Antipsychotic Medication Use Among Children and Risk of Diabetes Mellitus

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1 Antipsychotic Mediction Use Among Children nd Risk of Dibetes Mellitus AUTHORS: Susn E. Andrde, ScD, Jon C. Lo, MD, b Dougls Roblin, PhD, c Hssn Fouyzi, MS, Dniel F. Connor, MD, d Robert B. Penfold, PhD, e Mlini Chndr, MS, MBA, b George Reed, PhD, nd Jerry H. Gurwitz, MD Meyers Primry Cre Institute, School of Medicine, University of Msschusetts, Worcester, Msschusetts; b Division of Reserch, Kiser Permnente Northern Cliforni, Oklnd, Cliforni; c Center for Helth Reserch, Kiser Permnente Georgi, Atlnt, Georgi; d Deprtment of Psychitry, School of Medicine, University of Connecticut, Frmington, Connecticut; nd e Helth Services Reserch, Group Helth Reserch Institute, Settle, Wshington KEY WORDS second-genertion ntipsychotics, dibetes, children, dolescents ABBREVIATIONS SGA second-genertion ntipsychotic IRR incidence rte rtio CI confidence intervl ICD-9-CM Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction doi: /peds Accepted for publiction Aug 31, 2011 Address correspondence to Susn E. Andrde, ScD, Meyers Primry Cre Institute, University of Msschusetts, 630 Plnttion St, Worcester, MA E-mil: sndrde@ meyersprimry.org PEDIATRICS (ISSN Numbers: Print, ; Online, ). Copyright 2011 by the Americn Acdemy of Peditrics FINANCIAL DISCLOSURE: Dr Andrde hs received reserch funding from Novrtis Phrmceuticls in the pst. Dr Lo hs fmily member who receives reserch funding from Johnson nd Johnson nd GlxoSmithKline; the other uthors hve indicted they hve no finncil reltionships relevnt to this rticle to disclose. WHAT S KNOWN ON THIS SUBJECT: Numerous cse reports nd studies hve suggested link between ntipsychotic mediction use nd dibetes mellitus, impired glucose tolernce, nd insulin resistnce in dult popultions, lthough the evidence hs been inconsistent, prticulrly with regrd to the different effects of specific gents. WHAT THIS STUDY ADDS: The incidence of dibetes mong children inititing second-genertion ntipsychotic therpy ws higher thn the incidence mong children not using ny psychotropic medictions. No sttisticlly significnt difference in incidence ws found for children inititing second-genertion ntipsychotic therpy versus ntidepressnt therpy. bstrct OBJECTIVE: To ssess whether the risk of incident dibetes ws incresed with the use of second-genertion ntipsychotics (SGAs) in lrge diverse cohort of children. METHODS: A retrospective study ws conducted by using the dministrtive dtbses of 3 helth plns prticipting in the Helth Mintennce Orgniztion Reserch Network. Children 5 to 18 yers of ge who initited SGA therpy between Jnury 2001 nd December 2008 nd 2 comprison groups, nmely, nonusers of psychotropic drugs nd users of ntidepressnt medictions, were identified. Dignoses from inptient nd outptient records, phrmcy dispensings, nd outptient lbortory results were used to identify incident cses of dibetes. RESULTS: The crude incidence rte of dibetes for the SGA-exposed cohort ws 3.23 cses per 1000 person-yers (95% confidence intervl [CI]: ), compred with 0.76 cses per 1000 person-yers (95% CI: ) mong nonusers of psychotropic medictions nd 1.86 cses per 1000 person-yers (95% CI: ) mong ntidepressnt users. The risk of incident dibetes ws significntly incresed mong SGA users (undjusted incidence rte rtio: 4.24 [95% CI: ]) in comprison with nonusers of psychotropic medictions but ws not significntly incresed in comprison with ntidepressnt mediction users (undjusted incidence rte rtio: 1.74 [95% CI: ]). CONCLUSIONS: Although we found potentilly fourfold incresed rte of dibetes mong children exposed to SGAs, the findings were inconsistent nd depended on the comprison group nd the outcome definition. Peditrics 2011;128: PEDIATRICS Volume 128, Number 6, December

