Supplementary Online Content

Supplementary Online Content Anagnostou E, Aman MG, Handen BL, et al. Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autistic spectrum disorder: a randomized clinical trial. JAMA Psychiatry. Published online August 24, 2016. doi:10.1001/jamapsychiatry.2016.1232. etable 1. Effect of Metformin vs Placebo on Metabolic Parameters, ABC Subscales, and CGI Improvement etable 2. BMI Shift Table etable 3. Baseline Variables (Continuous) etable 4. Psychotropic Medications Used at Baseline etable 5. Unadjusted Summary Statistics Among All Participants Who Initiated Treatment etable 6. Site-Specific Effects of Metformin on 16-Week Changes in BMI z Scores etable 7. ITT Analysis: Effect of Metformin vs Placebo on Anthropometric Measurements, Metabolic Parameters, Behavioral Measures, and Clinical Global Impression efigure. Change in BMI vs Baseline BMI Scatterplot of 16-wk Change in BMI z Score vs Baseline BMI z Score This supplementary material has been provided by the authors to give readers additional information about their work. 2016 American Medical Association. All rights reserved. 1

Change in BMI vs. baseline BMI (200004 and 280664)] Error! Bookmark not defined. etable 1. Effect of Metformin vs Placebo on Metabolic Parameters, ABC Subscales, and CGI Improvement 1 16- week Chan ge Metformin (n = 28) Placebo (n = 32) Treatment Difference 95% CI p 16- week Change 95% CI p 16- week change 95% CI Total cholesterol (mg/dl) -1.05 (-8.76,6.67) 0.79-3.29 (-10.33,3.75) 0.35 2.25 (-8.17,12.66) 0.123 0.67 LDL (mg/dl) -4.41 (-10.47,1.64) 0.15-0.41 (-6.11,5.29) 0.89-4.00 (-12.29,4.29) 0.278 0.34 HDL (mg/dl) 3.27 (-1.41,7.94) 0.17-0.98 (-5.26,3.29) 0.65 4.25 (-2.04,10.54) 0.357 0.18 Triglycerides (mg/dl) 5.74 (-22.34,33.81) 0.68 6.18 (-19.62,31.98) 0.63-0.44 (- 36.97,36.09) 0.006 0.98 Glucose, fasting (mg/dl) -3.06 (-6.68,0.56) 0.10-2.41 (-5.76,0.94) 0.16-0.65 (-5.18,3.88) 0.064 0.78 Insulin, fasting (µiu/ml) 1.97 (-10.44,14.38) 0.75 2.95 (-8.44,14.35) 0.61-0.98 (- 17.82,15.85) 0.030 0.91 HOMA-IR 0.528 (-2.385,3.441) 0.72 0.593 (-2.074,3.261) 0.66-0.066 (- 3.986,3.855) 0.009 0.97 Hgb A1C (%) - 0.054 (-0.143,0.035) 0.23 0.033 (-0.047,0.114) 0.41-0.087 (- 0.206,0.032) 0.403 0.15 ABC Lethargy -2.08 (-4.80,0.63) 0.13-1.06 (-3.64,1.52) 0.41-1.02 (-4.54,2.50) 0.146 0.56 ABC Stereotypy -0.34 (-1.54,0.85) 0.57-1.16 (-2.30,-0.03) 0.04 4 0.82 (-0.72,2.36) 0.239 0.29 ABC Hyperactivity -1.14 (-3.79,1.50) 0.39-1.60 (-4.10,0.89) 0.20 0.46 (-3.09,4.00) 0.069 0.80 ABC Inappropriate Speech -0.67 (-1.37,0.03) 0.060-0.11 (-0.77,0.55) 0.74-0.56 (-1.50,0.38) 0.305 0.24 CGI Improvement -0.14 (-0.42,0.14) 0.32-0.06 (-0.33,0.21) 0.65-0.08 (-0.47,0.31) 0.107 0.68 Effect Size p 1 Results were obtained from linear contrasts of estimates from the shared-baseline, linear mixed model described in the Methods. 2016 American Medical Association. All rights reserved. 2

