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Efficacy and Tolerability of Second-Generation Antipsychotics in Children and Adolescents With Schizophrenia

Efficacy and Tolerability of Second-Generation Antipsychotics in Children and Adolescents With Schizophrenia
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  Efficacy and Tolerability of Second-Generation Antipsychotics in Children andAdolescents With Schizophrenia Sanjiv Kumra 1,2 , Joel V. Oberstar 2 , Linmarie Sikich 3 ,Robert L. Findling 4 , Jon M. McClellan 5 , SophiaVinogradov 6 , and S. Charles Schulz 2 2 UniversityofMinnesota, Minneapolis,MN;  3 University ofNorthCarolina, Chapel Hill, NC;  4 Case Western Reserve University,Cleveland, OH;  5 University of Washington, Seattle, WA; 6 DepartmentofVeteransAffairsMedicalCenterandUniversityof California San Francisco, San Francisco, CA Early-onset schizophrenia-spectrum (EOSS) disorders(onset of psychotic symptoms before 18 years of age) rep-resent a severe variant associated with significant chronicfunctional impairment and poor response to antipsychotictreatment. All drugs with proven antipsychotic effectsblock dopamine D 2  receptors to some degree. The ongoingdevelopment of the dopamine and other neurotransmitterreceptor systems during childhood and adolescence may af-fect clinical response and susceptibility to side effects inyouth. A literature search was conducted of clinical trialsof antipsychotics in children and adolescents with EOSSdisorders between 1980 and 2007 from the Medline data-base, reference lists, and conference proceedings. Trialswere limited to double-blind studies of duration of 4 ormore weeks that included 15 or more patients. Ten clinicaltrials were identified. Antipsychotic medications were con-sistently found to reduce the severity of psychotic symp-toms in children and adolescents when compared withplacebo. The superiority of clozapine has been now demon-strated relative to haloperidol, standard-dose olanzapine,and ‘‘high-dose’’ olanzapine for EOSS disorders. How-ever, limited comparative data are available regardingwhether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness.The available data from short-term studies suggest thatyouth might be more sensitive than adults to developing an-tipsychotic-related adverse side effects (eg, extrapyramidalside effects, sedation, prolactin elevation, weight gain). Inaddition, preliminary data suggest that SGA use can leadto the development of diabetes in some youth, a diseasewhich itself carries with it significant morbidity and mor-tality. Such a substantial risk points to the urgent need todevelop therapeutic strategies to prevent and/or mitigateweight gain and diabetes early in the course of treatmentin this population. Key words:  psychosis/atypical antipsychotic/weightmanagement/metabolic syndrome/cognitive deficits/double-blind treatment trial Introduction Many clinicians view schizophrenia in childhood or ad-olescence as relatively rare; however, this belief is notfully accurate. Although the prevalence of childhood-onset schizophrenia (onset of psychotic symptoms before13 years of age) is indeed very low (approximately 1/100cases of schizophrenia), 1 the incidence of schizophreniarisessharplyatabout12–14yearsofage. 2 Before18yearsof age, approximately 12%–33% of individuals withschizophrenia would develop the onset of their illness 3,4 and thus would be classified as having an early-onsetschizophrenia-spectrum (EOSS) disorder.When  Diagnosticand StatisticalManualofMental Dis-orders, Third/Fourth Edition  ( DSM-III/IV  ), criteria arerigorously applied, clinical and neurobiological studieshave demonstrated a number of phenomenological sim-ilarities in the presentation of schizophrenia-spectrumdisorders (ie, schizophrenia, schizoaffective disorder,schizophreniform disorder) in children/adolescents andadults with regard to the relative frequency of core psy-chotic symptoms (eg, auditory hallucinations, delusions,thought disorder), neurocognitive impairments, psycho-physiological abnormalities, and the presence of struc-tural brain abnormalities. 5,6 In comparison to adultswith schizophrenia, there is an increased rate of premor-bid abnormalities 7 and a rarity of well-formulated delu-sions reported by children/adolescents. 8 EOSS disorderpatients frequently manifest early impairments in expres-sive language, motor function, and transient symptomsof pervasive developmental disorder well in advance of the first onset of psychotic symptoms. 