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Autism Spectrum Disorder (ASD). This is a condition known as “Different Abilities.” is a neurodevelopmental disorder characterized by deficits in social communication, sensory processing alterations, and repetitive behaviors. Its global prevalence is estimated at 1 in 160 children, with a reported prevalence of 0.8% in Mexico. ASD is more commonly diagnosed in males, and prevalence data in Latin America are frequently underestimated due to socioeconomic barriers. As a multifactorial and highly heritable condition with a profound psychosocial impact that often triggers a grieving process within families, ASD requires an interdisciplinary approach in which behavioral interventions constitute the cornerstone of treatment, while pharmacological therapy serves as an off-label adjunct aimed exclusively at managing specific symptoms or comorbidities, such as Attention-Deficit/Hyperactivity Disorder (ADHD), epilepsy, and sleep disorders. Currently, only risperidone and aripiprazole have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of irritability associated with ASD. Nevertheless, the clinical profile observed in the region indicates that more than 50% of pediatric patients are exposed to polypharmacy, increasing the risk of drug interactions and adverse effects, primarily metabolic and neurological and compromising treatment adherence due to resistance to change and sensory barriers commonly experienced by children. In this context, the pharmacist emerges as an essential member of the multidisciplinary team, playing a crucial role in ensuring pharmacotherapeutic follow-up, identifying and resolving medication-related problems, and providing health education to caregivers.
Keywords: Autism Spectrum Disorder; pharmacotherapy; treatment adherence; pharmaceutical care; pediatrics; pharmacotherapeutic follow-up; AutismSpectrumDisorder; treatmentadherence; pharmaceuticalcare; pharmacotherapeuticfollow-up
AutismSpectrumDisorder(ASD)isagroupofneurodevelopmentaldisordersinwhichsymptomsresultfrom deficitsinneurobiologicalnetworkconnections.Itis primarilycharacterizedbyimpairmentsincommunicationandsocialinteraction, sensoryandcognitive development issues, and the presence of restricted andrepetitivebehaviors,interests,oractivities.Inaddition,thereisevidenceofapredispositiontoother typesofmentalhealthissuesandcomorbiditiesinpatientsdiagnosedwithASD.Thesemanifestationsbegin inearlychildhood,however,symptomsmaynotbecomeapparentuntilyearslater[1][2][3].
Overthepast20years,diagnosesofASDhaverisendramatically,tothepointwhereitisnowconsideredthe mostcommondevelopmentaldisorder[2].Following thepublicationofthefiftheditionoftheDiagnosticand StatisticalManualofMentalDisorders(DSM-5)in2013, ASDnowencompassesinasinglediagnosiswhatwas previously classified as Kanner’s autism, Asperger’s syndrome,childhooddisintegrativedisorder,andunspecifiedpervasivedevelopmentaldisorder. Thisrestructuringofthediagnosishascomplicatedepidemiologicalrecordsandtheclinicalperceptionofthecondition[1].
Epidemiologically, the World Health Organization (WHO)estimatesthat1in160childrenworldwidehas someformofASD,withahigherprevalenceamong boys.Epidemiologicaldatashowthattheprevalenceof ASDrangesfrom1%to1.5%,andspecificallyinMexico, theprevalenceis0.8%.Itisbelievedthattheincrease inASDinrecentyearsmaybeattributedtoimprovementsindetectionsystemsandchangesindiagnostic criteria; however,inLatinAmerica,thedataareheterogeneousandfrequentlyunderestimatedduetolimitationsinepidemiologicalsurveillancesystemsand socioeconomicbarriersthatcandelaydiagnosis[4]. ASD, being a neurodevelopmental disorder with a multifactorialetiology(genetic,neurological,andsocial),requiresamandatoryinterdisciplinaryapproach, whichincludesbehavioral,educational,psychological, and,ifnecessary,pharmacologicalinterventions.Itis importanttonoteregardingthislastpointthatpharmacologicaltreatmentiscomplementary,andthisis wherethepharmacistplaysanextremelyimportant roleaspartofthemultidisciplinaryteam.Theirinvolvementrangesfrommedicationdispensingandpharmaceuticalcaretohealtheducation,aswellaspromoting treatmentadherenceandpharmacotherapeuticmonitoringaspectsthatareparticularlycriticalinahighly vulnerablepopulationsuchaspediatricpatients,given thehighburdenofpolypharmacyassociatedwiththe condition[5].
Thepurposeofthisnarrativereviewistocompile,analyze,andsynthesizetheavailableevidenceonfourkey areas:acomprehensiveunderstandingofASD,availablepharmacologicaltreatments,thecircumstances in which they are necessary, and their implications, factorsthatinfluencetreatmentadherence;andthe importanceofthepharmacist’sroleinmanagingthis disorder.ThisresearchisprimarilyfocusedonthecontextoftheLatinAmericanpediatricpopulationandan audienceofhealthcareprofessionals,withaspecial emphasisonthepharmacyteam.
Themethodologyinvolvedcompilinganarrativebased on a selection of articles containing the keywords “autism,”“therapeuticadherence,”“ASDtreatment,” and“pharmacist”fromplatformssuchasElsevier,Sci- ELO,PubMed,andGoogleScholartodiscussfindings related to autism, its treatment, and the role of the pharmacistinthiscontext.
