Antipsychotic-related weight gain is a common clinically relevant side effect when treating psychotic disorders in pediatric populations, yet few predictors and no moderators of antipsychotic-related weight gain are known.
Methods:
The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study randomized 119 youths (age 8–19 years) with schizophrenia or schizoaffective disorder to 8 weeks of antipsychotic treatment with molindone, risperidone, or olanzapine and assessed treatment response and side effects. In this secondary analysis, we used multivariable linear regression and receiver operating characteristic analysis to investigate predictors and moderators of weight change and percent weight change from baseline to week 8.
Results:
Treatment assignment was the most discriminant predictor of weight change [F(2, 66) = 17.00, p < 0.001] and percent weight change [F(2, 66) = 16.85, p < 0.001]. Mean weight gain was 0.74 (standard deviation ±3.51) kg for molindone, 4.13 ± 3.79 kg for risperidone, and 7.29 ± 3.44 kg for olanzapine. After adjusting for treatment assignment, lower pretreatment hemoglobin A1C (HgbA1C) predicted more weight gain [F(1, 55) = 4.71, p = 0.03]. Diagnosis (schizoaffective vs. schizophrenia) moderated weight change [F(2, 63) = 6.02, p = 0.004] and percent weight change [F(2, 63) = 5.26, p = 0.008] such that schizoaffective diagnosis predicted larger weight gain for youths in the risperidone treatment arm. Age, sex, family income, baseline weight, and symptoms neither predicted nor moderated weight change or percent weight change.
Conclusion:
We identified prognostic subgroups and novel risk factors for antipsychotic-related weight gain. We confirmed that antipsychotic choice is extremely important for predicting future weight gain. We also found that younger age did not predict greater weight gain, in contrast to prior studies. Our findings require replication in an independent sample because we did not adjust for multiple comparisons to minimize false negatives. ClinicalTrials.gov Identifier: NCT00053703
Get full access to this article
View all access options for this article.
References
1.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, text revision: DSM-IV-TR. Washington, DC: American Psychiatric Association, 2000.
2.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fifth edition. Arlington, VA: American Psychiatric Publishing, 2013.
3.
AllisonDB, MackellJA, McDonnellDD: The impact of weight gain on quality of life among persons with schizophrenia. Psychiatr Serv, 54:565–567, 2003.
4.
AlmandilNB, LiuY, MurrayML, BesagFM, AitchisonKJ, WongIC: Weight gain and other metabolic adverse effects associated with atypical antipsychotic treatment of children and adolescents: A systematic review and meta-analysis. Pediatric Drugs, 15:139–150, 2013.
5.
CorrellCU, ManuP, OlshanskiyV, NapolitanoB, KaneJM, MalhotraAK: Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA, 302:1765–1773, 2009.
6.
CorrellCU, PenznerJB, ParikhUH, MughalT, JavedT, CarbonM, MalhotraAK: Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin N Am, 15:177–206, 2006.
7.
CuerdaC, Merchan-NaranjoJ, VelascoC, GutierrezA, LeivaM, de CastroMJ, ParelladaM, GiráldezM, BretónI, CamblorM: Influence of resting energy expenditure on weight gain in adolescents taking second-generation antipsychotics. Clin Nutr, 30:616–623, 2011.
8.
CzoborP, VolavkaJ, SheitmanB, LindenmayerJ-P, CitromeL, McEvoyJ, CooperTB, ChakosM, LiebermanJA: Antipsychotic-induced weight gain and therapeutic response: A differential association. J Clin Psychopharmacol, 22:244–251, 2002.
9.
De HertM, PeuskensB, van WinkelR, KalnickaD, HanssensL, Van EyckD, WyckaertS, PeuskensJ: Body weight and self-esteem in patients with schizophrenia evaluated with B-WISE®. Schizophr Res, 88:222–226, 2006.
10.
DengC, Weston-GreenK, HuangX-F: The role of histaminergic H1 and H3 receptors in food intake: A mechanism for atypical antipsychotic-induced weight gain?. Prog Neuropsychopharmacol Biol Psychiatry, 34:1–4, 2010.
11.
FDA: United states food and drug administration. Zyprexa and risperdal label. www.Fda.Gov Accessed July1, 2017.
12.
FraguasD, CorrellCU, Merchán-NaranjoJ, Rapado-CastroM, ParelladaM, MorenoC, ArangoC: Efficacy and safety of second-generation antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders: Comprehensive review of prospective head-to-head and placebo-controlled comparisons. Eur Neuropsychopharmacol, 21:621–645, 2011.
13.
FraguasD, Merchán-NaranjoJ, LaitaP, ParelladaM, MorenoD, Ruiz-SanchoA, CifuentesA, GiráldezM, ArangoC: Metabolic and hormonal side effects in children and adolescents treated with second-generation antipsychotics. The J Clin Psychiatry, 69:1166–1175, 2008.
