Gender-specific lipid profiles in patients with bipolar disorder

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<ul><li><p>werd, S</p><p>Keywords:DyslipidemiaBipolar disorderGenderInsulin resistanceMetabolic</p><p>slipgetpa</p><p>alitiesic synd</p><p>lipoprotein (LDL) cholesterol, triglycerides (TG), and high-densitylipoprotein cholesterol (HDL) are independent risk factors forcoronary heart disease (CHD) (NCEP, 2002). LDL remains theprimary treatment target of the National Cholesterol EducationProgram (NCEP) Adult Treatment Protocol (ATP) III (NCEP, 2002).</p><p>et al., 1991; Williams, 2004). These gender differences in lipidsappear to be highly correlated with age and abdominal obesity(Gostynski et al., 2004; Seidell et al., 1991). In the U.S., genderdifferences in lipid distribution appear to be changing. NationalHealth and Nutrition Examination Survey (NHANES) 2003e2006data showed a higher prevalence of lipid abnormalities in womenversus men (American Heart Association, 2010; Regitz-Zagroseket al., 2007), possibly driven by increasing obesity in women(Regitz-Zagrosek et al., 2007). Gender differences in lipids are</p><p>* Corresponding author. Tel.: 1 650 725 1774; fax: 1 650 724 9900.</p><p>Contents lists availab</p><p>Journal of Psych</p><p>lse</p><p>Journal of Psychiatric Research 45 (2011) 1036e1041E-mail address: mvemuri@stanford.edu (M. Vemuri).patients with bipolar disorder (BD) (Fagiolini et al., 2005;Fiedorowicz et al., 2008; Garcia-Portilla et al., 2008; Kilbourneet al., 2004; Sicras et al., 2008; Van Winkel et al, 2008), all ofwhich are modiable risk factors for cardiovascular disease (CVD)(Newcomer, 2009).</p><p>Evaluating dyslipidemia is a component of routine medicationmonitoring in BD, and thus places the treating psychiatrist in theposition of identifying modiable risk factors for CVD. Low-density</p><p>dyslipidemia, and possibly mood disorders (NCEP, 2002; Rasgonand Jarvik, 2004; Rasgon et al., 2002).</p><p>In the general population, women compared to men havehistorically lived longer, developed cardiovascular disease at anolder age, and had more favorable lipid proles (Regitz-Zagroseket al., 2007). Internationally, women compared to men consis-tently have more favorable lipid proles, lower TC, LDL, TG andhigher HDL (Gardner et al., 2000; Gostynski et al., 2004; Seidell1. Introduction</p><p>High rates of metabolic abnormdiabetes, obesity, and the metabol0022-3956/$ e see front matter 2011 Elsevier Ltd.doi:10.1016/j.jpsychires.2011.02.002LDL, HDL, TG) at clinicians discretion, a psychiatry clinic visit within 2 months of laboratory, and werenot medicated for dyslipidemia were included. IR was imputed from TG/HDL ratio.Results: Women, compared with men, had signicantly lower mean triglycerides (105.58 64.12 vs.137.99 105.14, p 0.009), higher mean HDL cholesterol (60.17 17.56 vs. 46.07 11.91 mg/dl,p &lt; 0.001), lower mean LDL cholesterol (109.84 33.47 vs. 123.79 35.96 mg/dl, p 0.004), and lowerTG/HDL ratio (1.98 1.73 vs. 3.59 3.14 p &lt; 0.001). Compared to men, women had a signicantly lowerprevalence of abnormal total cholesterol, LDL, TG, HDL, and TG/HDL ratio. No signicant differences werefound between men and women with regard to age, BMI, ethnicity, educational attainment, smokinghabits, bipolar illness type, illness severity or duration, or weight-liable medication exposure.Discussion: In outpatients with BD, women had more favorable lipid proles than men despite similardemographic variables. This sample of primarily Caucasian and educated patients, receiving vigilantclinical monitoring, may represent a relatively healthy psychiatric population demonstrating genderdifferences similar to those in the general population.</p><p> 2011 Elsevier Ltd. All rights reserved.