HHS Public Access Author manuscript Author Manuscript
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01. Published in final edited form as:
J Am Acad Child Adolesc Psychiatry. 2016 May ; 55(5): 415–423. doi:10.1016/j.jaac.2016.02.016.
Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder Dr. Lawrence Scahill, MSN, PhD, Emory University School of Medicine and Marcus Autism Center, Atlanta
Author Manuscript
Dr. Sangchoon Jeon, PhD, Yale University School of Nursing, West Haven, CT Dr. Susan J. Boorin, MSN, PhD, Yale University School of Nursing, West Haven, CT Dr. Christopher J. McDougle, MD, Harvard Medical School, Massachusetts General Hospital, and Lurie Center for Autism, Boston Dr. Michael G. Aman, PhD, Nisonger Center, Ohio State University, Columbus Dr. James Dziura, PhD, Yale School of Medicine, New Haven, CT
Author Manuscript
Dr. James T. McCracken, MD, Division of Child Psychiatry, University of California, Los Angeles Dr. Sonia Caprio, MD, Yale School of Medicine, New Haven, CT Dr. L. Eugene Arnold, MD, MEd, Nisonger Center, Ohio State University, Columbus Dr. Ginger Nicol, MD,
Author Manuscript
Correspondence to Lawrence Scahill, MSN, PhD, Marcus Autism Center, 1920 Briarcliff Road, Atlanta, GA 30329; [email protected]. Disclosure: Dr. Scahill has served as a consultant to Neuren, Bracket, MedAdvante, Roche, and Coronado. Dr. Aman has received research contracts, consulted with, served on advisory boards, or done investigator training for Biomarin Pharmaceuticals, BristolMyers Squibb, CogState, Inc., Confluence Pharmaceutica, CogState Clinical Trials, Ltd., Coronado Biosciences, Forest Research, Hoffman-La Roche, Janssen Pharmaceuticals/Johnson and Johnson, Lumos Pharma, MedAvante, Inc., Novartis, Pfizer, ProPhase LLC, and Supernus Pharmaceuticals. Dr. McCracken has received NIMH research grant and contract funds; consultant income from Roche; research contract support from Seaside Pharmaceuticals and Roche; speaker honoraria from the Tourette Syndrome Association; and study drug and placebo from Shire. Dr. Arnold has received research funding from Curemark, Forest, Eli Lilly and Co., Neuropharm, Novartis, Noven, Shire, Supernus, Young Living, NIH, and Autism Speaks, and has consulted with or been on advisory boards for Arbor, Gowlings, lronshore, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Roche, Seaside Therapeutics, Sigma Tau, Shire, Tris Pharma, and Waypoint, and has received travel support from Noven. Dr. Nicol has received research support from Pfizer, Inc. and Otsuka America, Inc. for investigator initiated research studies. She has served on an advisory board for Lundbeck. Dr. Vitiello has received salary support from NIH, income from private practice, and consultant fees from the American Physician Institute for Advanced Professional Studies. Drs. Jeon, Boorin, McDougle, Dziura, Caprio, and Mss. Deng and Challa report no biomedical financial interests or potential conflicts of interest. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Scahill et al.
Page 2
Washington University, St. Louis
Author Manuscript
Ms. Yanhong Deng, MPH, Yale University Ms. Saankari A. Challa, BA, and Emory University School of Medicine Dr. Benedetto Vitiello, MD National Institute of Mental Health (NIMH), Bethesda, MD
Abstract Objective—We examine weight gain and metabolic consequences of risperidone monotherapy in children with autism spectrum disorder (ASD).
Author Manuscript
Method—This was a 24-week, multisite, randomized trial of risperidone only versus risperidone plus parent training in 124 children (mean age 6.9 ± 2.35 years; 105 boys, 19 girls) with ASD and serious behavioral problems. We monitored height, weight, waist circumference, and adverse effects during the trial. Fasting blood samples were obtained pretreatment and at Week 16.