etable 2. BMI Shift Table Initial BMI Category Metformin Week 16 BMI Category Placebo 1. Normal 2. Overweight 3. Obese 1. Normal 2. Overweight 3. Obese 1. Normal 1 0 0 0 0 0 2. Overweight 1 2 1 0 3 1 3. Obese 0 0 23 0 1 27 Cross tabulation of baseline and week 16 BMI status Normal = 15th to <85th percentile, Overweight = 85th to <95th percentile, Obese = 95 t th percentile 2016 American Medical Association. All rights reserved. 3

etable 3. Baseline Variables (Continuous) O Difference of means Metformin Placebo 95% CI Variable Mean SD Min Max Mean SD Min Max Diff Lower Upper p age 12.88 2.85 7.6 17.4 12.68 2.64 7.2 16.8 0.21-1.21 1.62 0.77 Height z- score Weight z- score 0.55 0.87-1.0 2.9 0.61 1.06-1.7 2.6-0.06-0.56 0.45 0.82 2.15 0.70 0.9 3.8 2.21 0.59 1.0 3.1-0.06-0.39 0.28 0.72 BMI z-score 2.05 0.49 0.6 2.8 2.12 0.39 1.3 2.6-0.06-0.29 0.16 0.58 weight 77.48 25.44 32.9 133.2 76.44 23.04 35.5 123.8 1.03-11.5 13.56 0.87 BMI 29.80 6.08 18.8 45.1 29.83 5.44 21.5 42.1-0.03-3.01 2.95 0.99 Weight percentile BMI percentile Waist to hip ratio 96.47 4.33 82.4 100.0 97.05 4.14 84.0 99.9-0.58-2.77 1.61 0.60 96.57 5.46 71.2 99.8 97.55 2.30 90.3 99.6-0.98-3.09 1.14 0.39 97.10 5.45 86.4 107.3 97.46 6.00 86.2 108.9-0.37-3.34 2.61 0.81 IQ 68.91 25.14 40.0 116.0 84.10 20.30 40.0 112.0-15.2-27.9-2.53 0.020 CGI severity 4.71 0.71 3.0 6.0 4.53 0.80 3.0 6.0 0.18-0.21 0.58 0.36 Total cholesterol (mg/dl) 1 153.06 22.34 110.0 204.0 161.22 40.29 100.4 257.0-8.16-25.3 9.02 0.33 LDL (mg/dl) 91.80 21.13 41.0 129.0 89.28 33.13 44.4 166.0 2.52-12.1 17.18 0.73 HDL (mg/dl) 40.91 8.32 30.0 63.0 41.72 9.06 26.0 66.0-0.81-5.33 3.71 0.72 2016 American Medical Association. All rights reserved. 4

Difference of means Metformin Placebo 95% CI Variable Mean SD Min Max Mean SD Min Max Diff Lower Upper p Triglycerides (mg/dl) Glucose (mg/dl) Insulin (μiu/ml) 108.66 55.20 56.0 324.8 156.61 82.87 55.0 392.0-47.9-84.9-11.0 0.010 87.11 9.31 64.9 103.0 85.85 9.87 63.1 112.0 1.26-3.71 6.24 0.61 16.61 10.11 3.8 44.2 21.58 14.80 5.5 78.1-4.97-11.7 1.80 0.14 HOMA_IR 3.45 1.89 0.7 7.1 4.56 3.30 1.2 18.5-1.11-2.55 0.34 0.12 HgbA1C (%) 5.28 0.42 4.5 6.0 5.36 0.29 4.9 6.2-0.08-0.27 0.11 0.42 1 Please note that conversion factors to SI units for all variables are shown on next page 2016 American Medical Association. All rights reserved. 5

etable 3 (continued). SI/Conventional unit conversion factors Analyte Conventional Unit Conversion Factor 1 SI Unit Cholesterol (total) mg/dl 0.0259 mmol/l Cholesterol, low-density (LDL) mg/dl 0.0259 mmol/l Cholesterol, high-density (HDL) mg/dl 0.0259 mmol/l Triglycerides mg/dl 0.0113 mmol/l Glucose mg/dl 0.0555 mmol/l Insulin μiu/ml 6.945 pmol/l Hemoglobin A1c % of total hemoglobin 0.01 Proportion of total hemoglobin 1 Multiply value in convention units by stated conversion factor to yield the same value in SI units. 2016 American Medical Association. All rights reserved. 6