7 However, children 1 Towhomcorrespondenceshouldbeaddressed;DivisionofChildand Adolescent Psychiatry, University of Minnesota MedicalSchool, 2450 Riverside Avenue, F256/2B, Minneapolis, MN55454; tel: 612-273-9775, fax: 612-273-9779, e-mail:kumra002@umn.edu. Schizophrenia Bulletin  vol. 34 no. 1 pp. 60–71, 2008doi:10.1093/schbul/sbm109Advance Access publication on October 8, 2007  2007 The AuthorsThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNon-CommercialLicense(http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the srcinal work is properly cited. 60   b  y g u e  s  t   onF  e  b r  u a r  y1  6  ,2  0 1  6 h  t   t   p :  /   /   s  c h i  z  o ph r  e ni   a  b  ul  l   e  t  i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   with EOSS disorder and autistic disorder can be distin-guished on the basis of developmental history, clinicalfeatures, family history, and age at onset. 9 Higher ratesof psychiatric comorbidity in EOSS disorder (ie, atten-tion-deficit hyperactivity disorder, oppositional defiantdisorder, and major depressive disorder) appear to be an-other importantdevelopmentaldifference betweenadultsand youth with schizophrenia. 10 However, in children/adolescents pharmacological treatment of these comor-bid conditions is rare that may reflect a lack of empiri-cally driven guidelines for appropriate treatment and/or the hierarchical diagnostic system that is characteristicof   DSM-IV  . 10 It is important to note that psychoticsymptoms are not specific to schizophrenia, and the dif-ferential diagnosis of EOSS disorder would include sub-stance abuse, mood and anxiety disorders, and variousmedical conditions (eg, seizure disorders, infectious dis-ease, metabolic and endocrine disorders, central nervoussystem lesions, etc). Also, there are a sizable number of children and adolescents with subsyndromal conditionswho report psychotic symptoms that would not meetthe severity/duration criteria required by  DSM-IV   toqualify for a diagnosis of schizophrenia. 11 NaturalisticdatashowthatEOSSdisorderisachronic,disabling disease, which, in the majority of cases, requireslong-term antipsychotic medication treatment. 3,12–16 Studies of antipsychotic medications in adults withchronic schizophrenia may provide guidance for thetreatment of children and adolescents with schizophre-nia, but the treatment of pediatric patients has unique de-velopmental aspects. To date, all the drugs with provenantipsychotic effects block dopamine D 2  receptors tosome degree. Although the pathophysiology of schizo-phrenia remains unclear, it has been hypothesized thatincreased dopaminergic neurotransmission in the meso-limbic pathways produces the positive symptoms of the disease. 17,18 Based on this working hypothesis, it isthoughtthatantipsychoticmedicationsworkbyblockingdopamine D 2  receptors, thus dampening psychotic symp-toms. 19 Preclinical studies suggest that there are substan-tial changes occurring within the dopamine system andotherneurotransmittersystemsduringmidtolateadoles-cence in the prefrontal cortex (PFC) in normative devel-opment 20 that may have implications for understandingthe mechanism of onset of schizophrenia that typicallyoccurs during late adolescence and early adulthood. 21 Thespecificmaturationalchangesinthedopaminerecep-tor system include decreases in dopamine cell density 22 ;peaking of basal dopamine levels, 23 dopamine turn-over, 24 and dopaminergic PFC input 25 ; and changes inD 1  and D 2  receptor concentrations in the striatum. 26,27 Overall, these data suggest that, relative to adulthood,adolescence is characterized by increases in basal PFCdopamine levels. These maturational changes in the do-pamine receptor system (as well as other neurotransmit-ter systems) during childhood and adolescence couldpotentially have implications for clinical response aswell as an increased susceptibility to side effects (eg, ex-trapyramidal side effects [EPS], prolactin elevation,sedation, weight gain) observed in youth exposed to an-tipsychotic drugs.Aside from making the initial diagnosis, choice of an-tipsychotic is probably the most important decision thata child and adolescent psychiatrist makes in collaborat-ing with the patient/family in treating a young patientwith a schizophrenia-spectrum disorder. Over the pastfew years, second-generation antipsychotics (SGAs)have been preferred over first-generation antipsychotics(FGAs) in the treatment of EOSS disorder. 