Metabolic Effects of Antipsychotics on Adiposity and Insulin Sensitivity in Youths: A Randomized Clinical Trial
Open accessAbstract
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. Trial Registration: ClinicalTrials.gov identifier: NCT00205699.
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Antipsychotics produce neurologic and cardiometabolic side effects.
“Schizophrenia rarely remits completely with antipsychotics, and these medications also produce neurologic and cardiometabolic side effects.12”
From Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders (2021) · cites this paper as [12]
Blockbuster drugs for neurobehavioural conditions have not yielded blockbuster improvements.
“In contrast, “blockbuster drugs” for neurobehavioural conditions have not yielded blockbuster improvements.”
From Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders (2021) · cites this paper as [12]
Schizophrenia rarely remits completely with antipsychotics.
“Schizophrenia rarely remits completely with antipsychotics, and these medications also produce neurologic and cardiometabolic side effects.12”
From Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders (2021) · cites this paper as [12]
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Cites
Diagnostic and Statistical Manual of Mental Disorders
Williams, J. B. W., & First, M. B. (2013) · Oxford University Press eBooks · doi:10.1093/acrefore/9780199975839.013.104 · Cited by 109,841 · see citing works
Diagnostic and Statistical Manual of Mental Disorders.
Widiger, T. A. (2000) · Oxford University Press eBooks · doi:10.1037/10518-009 · Cited by 19,767 · see citing works
Role of Insulin Resistance in Human Disease
Reaven, G. M. (1988) · Diabetes · doi:10.2337/diab.37.12.1595 · Cited by 12,154 · see citing works
(1976) · Medical Entomology and Zoology · Cited by 8,899 · see citing works
Prevalence of Overweight and Obesity in the United States, 1999-2004
Ogden, C. L., Carroll, M. D., Curtin, L. R., McDowell, M. A., Tabak, C. J., & Flegal, K. M. (2006) · JAMA · doi:10.1001/jama.295.13.1549 · Cited by 8,720 · see citing works
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
DeFronzo, R. A., Tobin, J. D., & Andres, R. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.237.3.e214 · Cited by 7,425 · see citing works
Matsuda, M., & DeFronzo, R. A. (1999) · Diabetes Care · doi:10.2337/diacare.22.9.1462 · Cited by 5,621 · see citing works
Berenson, G. S., Srinivasan, S. R., Bao, W., Newman, W. P., Tracy, R. E., & Wattigney, W. A. (1998) · New England Journal of Medicine · doi:10.1056/nejm199806043382302 · Cited by 4,032 · see citing works
A Children's Global Assessment Scale (CGAS)
Shaffer, D. (1983) · Archives of General Psychiatry · doi:10.1001/archpsyc.1983.01790100074010 · Cited by 3,716 · see citing works
A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS
Simpson, G. M., B., M., B., G., Angus, J. W. S., P., F. R. C., & M., D. P. (1970) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1970.tb02066.x · Cited by 3,265 · see citing works
Prevalence of High Body Mass Index in US Children and Adolescents, 2007-2008
Ogden, C. L. (2010) · JAMA · doi:10.1001/jama.2009.2012 · Cited by 3,200 · see citing works
A Rating Scale for Drug-Induced Akathisia
Barnes, T. R. E. (1989) · The British Journal of Psychiatry · doi:10.1192/bjp.154.5.672 · Cited by 2,179 · see citing works
Childhood Adiposity, Adult Adiposity, and Cardiovascular Risk Factors
Juonala, M., Magnussen, C. G., Berenson, G. S., Venn, A., Burns, T. L., Sabin, M. A., Srinivasan, S. R., Daniels, S. R., Davis, P. H., Chen, W., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1010112 · Cited by 1,665 · see citing works
Second-Generation (Atypical) Antipsychotics and Metabolic Effects
Newcomer, J. W. (2005) · CNS Drugs · doi:10.2165/00023210-200519001-00001 · Cited by 1,334 · see citing works
Self-citationAnnals of the New York Academy of Sciences
Singh, R., Kølvraa, A. S., Bross, B. P., Jensen, U. B., Eiberg, H. H., F, & Rattang, S. I. S. (2019) · Annals of the New York Academy of Sciences · doi:10.1111/(issn)1749-6632 · Cited by 1,305 · see citing works
Prevalence and Treatment of Mental Disorders Among US Children in the 2001–2004 NHANES
Merikangas, K. R., He, J.-P., Brody, D., Fisher, P. W., Bourdon, K., & Koretz, D. S. (2010) · Pediatrics · doi:10.1542/peds.2008-2598 · Cited by 1,172 · see citing works
Correll, C. U. (2009) · JAMA · doi:10.1001/jama.2009.1549 · Cited by 1,050 · see citing works
Appendicular skeletal muscle mass: measurement by dual-photon absorptiometry
Heymsfield, S. B., Smith, R. C., Aulet, M., Bensen, B., Lichtman, S. W., Wang, J., & Pierson, R. (1990) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/52.2.214 · Cited by 819 · see citing works
Adolescent Self-assessment of Sexual Maturation
Neinstein, L. S. (1982) · Clinical Pediatrics · doi:10.1177/000992288202100806 · Cited by 783 · see citing works
Conduct disorder and oppositional defiant disorder in a national sample: developmental epidemiology
Maughan, B., Rowe, R., Messer, J., Goodman, R., & Meltzer, H. (2004) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2004.00250.x · Cited by 743 · see citing works
Effects of arterial versus venous sampling on analysis of glucose kinetics in man