2 The use of second-genertion ntipsychotics (SGAs) hs incresed drmticlly for children nd dolescents, 1 5 lthough the mjority of use in this popultion is off-lbel nd dt on sfety nd efficcy re limited. Dt from the Ntionl Ambultory Medicl Cre Survey nd the Ntionl Hospitl Ambultory Medicl Cre Survey indicte tht ntipsychotic prescribing incresed from 8.6 visits per 1000 US children (2 18 yers of ge) in to 39.4 visits per 1000 US children in Studies indicte incresed use mong very young children (2 5 yers of ge) 6 nd use of SGAs in combintion with other drugs. 7 In ddition, studies reported tht 15% of ntipsychotic users in the noninstitutionlized US popultion were children 4 nd tht lmost one-fourth of users in Medicid popultion were children. 8 Numerous cse reports nd studies hve suggested link between the use of ntipsychotic medictions nd dibetes mellitus, impired glucose tolernce, nd insulin resistnce in dult popultions, lthough the evidence hs been inconsistent, prticulrly with respect to the different effects of specific gents Furthermore, lthough studies indicted rpid effects on weight gin, ft mss, nd wist circumference in children, evidence suggesting n ssocition between impired glucose tolernce nd ntipsychotic use in children is limited. 8,20,23 Given the clinicl complictions (crdiovsculr, neurologic, nd renl) ssocited with dibetes, the clinicl nd public helth implictions of ny incresed risk in the peditric popultion with these gents re lrge. The objective of the present study ws to evlute the risk of incident dibetes mellitus ssocited with the use of SGAs in lrge diverse cohort of children treted in typicl clinicl prctice. METHODS Study Popultion A retrospective cohort study ws conducted by using the dministrtive dtbses of 3 Helth Mintennce Orgniztion Reserch Network helth plns from The helth plns enroll youths 5 to 18 yers of ge. Helth pln providers re llowed to prescribe both formulry nd nonformulry SGAs, lthough the cost for the ptient my be higher for nonformulry gent; the reltive rtes of use of specific gents t the 3 sites were similr during the observtion period. For ech helth pln, children nd dolescents 5 to 18 yers of ge who filled prescription for SGA between Jnury 1, 2001, nd December 31, 2008, were identified by using utomted phrmcy dispensing records. All medictions were identified through Ntionl Drug Codes. New users of SGAs were identified by selecting members whose initil dispensing ws preceded by 1 yer of continuous enrollment with drug benefits nd no dispensing of SGA in the previous 6 months. Two comprison groups were identified. Comprison group 1 included youths 5 to 18 yers of ge who did not receive ny psychotropic drugs during the observtion period, who were mtched individully 4:1 with subjects who were exposed to ntipsychotic medictions, with respect to ge, gender, nd enrollment (helth pln membership on the dte of initil dispensing of the ntipsychotic drug nd 1 yer previously). Comprison group 2 included youths 5 to 18 yers of ge who were new users of selective serotonin reuptke inhibitors or tricyclic ntidepressnts. Identicl membership nd benefits requirements were pplied to the comprison groups. Children with known preexisting dibetes mellitus were excluded from the study. Preexisting dibetes ws identified by using dministrtive dtbses to identify ptients with dignosis code for dibetes mellitus (Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction [ICD-9- CM] codes X) or dispensing of n ntidibetic mediction during the 12 months before the initil ntipsychotic dispensing dte or the strt of the follow-up period for the exposed nd comprison groups. Exposed person-time ws determined from the dispensing dtes nd the dys of supply dispensed, s documented in the utomted phrmcy records. A person s mediction exposure strted on the initil dte SGA (or ntidepressnt) ws dispensed nd extended until the erliest of (1) the occurrence of new-onset dibetes mellitus, (2) 1 yer fter the initition of mediction therpy, (3) the end of the study period (December 31, 2008), (4) helth pln