UI.

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Iron Status in Children and Adolescents Following Extended Risperidone Treatment

Chadi Calarge, and Ekhard Ziegler, 1 and Pediatrics2 The University of Iowa, Departments of Psychiatry
1-2 M.D. 2 M.D.
Dr. Calarge reports no competing interests. Dr. Ziegler has served as a consultant for Abbott Nutrition and Nestle/Gerber.

Introduction
Background: The rapid weight gain observed with second-generation antipsychotics (SGAs) requires an expansion in the blood volume. This increases the risk for iron deficiency as it adds further demands for iron, beyond the elevated need associated with normal growth during childhood and adolescence. Iron is a critical nutrient, both for oxygen transport as well as a cofactor for many enzymes, including in the brain (1). In fact, iron deficiency in rats has been associated with a reduction in the density of the dopamine D1 and D2 receptors and of the dopamine transporter (1). In addition, increasing evidence has linked iron status to symptom severity in ADHD and to sensitivity to psychostimulant treatment (1). How iron status changes following chronic treatment with SGAs in children and adolescents has not been explored neither has the prolactin response to SGAs. Prolactin is of interest since its release from the anterior pituitary is under tonic dopaminergic inhibition. Objective: To investigate the prevalence of iron depletion and deficiency in youth following long-term risperidone treatment and explore the association between iron status and serum prolactin.

Results
Prolactin Concentration, ng/ml

35 30 25 20 15 10 5 0

Prolactin Concentration & Iron Status

p<0.003 p<0.002

Table 1: Demographic and Clinical Characteristics Across the Three Iron-Status Groups
Iron-Deficient Iron-Deplete N=16 N=52 14 (88) 46 (88) 11.3 (0.7) 12.2 (0.4) 40/13/13/20/13 33/12/22/24/10 0.51 (0.28) 0.45 (0.22) 14 (88) 13 (81) 5 (31) 2 (13) 1 (6) 4 (25) 1 (6) 0.03 (0.01) 10.0 (2.9) 2.2 (0.4) 12 (75) 7 (44) 1 (6) 4 (25) 0.71 (0.15) 0.62 (0.13) 47 (90) 48 (92) 14 (27) 11 (21) 7 (13) 4 (8) 0 0.03 (0.00) 9.4 (1.6) 2.7 (0.2) 39 (75) 23 (44) 17 (3) 11 (21) Iron-Replete N=47 40 (85) 11.0 (0.4) 53/15/13/15/4 0.42 (0.16) 0.29 (0.14) 45 (96) 45 (96) 12 (26) 10 (21) 6 (13) 2 (4) 0 0.04 (0.00) 12.2 (1.7) 2.2 (0.2) 34 (72) 22 (47) 19 (40) 21 (45) p value >0.9 >0.1 >0.5 >0.4 >0.2 >0.3 >0.1 >0.9 >0.8 >0.8 <0.05 >0.1 >0.3 >0.4 >0.3 >0.9 >0.9 <0.04 <0.04

Methods
Participants: Medically healthy 7-17yo patients, treated with risperidone for 6 months, were enrolled (2). Patients concurrently receiving other antipsychotics and those with chronic medical conditions or with substance use disorders were excluded, as were pregnant females and those using hormonal contraception. Medical and psychiatric records were reviewed to extract relevant clinical information including all anthropometric data. The Child Behavior Checklist captured psychiatric symptoms. Iron intake during the week prior to study enrollment was estimated using the 2004 Block Kids Food Frequency Questionnaire (2). Upon enrollment, height and weight were measured following standard procedures (3). A fasting blood sample was obtained to measure serum prolactin and risperidone and 9-hydroxyrisperidone concentrations. Left-over serum, stored at -80 C, was used to measure ferritin (sF), transferrin receptor (sTfR), high sensitivity C-reactive protein (CRP), and interleukin-6 (IL-6). The study was approved by the local IRB and written consents and assents were obtained. Statistical Analysis: Weight and body mass index (BMI) were adjusted for age and sex using US normative data. Body iron (mg/kg) was estimated by: -[log(sTfR/sF)-2.8229]/0.1207, with negative values representing tissue iron deficiency (3). Following the World Health Organizations guidelines (4), the participants were divided into: 1) An iron-deficient group, 2) an iron-depleted group, and 3) an iron-replete group. Hyperprolactinemia was defined as a concentration > 15.2 ng/ml in males and > 23.3 ng/ml in females. Continuous and categorical variables were compared across the three iron status groups using ANOVA and Fishers test. Multivariable linear regression analysis explored the association between body iron, on the one hand, and CBCL-based psychiatric symptom severity, the weight-adjusted daily dose of psychostimulants or risperidone, and prolactin on the other, with adjustment for potential confounders.

