Hyperprolactinemia with antipsychotic drugs in children and adolescents

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Hyperprolactinemia with antipsychotic drugs in children and adolescents
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International Journal of Pediatric Endocrinology
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Rosenbloom, Arlan L.
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There is increasing use of antipsychotic drugs in pediatric and psychiatry practice for a wide range of behavioral and affective disorders. These drugs have prominent side effects of interest to pediatric endocrinologists, including weight gain and associated metabolic risk factors and hyperprolactinemia. The drugs block dopamine action, thus disinhibiting prolactin secretion. Hyperprolactinemia is especially prominent with first-generation antipsychotics such as haloperidol and the second-generation drugs, most commonly risperidone, with some patients developing gynecomastia or galactorrhea or, as a result of prolactin inhibition of gonadotropin releasing hormone from the hypothalamus, amenorrhea. With concern about the long-term effects of antipsychotics on bone mass and pituitary tumor formation, it is prudent to monitor serum prolactin levels in antipsychotic drug-treated pediatric patients and consider treatment with an agent less likely to induce hyperprolactinemia.
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Publication of this article was funded in part by the University of Florida Open-Access publishing Fund. In addition, requestors receiving funding through the UFOAP project are expected to submit a post-review, final draft of the article to UF's institutional repository, IR@UF, (www.uflib.ufl.edu/ufir) at the time of funding. The Institutional Repository at the University of Florida (IR@UF) is the digital archive for the intellectual output of the University of Florida community, with research, news, outreach and educational materials

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HindawiPublishingCorporation InternationalJournalofPediatricEndocrinology Volume2010,ArticleID159402, 6 pages doi:10.1155/2010/159402ReviewArticle HyperprolactinemiawithAntipsychoticDrugsin ChildrenandAdolescentsArlanL.RosenbloomDepartmentofPediatrics,UniversityofFloridaCollegeofMedicineChildren’sMedicalServicesCenter, 1701SW16thAvenueGainesville,FL32608,USA CorrespondenceshouldbeaddressedtoArlanL.Rosenbloom, rosenal@peds.u.edu Received26April2010;Revised16July2010;Accepted16July2010 AcademicEditor:MyronGenel Copyright2010ArlanL.Rosenbloom.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttribution License,whichpermitsunrestricteduse,distribution,andrepro ductioninanymedium,providedtheoriginalworkisproperly cited. Thereisincreasinguseofantipsychoticdrugsinpediatricandpsychiatrypracticeforawiderangeofbehavioralanda ective disorders.Thesedrugshaveprominentsidee ectsofinteresttopediatricendocrinologists,includingweightgainandassociated metabolicriskfactorsandhyperprolactinemia.Thedrugsbl ockdopamineaction,thusdisinhibitingprolactinsecretion. Hyperprolactinemiaisespeciallyprominentwithrst-generatio nantipsychoticssuchashaloperidolandthesecond-generation drugs,mostcommonlyrisperidone,withsomepatientsdevelopinggynecomastiaorgalactorrheaor,asaresultofprolactin inhibitionofgonadotropinreleasinghormonefromthehypothalamus,amenorrhea.Withconcernaboutthelong-terme ects ofantipsychoticsonbonemassandpituitarytumorformation,it isprudenttomonitorserumprolactinlevelsinantipsychotic drug-treatedpediatricpatientsandconsidertreatmentwithanagentlesslikelytoinducehyperprolactinemia.1.IntroductionThepracticeofpsychiatryandtheshifttononinstitutional