Author Manuscript
Results—In 97 patients with a mean of 22.9 ± 2.8 weeks risperidone exposure, there was a 5.4 ± 3.4 kg weight gain over 24 weeks (p < .0001); waist circumference increased from 60.7 ± 10.4 cm to 66.8 ± 11.3 cm (p 2 weeks exposure to risperidone at ≥ 1.5 mg/day were excluded. Entry requirements also included IQ ≥ 35, DSM-IV diagnosis of autism spectrum disorder (ASD; autistic disorder, Asperger’s disorder or pervasive developmental disorder – not otherwise specified [PDD-NOS]), serious behavioral problems (≥ 18 on the parent-rated Aberrant Behavior Checklist-Irritability subscale) and at least moderate on the Clinical Global Impression - Severity scale (see below). Measures in This Report Aberrant Behavior Checklist (ABC ).21,22—The ABC is a 58-item parent rating, scored from 0 to 3 with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech. The 15-item Irritability subscale includes items on tantrums, aggression, and self-injury.
Author Manuscript
Vineland Adaptive Behavior Scales (Vineland).23—The Vineland is a parent interview that provides standard scores (100 ± 15 adjusted for age and gender) for Communication, Socialization, and Daily Living. Autism Diagnostic Interview-Revised (ADI-R).24—The ADI-R is a semi-structured parent interview used to support the diagnosis of ASD. Tanner Stage of Sexual Maturation.25—Tanner staging was assigned at the pretreatment physical examination. The randomization was stratified by Tanner stage < 3 versus ≥ 3.
Author Manuscript
Height and Weight Collection—Height and weight were collected at baseline and monthly during the study. BMI was calculated as [weight (kg) / height (m2)]. We used BMI norms from the Centers for Disease Control to define normal weight (< 85th percentile), overweight (≥ 85th to < 95th percentile), and obese (≥ 95th percentile).26 BMI z-scores were used to track change in weight over time. Site clinical teams conferred with parents regarding continued risperidone treatment for any child who gained 20% of body weight over baseline and exceeded 95th percentile for weight for age and gender.
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01.
Scahill et al.
Page 5
Author Manuscript
Blood Pressure—Sitting blood pressure was obtained manually at baseline and each follow up visit. Blood pressure percentiles were based on age, gender, and height.27 Waist Circumference—Waist circumference (WC) was used to estimate visceral adipose tissue. Increased visceral adipose tissue is strongly associated with the adverse metabolic and cardiovascular effects of obesity. WC was measured monthly with a tape measure placed directly over the umbilicus. The values, inches rounded to the nearest quarter inch, were converted to centimeters to permit comparison to normative data for age and gender.28
Author Manuscript
Biochemical Measurements—Fasting laboratory tests: glucose, glycosylated hemoglobin (HbA1c), liver enzymes, and lipids were analyzed in a certified laboratory at each center. Archived fasting samples for adiponectin, insulin, and leptin levels collected at baseline and Week 16 were analyzed in duplicate at the General Clinical Research Center at Yale University using Linco radioimmunoassays. Derived Measures—The triglyceride/ high-density lipoprotein (HDL) ratio was used as a marker of cardiometabolic risk.29 A triglyceride/HDL ratio ≥ 2.0 in children is associated with insulin resistance and cardiometabolic abnormalities.30 Insulin resistance was estimated using homeostatic model assessment of insulin resistance (HOMA-IR): HOMA-R = Gb × Ib/k (Gb is the fasting glucose concentration, Ib is the fasting insulin concentration, and k (405) is a constant).31 Analytic Plan
Author Manuscript
Patients who dropped out before Week 14 (n=15) and patients who switched to aripiprazole at Week 8 (n=12) were censored. Baseline characteristics of the available sample were evaluated using frequency counts, means, and medians. We evaluated changes in weight, BMI, and waist circumference from baseline to Week 24 by paired t-test. Second, using generalized mixed effect model with autoregressive covariance structure within-subject correlation, we conducted growth curve analysis with BMI z-scores to examine the trend of weight gain from baseline to Week 24 for the entire sample. Using growth curve analysis, we also explored the impact of age (median split at age 7) and the effect of increased appetite on BMI z-scores. Third, we tracked change in weight classification (normal weight, overweight, or obese) from baseline to Week 24.26 Fourth, change in pretreatment and Week 16 values for glucose, liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), cholesterol, triglyceride, adiponectin, leptin, insulin, triglyceride/HDL ratio, HOMA-IR, and Hgb A1c were compared by paired t-test.