disenrollment, (5) switch to nother psychotropic therpy, s indicted by phrmcy records, or (6) discontinution of therpy, clculted s 30 dys fter exhustion of the estimted supply for successive prescriptions for the drug, s indicted by phrmcy records. Gps of 30 dys between the expected nd ctul refill dtes for successive prescriptions (on the bsis of supply dispensed) were counted s continuously exposed dys. For ptients included in the comprison group of nonusers of psychotropic drugs, exposed person-time strted on the mtched exposed ptient s initil dispensing dte (index dte) nd extended until the erliest of (1) the occurrence of new-onset dibetes mellitus, (2) 1 yer fter the index dte, (3) the end of the study period, or (4) helth pln disenrollment. These end points were chosen becuse the mjority of newly dignosed cses of dibetes mong children nd dolescents tking SGAs re reported to occur 1136 ANDRADE et l

3 within 6 months fter initition of therpy 24,25 nd the mjority of children in our study were exposed to SGAs for 1 yer. Min Outcome Mesures We used the computerized helth pln dtbses to identify potentil cses of dignosed nd/or treted dibetes mellitus. The specific criteri included (1) n inptient or outptient dignosis code for dibetes mellitus (ICD- 9-CM codes X), (2) dispensing of n ntidibetic mediction (single or combintion formultions, including insulin preprtions, pioglitzone, rosiglitzone, troglitzone, metformin, chlorpropmide, glipizide, glimepiride, glyburide, tolzmide, tolbutmide, sxgliptin, sitgliptin, exentide, miglitol, crbose, nteglinide, prmlintide, nd repglinide), or (3) lbortory test result of hemoglobin A1c level of 7%, fsting plsm glucose level of 126 mg/dl, or csul plsm glucose level of 200 mg/dl. Our primry definition for the outcome of interest ws dignosis code for dibetes mellitus or dispensing of n ntidibetic mediction (criteri 1 nd/or 2 described bove). Femle members 12 yers of ge who received metformin only were not included in this definition. We lso expnded our definition of dibetes to include n bnorml glucose lbortory test result (criteri 1, 2, nd/or 3), to test in secondry nlyses whether the ssocition of incident dibetes with SGA exposure might be sensitive to the definition of dibetes. Demogrphic nd Clinicl Chrcteristics of Ptients Helth pln dministrtive dtbses were used to obtin informtion on potentil confounders, including ge, gender, mentl helth nd developmentl conditions (schizophrenic disorders [ICD-9-CM codes ], mood disorders [ICD-9-CM codes , 300.4, , 311, nd 313.1], utism (ICD-9-CM codes ], disruptive behviorl disorders [ICD-9-CM codes 309.3, , , nd ]), orl corticosteroid use, frequency of mbultory cre visits, clendr yer of initition of psychotropic therpy, use of other psychotropic medictions (ntinxiety medictions or mood stbilizers), nd use of drugs to tret ttention-deficit/ hyperctivity disorder. Anlyses Incidence rtes for new-onset dibetes mellitus were estimted for children nd dolescents by using 2 cse definitions tht were bsed on the criteri described bove. Incidence rtes were clculted with 95% confidence intervls (CIs) ccording to the Poisson distribution. Multivrite Poisson regression ws used to estimte the strength of ssocition between SGA use (versus nonuse) nd new-onset dibetes mellitus, nd seprte nlyses were performed for the 2 comprison groups nd djustment for potentil confounders. Stt 11 (Stt Corp, College Sttion, TX) ws used to fit exct Poisson regression models. We lso performed secondry nlysis mtching the SGA users to ech of the 2 comprison groups by using propensity score methods. Propensity score mtching is considered n lterntive to multivrite modeling. 