careofseverepsychiatricdisordersaretheresultofantipsychoticmedications,beginningwithchlorpromazineinthe early1950s.Approximately10otherdrugs,knownasrstgenerationortypicalantipsychotics,followedoverthesubsequent30years.Thesedrugsweree ectiveintreatingpositive symptomsofpsychosissuchashallucinationanddelusion butdidnotalleviatethenegativesymptomsofwithdrawal, apathy,cognitiveimpairment,orlossofa ect.Furthermore, theywereassociatedwithfrequentextrapyramidalsymptoms,includingacutedystonia,akinesia,akathisia,tardive dyskinesia,andparkinsonism.Aseriesofnewerdrugsbegan emergingin1989,referredtoassecondgenerationoratypicalantipsychotics,thoughttobemoree ectivethantheolder agentsinalleviatingthenegative,cognitive,anda ective symptoms,withfewerextrapyramidaladversee ects[ 1 ]. Theantipsychoticdrugsdi erintheirsidee ectproles, astheya ectdi erentneuroreceptors(histamine, -adrenergic,muscarinic,dopamine,orserotonin).Theprincipal concernforendocrinologistswiththenewerdrugshasbeen themetabolice ectsofweightgain,glucoseintolerance, hyperlipidemia,andhypertension[ 2 ].Thisisparticularly importantwiththeincreasinguseoftheseagentsinpediatricstotreatbipolardisorder,schizophrenia,autism,oppositionalandotherbehaviordisturbances,Tourettedisorder, andpervasivedevelopmentaldisorder.In2003-2004,1%of allpediatricvisitsresultedintheprescriptionofatypical antipsychoticmedication[ 3 ].Theimportanceandimplicationsofthemetabolicsidee ectsofatypicalantipsychotics forpediatricpatientshavebeenrecentlyreviewed[ 1 4 ]. Thispaperwillexaminethesidee ectofhyperprolactinemiainchildrenandadolescentstreatedwithantipsychoticdrugs.2.PhysiologyProlactin,a198-aminoacidpolypeptide,issecretedbythe anteriorpituitarylactotrophcellsinapulsatilemanner with13-14peaksperday,thepeakamplitude60% abovenadir[ 5 ].Thereisalsoamarkedcircadianvariation withmaximumsecretion4hoursfromsleeponsetand

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2InternationalJournalofPediatricEndocrinology minimum6hoursafterwaking[ 6 ].Thus,therecanbeas muchasafourfoldvariationinleveldependingonthetime ofdayornightsamplingisdone;therearealsotransient mildincreasesrelatedtomeals,stress,andsexualactivity[ 7 ]. Prolactinlevelsarehigherduringmenstrualmidcycleandthe 2ndhalfofthecycle.Duringpregnancy,levelsrise1020fold,reaching200 g/Lattermand300 g/Lduringnursing [ 8 ].Normalupperlimitrangeis1525 g/L[ 7 ]. Prolactinstimulatesbreastenlargementduringpregnancyandmilkproductionduringlactation,whilereducing libidoandfertility,whichmayhaveevolutionary/survival signicance. Secretionofprolactinisinhibitedpredominantlyby dopamineproducedinthetuberoinfundibularneuronsof thehypothalamus,releasedfromnerveendingsinthe medianeminenceandcarriedthroughtheportalhypophysealcirculationtothepituitary,therebindingtodopamine D2receptorsonlactotrophs,inhibitingprolactingenetranscription[ 9 ].Antipsychoticdrugsarethoughttodisinhibit prolactinsecretionbyD2receptorblockade.Serotonin stimulatesprolactinsecretionviaserotonin5-HT1Aand5HT2receptors.Estrogens,bindingtospecicintracellular receptorsinlactotrophs,enhanceprolactingenetranscriptionandsynthesis[ 6 ].Theyalsoinhibitdopaminesynthesis inthetuberoinfundibularneuronsandreduceD2receptor levelsonlactotrophsinanimalmodels[ 10 11 ].3.EffectsofHyperprolactinemiaGonadotropinreleasinghormone(GnRH),releasedinapulsatilemannerfromthehypothalamus,stimulatesreleaseof luteinizinghormone(LH)andfolliclestimulatinghormone (FSH)fromtheanteriorpituitary.Prolactininhibitsthe releaseofGnRHinthehypothalamus.Thepositivefeedback ofestradiolonLHsecretioninwomenisalsoblocked.Consequently,estrogenlevelsinwomenandtestosteronelevels inmenaresuppressed,withmarkedindividualvariabilityin