Over the years, the concept of autism has evolved; for many years, it was used interchangeably with schizophrenia and psychosis. In 1940, Dr. Leo Kannerdevelopedthefirstmoderndescriptionsofwhat wenowconsiderAutismSpectrumDisorder.Starting in1980,itwasclassifiedasPervasiveDevelopmental Disorder(PDD),aclassificationthatwasrevisedin2013 withthepublicationofthefiftheditionoftheDSM-5.In thisedition,autismwasredefinedasAutismSpectrum Disorderandplacedwithinthecategoryofneurodevelopmentaldisorders,atermthatremainsinusetoday [5].
AccordingtotheWorldHealthOrganization’sInternationalClassificationofDiseasesandtheDiagnosticand StatisticalManualofMentalDisorders(DSM-5),itisdefinedbythepresenceofpersistentdeficitsincommunicationandsocialinteractionacrossmultiplecontexts, alongwithrestrictedandrepetitivepatternsofbehavior, interests, oractivities; thesedeficitscanleadto complicationsinpersonal,family,educational,occupational,andotherimportantareasoffunctioning.It is also noted that the manifestations of these disorderstypicallybegininearlychildhood,inmostcases startingat18months;amongthesemanifestationsare sensorydysfunctions(perceptionofvisual,auditory, tactile,orgustatorystimuli),motorandbehavioraldisturbances,sleepdisorders(prolongedorfragmented), orfeedingdisorders.Thirtytofortypercentmayhave intellectualdisabilities,and33%mayhaveearlyorlateonsetepilepsy,however,thesemanifestationsmayor maynotbeevidentuntilyearslater,whensocialdemandsexceedtheindividual’slimitedcapacity[1][3] [4].
TheDSM-5,publishedbytheAmericanPsychiatricAssociation, identifies the following severity levels for ASD:
Level 3: Requires substantial support. The patient exhibitsseveredeficitsinsocialcommunicationskills, hasdifficultyinteractingwithothers,rarelyinitiates a conversation, struggles to cope with change, and exhibitsrepetitivebehaviors.
Level2: Requiressubstantialsupport.Thepatientexhibitsdeficitsinverbalornonverbalcommunication skills,however,iscapableofinitiatingsocialinteractions on certain occasions, responds in a restricted andatypicalmannertoattemptsatsocialization,exhibits repetitive behavior, and has difficulty coping withchanges.
Level1: Requiressupport.Theyshowminimalinterest ininteractingwithothers,requiresupportinsocialsituations,havedifficultyplanningandorganizing,which interfereswiththeirindependence,andtheirrestricted behaviorsinterferewiththeirfunctioninginvarious contexts[4].
Thediagnosisisclinicalandconsistsofdirectobservationofbehavior,structuredinterviewswithcaregivers, andtheuseofstandardizedtoolssuchastheADOS (AutismDiagnosticObservationSchedule)andtheADI- R(AutismDiagnosticInterview-Revised).Theevaluationmustbeconductedbyamultidisciplinaryteam thatincludesneurologists,psychiatrists,psychologists, andspeechtherapists[3].
ThelackofstudiesonASDmeansthatindividualswith thisdisorderandtheirfamiliesdonotreceiveatimely andaccuratediagnosistoestablishatreatmentplan thatimprovestheirqualityoflife. Thisisbecause,in LatinAmerica,theshortageofprofessionalsspecializinginthisdisorderandthelackofadequateequipment resultinhighdiagnosticcosts,therebyhinderingboth diagnosisandresearchonASD.
Thisissueresultsininsufficientdataforepidemiologicaldatabases;however,itisknownthattheincidence ofthisconditionishighworldwideandhasbeenincreasingovertheyears.TheWorldHealthOrganization (WHO)indicatesthat1inevery160childrenworldwide hassomedegreeofautism,withahigherprevalence amongmales.
EpidemiologicaldatashowthattheprevalenceofASD isbetween1%and1.5%.InLatinAmerica,Mexicohas aprevalenceof0.87%;however,studiesinthisregion arescarce,makingitdifficulttodeterminetheepidemiologicalprofileofthearea[4].
ASDaffectsmenapproximatelyfourtimesmoreoften thanwomen,althoughrecentresearchsuggeststhat symptomsaremoreoftenmaskedinwomen,which canleadtoadelayedorincorrectdiagnosis. Comorbidityishigh: between70%and90%ofpeoplewith ASDhaveatleastoneassociateddisorder,themost commonbeingattention-deficit/hyperactivitydisorder(ADHD),intellectualdisability,epilepsy,sleepdisorders,andanxietydisorders[1].
Autismisaneurodevelopmentaldisorderwithamultifactorialetiology,inwhichvariousgeneticvariations interact with environmental factors. Approximately 100 genes that could influence the development of ASDhavebeenstudied,includingNLGN,PTEN,MECP2, ANK,SHANK,TBR1,SYNGAP1,BOLA2,andCDLK5.This pathogenicgeneticburdenismorecommoninwomen thaninmen[4].