26 By using dt for subjects exposed nd not exposed (in this cse, exposure is SGA use), model is built to predict exposure by using covrites (nd not the outcome). By using the probbility of exposure (propensity for exposure), individuls in the unexposed group re mtched to subjects in the exposed group, so tht comprison of outcomes is mde between groups with similr propensities for exposure. We estimted the probbility of receiving SGA by using logistic regression with the following vribles: ge, gender, mentl helth nd developmentl conditions (schizophreni, mood disorders, utism, nd disruptive behviorl disorders) within 6 months of initition of therpy or follow-up monitoring, orl corticosteroid use in the previous 3 months, frequency of mbultory cre visits in the previous 6 months, clendr yer of initition of therpy, use of other psychotropic medictions (ntinxiety medictions or mood stbilizers), nd use of drugs to tret ttention-deficit/hyperctivity disorder in the previous 6 months. Becuse children in comprison group 1 (who did not receive ny psychotropic drugs) were individully mtched to individuls who were exposed to ntipsychotic medictions, with respect to ge, gender, nd enrollment on the dte of initil dispensing of the ntipsychotic drug, these vribles were not evluted in the logistic regression models used to estimte the propensity scores. Dignostic mesures for the propensity score models showed dequte bility to distinguish SGA users from nonusers of psychotropic drugs nd ntidepressnt users (c sttistics of 0.95 nd 0.78, respectively). 27 From these models, we generted propensity scores, which were used to mtch SGA users to ech of the 2 comprison groups by using 1:1 nerestneighbor method without replcements. The closest comprison subject whose propensity score differed by 0.01 ws selected, nd unmtched individuls were not included. The study ws pproved by the institutionl review bord of ech prticipting orgniztion. RESULTS A totl of 9636 children nd dolescents initited SGA mediction therpy nd met eligibility criteri. Approximtely 60% of SGA users were mle, PEDIATRICS Volume 128, Number 6, December

4 TABLE 1 Bseline Chrcteristics of the Study Popultion SGA Use (N 9636) nd 46% were between the ges of 15 nd 18 yers. Tble 1 lists chrcteristics of the children exposed to SGAs nd the 2 comprison groups. A totl of 57 children were identified s hving incident dibetes, by using our primry criteri, during the follow-up period. For children with incident dibetes who received SGA, verge dily dosges were within recommended rnges. Among the children with incident dibetes, the men times to dignosis were 138 dys (SD: 90 dys) for users of SGAs (n 12), 173 dys (SD: 117 dys) for children who did not receive psychotropic medictions (n 26), nd 143 dys (SD: 119 dys) for users of ntidepressnts (n 19). The crude incidence rte of n (%) No Psychotropic Mediction Use (N ) Antidepressnt Use (N ) Gender Femle 3852 (40.0) (40.0) (62.1) Mle 5784 (60.0) (60.0) 9967 (38.0) Age 5to 10 y 1729 (17.9) 6916 (17.9) 2359 (9.0) 10 to 15 y 3471 (36.0) (36.0) 8084 (30.8) 15 to 19 y 4436 (46.0) (46.0) (60.2) Mentl helth dignoses Autism 561 (5.8) 37 (0.1) 222 (0.9) Disruptive behvior disorders 5318 (55.2) 1185 (3.1) 5689 (21.7) Mood disorders 6599 (68.5) 499 (1.3) (58.4) Schizophrenic disorders 472 (4.9) 1 (0.0) 24 (0.1) Proportions do not sum to 100%, becuse dignoses re not mutully exclusive nd mny children hd multiple mentl helth dignoses. dibetes for the SGA-exposed cohort ws 3.23 cses per 1000 person-yers (95% CI: ), compred with 0.76 cses per 1000 person-yers (95% CI: ) for the no-psychotropic mediction use cohort nd 1.86 cses per 1000 person-yers (95% CI: ) for the ntidepressnt-exposed cohort (Tble 2). Tble 3 shows the incidence rte rtios (IRRs) for the ssocition of SGA use nd dibetes for ech of the comprison groups. With the use of children who did not receive psychotropic medictions s the comprison group, exposure to SGAs ws found to be ssocited with dibetes (undjusted IRR: 4.24 [95% CI: ]). Other chrcteristics ssocited with dibetes were utism (undjusted IRR: [95% CI: ]), disruptive behvior disorders (undjusted IRR: 2.87 [95% CI: ]), nd mood disorders (undjusted IRR: 3.29 [95% CI: ]). A similr