Author Manuscript
To evaluate metabolic status by BMI category (normal, overweight, obese), we compared the number of patients in each group that exceeded thresholds for metabolic syndrome (adjusted for age, gender, and height as needed) at baseline and Week 16. The specific thresholds included: systolic or diastolic blood pressure ≥ 90th percentile, waist circumference ≥ 90th percentile, triglyceride level ≥ 90th percentile, HDL cholesterol ≤ 10th percentile, and glucose ≥ 100 mg/dL. 27,28,32,33 The proportion of patients exceeding the threshold for metabolic syndrome between baseline and Week 16 was examined with McNemar’s test for paired samples.
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01.
Scahill et al.
Page 6
Author Manuscript
To explore the consequences of the metabolic syndrome (pre-existing and new cases) at Week 16, we compared insulin, HOMA-IR, liver enzymes, HbA1c, triglyceride/HDL ratio, adiponectin, leptin, and waist circumference for cases of metabolic syndrome and non-cases using a nonparametric (Wilcoxon Rank Sum) test. All analyses were done using SAS 9.1. Given that this report is focused on safety, p values 95th percentile). Figure 1 shows the change in status for each BMI group at baseline (normal, overweight, or obese) across time. Of the 85 participants with complete height and weight data at Week 24, 29.4% were in the BMI normal weight group (24 from the normal weight group at baseline and one from the overweight group at baseline). By Week 24, the number of children in the obese category increased from 18 to 35. During the trial, 20 children gained 20% of weight over baseline and exceeded the 95th percentile for weight. Following discussion with parents, one of these 20 children and one other child exited the study due to weight gain.
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01.
Scahill et al.
Page 7
Author Manuscript
Growth curve analysis of BMI z-scores showed a rapid rise in the first 12 weeks with leveling off after Week 16. Figure 2a shows the significant change in BMI z-scores from 0.69 to 1.43 (0.74±0.064, p< .0001) over time. Figure 2b displays the change in BMI zscores for 75 participants with reported increase in appetite in the first 8 weeks of treatment compared to 22 participants without such reports. Increased appetite early in treatment predicted weight gain and higher BMI z-scores over time (p=.01). Dividing the sample at the median (≥ 7, n=49), younger children (< 7, n=48) showed a more rapid rise in BMI z-score (p=.009; Figure 2c). Compared to children with IQ ≥ 70 (n=54), there was no difference in BMI z-scores over time for those with IQ < 70 (n=43) (p=.13). Change in Biochemical Indices
Author Manuscript
As noted, 15 participants exited before Week 14, and12 participants switched to aripiprazole at Week 8. Biochemical data were also missing due to non-fasting, insufficient, or hemolyzed samples. Thus, the sample size varied slightly across biochemical tests. Table 3 presents results on several biochemical indices collected pretreatment and at Week 16. Although significant, the increases in mean glucose and HbA1c were modest. The number of children with a baseline glucose ≥ 100 mg/dL almost tripled from 4.8% (n=4) at baseline to 12.5% (n=11) at Week 16. There were significant increases in insulin, HOMA–IR, and leptin and a significant decrease in adiponectin. There were no significant mean changes for any blood lipids. ALT level increased from 17.8 mg/dL ± 6.8 to 20.7 ± 11.3 (p=.01), but there was no change in AST level (p = .42).
Author Manuscript
We used HOMA-IR (≥ 1.58), HbA1C (≥ 5.5), and ALT (> 35 mg/dL) as thresholds. At baseline, 40.6% of participants exceeded HOMA-IR, 25.5% HbA1C, and 3.5% ALT. At Week 16, 55.1%, 38.1%, and 6.8% of participants exceeded these thresholds, respectively. McNemar’s test for matched pairs showed no difference for ALT. However, significantly more participants exceeded threshold for HOMA-IR (χ2 =4.76, p=.03) and HbA1c (χ2 =6.54, p=.01) at Week 16 than at baseline. Table 4 provides counts of participants who met or exceeded biomarkers of metabolic syndrome at pretreatment and Week 16. At baseline 7 (8.4%) children met conventional criteria for metabolic syndrome (positive on 3 of 5 indices) compared to 19 (22.6%) at Week 16 (McNemar’s test χ2=8.00, p=.005). At Week 16, pre-existing or new cases of metabolic syndrome had higher triglyceride/HDL ratio than those not so classified (2.89 ± 1.18 versus 1.02 ± 0.57; p
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01. Published in final edited form as:
J Am Acad Child Adolesc Psychiatry. 2016 May ; 55(5): 415–423. doi:10.1016/j.jaac.2016.02.016.
Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder Dr. Lawrence Scahill, MSN, PhD, Emory University School of Medicine and Marcus Autism Center, Atlanta
Author Manuscript
Dr. Sangchoon Jeon, PhD, Yale University School of Nursing, West Haven, CT Dr. Susan J. Boorin, MSN, PhD, Yale University School of Nursing, West Haven, CT Dr. Christopher J. McDougle, MD, Harvard Medical School, Massachusetts General Hospital, and Lurie Center for Autism, Boston Dr. Michael G. Aman, PhD, Nisonger Center, Ohio State University, Columbus Dr. James Dziura, PhD, Yale School of Medicine, New Haven, CT
Author Manuscript
Dr. James T. McCracken, MD, Division of Child Psychiatry, University of California, Los Angeles Dr. Sonia Caprio, MD, Yale School of Medicine, New Haven, CT Dr. L. Eugene Arnold, MD, MEd, Nisonger Center, Ohio State University, Columbus Dr. Ginger Nicol, MD,
Author Manuscript
Correspondence to Lawrence Scahill, MSN, PhD, Marcus Autism Center, 1920 Briarcliff Road, Atlanta, GA 30329; [email protected]. Disclosure: Dr. Scahill has served as a consultant to Neuren, Bracket, MedAdvante, Roche, and Coronado. Dr. Aman has received research contracts, consulted with, served on advisory boards, or done investigator training for Biomarin Pharmaceuticals, BristolMyers Squibb, CogState, Inc., Confluence Pharmaceutica, CogState Clinical Trials, Ltd., Coronado Biosciences, Forest Research, Hoffman-La Roche, Janssen Pharmaceuticals/Johnson and Johnson, Lumos Pharma, MedAvante, Inc., Novartis, Pfizer, ProPhase LLC, and Supernus Pharmaceuticals. Dr. McCracken has received NIMH research grant and contract funds; consultant income from Roche; research contract support from Seaside Pharmaceuticals and Roche; speaker honoraria from the Tourette Syndrome Association; and study drug and placebo from Shire. Dr. Arnold has received research funding from Curemark, Forest, Eli Lilly and Co., Neuropharm, Novartis, Noven, Shire, Supernus, Young Living, NIH, and Autism Speaks, and has consulted with or been on advisory boards for Arbor, Gowlings, lronshore, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Roche, Seaside Therapeutics, Sigma Tau, Shire, Tris Pharma, and Waypoint, and has received travel support from Noven. Dr. Nicol has received research support from Pfizer, Inc. and Otsuka America, Inc. for investigator initiated research studies. She has served on an advisory board for Lundbeck. Dr. Vitiello has received salary support from NIH, income from private practice, and consultant fees from the American Physician Institute for Advanced Professional Studies. Drs. Jeon, Boorin, McDougle, Dziura, Caprio, and Mss. Deng and Challa report no biomedical financial interests or potential conflicts of interest. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Scahill et al.
Page 2
Washington University, St. Louis
Author Manuscript
Ms. Yanhong Deng, MPH, Yale University Ms. Saankari A. Challa, BA, and Emory University School of Medicine Dr. Benedetto Vitiello, MD National Institute of Mental Health (NIMH), Bethesda, MD
Abstract Objective—We examine weight gain and metabolic consequences of risperidone monotherapy in children with autism spectrum disorder (ASD).
Author Manuscript
Method—This was a 24-week, multisite, randomized trial of risperidone only versus risperidone plus parent training in 124 children (mean age 6.9 ± 2.35 years; 105 boys, 19 girls) with ASD and serious behavioral problems. We monitored height, weight, waist circumference, and adverse effects during the trial. Fasting blood samples were obtained pretreatment and at Week 16.