theprolactinlevelcausinggonadalhypofunction. Inchildrenandadolescents,hyperprolactinemiaresultingfromprolactinomas,whicharerare,canresultin galactorrhea,amenorrhea,gynecomastia,andmaturational delaywithgrowthfailure[ 12 ].Ofconcernisthepotential e ectoftheinducedhypogonadotropismstateonthecritical peakboneformationofadolescenceandthemaintenanceof bonedensitythroughadulthood.4.EffectsofPsychotropicDrugson ProlactinSecretionPsychiatricdisordersmaybeassociatedwithmodestelevationsinserumprolactinconcentrationsasastressphenomenon[ 13 ].Furtherprolactinelevationcanbemeasured withinminutestohoursafterthestartoftreatmentwithrstgenerationantipsychoticdrugs,withlevelsupto10-foldafter severalweeksattherapeuticdosages.Levelstypicallyfallto normalwithin2to4daysofstoppingthedrugsbutmaytake upto3weekstoreturntonormal[ 14 ]. Inadultpsychiatricpatientsclozapineandquetiapine didnotraiseplasmaprolactinlevelsatanydosage.Olanzapineonlydidsoathigherdosages,butrisperidoneand amisulpridecausedmarked,sustainedincreaseinserum prolactinlevelsinasubstantialnumberofpatients[ 14 ]. Aripiprazole,arelativelynewatypicalantipsychotic,also doesnotappeartoincreaseprolactinlevels[ 15 ].Ziprasidone causedonlytransientelevationsinpsychiatricpatientsand healthyvolunteers[ 16 ]. Areviewpublishedin2004of14reportsofthee ects ofbothrst-andsecond-generationantipsychoticagentsin childrenandadolescentsincluded276patientsofwhom49 hadprolactinelevations[ 17 ].Areportof35patientsaged 919yearsfoundnoprolactinelevationwithclozapine,but in9of10withhaloperidoland7of10witholanzapine [ 18 ].Inanotherstudyof11outpatientsaged417years treatedwithrisperidone,9developedhyperprolactinemia ofwhomonehadamenorrhea,andonehadgynecomastia [ 19 ].Afurtherstudyreportedthatprolactinlevelswere increasedinall34patientsaged514yearstreatedwith risperidone[ 20 ].Hyperprolactinemiawasalsonotedin pediatricpatientsusingziprasidoneandolanzapine.Aswith adults,ziprasidone-associatedprolactinelevationwasmild andtransient,butassociatedwithmildgynecomastia[ 21 ] andinonecasewithgalactorrheathatresolvedafterdrug discontinuation[ 22 ].Twostudiesofthee ectsofquetiapine ledtoslightlydi eringresults:oneshowednoincreasein prolactinlevelsin101215-year-oldchildrenwhiletheother studyof151317-year-oldsfoundaslightincreaseofno clinicalsignicance,fromameanof11.3to14.4ng/mL[ 17 ]. Clozapinewasnotassociatedwithincreasedprolactinlevels, andthesinglepatientwhodevelopedgalactorrheawith risperidonehadresolutionoftheproblemwhenswitchedto clozapine[ 23 ]. Aretrospectivestudyanalyzedprolactinlevelsand hyperprolactinemiaattributablesidee ectsfrom5clinical trialsinvolving592childrenandadolescentsofsubaverage intelligencewithconductorotherdisruptivebehavior disordersaged5to15yearstreatedwithrisperidone.There wasaweake ectofrisperidoneonprolactinconcentrations duringshort-termtreatmentandlessere ectwithlong-term treatment,withsidee ectsofgynecomastia,amenorrhea, orgalactorrheainonly2.2%[ 24 ].Theserelativelybenign ndingshavebeenattributedtolowdrugdosagefor behavioralratherthanpsychiatricdisordersanddecreasing complianceovertime[ 25 ]. Quitedi erentndingsemergedfromasmalldoubleblindplacebo-controlledstudyofthee ectofrelativelylow doserisperidoneonprolactinemiain10childrenandadolescentswithmentalretardationandpervasivedevelopmental disorders.Prolactinlevelsapproximatelytripled,andthis increasewassustainedforamean33weeksoftreatment[ 26 ]. Threeadolescentswerereportedwithrisperidoneinducedhyperprolactinemiaresultingingynecomastiain oneboythatclearedanddidnotrecurwitholanzapine, gynecomastiawithgalactorrheainanotherboywithcomparableprolactinemiathatresolvedwhenhewasswitched toclozapine,andamenorrheaandgalactorrheainthethird patientthatresolvedwhenshewaschangedtoquetiapine.