Male sex, n (%) Age, years, mean (sd) Tanner Stage I/II/III/IV/V, % Age- and Sex-Adjusted Measures Enrollment BMI z Score, mean (sd) Change in BMI z Score, mean (sd) Psychopathology ADHD, n (%) DBD, n (%) Anxiety Disorder, n (%) Tic Disorder, n (%) PDD, n (%) Depressive Disorder, n (%) Psychosis, n (%) Psychopharmacology Risperidone dose, mg/kg/d, mean (sd) Serum Concentration, ng/ml, mean (sd) Treatment Duration, yrs, mean (sd) Psychostimulants, n (%) SSRIs, n (%) 2-agonsits, n (%) Multivitamin Use, n (%)

Replete

Deplete

Deficient

There was no significant association between body iron and the T score on any of the CBCL factors (Spearmans rho ranged between -0.21 and 0.13). Controlling for the weight-adjusted daily dose of psychostimulants and risperidone did not alter the results. There was also no significant association between body iron and the weight-adjusted daily dose of psychostimulants after controlling for age, sex, and the weight-adjusted daily dose of risperidone or between body iron and the weightadjusted daily dose of risperidone after controlling for age, sex, and the weight-adjusted daily dose of psychostimulants.

Conclusions
The prevalence of iron deficiency and depletion in youth chronically treated with risperidone is high (59%) and potentially linked to the magnitude of weight gain and subclinical inflammation. Iron deficiency was associated with higher prolactin concentration but not with the severity of psychiatric symptoms or with the dose of the two classes of drugs that directly modulate central dopaminergic signaling.
References: 1. Calarge C, Farmer C, DiSilvestro R, et al.: Serum ferritin and amphetamine response in youth with attentiondeficit/hyperactivity disorder. Journal of child and adolescent psychopharmacology 2010; 20:495-502. 2. Calarge CA, Zimmerman B, Xie D, et al.: A crosssectional evaluation of the effect of risperidone and selective serotonin reuptake inhibitors on bone mineral density in boys. The Journal of clinical psychiatry 2010; 71:338-347. 3. Cook JD, Flowers CH, Skikne BS: The quantitative assessment of body iron. Blood 2003; 101:3359-3364. 4. WHO: Serum ferritin concentrations for the assessment of iron status and iron deficiency in populations. Geneva, Switzerland, WHO, 2011. Acknowledgements: This work was funded by NARSAD, the NIMH (R21MH080968-01A1 and K23MH085005) and the NCRR (RR024979). Contact: chadi-calarge@uiowa.edu

Table 2: Laboratory Measures Across the Three Iron Status Groups

Iron-Deficient N=16 9.4 (1.7) 11 (69) 17.5 (1.3) 16 (100) -4.26 (0.77) 29.4 (3.6) 11 (69) 0.4 (0.5) 0.41 (0.21) Iron-Deplete N=52 5.4 (1.0) 52 (100) 5.6 (0.7) 2 (4) -2.81 (0.43) 18.9 (2.0) 32 (620 1.0 (0.3) 0.07 (0.12) Iron-Replete N=47 21.7 (1.0) 0 5.4 (0.8) 1 (2) 3.41 (0.45) 20.4 (2.1) 26 (55) 0.5 (0.3) -0.30 (0.14) p value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.05 >0.6 >0.2 <0.02

Ferritin Concentration, ng/ml, mean (se) Ferritin < 12 ng/ml, n (%) sTfR Concentration, g/ml, mean (se) sTfR > 8.3 g/ml, n (%) Body Iron, mg/kg, mean (se) Prolactin Concentration, ng/ml, mean (se) Hyperprolactinemia, n (%) CRP Concentration, mg/l, mean (se) IL-6 Concentration (log), pg/ml, mean (se)

High sensitivity C-reactive protein and interleukin-6 were available for only 69 participants.

After controlling for age, sex, and risperidone treatment duration, the change in BMI z score was inversely associated with estimated body iron (= -1.30, p<0.02). We also found IL-6 to be inversely related to body iron (Pearsons rho= 0.28, p<0.02) and sF (Pearsons rho= -0.20, p<0.1). After controlling for age, sex, BMI, the weight adjusted daily dose of psychostimulants, and serum risperidone concentration, body iron was inversely associated with prolactin (= -0.65, p<0.02). (Figure)