Author Manuscript
Results—In 97 patients with a mean of 22.9 ± 2.8 weeks risperidone exposure, there was a 5.4 ± 3.4 kg weight gain over 24 weeks (p < .0001); waist circumference increased from 60.7 ± 10.4 cm to 66.8 ± 11.3 cm (p 2 weeks exposure to risperidone at ≥ 1.5 mg/day were excluded. Entry requirements also included IQ ≥ 35, DSM-IV diagnosis of autism spectrum disorder (ASD; autistic disorder, Asperger’s disorder or pervasive developmental disorder – not otherwise specified [PDD-NOS]), serious behavioral problems (≥ 18 on the parent-rated Aberrant Behavior Checklist-Irritability subscale) and at least moderate on the Clinical Global Impression - Severity scale (see below). Measures in This Report Aberrant Behavior Checklist (ABC ).21,22—The ABC is a 58-item parent rating, scored from 0 to 3 with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech. The 15-item Irritability subscale includes items on tantrums, aggression, and self-injury.
Author Manuscript
Vineland Adaptive Behavior Scales (Vineland).23—The Vineland is a parent interview that provides standard scores (100 ± 15 adjusted for age and gender) for Communication, Socialization, and Daily Living. Autism Diagnostic Interview-Revised (ADI-R).24—The ADI-R is a semi-structured parent interview used to support the diagnosis of ASD. Tanner Stage of Sexual Maturation.25—Tanner staging was assigned at the pretreatment physical examination. The randomization was stratified by Tanner stage < 3 versus ≥ 3.
Author Manuscript
Height and Weight Collection—Height and weight were collected at baseline and monthly during the study. BMI was calculated as [weight (kg) / height (m2)]. We used BMI norms from the Centers for Disease Control to define normal weight (< 85th percentile), overweight (≥ 85th to < 95th percentile), and obese (≥ 95th percentile).26 BMI z-scores were used to track change in weight over time. Site clinical teams conferred with parents regarding continued risperidone treatment for any child who gained 20% of body weight over baseline and exceeded 95th percentile for weight for age and gender.
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01.
Scahill et al.
Page 5
Author Manuscript
Blood Pressure—Sitting blood pressure was obtained manually at baseline and each follow up visit. Blood pressure percentiles were based on age, gender, and height.27 Waist Circumference—Waist circumference (WC) was used to estimate visceral adipose tissue. Increased visceral adipose tissue is strongly associated with the adverse metabolic and cardiovascular effects of obesity. WC was measured monthly with a tape measure placed directly over the umbilicus. The values, inches rounded to the nearest quarter inch, were converted to centimeters to permit comparison to normative data for age and gender.28
Author Manuscript
Biochemical Measurements—Fasting laboratory tests: glucose, glycosylated hemoglobin (HbA1c), liver enzymes, and lipids were analyzed in a certified laboratory at each center. Archived fasting samples for adiponectin, insulin, and leptin levels collected at baseline and Week 16 were analyzed in duplicate at the General Clinical Research Center at Yale University using Linco radioimmunoassays. Derived Measures—The triglyceride/ high-density lipoprotein (HDL) ratio was used as a marker of cardiometabolic risk.29 A triglyceride/HDL ratio ≥ 2.0 in children is associated with insulin resistance and cardiometabolic abnormalities.30 Insulin resistance was estimated using homeostatic model assessment of insulin resistance (HOMA-IR): HOMA-R = Gb × Ib/k (Gb is the fasting glucose concentration, Ib is the fasting insulin concentration, and k (405) is a constant).31 Analytic Plan
Author Manuscript
Patients who dropped out before Week 14 (n=15) and patients who switched to aripiprazole at Week 8 (n=12) were censored. Baseline characteristics of the available sample were evaluated using frequency counts, means, and medians. We evaluated changes in weight, BMI, and waist circumference from baseline to Week 24 by paired t-test. Second, using generalized mixed effect model with autoregressive covariance structure within-subject correlation, we conducted growth curve analysis with BMI z-scores to examine the trend of weight gain from baseline to Week 24 for the entire sample. Using growth curve analysis, we also explored the impact of age (median split at age 7) and the effect of increased appetite on BMI z-scores. Third, we tracked change in weight classification (normal weight, overweight, or obese) from baseline to Week 24.26 Fourth, change in pretreatment and Week 16 values for glucose, liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), cholesterol, triglyceride, adiponectin, leptin, insulin, triglyceride/HDL ratio, HOMA-IR, and Hgb A1c were compared by paired t-test.