14.
FrazierJA, McClellanJ, FindlingRL, VitielloB, AndersonR, ZablotskyB, WilliamsE, McNamaraNK, JacksonJA, RitzL: Treatment of early-onset schizophrenia spectrum disorders (TEOSS): Demographic and clinical characteristics. J Am Acad Child Adolesc Psychiatry, 46:979–988, 2007.
15.
FreedmanDS, DietzWH, SrinivasanSR, BerensonGS: The relation of overweight to cardiovascular risk factors among children and adolescents: The Bogalusa Heart Study. Pediatrics, 103:1175–1182, 1999.
16.
GabrielD, JakubovskiE, TaylorJH, ArtukogluBB, BlochMH: Predictors of treatment response and drop out in the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Psychiatry Res, 255:248–255, 2017.
17.
HennekensCH, HennekensAR, HollarD, CaseyDE: Schizophrenia and increased risks of cardiovascular disease. Am Heart J, 150:1115–1121, 2005.
18.
KaySR, FiszbeinA, OpferLA: The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull, 13:261, 1987.
19.
KiernanM, KraemerHC, WinklebyMA, KingAC, TaylorCB: Do logistic regression and signal detection identify different subgroups at risk? Implications for the design of tailored interventions. Psychol Methods, 6:35–48, 2001.
20.
KleinDJ, CottinghamEM, SorterM, BartonBA, MorrisonJA: A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry, 163:2072–2079, 2006.
21.
KroezeWK, HufeisenSJ, PopadakBA, RenockSM, SteinbergS, ErnsbergerP, JayathilakeK, MeltzerHY, RothBL: H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology, 28:519–526, 2003.
22.
KuczmarskiRJ, OgdenCL, Grummer-StrawnLM, FlegalKM, GuoSS, WeiR, MeiZ, CurtinLR, RocheAF, JohnsonCL: CDC growth charts: United states. Adv Data. 1–27, 2000.
23.
LeuchtS, KaneJM, KisslingW, HamannJ, EtschelE, EngelRR: What does the PANSS mean?. Schizophr Res, 79:231–238, 2005.
24.
LiebermanJA, StroupTS, McEvoyJP, SwartzMS, RosenheckRA, PerkinsDO, KeefeRS, DavisSM, DavisCE, LebowitzBD: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med, 353:1209–1223, 2005.
MaayanL, CorrellCU: Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol, 21:517–535, 2011.
27.
ManuP, DimaL, ShulmanM, VancampfortD, De HertM, CorrellC: Weight gain and obesity in schizophrenia: Epidemiology, pathobiology, and management. Acta Psychiatr Scand, 132:97–108, 2015.
28.
Martínez-OrtegaJM, Funes-GodoyS, Díaz-AtienzaF, Gutiérrez-RojasL, Pérez-CostillasL, GurpeguiM: Weight gain and increase of body mass index among children and adolescents treated with antipsychotics: A critical review. Eur Child Adolesc Psychiatry, 22:457–479, 2013.
29.
McClellanJ, SikichL, FindlingRL, FrazierJA, VitielloB, HlastalaSA, WilliamsE, AmblerD, Hunt-HarrisonT, MaloneyAE: Treatment of early-onset schizophrenia spectrum disorders (TEOSS): Rationale, design, and methods. J Am Acad Child Adolesc Psychiatry, 46:969–978, 2007.
30.
MitchellAJ, VancampfortD, De HerdtA, YuW, De HertM: Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizophr Bull, 39:295–305, 2013.
31.
MostafaviS-A, SolhiM, MohammadiM-R, AkhondzadehS: Melatonin for reducing weight gain following administration of atypical antipsychotic olanzapine for adolescents with bipolar disorder: A randomized, double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol, 27:440–444, 2017.
32.
PaeratakulS, LovejoyJ, RyanD, BrayG: The relation of gender, race and socioeconomic status to obesity and obesity comorbidities in a sample of us adults. Int J Obes, 26:1205, 2002.
33.
ParkM, FalconerC, VinerR, KinraS: The impact of childhood obesity on morbidity and mortality in adulthood: A systematic review. Obes Rev, 13:985–1000, 2012.
34.
PatelA, ChanW, AparasuRR, Ochoa-PerezM, ShererJT, MedhekarR, ChenH: Effect of psychopharmacotherapy on body mass index among children and adolescents with bipolar disorders. J Child Adolesc Psychopharmacol, 27:349–358, 2017.
35.
QuintanaH, WilsonMS2nd, PurnellW, LaymanAK, MercanteD: An open-label study of olanzapine in children and adolescents with schizophrenia. J Psychiatr Pract, 13:86–96, 2007.
36.