McGuire, E. A., Helderman, J. H., Tobin, J. D., Andres, R., & Berman, M. D. (1976) · Journal of Applied Physiology · doi:10.1152/jappl.1976.41.4.565 · Cited by 704 · see citing works
Adolescents' Self-Assessment of Sexual Maturation
Duke, P. M., Litt, I. F., & Gross, R. T. (1980) · PEDIATRICS · doi:10.1542/peds.66.6.918 · Cited by 685 · see citing works
Free Fatty Acids and Pathogenesis of Type 2 Diabetes Mellitus
Bergman, R. N., & Ader, M. (2000) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(00)00323-4 · Cited by 622 · see citing works
Finegood, D. T., Bergman, R. N., & Vranić, M. (1987) · Diabetes · doi:10.2337/diab.36.8.914 · Cited by 546 · see citing works
Srinivasan, S. R., Myers, L., & Berenson, G. S. (2002) · Diabetes · doi:10.2337/diabetes.51.1.204 · Cited by 480 · see citing works
Psychometric characteristics of the aberrant behavior checklist.
Aman, M. G., Singh, N. N., Stewart, A. W., & Field, C. J. (1985) · PubMed · Cited by 458 · see citing works
Gungor, N., Saad, R., Janosky, J., & Arslanian, S. (2004) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2003.09.045 · Cited by 457 · see citing works
Lieberman, J. A., Tollefson, G. D., Tohen, M. F., Green, A. I., Gur, R. E., Kahn, R. S., McEvoy, J. P., Perkins, D. O., Sharma, T., Zipursky, R. B., et al. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.8.1396 · Cited by 400 · see citing works
Abate, N., Burns, D., Peshock, R. M., Garg, A., & Grundy, S. M. (1994) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)40090-2 · Cited by 335 · see citing works
Further Measures of the Psychometric Properties of the Children's Global Assessment Scale
Bird, H. (1987) · Archives of General Psychiatry · doi:10.1001/archpsyc.1987.01800210069011 · Cited by 331 · see citing works
Blood sample volumes in child health research: review of safe limits
Howie, S. R. C. (2010) · Bulletin of the World Health Organization · doi:10.2471/blt.10.080010 · Cited by 286 · see citing works
Lenze, E. J., Mulsant, B. H., Blumberger, D. M., Karp, J. F., Newcomer, J. W., Anderson, S. J., Dew, M. A., Butters, M. A., Stack, J. A., Begley, A. E., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00308-6 · Cited by 283 · see citing works
Self-citationBroadened Use Of Atypical Antipsychotics: Safety, Effectiveness, And Policy Challenges
Crystal, S., Olfson, M., Huang, C. S., Pincus, H. A., & Gerhard, T. (2009) · Health Affairs · doi:10.1377/hlthaff.28.5.w770 · Cited by 268 · see citing works
Treatment of Young People With Antipsychotic Medications in the United States
Olfson, M., King, M. D., & Schoenbaum, M. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2015.0500 · Cited by 252 · see citing works
Antipsychotics and the Risk of Type 2 Diabetes Mellitus in Children and Youth
Bobo, W. V., Cooper, W. O., Stein, C. M., Olfson, M., Graham, D. J., Daugherty, J. R., Fuchs, D. C., & Ray, W. A. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.2053 · Cited by 229 · see citing works
Assessing Body Composition among 3‐ to 8‐Year‐Old Children: Anthropometry, BIA, and DXA
Eisenmann, J. C., Heelan, K. A., & Welk, G. J. (2004) · Obesity Research · doi:10.1038/oby.2004.203 · Cited by 228 · see citing works
JENSEN, M. D., Kanaley, J. A., Roust, L. R., O’Brien, P. C., BRAUN, J. S., DUNN, W. L., & Wahner, H. W. (1993) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(12)60695-8 · Cited by 213 · see citing works
Teff, K. L., Rickels, M. R., Grudziak, J., Fuller, C., Nguyen, H.-L., & Rickels, K. (2013) · Diabetes · doi:10.2337/db13-0430 · Cited by 195 · see citing works
Abbasi, A., Juszczyk, D., van Jaarsveld, C. H. M., & Gulliford, M. C. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2017-00044 · Cited by 165 · see citing works
Metabolic Screening in Children Receiving Antipsychotic Drug Treatment
Morrato, E. H., Nicol, G. E., Maahs, D. M., Druss, B. G., Hartung, D. M., Valuck, R. J., Campagna, E. J., & Newcomer, J. W. (2010) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpediatrics.2010.48 · Cited by 148 · see citing works
Self-citationArslanian, S. A., & Kalhan, S. C. (1994) · Diabetes · doi:10.2337/diab.43.7.908 · Cited by 144 · see citing works
Deivanayagam, S., Mohammed, B. S., Vitola, B. E., Naguib, G., Keshen, T. H., Kirk, E. P., & Klein, S. (2008) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/88.2.257 · Cited by 117 · see citing works
Lockner, D. W., Heyward, V. H., Baumgartner, R., & Jenkins, K. A. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06423.x · Cited by 102 · see citing works
Siegel, M. J., Hildebolt, C. F., Bae, K. T., Hong, C. W., & White, N. H. (2007) · Radiology · doi:10.1148/radiol.2423060111 · Cited by 100 · see citing works
Multiorgan insulin sensitivity in lean and obese subjects
Conte, C., Fabbrini, E., Kars, M., Mittendorfer, B., Patterson, B. W., & Klein, S. (2012) · Diabetes Care · doi:10.2337/dc11-1951 · Cited by 99 · see citing works
Self-citationThe Reference Child and Adolescent Models of Body Composition: A Contemporary Comparisona
Ellis, K. J., Shypailo, R. J., Abrams, S. A., & Wong, W. W. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06486.x · Cited by 98 · see citing works
Insulin dose response analysis of free fatty acid kinetics.