Author Manuscript
To evaluate metabolic status by BMI category (normal, overweight, obese), we compared the number of patients in each group that exceeded thresholds for metabolic syndrome (adjusted for age, gender, and height as needed) at baseline and Week 16. The specific thresholds included: systolic or diastolic blood pressure ≥ 90th percentile, waist circumference ≥ 90th percentile, triglyceride level ≥ 90th percentile, HDL cholesterol ≤ 10th percentile, and glucose ≥ 100 mg/dL. 27,28,32,33 The proportion of patients exceeding the threshold for metabolic syndrome between baseline and Week 16 was examined with McNemar’s test for paired samples.
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01.
Scahill et al.
Page 6
Author Manuscript
To explore the consequences of the metabolic syndrome (pre-existing and new cases) at Week 16, we compared insulin, HOMA-IR, liver enzymes, HbA1c, triglyceride/HDL ratio, adiponectin, leptin, and waist circumference for cases of metabolic syndrome and non-cases using a nonparametric (Wilcoxon Rank Sum) test. All analyses were done using SAS 9.1. Given that this report is focused on safety, p values 95th percentile). Figure 1 shows the change in status for each BMI group at baseline (normal, overweight, or obese) across time. Of the 85 participants with complete height and weight data at Week 24, 29.4% were in the BMI normal weight group (24 from the normal weight group at baseline and one from the overweight group at baseline). By Week 24, the number of children in the obese category increased from 18 to 35. During the trial, 20 children gained 20% of weight over baseline and exceeded the 95th percentile for weight. Following discussion with parents, one of these 20 children and one other child exited the study due to weight gain.
J Am Acad Child Adolesc Psychiatry. Author manuscript; available in PMC 2017 May 01.
Scahill et al.
Page 7
Author Manuscript
Growth curve analysis of BMI z-scores showed a rapid rise in the first 12 weeks with leveling off after Week 16. Figure 2a shows the significant change in BMI z-scores from 0.69 to 1.43 (0.74±0.064, p< .0001) over time. Figure 2b displays the change in BMI zscores for 75 participants with reported increase in appetite in the first 8 weeks of treatment compared to 22 participants without such reports. Increased appetite early in treatment predicted weight gain and higher BMI z-scores over time (p=.01). Dividing the sample at the median (≥ 7, n=49), younger children (< 7, n=48) showed a more rapid rise in BMI z-score (p=.009; Figure 2c). Compared to children with IQ ≥ 70 (n=54), there was no difference in BMI z-scores over time for those with IQ < 70 (n=43) (p=.13). Change in Biochemical Indices
Author Manuscript
As noted, 15 participants exited before Week 14, and12 participants switched to aripiprazole at Week 8. Biochemical data were also missing due to non-fasting, insufficient, or hemolyzed samples. Thus, the sample size varied slightly across biochemical tests. Table 3 presents results on several biochemical indices collected pretreatment and at Week 16. Although significant, the increases in mean glucose and HbA1c were modest. The number of children with a baseline glucose ≥ 100 mg/dL almost tripled from 4.8% (n=4) at baseline to 12.5% (n=11) at Week 16. There were significant increases in insulin, HOMA–IR, and leptin and a significant decrease in adiponectin. There were no significant mean changes for any blood lipids. ALT level increased from 17.8 mg/dL ± 6.8 to 20.7 ± 11.3 (p=.01), but there was no change in AST level (p = .42).
Author Manuscript
We used HOMA-IR (≥ 1.58), HbA1C (≥ 5.5), and ALT (> 35 mg/dL) as thresholds. At baseline, 40.6% of participants exceeded HOMA-IR, 25.5% HbA1C, and 3.5% ALT. At Week 16, 55.1%, 38.1%, and 6.8% of participants exceeded these thresholds, respectively. McNemar’s test for matched pairs showed no difference for ALT. However, significantly more participants exceeded threshold for HOMA-IR (χ2 =4.76, p=.03) and HbA1c (χ2 =6.54, p=.01) at Week 16 than at baseline. Table 4 provides counts of participants who met or exceeded biomarkers of metabolic syndrome at pretreatment and Week 16. At baseline 7 (8.4%) children met conventional criteria for metabolic syndrome (positive on 3 of 5 indices) compared to 19 (22.6%) at Week 16 (McNemar’s test χ2=8.00, p=.005). At Week 16, pre-existing or new cases of metabolic syndrome had higher triglyceride/HDL ratio than those not so classified (2.89 ± 1.18 versus 1.02 ± 0.57; p