RatzoniG, GothelfD, Brand-GothelfA, ReidmanJ, KikinzonL, GalG, PhillipM, ApterA, WeizmanR: Weight gain associated with olanzapine and risperidone in adolescent patients: A comparative prospective study. J Am Acad Child Adolesc Psychiatry, 41:337–343, 2002.
37.
ReynoldsGP, ZhangZ-J, ZhangX-B: Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet, 359:2086–2087, 2002.
38.
SachsGS, GrossmanF, GhaemiSN, OkamotoA, BowdenCL: Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: A double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry, 159:1146–1154, 2002.
39.
SaddichhaS, AmeenS, AkhtarS: Predictors of antipsychotic-induced weight gain in first-episode psychosis: Conclusions from a randomized, double-blind, controlled prospective study of olanzapine, risperidone, and haloperidol. J Clin Psychopharmacol, 28:27–31, 2008.
40.
SaferDJ: A comparison of risperidone-induced weight gain across the age span. J Clin Psychopharmacol, 24:429–436, 2004.
41.
SchimmelmannBG, Mehler-WexC, LambertM, Schulze-zur-WieschC, KochE, FlechtnerHH, GierowB, MaierJ, MeyerE, Schulte-MarkwortM: A prospective 12-week study of quetiapine in adolescents with schizophrenia spectrum disorders. J Child Adolesc Psychopharmacol, 17:768–778, 2007.
42.
SikichL, FrazierJA, McClellanJ, FindlingRL, VitielloB, Louise RitzM, AmblerD, PugliaM, MaloneyAE, MichaelE: Double-blind comparison of first-and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: Findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry, 165:1420–1431, 2008.
43.
StahlS, MignonL, MeyerJ: Which comes first: Atypical antipsychotic treatment or cardiometabolic risk?. Acta Psychiatr Scand, 119:171–179, 2009.
44.
TaylorJ, XuY, LiF, ShawM, DziuraJ, CaprioS, TamborlaneW, NowickaP, SavoyeM: Psychosocial predictors and moderators of weight management programme outcomes in ethnically diverse obese youth. Pediatr Obes, 12:453–461, 2017.
45.
TaylorJH, JakubovskiE, BlochMH: Predictors of anxiety recurrence in the coordinated anxiety learning and management (CALM) trial. J Psychiatr Res, 65:154–165, 2015.
46.
TaylorJH, LebowitzER, JakubovskiE, CoughlinCG, SilvermanWK, BlochMH: Monotherapy insufficient in severe anxiety? Predictors and moderators in the child/adolescent anxiety multimodal study. J Clin Child Adolesc Psychol, 47:266–281, 2018.
47.
TaylorJJr, BelayB, ParkS, OnufrakS, DietzW: Association of church-sponsored activity participation and prevalence of overweight and obesity in African American Protestants, National Survey of American Life, 2001–2003. Ethn Dis, 23:322–328, 2012.
48.
TeffKL, RickelsMR, GrudziakJ, FullerC, NguyenH-L, RickelsK: Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease. Diabetes, 62:3232–3240, 2013.
49.
VancampfortD, De HertM, StubbsB, WardPB, RosenbaumS, SoundyA, ProbstM: Negative symptoms are associated with lower autonomous motivation towards physical activity in people with schizophrenia. Compr Psychiatry, 56:128–132, 2015.
50.
WangY, ZhangQ: Are American children and adolescents of low socioeconomic status at increased risk of obesity? Changes in the association between overweight and family income between 1971 and 2002. Am J Clin Nutr, 84:707–716, 2006.
51.
WuX, HuangZ, WuR, ZhongZ, WeiQ, WangH, DiaoF, WangJ, ZhengL, ZhaoJ: The comparison of glycometabolism parameters and lipid profiles between drug-naive, first-episode schizophrenia patients and healthy controls. Schizophr Res, 150:157–162, 2013.
52.
YarlagaddaA, TaylorJHJr, HampeCS, AlfsonE, ClaytonAH: Gad65 antibodies, chronic psychosis, and type 2 diabetes mellitus. Innov Clin Neurosci, 8:34, 2011.
53.
YesavageJA, HoblynJ, SheikhJ, TinklenbergJR, NodaA, O'HaraR, FennC, MumenthalerMS, FriedmanL, KraemerHC: Age and disease severity predict choice of atypical neuroleptic: A signal detection approach to physicians' prescribing decisions. J Psychiatr Res, 37:535–538, 2003.
54.
ZhangJ-P, LenczT, ZhangRX, NittaM, MaayanL, JohnM, RobinsonDG, FleischhackerWW, KahnRS, OphoffRA: Pharmacogenetic associations of antipsychotic drug-related weight gain: A systematic review and meta-analysis. Schizophr Bull, 42:1418–1437, 2016.
55.
ZimmermannU, KrausT, HimmerichH, SchuldA, PollmächerT: Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients. J Psychiatr Res, 37:193–220, 2003.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