Theetiologyofautisminvolvesasignificantandhighly diversegeneticinfluence;amutationinasinglegene maybesufficienttocauseit,ormorethan1,000genes mayberequired,anddifferentgeneticmechanisms maybeatplay.
ASDisassociatedwithalterationsinfunctionalbrain connectivity,particularlyinnetworksinvolvingtheprefrontalcortex,thelimbicsystem,andthecerebellum. Imbalances have been described in the glutamatergic,GABAergic,dopaminergic,andserotonergicneurotransmissionsystems,whichcurrentlyconstitutethe mainpharmacologicaltargets[6].
Variousstudiesindicatethattheremaybeahistoryof perinatalneurologicalriskandaprevalenceofsymptomsinpreterminfants(PTIs)orthosewithlowbirth weight(LBW).Sinceautismhasahighlyheritablegeneticbasis,itisestimatedthatitmayoccurmorefrequentlyiftherearefamilymemberswithASDoranotherneurodevelopmentaldisorder[1].
ASDhasaprofoundimpactonfamilies,especiallyon primarycaregivers, whomaygothroughaseriesof stagessimilartothoseofgrief.Initially,theymayexperienceastateofshockcausedbyunexpectednews,in thiscase,theASDdiagnosis.Thisisfollowedbyastage ofdenial,duringwhichtheymayseeksecondopinions inthehopethatthediagnosiswillbedifferent. This isquicklyfollowedbythephaseofirritationandguilt, during which parents try to uncover the underlying causeofthechild’scondition.Subsequently,thestage ofdespairsetsin,whichcandevelopintoadepressive state,andfinally,thestageofacceptance.Thismayoccurafterreceivingrelevantscientificinformationabout thecondition,therebyfacilitatinganappropriateinterventionmodel.ReceivinganASDdiagnosistriggers acrisiswithinthefamily. QualitativestudiesofLatin Americanfamiliesindicatenegativerepercussionson thefamilyenvironment,stemmingfrommentalhealth issuessuchasstress,depression,and/oranxiety.Additionally,familiesexperiencesocialoverloadanddifficultiesinaccessingreliableinformationandsupport services[7].
ThesocialstigmaassociatedwithASDalsorepresents a significant barrier; it has been reported that familiesoftenfacenegativejudgments,experiencepooror non-existentemotionalsupport,aswellasrejection and/ordiscriminationineducationalandcommunity settings,whichcannegativelyimpactboththesupport familiesreceiveandparentalstresslevels,aswellas theirqualityoflifeandtheirabilitytoseekspecialized care[8].
LackofawarenessandsocioculturalbeliefsaboutASD canleadtodelayeddiagnoses,therebyhinderingearly interventionforitstreatment. Inamultidisciplinary model, thiscanimpedepharmacologicaltreatment whennecessary;intheLatinAmericancontext,medicationadherencemaybecompromisedduetosocial, economic,family,andindividualfactors[9].
Itisessentialtounderstandthat,todate,thereisno medicationthatcuresASDoraltersthecourseorcause ofthecondition.Pharmacologicaltreatmentisaimed solelyatmanagingspecificsymptomsthatmayarise inpatientswithASDandthatcanaffecttheirfunctioningandqualityoflife,suchasirritability,impulsivity, andhyperactivity;itmayalsobeaimedatmanaging associatedcomorbiditiessuchasepilepsy,anxiety,depression, hyperactivity, obsessive-compulsivedisorder,ADHD,tics,eatingdisorders,sleepdisorders,and seizures,amongothers[10][11].
ItisimportanttonotethatthetreatmentofASDtakes amultidisciplinaryapproach;therefore,acomprehensivetreatmentplanisnecessary,withbehavioraland psychoeducational interventions as its core components,whiletheuseofmedicationservesasasupplementtothecoretreatment. Thedecisiontoinitiate pharmacologicaltreatmentmustbemadewithcaution,weighingtheexpectedbenefitsagainsttherisks thatmayariseduringtreatment,suchaspotentialadverseeffects;thisiswhereparentsplayafundamental roleinthetherapeuticpartnership[10].
Theprescriptionofmedicationsinpediatricpatients mustbeapproachedwithcare,asmanyofthedrugs usedlackvalidatedclinicaltrialsinchildrenwithASD; consequently,thereislimitedinformationonsafety andefficacy, andtheiruseisprimarilybasedonofflabel evidence. This lack of information can be attributedtothedifficultiesindevelopingandapprovingpharmacologicaltreatmentsforASDduetoclinical,genetic,andpathophysiologicalheterogeneity,a lackoffollow-upstudies,andthedifficultyinobtaining parentalconsent[11][12].
Thechoiceofpharmacologicaltreatmentshouldbe basedonthetargetsymptom,thatis,thosebehaviors orsymptomsthatmostsignificantlyimpactthequality oflifeofboththepatientandtheirfamily[13].Thisis whytreatmentmustbespecificandtailoredtoeach patient,takingintoaccountage,symptoms,anddiagnosis;thegoaloftreatmentistoimprovethecourseof ASDandpreventadditionaldifficultiesinlearningand cognitivedecline[14].