Jensen, M., & Nielsen, S. (2007) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2006.08.022 · Cited by 81 · see citing works
Vitola, B. E., Deivanayagam, S., Stein, R. I., Mohammed, B. S., Magkos, F., Kirk, E. P., & Klein, S. (2009) · Obesity · doi:10.1038/oby.2009.171 · Cited by 80 · see citing works
Rubin, D. M., Kreider, A. R., Matone, M., Huang, Y.-S. V., Feudtner, C., Ross, M., & Localio, A. R. (2015) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/jamapediatrics.2015.0285 · Cited by 77 · see citing works
Reliability and Stability of a Semistructured DSM-IV Interview Designed for Family Studies
Todd, R. D., Joyner, C. A., Heath, A. C., Neuman, R. J., & Reich, W. (2003) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200312000-00013 · Cited by 73 · see citing works
Moreno, C., Merchán‐Naranjo, J., Álvarez, M., Baeza, I., Alda, J. A., Martínez‐Cantarero, C., Parellada, M., Sánchez, B., de la Serna, E., Giráldez, M., et al. (2010) · Bipolar Disorders · doi:10.1111/j.1399-5618.2010.00797.x · Cited by 54 · see citing works
Newcomer, J. W., Weiden, P. J., & Buchanan, R. W. (2013) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.12028ah1 · Cited by 51 · see citing works
Self-citationBaeza, I., Vigo, L., de la Serna, E., Calvo, R. M., Merchán‐Naranjo, J., Rodríguez-Latorre, P., Arango, C., & Castro‐Fornieles, J. (2016) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-016-0866-x · Cited by 49 · see citing works
The Metabolic Syndrome During Atypical Antipsychotic Drug Treatment: Mechanisms and Management
Baptista, T., Mendoza, S., Beaulieu, S., Bermúdez, A., & Martinez, M. (2004) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2004.2.290 · Cited by 42 · see citing works
[Tardive dyskinesia. AIMS (Abnormal Involuntary Movement Scale) as a diagnostic and research tool].
Burti, L., Parolin, A., & Zanotelli, R. (1981) · PubMed · Cited by 13 · see citing works
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- Authors
- Nicol, G. E., Yingling, M. D., Flavin, K. S., Schweiger, J. A., Patterson, B. W., Schechtman, K. B., & Newcomer, J. W.
- Affiliations
- Washington University in St. Louis (US)
- Florida Atlantic University (US)
- Corresponding author
- Newcomer, John W.
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2018-08-01
- Volume
- 75
- Issue
- 8
- Pages
- 788
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6143095
- OpenAlex
- W2808559700
- Cited by
- 83
- References
- 55
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 23 · 2020: 8 · 2019: 11 · 2018: 3
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000448, UL1TR002345)
- National Institute of Mental Health (R01MH072912)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092950, P30DK056341)
- National Center for Research Resources (UL1RR024992)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Keywords
- antipsychotic drugs, adiposity, insulin sensitivity, aripiprazole, olanzapine, risperidone, youth, disruptive behavior disorders, aggression, fat mass, abdominal fat, hepatic insulin sensitivity, adipose tissue insulin sensitivity, metabolic side effects, obesity risk, hyperinsulinemic-euglycemic clamp, dual-energy X-ray absorptiometry
- MeSH terms
- Problem Behavior, Aripiprazole, Olanzapine, Adolescent, Mental Disorders, Child, Female, Humans, Insulin Resistance, Male, Antipsychotic Agents, Absorptiometry, Photon, Treatment Outcome, Risperidone, Abdominal Fat, Intention to Treat Analysis, Drug-Related Side Effects and Adverse Reactions
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