 b.001Cardiovascular/diabetes family history, % 48 46.6 0.015 1 .902

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rates ranging from 16% to 17.8% [28,31–33]. Thus, subjectswith BD are at higher risk for developing MetS than theItalian general population.

Various studies conducted in bipolar samples reportprevalence rates from 21–22% in European subjects [23,24]to 30–49% in U.S. subjects [22]. Our 25.3% prevalence rateis consistent with those reported in European studies andlower than the rates reported in U.S. studies. Nevertheless,rates of MetS in the general population have consistentlybeen lower for European than for U.S. populations,suggesting a generally higher risk for MetS in U.S. patients,probably due to lifestyle differences.

When analyzing the prevalence of the single componentsof MetS in our population, we found that abdominal obesityis the most common metabolic abnormality, followed byhypertension and hypertriglyceridemia and low HDL-Clevels. Our patients with BD display a very similar pattern ofmetabolic abnormalities to that seen in Spanish patients, withthe exception of hypertension, which was more prevalent inour sample and similar to U.S. rates. This observation givesstrength to the hypothesis that the different nutritionalpatterns seen in the Mediterranean area could play a role indetermining a lower risk for MetS and, specifically,hypertriglyceridemia in these patients.

Sociodemographic characteristics such as gender andyears of education were not associated to MetS. Thesefindings are in line with a recent study conducted on aNorwegian sample that did not find any difference regardinggender and education in patients versus controls, despite themetabolic disturbances that were more represented in thepatient group [34].

A higher age, a long duration of bipolar illness and ahigher prevalence of obesity were initially associated to thepresence of MetS. However, after these significant variableswere entered in a logistic regression analysis, duration ofillness was no longer significantly associated with MetS,showing that this association was a by-product of older age.Our results are very similar to those reported in the recentstudy by van Winkel et al. [35], in which patients withBD and MetS were older and more overweight/obese thanthose without.

Aging is commonly accompanied by a loss of musclemass and by an increase in body fat, particularly in theabdomen; both of these changes can increase insulinresistance and eventually lead to MetS [25].

Obesity, particularly central obesity, is associated to ahigher rate of flux of adipose tissue-derived free fatty acids tothe liver, eventually leading to dyslipidemia. Moreover,visceral adipose tissue is a source of tumor necrosis factor-alpha and is associated with a decreased production ofadiponectin: both these factors may lead to insulin resistance[36,37]. Finally, an increase in circulating fatty acids and ininsulin resistance may lead to the development of hyperten-sion [38].

Once established, MetS is a strong risk factor forcardiovascular disease and/or diabetes. This association isalso highlighted by our data, as 60% of our patients withMetS have a medical history of cardiovascular diseaseor diabetes.

When we used the IDF criteria, we obtained a slightlyhigher prevalence of MetS of 30%: seven patients that didnot have MetS with the ATP III criteria endorsed the

322 V. Salvi et al. / General Hospital Psychiatry 30 (2008) 318–323

diagnosis with the IDF criteria. To date, prospective andcross-sectional studies trying to address the usefulness ofapplying the IDF diagnostic criteria failed to show strongassociations with adverse cardiovascular outcomes [39–41].In our study, the few patients diagnosed with the IDF criteriabut not with the ATP III criteria displayed the samecardiovascular illness and diabetes comorbidity rate ofpatients without MetS; thus, we can conclude that in oursmall sample of patients with BD, IDF criteria could notidentify patients at current high risk for cardiovasculardisease or diabetes. However, whether these patients will beat high risk for adverse cardiovascular outcomes in the futureshould be assessed through larger, prospective studies.Interestingly, our patients with comorbidity for cardiovas-cular disease or diabetes had a significantly higher rate ofcardiovascular family history, while patients with MetS didnot (data not shown). Therefore, it can be hypothesized that,in patients with BD, MetS is likely driven by illness-relatedrisk factors, such as unhealthy lifestyles, stress or prolongedmedication regimen, more than by constitutional factors.This hypothesis, if confirmed by further studies, has relevantimplications, suggesting that a systematic preventionprogram based on lifestyle changes and review of weight-inducing medications might effectively reduce the risk forcardiovascular events and eventually death in these patients,since they would not display a higher genetic diathesis forcardiovascular disease or diabetes than the general popula-tion. Clearly, further prospective studies should be aimed atconfirming this preliminary finding.

One limitation of this study is its cross-sectional design:cross-sectional data can only show measures of association,without allowing inferences on the causal relationshipbetween the variables. Nevertheless, they can be used ashypotheses generators, to be tested in longitudinal observa-tions. Furthermore, the significant association betweenobesity and MetS and, moreover, its association withcardiovascular disease or diabetes confirm the utility of asystematic screening for metabolic abnormalities in patientswith BD, which should be performed even in busypsychiatric hospital settings in order to identify patients atrisk for adverse cardiovascular outcomes.

Another limitation of the study is the lack of a controlgroup from the general population. However, the subjects inour study are similar to the individuals included in otherstudies on the Italian general population [28,31–33] withregard to mean age, gender distribution and ethnicity;therefore, the MetS rate in our patients can be indirectlybut reliably compared to the very homogeneous ratesobtained in those studies.

In conclusion, notwithstanding the healthy nutritionalhabits that characterize Mediterranean populations, Italianpatients with BD are at high risk of MetS. Weight and waistcircumference assessment and blood examinations should beroutinely performed in this patient population, whose generalmedical issues are frequently neglected. Simple preventionprograms such as lifestyle interventions or nutritional

counseling might have a huge impact in reducing theincidence of MetS and, consequently, the risk of adversecardiovascular outcome in patients with BD.

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