etable 4. Psychotropic Medications Used at Baseline Medication Percentage using at baseline Metformin Placebo N % N % Alpha 2-Adrenergic Agonists 9 32% 10 31% Antidepressants 15 54% 17 53% Antipsychotics 28 100% 32 100% Benzodiazepines 1 4% 4 13% Beta Blockers 0 0% 0 0% CNS stimulants 6 21% 10 31% Mood stabilizers 2 7% 3 9% Norepinephrine re-uptake inhibitor 1 4% 3 9% 2016 American Medical Association. All rights reserved. 7

etable 5. Unadjusted Summary Statistics Among All Participants Who Initiated Treatment Metformin (n=28) Placebo (n=32) Baseline Final Visit Delta Baseline Final Visit Delta N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD N Mean SD Measure Study Week 28 0.00 0.00 28 15.14 2.45 28 15.14 2.45 32 0.00 0.00 32 15.51 3.24 32 15.51 3.24 BMI z-score 28 2.05 0.49 28 1.98 0.54 28-0.07 0.14 32 2.12 0.39 32 2.13 0.39 32 0.02 0.10 Weight z-score 28 2.15 0.70 28 2.06 0.76 28-0.09 0.14 32 2.21 0.59 32 2.25 0.57 32 0.03 0.12 BMI (kg/m 2 ) 28 29.80 6.08 28 29.45 6.19 28-0.35 0.96 32 29.83 5.44 32 30.35 5.52 32 0.52 0.93 Weight (kg) 28 77.48 25.44 28 77.64 25.67 28 0.16 2.44 32 76.44 23.04 32 79.20 22.88 32 2.76 2.46 BMI percentile (%) 28 96.57 5.46 28 95.66 7.34 28-0.91 2.47 32 97.55 2.30 32 97.65 2.21 32 0.09 0.75 Weight percentile (%) 28 96.47 4.33 28 95.36 6.19 28-1.11 2.53 32 97.05 4.14 32 97.35 3.76 32 0.30 1.65 Waist-hip ratio (%) 28 97.10 5.45 28 97.23 4.17 28 0.14 4.08 32 97.46 6.00 32 97.97 5.33 32 0.50 3.45 Total cholesterol (mg/dl) 28 153.06 22.34 28 152.16 27.85 28-0.91 16.34 32 161.22 40.29 32 157.66 41.11 32-3.55 19.76 LDL (mg/dl) 28 91.80 21.13 28 86.96 26.13 28-4.84 15.19 31 89.28 33.13 32 89.69 33.45 31-0.80 13.71 HDL (mg/dl) 28 40.91 8.32 28 43.90 15.91 28 2.99 15.00 32 41.72 9.06 32 40.63 9.19 32-1.09 6.07 Triglycerides (mg/dl) 28 108.66 55.20 28 125.17 56.64 28 16.51 71.28 32 156.61 82.87 32 152.04 93.47 32-4.58 69.10 Glucose, fasting (mg/dl) 28 87.11 9.31 28 84.54 9.74 28-2.57 10.78 32 85.85 9.87 32 83.99 9.23 32-1.86 8.19 Insulin, fasting (µiu/ml) 27 16.61 10.11 28 20.37 36.16 27 3.92 31.99 31 21.58 14.80 32 23.81 24.22 31 2.35 25.69 HOMA-IR 27 3.45 1.89 28 4.49 8.70 27 1.07 8.30 31 4.56 3.30 32 4.90 4.62 31 0.36 5.24 Hgb A1C (%) 27 5.28 0.42 28 5.23 0.43 27-0.05 0.18 32 5.36 0.29 32 5.38 0.33 32 0.03 0.24 2016 American Medical Association. All rights reserved. 8

etable 6. Site-Specific Effects of Metformin on 16-Week Changes in BMI z Scores Treatment Difference 16-week change 95% CI Effect size P 1 Vanderbilt University -0.138 (-0.267,-0.009) 1.172 0.036 University of Pittsburgh -0.118 (-0.233,-0.003) 1.002 0.044 Holland Bloorview Rehabilitation Hospital -0.075 (-0.184,0.035) 0.634 0.18 Nationwide Children s Hospital -0.077 (-0.189,0.036) 0.650 0.18 1 3-DF site x treatment interaction p = 0.91. 2016 American Medical Association. All rights reserved. 9