Currently,therearenoapprovedmedicationsforcore symptoms and/or comorbidities; most of the drugs usedarepsychotropicandaffectthecentralnervous system,andonlyrisperidoneandaripiprazoleareauthorizedbytheFDAforcomorbidities.Whichiswhybehavioraltreatments,supportivetherapies,educational support,andparenttrainingremainthefoundationof ASDinterventions,withpharmacologicalinterventions beinglimited;forthese,regularmonitoringofclinical responseandadverseeffectsisessential[11][12]. The following table lists the medications most commonlyusedinMexicofortheadjunctivepharmacologicaltreatmentofASD:
Table 1. MedicationsmostcommonlyusedinMexico foradjunctivepharmacologicaltreatmentofASD
-Risperidone
-Aripiprazole Antidepressants -Fluoxetine Stimulantsandnonstimulants -Atomoxetine Antiepileptics -Valproicacid Sleepaid -Melatonin
GiventheheterogeneityofASD,therearemedications used to manage symptoms or comorbid conditions thatmayarise. Theseincludeantipsychotics,which aretypicallyprescribedtotreatconditionscharacterizedbypsychoticepisodesandareprimarilyusedfor schizophrenia.“Autismisnotadisease”isacondition thatvariesintermsofabilities;eachcaseisdifferent, whichcomplicatesthechoiceofpharmacologicaltreatment. Thereareoptionsforspeechtherapy,occupational therapy, and psychological therapy that help improvetheirabilitiesandbehavior.
Antipsychotics are classified into two groups: firstgenerationantipsychotics,which,withintheirmechanismofaction,showagreateraffinityfordopamine D2receptors,whichcanleadtoahigherincidenceof extrapyramidaleffects;ontheotherhand,thereare second-generation antipsychotics, better known as atypicalantipsychotics,sonamedfortheirlowaffinityfordopaminereceptors,withlessevidenceofextrapyramidalcrises.
InAutismSpectrumDisorder,theuseofatypicalantipsychoticsisprevalentduetotheirlowerincidence ofadverseeffects; amongthese,theFoodandDrug Administration(FDA)hasapprovedonlyrisperidone andaripiprazoleforitstreatment,withrisperidonebeingthefirst-linemedicationforthemanagementof childrenwithASD[6].
Risperidonewasthefirstantipsychotictobeapproved bytheFDAin2006forchildrenaged5to16yearsfor thetreatmentofirritability,disruptivebehaviors,selfharmoraggressiontowardothers,andsuddenmood swings;itisthedrugwiththemoststudiesregarding itsoutcomesinthisdisorderandtheefficacyachieved [6][15][16].Itisanantidopaminergicneurolepticbelongingtothebenzisoxazoleclass,withhighaffinityfor serotonergicanddopaminergicreceptorsandlower affinityforadrenergicandhistaminergicreceptors.Itis anantagonistofdopamineD2receptorslocatedinthe mesolimbicpathwayand,toagreaterextent,actsas anantagonistonserotonintype2(5-HT2)inthefrontal cortex; italsoexertsmoderateblockadeonalpha-1 adrenergic receptors and mild blockade on alpha-2 adrenergicandhistamineH1receptors;thesereceptorsmodulatethereleaseofneurotransmitterssuch asdopamine,norepinephrine,glutamate,GABA,and acetylcholine,amongothers;bydecreasingtheactivityofdopaminergicpathways,mooddisorderscanbe improved[12][15][17].
Thedosageofrisperidonemayvarydependingonthe clinicalpresentation.Inthepediatricpopulation,for childrenweighingmorethan50kg,itisrecommended to start treatment with a dose of 0.5 mg once daily, whichcanbeadjustedbasedonthepatient’sresponse; withanoptimaldoseof1mg/day. Forpediatricpatientsweighinglessthan50kg,aninitialdoseof0.25 mgisrecommended,withanoptimaldoseof0.5mg/dayforthisgroup[17][18].
Itisabsorbedorallywithoutbeingaffectedbyfood, with a bioavailability of 75–90%. It reaches peak plasmaconcentrationswithin1–2hours,hashighaffinityforplasmaproteins(88%proteinbinding),andis highlyfat-soluble.Itshalf-lifeis3hours,anditismetabolizedintheliver;oneweekafteradministration,it isexcretedintheurineand,toalesserextent,inthe feces[14][18].
Sideeffectsandadversereactionscanvarydepending onthedoseandthepatient;amongthemostcommon aresedation,drowsiness,insomnia,headache,sleep disturbances,agitation,depression,anxiety,dizziness, tremor,mania,andundoubtedlyoneofthemostcommon is metabolic changes, including an increase in bodymassindex.Thepatient’sprogressandmetabolic parameters(weight,bloodglucose,andlipidprofile) mustbecloselymonitored[6][17][18].
Aripiprazole, like risperidone, is an atypical antipsychoticthatwasapprovedbytheFDAin2009forthe treatmentofirritabilityassociatedwithASDinpatients aged6to17years,althoughithasalsobeenusedin patientsasyoungas4yearsold[6][11].Itisapartial agonistofdopamineD2andserotonin5HT1areceptorsandanantagonistofserotonin5HT2areceptors. Studieshavedemonstrateditsefficacyatdosesranging from 5 mg to 15 mg/day, improvements can be observed8weeksaftertreatmentbeginsandshowcognitiveandbehavioralimprovementssimilartothose ofrisperidone,reducinghyperactivity,irritability,and stereotypies,andleadingtoanimprovementinoverall functioning[6][11].