ssocition ws found between SGA use nd the risk of dibetes in multivrite nlyses. No sttisticlly significnt ssocition ws found between dibetes nd ny chrcteristic other thn SGA exposure fter stepwise inclusion of covrites (dt not shown). No sttisticlly significnt ssocition ws found for dibetes nd exposure to SGAs with the use of ntidepressnt users s the comprison group (undjusted IRR: 1.74 [95% CI: ]). For the combined popultion of children exposed to SGAs nd children exposed to ntidepressnts, no sttisticlly significnt ssocition ws found for dibetes nd ny chrcteristic (demogrphic, helth cre utiliztion, or clinicl or mentl helth) evluted. In the propensity score mtching, 2531 children in the SGA-exposed group (26%) were mtched to children in comprison group 1 (no psychotropic use) nd 8012 (83%) were mtched to children in comprison group 2 (ntidepressnt use). Even fter the mtching, there were sttisticlly significnt differences between the groups in number of chrcteristics, lthough TABLE 2 Incidence of Dibetes in the Study Popultion Totl Exposure Time, Person-Yers Incident Cses of Dibetes, n Dibetes, Crude Incidence Rte (95% CI), Cses per 1000 Person-Yers Incident Cses of Dibetes or Abnorml Glucose Lbortory Vlue, n b Dibetes or Abnorml Glucose Lbortory Vlue, Crude Incidence Rte (95% CI), Cses per 1000 Person-Yers b SGA use ( ) ( ) Aripiprzole ( ) ( ) Clozpine ( ) ( ) Olnzpine ( ) ( ) Quetipine ( ) ( ) Risperidone ( ) ( ) Ziprsidone ( ) ( ) No psychotropic mediction use ( ) ( ) Antidepressnt use ( ) ( ) Primry definition of dibetes, tht is, dignosis of dibetes or dispensing of ntidibetic mediction. b Secondry definition of dibetes, tht is, dignosis of dibetes, dispensing of ntidibetic mediction, hemoglobin A1c level of 7%, fsting plsm glucose level of 126 mg/dl, or csul plsm glucose level of 200 mg/dl ANDRADE et l

5 TABLE 3 Assocition Between SGA Use nd Dibetes IRR (95% CI) Undjusted After Propensity Score Mtching Comprison group 1: no psychotropic mediction use 4.24 ( ) 4.47 ( ) Comprison group 2: ntidepressnt use 1.74 ( ) 3.58 ( ) Propensity scores were generted nd were used to mtch SGA users to ech of the 2 comprison groups by using 1:1 nerest-neighbor method without replcements; 2531 children in the SGA-exposed group (26%) were mtched to children in comprison group 1 (no psychotropic mediction use), nd 8012 (83%) were mtched to children in comprison group 2 (ntidepressnt use). the bsolute differences were smll for most chrcteristics. For the mtched SGA use nd no-psychotropic mediction use groups, the lrgest differences were observed for ge (38% of SGA users were 15 yers of ge, compred with 44% in the comprison group), yer of initition of therpy or follow-up monitoring (17% of SGA users initited follow-up monitoring in clendr yer 2008, compred with 13% in the comprison group), nd utism (3% of SGA users were dignosed s hving utism, compred with 2% in the comprison group). The SGA nd ntidepressnt groups were more similr fter mtching, nd there were slight differences in mentl helth dignoses (with bsolute differences between the groups of 2 percentge points). In totl, there were 3 incident cses of dibetes in the mtched SGA nd no-psychotropic mediction groups nd 13 incident cses of dibetes in the mtched SGA nd ntidepressnt groups. The IRRs for the ssocition between dibetes nd SGA use were 4.47 (95% CI: ) for comprison group 1 (no psychotropic use) nd 3.58 (95% CI: ) for comprison group 2 (ntidepressnt use) (Tble 3). A totl of 104 children exhibited the secondry outcome of dignosis of dibetes mellitus, dispensing of n ntidibetic mediction, or n bnorml glucose lbortory test result during the follow-up period. Undjusted nd multivrite nlyses suggested similr ssocitions between this secondry outcome nd SGA exposure s were observed for the primry outcome (Tble 2), lthough the IRRs with the ntidepressnt users s the comprison group were ttenuted (undjusted IRR: 0.81 [95% CI: ]). DISCUSSION We conducted