etable 7. ITT Analysis: Effect of Metformin vs Placebo on Anthropometric Measurements, Metabolic Parameters, Behavioral Measures, and Clinical Global Impression 1 Metformin (n = 29) Placebo (n = 32) Treatment Difference 16-week 16-week 16-week Effect 95% CI p 95% CI p 95% CI Change Change change Size p BMI z-score -0.080 (-0.125,-0.035) <.001 0.016 (-0.026,0.059) 0.44-0.096 (-0.158,-0.035) 0.816 0.003 Weight z-score -0.099 (-0.150,-0.048) <.001 0.035 (-0.013,0.084) 0.15-0.134 (-0.204,-0.064) 1.040 <.001 BMI raw (kg/m 2 ) -0.427 (-0.792,-0.061) 0.023 0.524 (0.177,0.870) 0.004-0.951 (-1.454,-0.447) 1.011 <.001 Weight raw (kg) 0.064 (-0.882,1.010) 0.89 2.801 (1.904,3.698) <.001-2.737 (-4.040,-1.434) 1.136 <.001 BMI percentile (%) -0.825 (-1.448,-0.203) 0.010 0.034 (-0.564,0.631) 0.91-0.859 (-1.653,-0.065) 0.465 0.035 Weight percentile (%) -1.104 (-1.885,-0.324) 0.006 0.312 (-0.432,1.057) 0.41-1.417 (-2.490,-0.343) 0.647 0.011 Waist-hip ratio (%) 0.268 (-1.053,1.589) 0.69 0.482 (-0.783,1.746) 0.45-0.214 (-1.883,1.455) 0.056 0.80 Total cholesterol (mg/dl) -1.08 (-8.80,6.63) 0.78-3.32 (-10.36,3.72) 0.35 2.24 (-8.17,12.64) 0.123 0.67 LDL (mg/dl) -4.45 (-10.50,1.61) 0.15-0.46 (-6.16,5.24) 0.87-3.99 (-12.27,4.29) 0.277 0.34 HDL (mg/dl) 3.24 (-1.44,7.91) 0.17-1.02 (-5.29,3.25) 0.64 4.26 (-2.03,10.54) 0.358 0.18 Triglycerides (mg/dl) 6.17 (-21.86,34.21) 0.66 6.71 (-19.06,32.48) 0.60-0.53 (-37.04,35.98) 0.007 0.98 Glucose, fasting (mg/dl) -3.13 (-6.75,0.48) 0.088-2.50 (-5.85,0.84) 0.14-0.63 (-5.16,3.90) 0.062 0.78 Insulin, fasting (μiu/ml) 2.01 (-10.40,14.41) 0.75 2.98 (-8.41,14.38) 0.60-0.98 (-17.80,15.85) 0.030 0.91 HOMA-IR 0.54 (-2.37,3.45) 0.71 0.61 (-2.06,3.27) 0.65-0.06 (-3.98,3.86) 0.008 0.97 Hgb A1C (%) -0.054 (-0.143,0.035) 0.23 0.034 (-0.047,0.114) 0.40-0.088 (-0.207,0.032) 0.405 0.15 ABC Irritability -1.06 (-3.23,1.12) 0.34-1.01 (-3.09,1.07) 0.34-0.05 (-3.00,2.90) 0.008 0.98 ABC Lethargy -1.27 (-4.03,1.48) 0.36-1.40 (-4.05,1.25) 0.30 0.12 (-3.56,3.81) 0.018 0.95 ABC Stereotypy -0.26 (-1.43,0.91) 0.66-1.21 (-2.33,-0.08) 0.036 0.95 (-0.57,2.47) 0.276 0.22 ABC Hyperactivity -1.09 (-3.67,1.49) 0.40-1.66 (-4.13,0.81) 0.18 0.57 (-2.92,4.06) 0.086 0.74 ABC Inappropriate -0.75 (-1.44,-0.06) 0.035-0.12 (-0.78,0.54) 0.72-0.63 (-1.57,0.31) 0.343 0.19 Speech CGI Improvement -0.14 (-0.41,0.14) 0.32-0.06 (-0.32,0.20) 0.65-0.08 (-0.46,0.30) 0.102 0.69 1 Results were obtained from linear contrasts of estimates from the shared-baseline, linear mixed model described in the Methods. 2016 American Medical Association. All rights reserved. 10

efigure. Change in BMI vs Baseline BMI Scatterplot of 16-wk Change in BMI z-score vs Baseline BMI z Score BMI z score change Baseline BMI z score 2016 American Medical Association. All rights reserved. 11