Regarding side effects, they are similar to those of risperidoneandareoftenlesssevereinsomecases; thesemayincludesedation,drowsiness,weightgain, increasedappetite,vomiting,and,inthelongterm,extrapyramidalsymptoms.Studiessuggesttheneedfor constantmonitoringduringaripiprazoletreatment,as asignificantreductioninhigh-densitylipoproteins,a slightincreaseintotalcholesterol,low-densitylipoproteins,triglycerides,andbloodglucosewerereported in[6][11].
Other atypical antipsychotics used for autism spectrumdisorderincludeolanzapine,quetiapine,clozapine,andhaloperidol;however,theevidenceisvery limited,astherearefewstudiesinvolvingsmallgroups, andnoneofthemareapprovedintheirproductlabels fortheindicationofcontrollinginappropriateordisruptivebehaviors.Studiesmentionthattheyshowa goodresponseincasessuchasschizophrenia, ASD, and PDD, but they also mention that they may producelong-termextrapyramidaladverseeffects;however,thishasnotyetbeenproven[13][19].
For olanzapine, there are double-blind, placebocontrolledstudiesinvolvingchildrenaged6to14years; however,thesamplesizewasverysmall,consistingof only11children.Thestudylasted6weeksandshowed improvementonthePediatricGlobalClinicalImpressionScale;however,significantweightgainwasalso reportedinpatients,whichoftenlimitsitsuse[11].On theotherhand,clozapineisnottypicallyusedasafirstlinetreatmentbecauseitisimpractical,asitrequires constantmonitoringsuchasperiodiclaboratorytests andduetoitspotentialforsignificantadverseeffects, includingagranulocytosisandmyocarditis,aswellas weightgain,constipation,metabolicsyndrome,and drowsiness[6][11].
Haloperidol,atypicalantipsychotic,liketheprevious ones,hasverylittleevidenceregardingitsuseinpatients with ASD. One study compared the effect of haloperidolatdosesbetween1and1.5mg/kg/dayin patientsaged10to36years,reportingagreaterreductioninirritability,disruptivebehaviors,andhyperactivity;itmaycauseadverseeffectssuchassedation, constipation,weightgain,andliverfunctionabnormalities,amongothers. Inchildren,psychomotorretardationandtheonsetofextrapyramidalsymptomsare ofgreaterconcernbecausethesepatientswillrequire treatmentforextendedperiods[13][14].
Finally,amongfirst-generationantipsychoticsislevomepromazine,whichactsbyblockingpostsynaptic mesolimbicdopaminergicreceptorsandiscapableof exertingcentralandperipheraleffectsonadrenergic, muscarinic,andserotonergicreceptors,resultinginimprovedmentalsymptoms,suchasrelieffromdelirium, agitation,restlessness,andmentalconfusion. Ithas beenusedinchildrenaged4to10yearsatdosesof0.1 to0.2mg/kg/day. Thehighprevalenceofneurologicalandanticholinergicadverseeffects,amongothers, isnoteworthy; therefore, itmustbemonitoredbya specialistsuchasapharmacist[20].
Studiessuggestthatdysregulationofserotoninhomeostasisinthecentralnervoussystemmaybelinkedto thedevelopmentofASD,buttheexactreasonremains unknown. Serotonin is a neurotransmitter that has beenshowntobeinvolvedinpsychiatricconditions suchasASD,asitslevelsmaybeelevatedordecreased, asmaythoseofdopamineandnorepinephrine,this canleadtocertainsymptomssuchasself-injuriousbehaviorsandcomorbiditieslikeanxiety,depression,and obsessive-compulsivedisorder[12][14].Currently,the mostcommonlyusedmedicationsareselectiveserotonin reuptake inhibitors (SSRIs). Their mechanism ofactioninvolvesinhibitingthepresynapticreuptake ofserotonin,therebyincreasingserotonin,dopamine, andnorepinephrinelevelsinvariouspartsofthebrain. Althoughtheyareconsideredfirst-linetreatmentsfor neurotypical individuals, their use for treating core ASDsymptomsisnotsupported.Studiesindicatethat autisticpatientsaremorelikelytoexperienceadverse events,suchasgastrointestinaldisturbances,amotivationalsyndrome,orbehavioraldisinhibition,whichcan leadtoincreasedirritabilityandaggression,therefore, cautionmustbeexercisedwithdosing,andmonitoring byaspecializedpharmacistisrequired[11][12][13].
Fluoxetine, a member of the SSRI class, has been widely used in children with Autism Spectrum Disorder. Although it is not approved by the FDA, it hasbeenreportedtobeeffectiveatdosesbetween 20 and 40 mg/day in reducing anxiety, depression, obsessive-compulsivedisorder,andrepetitivebehaviors;however,multiplesignificantadverseeffectshave beennoted,suchasrestlessness,hyperactivity,agitation,insomnia,decreasedappetite,andevensuicidal thoughts, which were dose-dependent and demonstratedthatnotallpatientstoleratethemedication well.Therefore,itisrecommendedtostartwithalow doseandgraduallyincreaseittohalfthemaximum safe dose depending on the patient’s response [11] [12][13][14][21].