</p><p>such as dyslipidemia,rome (MetS) occur in</p><p>The ratio of TG to HDL cholesterol (TG/HDL) has been proposed asa proxy marker of insulin resistance (IR) (McLaughlin et al., 2005),a condition in which tissue responsiveness to the normal action ofinsulin is impaired, and is related to the development of diabetes,Accepted 4 February 2011</p><p>ment. BD patients (n 234; 61% female; 42% Type I, 47% Type II, 11% NOS) with a mean age of 40.3 14.0years, mean BMI 26.8 6.4, and 81% Caucasian, who had one of four lipid measures (total cholesterol,31 January 2011 2000 and 2007 were evaluated. Patients were followed longitudinally and received naturalistic treat-Gender-specic lipid proles in patients</p><p>Mytilee Vemuri*, Heather A. Kenna, Po W. Wang, TDepartment of Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Roa</p><p>a r t i c l e i n f o</p><p>Article history:Received 15 April 2010Received in revised form</p><p>a b s t r a c t</p><p>Objective: High rates of dydisorder (BD). We assessedMethods: Data from 491 ou</p><p>journal homepage: www.eAll rights reserved.ith bipolar disorder</p><p>ence A. Ketter, Natalie L. Rasgontanford, CA 94305-5723, United States</p><p>idemia and insulin resistance (IR) are reported in patients with bipolarnder effects upon rates of dyslipidemia/IR in outpatients with BD.tients (ages 18e88) seen in the Stanford Bipolar Disorders clinic between</p><p>le at ScienceDirect</p><p>iatric Research</p><p>vier .com/locate/psychires</p></li><li><p>iatriattributed to sex steroid hormone inuence on lipids and on sexdifferences in fat distribution; specically abdominal fat tissue ismore abundant in men compared to premenopausal womenfavoring development of insulin resistance (IR), dyslipidemia andhypertension (Regitz-Zagrosek et al., 2007). After menopause,lipoprotein concentrations and fat distribution shift to a more malepattern (Ley et al., 1992).</p><p>In contrast to gender differences in the general population,women in psychiatric populations appear to have higher rates ofmodiable CVD risk factors, such as obesity (Wang et al., 2006) andMetS (McEvoy et al., 2005; Teixeira and Rocha, 2007), relative tomen, suggesting substantive vulnerability to CVD and its riskfactors in women with mental illness. While women with BDhave high rates of dyslipidemia (Stemmle et al., 2009), genderdifferences in dyslipidemia have not been well characterized inpsychiatric populations. In this study, we compared lipid valuesbetween female and male outpatients with bipolar disorder (BD).Given existing published data suggesting women with mentalillness have a higher vulnerability to CVD and its risk factors, wehypothesized that women with BD would have less favorable lipidproles than men.</p><p>2. Methods</p><p>The study was approved by the Stanford University Adminis-trative Panel on Human Subjects, and patients provided verbal andwritten informed consent prior to participation. Data wereanalyzed from all outpatients (age 18e88) seen in the Stanfordoutpatient Bipolar Disorders clinic between January 2000 and June2007 who had consented to longitudinal data review of theirmedical records and who were seen for ongoing evaluation. Indi-viduals seen for one-time consultations were not included. A totalof 491 patient records were reviewed. Patients were included inanalysis (n 234) if the following criteria were met: a) patient metDSM-IV diagnostic criteria for bipolar disorder b) patient receivedone of four concurrent lipid measures within twomonths of a clinicvisit including: Total cholesterol (TC) (n 256), Triglycerides (TG)(n 253), Low-Density Lipoprotein (LDL) (n 238), High-DensityLipoprotein (HDL) (n 250), and c) were not concurrently treatedwith lipid-lowering medications. In this sample, neither genderwas signicantly more likely to be treated with a lipid-loweringmedication (c2 2.05, p 0.152), nor were there signicantdifferences in lipid values by gender within the 22 patients treatedwith lipid-lowering medication.