retrospective cohort study tht included 9000 children nd dolescents who initited therpy with SGAs, to investigte possible ssocition between SGA use nd the risk of dibetes mellitus. Estimtes of the effect of SGA use were determined with 2 seprte comprison groups. The findings differed depending on the comprison group nd the definition of the outcome of interest. We found n incresed incidence of dibetes mong children within the first yer fter initition of SGA therpy, compred with children who were not using ny psychotropic medictions. This finding persisted when the incidences of both dibetes nd bnorml glucose lbortory vlues were evluted. We found no sttisticlly significnt difference in the risk of dibetes mong children inititing SGA therpy, compred with those inititing ntidepressnt therpy; however, the IRR estimte fter propensity score mtching ws of mrginl significnce. Different effects of specific SGA medictions on weight gin nd insulin resistnce hve been suggested to influence the risk for dibetes mellitus. 28,29 Clozpine nd olnzpine seem to hve the highest risk of weight gin, followed by quetipine. 30,31 Possible mechnisms include ntgonism of serotonin 5-HT 1A/2A/2C receptors, resulting in inhibition of insulin relese, insulin resistnce, or impirment of glucose utiliztion Effects of the SGAs on 2 -drenergic receptors lso my influence pncretic -cell function. 31 Previous evidence suggested tht youths receiving SGAs experience dverse chnges in body composition nd metbolic prmeters even fter short-term therpy. The nonrndomized Second-Genertion Antipsychotic Tretment Indictions, Effectiveness, nd Tolerbility in Youth study found significnt increses in body composition prmeters such s weight, ft mss, nd BMI for ll ntipsychotic medictions ssessed (ripiprzole, olnzpine, quetipine, nd risperidone) fter medin of 10.8 weeks of tretment, compred with n untreted comprison group; ptients receiving olnzpine experienced the highest incidence rtes of hyperglycemi nd metbolic syndrome. 20 A retrospective study tht used Medicid clims dt reported higher rtes of either dignosis of glucose disturbnce or ntidibetic mediction dispensing within 6 months fter initition of therpy mong children receiving SGAs, compred with group of children receiving lbuterol. 8 Evlutions of cse series of spontneous reports to the US Food nd Drug Administrtion MedWtch drug surveillnce system indicted tht the mjority of newly dignosed cses nd excerbtions of preexisting dibetes mong children nd dolescents receiving SGAs were reported within 6 months fter initition of therpy. 24,25 The choice of n pproprite comprison group is crucil to n understnding of the ssocition between SGA use nd dibetes, becuse of confounding ccording to indiction nd potentil detection bis. Therefore, in ddition to evluting the ssocition by using comprison group of children not ex- PEDIATRICS Volume 128, Number 6, December

6 posed to psychotropic medictions, we evluted the ssocition by using group of children exposed to ntidepressnt medictions. This pproch llowed us to select children more likely to be similr to SGA users in terms of tretment for mentl helth conditions nd the potentil for detection/dignosis of dibetes. Recent published studies reported n ssocition between ntidepressnt use nd the risk of dibetes, prticulrly mong long-term users of ntidepressnts or ptients receiving high doses of ntidepressnt medictions 34,35 ; evidence is conflicting regrding such n ssocition. 36 If cusl ssocition exists between ntidepressnt mediction use nd dibetes, then the use of this comprison group might hve ttenuted n ctul ssocition between SGA use nd dibetes in the present study. Our study evluted the ssocition with SGA medictions in lrge diverse cohort of well-chrcterized peditric ptients from 3 geogrphiclly distributed helth plns tht monitor ptients for longitudinl exposures nd clinicl outcomes. An dditionl REFERENCES 1. Cooper WO, Hickson GB, Fuchs C, Arbogst PG, Ry WA. New users of ntipsychotic medictions mong children enrolled in TennCre. Arch Peditr Adolesc Med. 2004; 158(8): Cooper WO, Arbogst PG, Ding H, Hickson GB, Fuchs DC, Ry WA. Trends in prescribing of ntipsychotic medictions for US children. Ambul Peditr. 