Sertralineisconsideredafirst-linetreatmentfordepressionandanxiety;itistheonlyoneapprovedfor useinpediatricpatients.Itisrecommendedthattreatmentbeginwithalowdoseof25mg/dayduringthe firstweekandthenbeincreasedtoamaximumof50 mg/day during the second week. It is administered asasinglenightlydose,notexceeding75mg/dayin children,ashigherdosesmayincreasetheriskofside effects. The medication should be continued for at least8weekstoconfirmitseffectiveness,anddiscontinuationshouldbegradualtoavoidsideeffectssuch aswithdrawalsyndrome[13][14][21].
Itisanon-stimulantmedicationthatinhibitsthepresynapticnorepinephrinetransporterinthecentralcortex. The WHO classifies it as a centrally acting sympathomimetic,itpreventsthereuptakeofnorepinephrine throughoutthebrain, leadingtoincreasedlevelsof dopamineandnorepinephrineintheprefrontalcortex,andhasthereforebeenreportedaseffectiveand identifiedasafirst-linemedicationforthetreatmentof attention-deficit/hyperactivitydisorder(ADHD),which often presents as a comorbidity of ASD and may be accompaniedbyirritability.Studiessuggestadoseof approximately1.5mg/kg/day,notexceeding100mg/day.Regardingitsadverseeffects,thesemayinclude lossofappetite,changesinheartrateandbloodpressure,abdominalpain,nausea,vomiting,weightloss, andliverdamage,amongothers[12][16][22].
Itisconsideredamood-stabilizingmedicationandcan thereforebeusedinpatientswithASDtotreatbehavioraldysregulation,suchasirritability,aggression,hyperactivity,andcertaincomorbiditiessuchasepilepsy, manic episodes, and bipolar disorder. It works by inhibiting enzymes that reduce GABA metabolism andincreasingGABAergicneurotransmission.Recommendeddosesrangefrom10to15mg/kg/day.Sideeffectsmayincludenausea,anorexia,lethargy,tremors, edema,hepatotoxicity,andpancreatitis,particularly inpediatricpatients[11][12][21].
Itisapsychostimulantthatselectivelyinhibitsthereuptakeofnorepinephrineanddopamine,increasingthe actionofbothintheprefrontalcortexandotherbrain areas.Studieshavebeenconductedinchildrenaged5 to13years,usingmaximumdosesof0.5mg/kg/day, reportingimprovementsinimpulsivity,hyperactivity, stereotypies,andrepetitivebehaviors.Adverseeffects identifiedincludeddecreasedappetite,insomnia,irritability,hyporexia,headache,andchangesinblood pressure,heartrate,andhormonalsystems[11][12] [16][22].
Variousstudiesconductedovertimehaveshownthat sleep disorders occur two to three times more frequently in children with ASD, presenting with impairedsleepqualityandreducedsleepefficiency,difficultyfallingasleep,frequentawakenings,andanxiety,amongothersymptoms.Thiscontributestodaytimesleepinessandirritability, whichiswhyitisoften prescribedas atreatmentforsleep disordersin autisticpatients.Itisrecommendedtoadministerit30 to60minutesbeforebedtime;forinfants,upto1mg isrecommended;forchildren,2.5to3mg;and5mg foradolescents.Sideeffectsmayincludeabdominal cramps, decreased alertness, dizziness, drowsiness, andheadache[11][12][16][21].
ApharmacoepidemiologicalstudyconductedinMexicoanalyzedmedicationusepatternsinchildrenwith ASD,documentingapredominanceofprescriptions foratypicalantipsychotics,followedbystimulantsand anticonvulsants. Ahighfrequencyofpolypharmacy wasobserved,withmorethan50%ofpatientsreceivingtwoormoredrugssimultaneously.Thissituation increases the risk of drug interactions and adverse effects,reinforcingtheneedforspecializedpharmacotherapeuticmonitoring,aswellasspecializedpharmacystaff[12].
Pharmacotherapymonitoringinpolypharmacypediatricpatientswithintellectualdisabilities,including those with ASD, has revealed frequent medicationrelatedproblems(MRPs),suchasunmetneeds,inappropriatedosing,andinteractions.Thedetectionand resolutionoftheseproblemsbyclinicalpharmacists hasbeenshowntoimprovehealthoutcomesandqualityoflifeforthesepatients[21].
Therapeutic adherence is defined as the extent to whichaperson’sbehavior(takingmedication,followingadiet,orimplementinglifestylechanges)aligns with the recommendations agreed upon with the healthcare team. In the context of ASD, adherence isparticularlycomplexduetothedisorder’sinherent characteristics,suchasresistancetochangeandsensorydifficulties,whichcaninterferewithmedication administration[23].
Adherence should be understood as a multidimensionalphenomenonthatencompassesnotonlytakingmedicationcorrectlybutalsoattendingfollow-up appointments,undergoingmonitoringtests,andimplementingrecommendedbehavioralchanges.Inthe caseofchildrenwithASD,theresponsibilityforadherencefallsprimarilyonthecaregiver, whichaddsan additionallayerofcomplexitytotheprocess[7].