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InternationalJournalofPediatricEndocrinology3 Theirprolactinlevelswere2100,1670,and1990mIU/L(58, 46,and55 g/L)whentheywerehyperprolactinemicand reducedto63,90,and191mIU/L(2,2.5,and5.3 g/L) afterresolution[ 27 ].Among10psychoticadolescentstreated withrisperidone,HolzerandEaphad3malesdeveloping gynecomastiaand2femalesdevelopinggalactorrhea,along with3othershavinghyperprolactinemiawithoutsymptoms [ 25 ]. Sixteenadolescentsaged1317yearswithsubaverageintelligenceanddisruptivebehaviordisorderstreated witholanzapinefor8weekshadsignicantelevationsin serumprolactinlevels,frombaseline9 76 1to24 819 8(SD) g/Lwithoutanysymptomsorsignsofhyperprolactinemia[ 28 ]. AstudyfromItalycomparedshort-andlong-term e ectsonprolactinofrisperidoneandolanzapinein42 childrenandadolescentstreatedforayear[ 29 ].Theyfound thatafteradjustingfordoseandthegreaterpotencyof risperidone,theincreaseinprolactinlevelsduringrisperidonetreatmentwas10.7timeshigherthanthatduring olanzapinetreatment.Onlyonesubjecthadasymptom ofhyperprolactinemia,transientmildgalactorrheawith risperidonewhichresolvedwithoutachangeintherapy. Similarly,arandomizedcomparisonofquetiapineand risperidonein221518-year-oldadolescentswithnew-onset psychosisfoundprolactinelevationin91%ofthosetreated withrisperidoneversus9%ofthosetreatedwithquetiapine [ 30 ]. Dutchinvestigatorshaverecentlyconductedanextensive literaturereviewofstudiesofantipsychoticmedication e ectsonprolactinlevelandassociatedsidee ectsin childrenandadolescents[ 31 ].Theyfound29publications withstudydurationslongerthan3weeks.Twentyofthese wereconcerningrisperidone,7olanzapine,5quetiapine, 4haloperidol,3pimozide,2clozapine,and1ziprasidone. Theyfoundthatallantipsychoticswiththeexceptionof clozapine,ziprasidone,andquetiapineincreasedthemean prolactinlevelfrom8to2528ng/mL.Theincidenceof hyperprolactinemiawas90%withhaloperidol,80%with pimozide,62%withrisperidone,31%witholanzapine, and12%withquetiapine.Risperidone,olanzapine,and pimozidewereseentoinduceapersistentelevationin prolactinlevels.Associatedgynecomastia,galactorrhea,or irregularmenseswerereportedin4.8%ofthechildren andadolescents.Datafromthisreviewandsubsequent reportsaresummarizedin Table1 .Interpretationofthe numerousstudiesisconfoundedbyvariationinstudydesign, diagnoses,dosages,andagedistribution,varyinguseof concomitantmedication,shortdurationofsomestudies, complianceuncertainty,lackofprolactinbaselinevalues (onefourthofthestudiesanalyzedbyRokeetal.[ 31 ]),and othermissingdataasnotedinthetable.Furthermore,single measurementsofprolactinaresubjecttodiurnalvariation andstressinuence.Theremayalsobepublicationbias,as alldataonprolactinvaluesfrommanufacturers'leshave notbeenpublished[ 31 ].Thee ectsofhyperprolactinemia maybeunderestimatedbecausetheydependonself-report, andmaybemistakenforcommonadolescentproblemsof gynecomastiaandirregularmenstrualcycles. Thedegreeofhyperprolactinemiainducedbyshorttermrisperidonetreatmentinchildrenandyouthisdose dependent[ 17 33 ].Thisdosedependencyislinkedtoplasma concentrationsofbothrisperidoneanditsactivemetabolite 9-hydroxyrisperidone[ 33 ].CYP2D6isprimarilyresponsible fortheconversionofrisperidoneto9-hydroxyrisperidone. Inanexaminationofthepossibleroleofactivityofthis enzymeinrisperidone-inducedprolactinreleaseinchildren, Troostetal.[ 34 ]foundapositivecorrelationofthefourfold elevationinserumprolactinlevelat8and24weekswithdose perkilogrambodyweight( r=0 65, P<. 001),number offunctionalCYP2D6genes,serum9-hydroxyrisperidone concentration( r=0 66, P<. 001)andnegativecorrelation withtherisperidone/9-hydroxyrisperidoneratio( r=Š0 57, P=. 004)butnotwithrisperidoneconcentration( r= Š0 24, P=. 