2006;6(2): Curtis LH, Msselink LE, Ostbye T, et l. Prevlence of typicl ntipsychotic drug use mong commercilly insured youths in the United Sttes. Arch Peditr Adolesc Med. 2005;159(4): Domino ME, Swrtz MS. Who re the new users of ntipsychotic medictions? Psychitr Serv. 2008;59(5): Ptel NC, Crismon ML, Hogwood K, et l. Trends in the use of typicl nd typicl ntipsychotics in children nd dolescents. J Am Acd Child Adolesc Psychitry. 2005;44(6): Olfson M, Crystl S, Hung C, Gerhrd T. strength of our study ws the bility to identify nd to evlute glucose lbortory vlues within this popultion. One limittion of our study ws the smll number of cses identified, which precluded detiled evlution of the ssocitions between individul gents nd the risk of dibetes, s well s investigtion of whether the risk vried in reltion to dose. In ddition, only dignosed cses of dibetes were identified; therefore, cses of dibetes might hve been undetected in our study popultion. It ws not possible to differentite type 1 from type 2 dibetes mellitus by using dministrtive dt. The potentil pthophysiologic effects of SGA use would be expected to increse the risk of only type 2 dibetes. The likely effect of this misclssifiction would be tht our IRR estimte ws bised towrd the null. Finlly, residul confounding ws possible, becuse we did not evlute potentil confounders such s bseline BMI, diet, exercise, rce/ethnicity, severity of underlying mentl helth conditions, or long-term use. We performed secondry nlyses by using propensity score methods to djust for potentil confounding; however, estimtes of the ssocition were imprecise becuse of the low mtching rtes. CONCLUSIONS We found potentilly fourfold incresed rte of dibetes mong children exposed to SGAs in comprison with children not exposed but no sttisticlly significntly incresed rte in comprison with children exposed to ntidepressnt medictions. Given the clinicl complictions ssocited with dibetes, the potentilly incresed risk of dibetes with these gents in the peditric popultion is n importnt drug sfety nd public helth issue. Limittions of the present study, including the smll number of cses, suggest tht dditionl reserch is needed to define the nture nd mgnitude of the dibetes risk ssocited with SGA use mong children. ACKNOWLEDGMENT This study ws supported through funding from Agency for Helthcre Reserch nd Qulity grnt 1U18HS Trends in ntipsychotic drug use by very young, privtely insured children. JAm Acd Child Adolesc Psychitry. 2010;49(1): Mojtbi R, Olfson M. Ntionl trends in psychotropic mediction polyphrmcy in office-bsed psychitry. Arch Gen Psychitry. 2010;67(1): Morrto EH, Druss B, Hrtung DM, et l. Metbolic testing rtes in 3 stte Medicid progrms fter FDA wrnings nd ADA/APA recommendtions for secondgenertion ntipsychotic drugs. Arch Gen Psychitry. 2010;67(1): Frwell WR, Stump TE, Wng J, Tfesse E, L Itlien G, Tierney WM. Weight gin nd new onset dibetes ssocited with olnzpine nd risperidone. J Gen Intern Med. 2004; 19(12): Ginfrncesco FD, Grogg AL, Mhmoud RA, Wng RH, Nsrllh HA. Differentil effects of risperidone, olnzpine, clozpine, nd conventionl ntipsychotics on type 2 dibetes: findings from lrge helth pln dtbse. J Clin Psychitry. 2002;63(10): GinfrncescoF, WhiteR, WngRH, NsrllhHA. Antipsychotic-induced type 2 dibetes: evidence from lrge helth pln dtbse. J Clin Psychophrmcol. 2003;23(4): Kornegy CJ, Vsilkis-Scrmozz C, Jick H. Incident dibetes ssocited with ntipsychotic use in the United Kingdom Generl Prctice Reserch Dtbse. J Clin Psychitry. 2002;63(9): Koro CE, Fedder DO, L Itlien GJ, et l. Assessment of independent effect of olnzpine nd risperidone on risk of dibetes mong ptients with schizophreni: popultion bsed nested cse-control study. BMJ. 2002;325(7358): Lmbert BL, Chng KY, Tfesse E, Crson W. Assocition between ntipsychotic tretment nd hyperlipidemi mong Cliforni Medicid ptients with schizo ANDRADE et l