ThefactorsinfluencingadherenceinchildrenwithASD arenumerousandareintricatelyinterrelated.Among the patient related factors, the following stand out: sensorydifficultieswithswallowingmedication, behavioralresistancetonewroutines,andthepresence ofcomorbiditiesthatcomplicatemanagement.Drug relatedfactorsincludetaste,dosageform,dosingfrequency,andthepresenceofadverseeffects[23]. Caregiverrelatedfactorsareparticularlyrelevant.Educationallevel,beliefsaboutmedication,theburden ofcare,andavailablesocialsupportdirectlyinfluence adherence.CaregiverswithlimitedknowledgeofASD orwithmisconceptionsaboutpsychiatricmedications tendtoshowloweradherence,sometimesdiscontinuingtreatmentwithoutconsultingthephysician[7]. Systemicfactorssuchasaccesstohealthservices,medication availability, treatment cost, and the quality ofthedoctor-patient-familyrelationshipalsosignificantlyinfluenceadherence.InLatinAmericancontexts, economicandgeographicbarriersarefrequentdeterminantsoftreatmentdiscontinuation[4].
Cultural beliefs surrounding ASD and psychotropic medicationareoneofthemainbarrierstoadherence inLatinAmerica.AstudyconductedinLima,Peru,identifiedcommonmisconceptionsamongparentsofchildrenwithASD,includingtheassociationofantipsychoticswithaddiction,thefearthatmedicationswill “changethechild’spersonality,”ortheperceptionthat ASDcanbecuredthroughdietoralternativetherapies [7]. Although in the case of homeopathic medicine whichisadifferenttypeofmedicinetheresultsspeak for themselves, it does not cause lethargy, and it is urgenttoconductresearchtodistinguishtherapeutic effectsthatcauselethargyandarenonspecific,thisis whyresearchplaysacrucialroleinthetreatmentof ASD.
ArecentstudypublishedonZenododocumentedthe influenceofculturalbeliefsonthemedicationmanagementofparentsofchildrenwithASD,showingthatmistrustofconventionaltreatmentandapreferencefor traditionalremediesareprevalentfactorsthatpharmacistsmustactivelyaddressthroughculturallysensitive communicationstrategies[9].
Health education aimed at caregivers should considerthesebeliefsasastartingpoint,adoptinganapproachofinterculturalrespectthatdoesnotinvalidate thecaregiver’sperspectivesbutprovidesscientifically groundedinformationinanaccessibleandempathetic manner. Pharmacists,duetotheirroleinthehealthcaresystemandtheirfrequentcontactwithfamilies, areinauniquepositiontocarryoutthiseducational work[24].
Strategiestoimproveadherencein[ASD]shouldbe individualizedandmultifaceted.Fromapharmacological perspective, simplifying the treatment regimen, selecting appropriate dosage forms (oral solutions, extended-releaseformulations),andtakingthechild’s sensorypreferencesintoaccountcanmakeiteasierfor thechildtotakethemedication.Theuseofpillorganizers,alarms,andmedicationlogscanhelpcaregivers tracktheregimen[23].However,inthecaseofmedicationfor[ASD]combinedwithpsychiatrictreatment, itcannotbeindividualizedortailoredtoeachspecific case, aseverycaseof[ASD]isunique; therefore, researchisurgentlyneededtoprovidesubstantialand effectiveinterventionsforthesetypesofcases. Educating the caregiver about treatment goals, the mechanismsofactionofthemedications,expected sideeffects,andwarningsignsisessential.Structured psychoeducationalinterventionshavebeenshownto significantlyimproveadherenceandcaregiversatisfaction.Regularfollow-upbythehealthcareteam,includingthepharmacist,helpstodetectadherencebarriers earlyandimplementtimelysolutions[5].
Pharmacists are healthcare professionals with specializedtraininginpharmacology,pharmacokinetics, pharmacotherapy,andpharmaceuticalcareskillsthat uniquelypositionthemtocontributetothecomprehensivemanagementofpatientswithASD.Theireffectiveintegrationintothemultidisciplinaryteam,alongsideneurologists,psychiatrists,therapists,psychologists,andsocialworkersisessentialtoensuringthe safetyandeffectivenessofpharmacologicaltreatment [25].
Despitethispotential,inmanyLatinAmericancontexts, thepharmacistremainsaperipheralfigureinASDmanagement,limitedtodispensingdutieswithoutactive participationintherapeuticdecisions.Themeaningful integrationofpharmacistsintospecializedASDcare teamsremainsanunmetneedintheLatinAmerican healthcaresystem[5].
Pharmacotherapy monitoring (PTM) is the service throughwhichthepharmacisttakesresponsibilityfor thepatient’smedication-relatedneeds,andidentifies, prevents,andresolvesmedication-relatedproblems (MRPs)inacontinuous,systematic,anddocumented manner.InchildrenwithASD,PTMisparticularlyimportantgiventhecomplexityofthemedicationregimen andthevulnerabilityofthispopulation[21]. PTMinpediatricpatientswithASDshouldincludeperiodicreviewofallprescribedmedications,evaluationof eachdrug’seffectivenessinrelationtoitsspecifictherapeuticgoals,monitoringofsafetyparameters(weight, bloodpressure,bloodglucose,prolactininthecase ofantipsychotics),anddetectionofdruginteractions [12][18].