26).Thus,morerapidCYP2D6metabolism maybeariskfactorforhyperprolactinemiawithrisperidone. PolymorphicvariationinthedopamineD2receptormay beanotherpharmacogeneticfactordeterminingriskfor risperidone-inducedhyperprolactinemiainchildrenand adolescents.Twovariantswereidentiedthatwereassociated withhigherprolactinconcentrationinastudyof107patients treatedforupto3years[ 32 ]. Becausesecond-generationantipsychoticsarebeing increasinglyprescribedforchildrenandadolescentswith conditionsthatarenotpsychosesandthatarealsotreated withstimulants,thepotentialmitigatinge ectofthestimulantsonthesidee ectsoftheantipsychoticshasbeen examined[ 35 ].Stimulantdrugshaveoppositee ectson thedopaminereceptorthandotheantipsychotics.Subjects were153419-year-oldstreatedwithantipsychotics,71 ofwhomwerecoprescribedstimulants.Theantipsychotic drugsincludedrisperidone(33%),aripiprazole(30%),quetiapine(18%),olanzapine(12%),andziprasidone(6%). Inadditiontonoe ectofcotreatmentwithstimulantson thesidee ectofhyperprolactinemia,therewasnoe ect onbodycomposition,metabolicparameters,sedation,or overalle cacyoftheantipsychoticagent.5.PotentialLong-TermEffectsof PsychotropicDrugs5.1.BoneMineralDensity(BMD). Antipsychotic-induced hyperprolactinemiainadultswithschizophreniahasbeen associatedwithreducedBMDandincreasedfracturerisk [ 36 37 ].Theinitialreportofthee ectofpsychotropic drugsonBMDinchildrenwasacross-sectionalstudy thatinvolved83boysaged7to17yearstreatedwith risperidoneforanaverageof3yearsandselectiveserotonin reuptakeinhibitors(SSRIs)[ 38 ].Withadjustmentforthe stageofsexualmaturation,height,andbodymassindex, anegativeassociationwasfoundbetweenserumprolactin levelandtrabecularvolumetricBMDatthedistalradius. Furthermore,treatmentwithSSRIswasassociatedwith lowertrabecularBMDattheradiusandBMDZ-scoreatthe lumbarspine.LumbarspineBMDZ-scoredidnotcorrelate withprolactinemia.Infemaleswithprolactinsecreting tumors,hyperprolactinemiae ectsonBMDaremediated

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4InternationalJournalofPediatricEndocrinologyTable 1:E ectsofrisperidone,olanzapine,haloperidol,quetiapine,clozapine,ziprasidone,andpimozideonprolactin(PRL)levelandPRL relatedsidee ects[gynecomastia(GCM),galactorrhea(GLR),andirregularmenses(IM)inchildrenandadolescents.Weightedaverages (adjustedfornumbersofsubjectsperstudy)aregivenfortheanalysisofRokeetal.[ 31 ]withthenumberofstudiesanalyzedshownin parentheses.Subsequentindividualstudiesareseparatelyindicated,withstandarddeviationsinparentheses.Dashesindicateabsentdata. DrugNumber Age (years) Dose (mg/day) Duration (weeks) PRL baseline ng/mL PRL endpoint ng/mL %with PRL > nl upper limit % GCM % GLR %IM Rokeetal.[ 31 ] (20) risperidone1390 9.71.634.88.221.661.73.00.56.2 Migliardietal. [ 29 ] risperidone6(female) 12.8(2.3)1.9(1.1)528.4(2.1)23.4(7.6)0 22(male) 10.1(2.8)1.7(1.2)526.5(1.9)14.9(8.6)0 Swadietal.[ 30 ] risperidone11 < 19691 Calargeetal. [ 32 ] risperidone107 717mean-365081133 Rokeetal.[ 31 ] (7) olanzapine170 14.42.72811.124.2316.22.82.4 Migliardietal. [ 29 ] olanzapine6(female) 14.3(2.1)6.7(3)528.8(3.8)18(5.2)00 7(male) 14(1.9)7.5(2.5)527.8(2.4)11.3(4.9)0 Swadietal.[ 30 ] olanzapine11 < 1969 Rokeetal.[ 31 ] (5) quetiapine72 13.9378.549.68.49.30000 (4) haloperidol56 12.77.26.57.729.1906.7015.4 (3) pimozide46 10.33.721.29.324.780 (2) clozapine30 14.527069.611.60000 (1) ziprasidone6 14.5(1.8)98(40)8.6(6.6)8.6(6.6)12(8)0000 Oneindividualtransientlywithoutdosagechange.byhypogonadism[ 39 ].However,inthisstudy,serum testosteroneconcentrations,adjustedformaturationalstage, werenota ectedbyhyperprolactinemia,suggestingadirect e ectofthehyperprolactinemiaonboneturnover[ 38 ]. Prolactinreceptorshavebeenfoundinosteoblasts,and animalstudiesindicatethathyperprolactinemiaactivates thephosphoinositide3-kinasepathwaysviatheprolactin