</p><p>2.1. Intake evaluations and clinical follow-up</p><p>Baseline clinical evaluations were performed using theSystematic Treatment Enhancement Program for Bipolar Disorder(STEP-BD) Affective Disorders Evaluation (ADE) (Sachs et al., 2003)to establish psychiatric diagnosis of BD, and to derive clinicalinformation including age, current and previous medication treat-ment, years since rst episode, bipolar illness type, and height.Demographic information, including self-reported gender, race,and education attainment was collected by patient self-assess-ments and interview. Patients received naturalistic treatmentguided by model practice procedures, which included publishedpharmacotherapy guidelines (Dennehy et al., 2007). Clinical infor-mation, including psychotropic treatment, weight, and illnessseverity, measured by Clinical Global Inventory (CGI), was longi-tudinally collected using STEP-BD Clinical Monitoring Form (CMF)(Sachs et al., 2002).</p><p>For analytic purposes, patients were classied into three medi-cation categories based on the medication taken at time of veni-</p><p>M. Vemuri et al. / Journal of Psychpuncture: 1) weight-liable mood stabilizer/antipsychotic (i.e.associated with substantive weight-gain risk): lithium (Bowdenet al., 2000), valproate (Bowden et al., 2000), oxcarbazepine(Vieta et al., 2008), olanzapine (Tohenet al., 2006), clozapine (Allisonet al., 1999), quetiapine (Weisler et al., 2009), risperidone (Quirozet al., 2010), or aripiprazole (Keck et al., 2006); 2) non-weight-liable mood stabilizer/antipsychotic (associated with non-substan-tive weight-gain risk): lamotrigine (Sachs et al., 2006), ziprasidone(Bowden et al., 2009) or carbamazepine (Weisler et al., 2006), or 3)no mood stabilizer/antipsychotic. Only second-generation antipsy-chotics, if any, were received by patients in the present analysis.Patients were only included in a mood stabilizer/antipsychoticcategory if they had been treated for aminimum of sixmonths withthe above mentioned medication classes. If patients were concur-rently treated with both weight-liable and non-weight-liablemedications, they were included in the weight-liable group.</p><p>2.2. Assessment of lipids and metabolic function</p><p>Fasting blood lipid panels and thyroid function laboratorieswere obtained at clinician discretion during each patients treat-ment as part of routine screening and follow-up. The most recentlaboratory assessment for each patient during period from January2000 to June 2007 was used in this analysis. Body Mass Index (BMI;in kg/m2) was assessed based on height at intake and weight notedat the time of clinical assessment, within two months of laboratorydate.</p><p>2.3. Statistics</p><p>All statistical analyses were performed using the SPSS softwarefor windows, version 17.0 (SPSS, Chicago, Ill). Gender differences indemographic and clinical variables and lipid values were evaluatedusing t-tests, chi-square tests and Fishers exact tests. Genderdifferences in prevalence of abnormal lipid values were evaluatedusing chi-square tests. Pearson correlations were used to assessassociations of the blood lipid values with age, BMI, illness dura-tion, education level, CGI score, and years since rst episode in thesample as awhole, and variables that were found to be signicantlyassociated with mean lipid values were included in the nalmultivariate analysis of variance (MANOVA) of gender differencesin blood lipid parameters. One-way ANOVAs were used to assessdifferences in blood lipid levels by medication categories (weight-liable, non-weight-liable, or none), bipolar illness type, hypothy-roidism, or nicotine use. All statistical tests used a 0.05 signicancelevel, with no correction for multiple comparisons.