AfundamentalcomponentofPTMistheassessment ofadherence.Thepharmacistcanusevalidatedtools suchastheMorisky-Greentest, countingdispensed medications,orsimplyconductingamotivationalinterviewwiththecaregivertoidentifypatternsofnonadherenceanddesignspecificinterventions[23].
PolypharmacyiscommoninASDandcarriesahighrisk ofdruginteractions. Pharmacists,withtheirspecializedknowledgeofpharmacologyandpharmacotherapy,aretheprofessionalsbestequippedtodetectand evaluatetheseinteractions.Combinationsofantipsychotics with stimulants, anticonvulsants, or antidepressantsareparticularlycommonandrequireclose monitoring[12].
Theearlydetectionofadversedrugreactions(ADRs) isanotherkeyroleofthepharmacist.Inchildrenwith ASD,manyADRsmaygounnoticedorbemistakenfor symptomsofthedisorderitself,whichcanleadtounnecessaryescalationoftreatment.Effectivecommunicationwiththecaregiveraboutwarningsignsandthe creationofaccessiblereportingchannelsarevaluable strategiesinthiscontext[18][24].
Thepharmacist’seducationalroleisparticularlyvaluableinASD.Caregiversoftenhavequestionsaboutthe safetyofpsychiatricmedications,theexpectedtime torespond,andthedurationoftreatment.Thepharmacistcanprovideclear,accurateinformationtailored tothecaregiver’slevelofunderstanding, helpingto dispelmisconceptionsandstrengthenthetherapeutic alliance[7][9].
Pediatricpharmaceuticalcarerequiresacollaborative process involving the child, parents, physician, and pharmacist.Effectivecommunication,tailoredtoeach family’sculturalandeducationalbackground,isthe cornerstone of this collaboration. The use of visual educationalmaterials,simplelanguage,andindividualizedcounselingsessionshasbeenshowntoimprove understandingandadherenceinthispopulation[25].
DespitethepotentialvalueofpharmacistsinthemanagementofASD,significantchallengeslimittheireffective involvement. The lack of specific training in neurodevelopmentandchildpsychiatryinpharmacy programs,theabsenceofstandardizedpharmaceuticalcareprotocolsforASD,andthelimitedintegration ofpharmacistsintomultidisciplinaryteamsareobstaclesrecognizedintheliterature[5][24].
ResearchonpharmaceuticalcareinASDisstillinits earlystages,withalimitednumberofhigh-qualitystudiesevaluatingtheimpactofpharmacistinterventions onclinicallyrelevantoutcomes.Thedevelopmentof specifictrainingprograms,thecreationofclinicalpracticeguidelinesthatincludethepharmacist’srole,and investmentinappliedresearchareidentifiedneedsto strengthenthisfield[21][24].
AutismSpectrumDisorder[ASD]isahighlycomplex and heterogeneous neurodevelopmental condition whosemanagementrequiresacomprehensive,multidisciplinary,andindividualizedapproach.Understandingitsmultifactorialetiology,neurobiology,andpsychosocialimpactisessentialforanyhealthcareprofessionalwhocaresforthispopulation.
Althoughpharmacologicaltreatmentof[ASD]isnot curing, it offers effective options for managing specificbehavioralsymptomsthatimpactfunctioningand quality of life. Atypical antipsychotics, particularly risperidone and aripiprazole, have the strongest evidencebase;however,theirusemustbecarefullymonitoredduetotheriskofmetabolicandneurologicaladverseeffects.Thisimpliesthattheyarenotspecificto everycase,andthereisnoone-size-fits-alltreatment. TherapeuticadherenceisakeychallengeinthemanagementofASD,influencedbyfactorsrelatedtothepatient,thecaregiver,themedication,andthehealthcare system. Culturalanderroneousbeliefsheldbycaregiversareparticularlysignificantdeterminantsinthe LatinAmericancontextandmustbeaddressedthrough culturallysensitiveeducationalstrategies. The pharmacist, as a professional with specialized traininginpharmacotherapyandpharmaceuticalcare, playsastrategicroleinthemanagementofASDthat goesbeyonddispensing.Pharmacotherapeuticmonitoring,thedetectionofADRsanddruginteractions, caregivereducation,andthepromotionofadherence arefunctionsthatthepharmacistcanandshouldperformwithinthemultidisciplinaryteam. However, it isnecessarytoinvestinspecifictraining,appliedresearch,andintegrationmodelsthatallowthispotential tobetranslatedintoconcretebenefitsforpatientsand theirfamilies.
Morehigh-qualitystudiesareneededintheLatinAmericancontexttoevaluatetheeffectivenessofpharmaceuticalinterventionsfor[ASD],aswellasthedevelopmentofclinicalpracticeguidelinesthatformallyrecognizetheroleofthepharmacistinmanagingthiscondition.Thesearchformedications,regardlessoftheir nature, that work effectively and are tailored to the individualcase.