8/3/2019 Metabolic Effects of Slope_AACAP_2011

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UI.CAPSUL

Trajectory of Risperidone-induced Weight Gain in Youth and Cardio-Metabolic Sequelae

Background: A growing number of studies have linked atypical

antipsychotics (AAPs) to significant weight gain in children (1).Insulin resistance and dyslipidemia are common sequelae.

However, most of the currently available AAP studies are of relatively

short duration. Furthermore, in light of the significant inter-individualvariability in weight gain from AAPs, the effect of the trajectory ofweight gain on the emergence of cardio-metabolic abnormalities has

not been investigated, to our knowledge.

This issue is significant since potentially modifiable factors (e.g.,medication dose) have been implicated in the long-term trajectory ofAAP-related weight gain (2). Moreover, a differential rate of AAP-

related weight gain might involve different mechanistic processes(e.g., differential body fat distribution or differential duration ofchronic inflammation.)

Objective: To investigate whether the rate at which weight is gainedduring long-term risperidone treatment in youth affects thedevelopment of cardio-metabolic abnormalities.

Chadi A. Calarge, M.D.; Diqiong Xie, M.S., Trudy L. Burns, Ph.D.

Introduction

Methods

Conclusions

References:1. Sikich L, Frazier JA, McClellan J, et al.: Double-blind comparison of first-and second-generation antipsychotics in early-

onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrumdisorders (TEOSS) study. Am J Psychiatry 2008; 165:1420-1431.2. Calarge C, Xie D, Zimmerman B: Clinical Predictors of Weight Change During Long-Term Risperidone Treatment, in 51stNCDEU Meeting, Boca Raton, FL, June 13-16, 2011, 2011.3. Calarge CA, AcionL, Kuperman S, et al.: Weight gain and metabolic abnormalities during extended risperidone treatment

in children and adolescents. J Child Adolesc Psychopharmacol2009a; 19:101-109.4. EisenmannJC, On the use of continuous metabolic syndrome score in pediatric research. Cardiovasc Diabetol 2008; 7:17.

Acknowledgements: This work was funded by National Institute of Mental Health (5R34MH071683 and

K23MH085005) and the National Center for Research Resources (UL1RR025755). Contact: chadi-calarge@uiowa.edu

Participants: Medically healthy 7 to 17 year-old patients, treated with

risperidone for 6 months or more, were recruited from child psychiatryclinics (3). Patients concurrently receiving other antipsychotics andthose with chronic medical or neurological conditions or with active

substance use disorders were excluded, as were pregnant females andthose using hormonal contraception.

Medical and psychiatric records were reviewed to extract relevantclinical information including all anthropometric data.

Upon enrollment, height, weight, and vital signs were measuredfollowing standard procedures (3). Triceps and subscapular skinfoldthickness was measured with a Lange caliper.

A fasting blood sample was obtained to measure insulin, glucose, a

lipid profile, high sensitivity C-reactive protein (hsCRP), leptin, andadiponectin.

The study was approved by the local IRB and written consents andassents were obtained.

Statistical Analysis: As reported previously (3), weight, BMI, andsystolic and diastolic blood pressure were adjusted for age and sex(and height for blood pressure) using US normative data. Body fat

content was estimated using skinfold thickness measurements.HOMA-IR was estimated from insulin (IU/ml) x glucose (mg/dl)/405.

Weight (BMI) z scores were regressed on (log) time (3). The slopeestimate generated by this regression model was normalized (bydividing it by its standard error); it was then entered as a predictor

variable in a multivariable linear regression analysis to model thevarious metabolic outcomes. Endpoint (i.e., obtained at enrollment)weight (BMI) z score, age, and sex were entered as covariates. HOMA-

IR, triglycerides, leptin, and hsCRP were log transformed to normalizetheir distribution.

A metabolic syndrome score, incorporating waist circumference, meanarterial blood pressure, the negative of HDL, (log) triglycerides, and(log) HOMA-IR was generated following Eisenmann (4).

All analyses involving laboratory tests (except for hsCRP) wererestricted to fasting individuals (6 could not fast).

All contributors report no competing interests.

ResultsOf those enrolled in the study (n=163), 105 (88% males) had the

necessary data to compute a weight (BMI) z score slope (Table 1).

After adjusting for endpoint weight z score, age, and sex, there

was no significant association between the standardized slope ofweight z score and waist circumference, systolic or diastolic bloodpressure, total or HDL cholesterol, or triglycerides.

Also, after adjusting for endpoint BMI z score, age, and sex, there

was no significant association between the slope of BMI z scoreand waist circumference, percent body fat, systolic or diastolicblood pressure, glucose, total insulin, total or HDL cholesterol,

triglycerides, the metabolic syndrome score, or hsCRP.

The tempo of weight and BMI z score change, during long-term risperidonetreatment, influences the emergence of an atherogenic profile.

Indexes of early metabolic dysfunction (e.g., triglycerides, HDL cholesterol,

and HOMA-IR) are significantly associated with a faster rate of weight gain.Outcomes that are slower to be affected (e.g., blood pressure) tend to show noeffect at this relatively early stage.

The discrepancy between findings with weight and BMI z scores likely reflectsthe smaller number of BMI data points.

Table1: Clinical Characteristics of the Sample

Characteristic Mean or N SD or %

Age, years 11.2 2.7

Psychiatric Diagnoses:Disruptive Behavior DisorderADHDAnxiety DisorderTic DisorderAutism Spectrum DisorderDepressive DisorderPsychotic Disorder

969435191391

919033181291

Pharmacotherapy:Risperidone Dose, mg/kg/dRisperidone Treatment Duration, yrsPsychostimulantsSSRIs2-agonists

Mood Stabilizers

0.031.88755434

5

0.021.03715132

5

Anthropometric Measures:Baseline Wt z ScoreBaseline BMI z ScoreEndpoint Weight z ScoreEndpoint BMI z ScorePercent Body FatWaist Circumference, cm

0.10.10.60.7

20.470.4

1.11.11.11.08.912.7

Blood Pressure:Systolic BP z ScoreDiastolic BP z Score

0.2-0.0

1.00.7

Table2: Laboratory Characteristics of the Sample

Characteristic Mean SD

Glucose Homeostasis:Glucose (mg/dl)Total Insulin (IU/ml)HOMA-IR

90.06.71.5

8.34.81.1

Lipids:HDL Cholesterol (mg/dl)Total Cholesterol (mg/dl)LDL Cholesterol (mg/dl)Triglycerides (mg/dl)

57.7158.488.559.9

13.924.621.135.8

Metabolic Syndrome Score -0.0 3.2

Regulatory Hormones:Leptin (ng/ml)Adiponectin (g/ml)

5.615.0

5.27.0

Inflammatory Marker:

hsCRP (mg/l) 0.6 1.2

Table 3: Significant AssociationsBetween the Standardized Slope of Weight (BMI) z Score and Cardio-

Metabolic Risk Factors While Controlling for Age, Sex, and Endpoint Weight (BMI) z Score

Outcome Predictors estimate (95% C.I.) P R2

Percent Fa t Endpo in t weigh t z score

Slope of weight z score

5.45 (4.256.65)

0.36 (-0.030.75)