TY - JOUR
T1 - Metabolic effects of antipsychotics on adiposity and insulin sensitivity in youths a randomized clinical trial
AU - Nicol, Ginger E.
AU - Yingling, Michael D.
AU - Flavin, Karen S.
AU - Schweiger, Julia A.
AU - Patterson, Bruce W.
AU - Schechtman, Kenneth B.
AU - Newcomer, John W.
N1 - Funding Information:
research funding from the National Institute of Mental Health (NIMH), Otsuka America Pharmaceutical Inc, Alkermes PLC, The Sidney R. Baer Jr Foundation, and the Center for Brain Research in Mood Disorders at Washington University in St Louis. Dr Schechtman reported research funding from the NIMH, the National Heart, Lung, and Blood Institute, the National Institute of Aging, the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases. Dr Newcomer reported research funding from the National Institutes of Health (NIH) and Otsuka America Pharmaceutical Inc, in the 3 years before this study; serving as a consultant for Reviva Pharmaceuticals, Sunovion Pharmaceuticals Inc, Indivior, Otsuka America Pharmaceutical Inc, and Alkermes PLC, and serving as a consultant to litigation; serving on a data safety monitoring board for Amgen Inc; and receiving honoraria for continuing medical education from the American Society for Clinical Psychopharmacology. No other disclosures were reported.
Funding Information:
Funding/Support: This study was supported by grant MH072912 (principal investigator, Dr Newcomer) from the NIMH, grant UL1 RR024992 from the National Center for Research Resources (NCRR), a component of the NIH and the NIH Roadmap for Medical Research, and grant P30 DK056341 from the NIH (Washington University School of Medicine in St Louis Nutrition Obesity Research Center); by the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences of the NIH; and in part by the Sidney R. Baer Jr Foundation and the Healthy Mind Lab at Washington University.
Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
PY - 2018/8
Y1 - 2018/8
N2 - IMPORTANCE Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths. OBJECTIVE To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017. INTERVENTIONS Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49). MAIN OUTCOMES AND MEASURES Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers. RESULTS The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments. CONCLUSIONS AND RELEVANCE Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths.
AB - IMPORTANCE Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths. OBJECTIVE To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017. INTERVENTIONS Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49). MAIN OUTCOMES AND MEASURES Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers. RESULTS The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments. CONCLUSIONS AND RELEVANCE Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths.
UR - http://www.scopus.com/inward/record.url?scp=85051049702&partnerID=8YFLogxK
U2 - 10.1001/jamapsychiatry.2018.1088
DO - 10.1001/jamapsychiatry.2018.1088
M3 - Article
C2 - 29898210
AN - SCOPUS:85051049702
SN - 2168-622X
VL - 75
SP - 788
EP - 796
JO - JAMA psychiatry
JF - JAMA psychiatry
IS - 8
ER -