7 phreni. J Clin Psychophrmcol. 2005; 25(1): Mmdni M. Antipsychotics nd dibetes: is there n ssocition? Phrmcoepidemiol Drug Sf. 2005;14(6): Moisn J, Gregoire JP, Gudet M, Cooper D. Exploring the risk of dibetes mellitus nd dyslipidemi mong mbultory users of typicl ntipsychotics: popultion-bsed comprison of risperidone nd olnzpine. Phrmcoepidemiol Drug Sf. 2005;14(6): Østbye T, Curtis LH, Msselink LE, et l. Atypicl ntipsychotic drugs nd dibetes mellitus in lrge outptient popultion: retrospective cohort study. Phrmcoepidemiol Drug Sf. 2005;14(6): Smith M, Hopkins D, Peveler RC, Holt RI, Woodwrd M, Ismil K. First- v. secondgenertion ntipsychotics nd risk for dibetes in schizophreni: systemtic review nd met-nlysis. Br J Psychitry. 2008; 192(6): Sumiyoshi T, Roy A, Anil AE, Jythilke K, Ertugrul A, Meltzer HY. A comprison of incidence of dibetes mellitus between typicl ntipsychotic drugs: survey for clozpine, risperidone, olnzpine, nd quetipine. J Clin Psychophrmcol. 2004; 24(3): Correll CU, Mnu P, Olshnsky V, Npolitno B, Kne JM, Mlhotr AK. Crdiometbolic risk of second-genertion ntipsychotic medictions during first-time use in children nd dolescents. JAMA. 2009;302(16): Sikich L, Frzier JA, McClelln J, et l. Double-blind comprison of first- nd second-genertion ntipsychotics in erlyonset schizophreni nd schizo-ffective disorder: findings from the Tretment of Erly-Onset Schizophreni Spectrum Disorders (TEOSS) study. Am J Psychitry. 2008; 165(11): Sikich L, Hmer RM, Bshford RA, Sheitmn BB, Liebermn JA. A pilot study of risperidone, olnzpine, nd hloperidol in psychotic youth: double-blind, rndomized, 8-week tril. Neuropsychophrmcology. 2004;29(1): Fedorowicz VJ, Fombonne E. Metbolic side effects of typicl ntipsychotics in children: literture review. J Psychophrmcol. 2005;19(5): Koller EA, Cross JT, Schneider B. Risperidone-ssocited dibetes mellitus in children. Peditrics. 2004;113(2): Koller E, Mlozowski S, Doriswmy PM. Atypicl ntipsychotic drugs nd hyperglycemi in dolescents. JAMA. 2001;286(20): Stürmer T, Joshi M, Glynn RJ, et l. A review of the ppliction of propensity score methods yielded incresing use, dvntges in specific settings, but not substntilly different estimtes compred with conventionl multivrible methods. J Clin Epidemiol. 2006;59(5): Hrrell FE Jr, Lee KL, Mrk DB. Multivrible prognostic models: issues in developing models, evluting ssumptions nd dequcy, nd mesuring nd reducing errors. Stt Med. 1996;15(4): Henderson DC, Cgliero E, Copelnd PM, et l. Glucose metbolism in ptients with schizophreni treted with typicl ntipsychotic gents: frequently smpled intrvenous glucose tolernce test nd miniml model nlysis. Arch Gen Psychitry. 2005; 62(1): Bergmn RN, Ader M. Atypicl ntipsychotics nd glucose homeostsis. J Clin Psychitry. 2005;66(4): Newcomer JW. Second-genertion (typicl) ntipsychotics nd metbolic effects: comprehensive literture review. CNS Drugs. 2005;19(suppl 1): Schwenkreis P, Assion HJ. Atypicl ntipsychotics nd dibetes mellitus. World J Biol Psychitry. 2004;5(2): Mir S, Tylor D. Atypicl ntipsychotics nd hyperglycemi. Int Clin Psychophrmcol. 2001;16(2): Liebzeit KA, Mrkowitz JS, Cley CF. New onset dibetes nd typicl ntipsychotics. Eur Neuropsychophrmcol. 2001;11(1): Andersohn F, Schde R, Suiss S, Grbe E. Long-term use of ntidepressnts for depressive disorders nd the risk of dibetes mellitus. Am J Psychitry. 2009;166(5): Kivimäki M, Hmer M, Btty GD, et l. Antidepressnt mediction use, weight gin nd risk of type 2 dibetes: popultion-bsed study. Dibetes Cre. 2010;33(12): Knol MJ, Geerlings MI, Egberts AC, Gorter KJ, Grobbee DE, Heerdink ER. No incresed incidence of dibetes in ntidepressnt users. Int Clin Psychophrmcol. 2007;22(6): PEDIATRICS Volume 128, Number 6, December