</p><p>3. Results</p><p>Of the 234 patients included in the analysis 61% were female,81% were Caucasian, 42% had Bipolar I Disorder, 47% had Bipolar IIDisorder, and 11% had Bipolar Disorder Not Otherwise Specied.The mean standard deviation age was 40.3 14.0 years, andmean BMI was 26.8 6.4. Demographic and clinical characteristicsof all 234 patients included in the analysis are presented by genderin Table 1. Patients in our sample tended to be relatively afuent,well-educated, and Caucasian. No signicant differences werefound between men and womenwith regard to age, BMI, ethnicity,educational attainment, smoking habits, TSH, bipolar illnesssubtype, illness severity or duration, or weight-liable medicationexposure. Mean lipid values for men and women are presented inTable 2 and Fig.1. Prevalence of abnormal lipid values are presentedin Table 3. Compared to men, women had signicantly lower meantriglycerides (105.58 64.12 vs. 137.99 105.14 mg/dl, p 0.009),LDL (109.84 33.47 vs.123.79 35.96 mg/dl, p 0.003) and TG/</p><p>c Research 45 (2011) 1036e1041 1037HDL ratio (1.98 1.73 vs.3.59 3.14, p &lt; 0.001), and signicantly</p></li><li><p>Table 1Demographic and clinical characteristics of study sample by gender (N 234).</p><p>Men(n 91)</p><p>Women(n 143)</p><p>Statistic p value</p><p>Mean SDAge (yrs) 40.59 14.66 40.05 13.66 t 0.287 0.774BMI 27.61 6.06 26.33 6.53 t 1.444 0.150CGI 2.71 1.16 2.8 12.1 t 0.544 0.587Yrs since rst</p><p>episode21.36 15.11 22.03 12.93 t 0.363 0.717</p><p>n (%)</p><p>M. Vemuri et al. / Journal of Psychiatr1038Caucasian 72 (79%) 118 (83%) c2 0.420 0.517College graduates 30 (33%) 46 (32%) c2 0.068 0.794Daily smokers 13 (14%) 19 (13%) c2 0.054 0.816Bipolar typeBipolar I 41 (45%) 57 (40%) c2 5.760 0.056Bipolar II 35 (38%) 75 (52%)Bipolar NOS 14 (15%) 11 (7%)</p><p>TSH category&gt;Reference range 2 (2%) 4 (3%) c2 0.303 0.859Normal range 60 (66%) 93 (65%)</p></li><li><p>M. Vemuri et al. / Journal of Psychiatripopulations, such as individuals with certain psychiatric illnesses,women compared to men may be equally or more vulnerable toobesity, abdominal fat deposition and to consequent dyslipidemia.However, in our sample of relatively afuent and educated bipolarpatients women compared to men had a statistically similar rate ofobesity, perhaps accounting for gender-related differences in lipidshaving a pattern similar to that seen in the general population.</p><p>In our study, no signicant differences were found in BMI or anylipid value by weight liability of medication in either women ormen. This nding was in contrast to evidence suggesting a rela-tionship between weight-liable medications, such as olanzapineand clozapine, to weight-gain and dyslipidemia (Birkenaes et al.,2008; Weiden, 2007), and evidence demonstrating lower HDL</p><p>Fig. 1. Unadjusted group means standard error for each assessed lipid value (Total c</p><p>Table 3Prevalence of abnormal lipid values by gender.</p><p>Women Men c2 p value</p><p>% (n/N)</p><p>Total cholesterol 200 mg/dl 36 (51/143) 49 (44/90) 4.0 0.045LDL 160 mg/dl 9 (12/134) 18 (15/82) 4.055 0.044TG 150 mg/dl 19 (27/139) 31 (28/91) 3.890 0.049HDL </p></li><li><p>iatrRole of funding source</p><p>Dr. Vemuris scholarship was supported by NIMH T-32 TrainingGrant. The NIMH had no further role in study design, in thecollection, analysis and interpretation of data, in the writing of thereport, and in the decision to submit the paper for publication.</p><p>Conict of interestDr. Rasgon has received grant/research support from Bayer</p><p>Pharmaceuticals, Abbott Laboratories, GlaxoSmithKline, ForrestLaboratories, Pzer Inc, Wyeth-Arest; has served as a consultant forForest Laboratories and Wyeth-Arest; and has received lecturehonoraria from Bristol-Myers Squibb Corp., and Pzer Inc.</p><p>Dr. Ketter has received grant/research support from AbbottLaboratories, Inc. AstraZeneca Pharmaceuticals LP, Bristol-MyersSquibb Co., Cephalon Inc., Eli Lilly and Co., GlaxoSmithKline, PzerInc., Repligen Corporation,...</p></li></ul>

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