receptorstosuppressalkalinephosphataseactivity[ 40 ]. ThendingthatSSRItreatmentwasassociatedwith reducedBMDcouldreectane ectonprolactinemia. However,noindependente ectofSSRIsonprolactin concentrationwasfoundinanearlierstudybythese authors[ 32 ],andthenegativeassociationbetweenSSRIsand BMDwasfoundafteradjustmentfornumerouscovariates includingprolactinemia.Serotoninhasaroleinosteoclast di erentiationandactivity[ 41 ].ThestudyofCalargeetal. [ 38 ]islimitedbythedependenceonasinglemeasurement ofserumprolactinwhichcanvarybytimeofdayand stresslevel,andabsenceofmeasuresofboneturnover.The authorsrecognizethatitisprematuretomakeanydenitive conclusionsaboutthee ectofpsychotropicmedicationson bonemineralization[ 38 ]. 5.2.PituitaryTumors. Notinghigher-than-expectedpostmarketingreportsofpituitarytumorsassociatedwith risperidone,Szarfmanetal.[ 42 ]analyzedpatternsofthese tumorsintheUnitedStatesFoodandDrugAdministrationAdverseEvent(AE)ReportingSystemdatabase. Theysoughtdisproportionatereportingpatternsofpituitary tumorreportsforantipsychoticswithdi erenta nitiesfor blockingD2receptors(aripiprazole,clozapine,olanzapine, quetiapine,risperidone,ziprasidone,andhaloperidol).The rankorderofthestrengthoftheassociationbetweenthedrug andthedevelopmentofpituitarytumorscorrespondedto thea nityofthese7drugsfortheD2receptor.Inchildren7 18yearsofage,therewas1AEofpituitarytumorassociated witholanzapineand3withrisperidone.Theauthorsnote theimportanceofthesendingsforchildrenbecausethe symptomsofapituitaryexpandingmassmaynotbeas readilyevaluatedinthosewithmentalillnessorserious behavioralproblemsandthatdelayeddetectioncanresultin hemorrhageoropticnervecompression.6.ConclusionSecond-generationantipsychoticsarebeingincreasinglyprescribedforchildrenandadolescentswithawiderangeof behavioraldisturbancesinadditiontopsychoses,resultinginmetabolicandhormonalchangesofimportance totheconsultingpediatricendocrinologist.Inaddition toweightgainandassociatedcomorbiditiesofinsulin resistance,hyperprolactinemiaisacommonsidee ect

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InternationalJournalofPediatricEndocrinology5 resultingfromtheinhibitionofdopamineaction.Firstgenerationantipsychotics,particularlyhaloperidol,andthe second-generationantipsychoticdrugs,mostprominently risperidone,appeartobeassociatedwiththegreatestrisk forhyperprolactinemia;sometreatedindividualsdeveloping hyperprolactinemiawillhavegalactorrhea,amenorrhea,or gynecomastia.Hyperprolactinemiamayhaveadeleterious e ectonpeakbonemassattainmentandincreaselongtermosteopeniarisk,evenintheabsenceofovertsymptoms orsignsofhyperprolactinemia.Thisadversee ectmaybe enhancedbythecommonlyassociatedtreatmentwithSSRIs. Thee ectofpsychotropicdrugsonbonemassaccrualneeds furtherstudy.Thesuggestionofagreaterriskforpituitary tumorsrelatedtodruga nityforD2receptorsalsorequires continuedstudy.Thus,inadditiontosurveillancefor signsandsymptomsofhyperprolactinemiainchildrenand adolescentstakingantipsychoticmedications,monitoring serumprolactinconcentrationsiswarranted.Inthepresence ofhyperprolactinemia,cessationofantipsychotictherapyor changingtoaformulationlesslikelytoraiseprolactinlevels shouldbeconsidered.DisclosureTheauthorisaconsultanttoalawrmpursuinglitigationwithmanufacturersofsecond-generationantipsychotic drugs.References[1]V.DavisandA.L.Rosenbloom,"Metabolice ectsofantipsychoticdrugs," PediatricDiabetes ,vol.7,no.3,pp.176186, 2006. [2]AmericanDiabetesAssociation,AmericanPsychiatricAssociation,AmericanAssociationofClinicalEndocrinologists, NorthAmericanAssociationfortheStudyofObesity,"Consensusdevelopmentconferenceonantipsychoticdrugsand obesityanddiabetes," DiabetesCare ,vol.27,no.2,pp.596 601,2004. 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