28 However,increasing concerns about the adverse side effects associ-ated with SGA treatment in children and adolescentspoint to the need to reexamine the risk/benefit of theseagents. This descriptive review aims to systematically ex-amine the evidence from randomized, double-blind com-parison studies supporting the use of antipsychotics inEOSS disorder. The implications of recent treatment re-search are discussed including the identification of highpriority areas for future research in this population. Methods Asystematicliterature searchusingtheMedlinedatabasewas performed to identify all random assignment, con-trolled pediatric clinical trials of antipsychotics in chil-dren and adolescents with schizophrenia-spectrumdisorders whose results were published in the peer-reviewed literature from 1970 to 2007. Because wewereaware ofseveraltreatmentstudiesthat were recentlycompleted, we queried investigators and contacted man-ufacturers to locate additional studies and included dataobtained from conference proceedings. Trials limited todouble-blind studies of duration of 4 or more weeks with15 or more patients were included in this review. Results We identified 10 double-blind studies that met our crite-ria for final review. These studies and their findings arepresented below and summarized in table 1 by drug class(FGA, 3 studies; SGA, 7 studies). First-Generation Antipsychotics There have been 3 major studies that have examined theefficacyofFGAs inthe treatmentof EOSSdisorder. Twoof these utilized placebo controls and found a modest butsignificant superiority of active medication for acute pos-itive symptoms over placebo: a crossover trial of moder-ate dose haloperidol (average daily dose 95 CPZequivalents) in 16 children 29 and a 3-arm, parallel groupstudy comparing loxitane (average daily dose 875 CPZequivalents), haloperidol (average daily dose 490 CPZ Efficacy and Tolerability of Second-Generation Antipsychotics 61   b  y g u e  s  t   onF  e  b r  u a r  y1  6  ,2  0 1  6 h  t   t   p :  /   /   s  c h i  z  o ph r  e ni   a  b  ul  l   e  t  i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   Table 1.  Characteristics of Studies Included in the ReviewAuthorsDrugs, Mean DailyDose (SD) Duration Participants Effectiveness Adverse Effects LimitationsPool et al 30 Loxapine, 87.5 mg;haloperidol, 9.8 mg;placebo4 weeks  N   =  75, mean age: ; 15.5 yearsBoth treatmentssignificantly reducedBPRS total ratingscompared with placebo.No significant differencesobserved between activetreatment groups.EPS (eg, muscle rigidity)noted in 19 (73%) of 26receiving loxapine and18 (72%) of 25 subjectsreceiving haloperidol.Sedation alsoproblematic.Short duration of treatment; smallsample sizeRealmuto et al 31 Thiothixene, 16.2 mg;thioridazine, 178 mg6 weeks  N   =  21, mean age: ; 15.5 yearsBoth treatmentssignificantly reducedBPRS total scores.Clinical improvementnoted within the first7 days of treatment.Marked sensitivity tosedative effects of medication, dosereductions required forboth medicationsShort duration of treatment, smallsample sizeSpencer et al 29 Crossover design:haloperidol, 1.8 mg,vs placebo6 weeks  N   =  16, mean age(SD): ; 8.9 yearsCGI-I much/very muchimproved: 12 (75%) of 16; marked reductionin severity of persecutoryideation andhallucinationsSedation observed atoptimal dosesShort duration of treatment, smallsample sizeKumra et al 69 Clozapine, 176 mg(149); haloperidol,16 mg (8)6 weeks  N   =  21, mean age(SD): 14.0  6  2.3yearsClozapine  >  haloperidolin terms of positive(SAPS total) and negativesymptoms (SANS total)One third of clozapine-treatedpatients discontinuedtreatment prematurelydue to neutropenia orseizuresShort durationof treatmentSikich et al 64 Risperidone, 4 mg (1.2);olanzapine, 12.3 mg(3.5); haloperidol,5.0 mg (2)8 weeks  N   =  50, mean age(SD): 14.7  6  2.7years; broadrange of childrenwith psychoticdisorders includedAll treatments significantlyreduced BPRS-C totalscores from baselineto end point; CGI-Imuch/very muchimprovedand    20% BPRS-Creduction: 74%risperidone,88% olanzapine, 54%haloperidolPrevalence of extrapyramidalsymptomsand weight gain higherand more severe in youthcompared with publisheddata from adult studiesShort duration of treatment, differencesin the diagnosisacross the treatmentgroups, concomitantuse of antidepressantsand/or mood stabilizersShaw et al 68 Clozapine, 327 mg(113); olanzapine,18.1 mg (4.3)8 weeks  N   =  25, meanage:  ; 12 yearsClozapine  >  olanzapinewith respect toimprovement in negativesymptoms (SANS)Marked weight gainat 4 kg during the8-week trial noted inboth groups, at 2-yearfollow-up, 6 (40%) of 15 patients were observedto have dyslipidemiaShort duration of treatment, studypowered to detectonly large treatmenteffects  6   2     S  .K umr  a  e  t    a l       .    b  y  g  u  e  s  t  o  n   F  e  b  r  u  a  r  y  1  6 ,  2  0  1  6  h  t  t  p :  /  /  s  c  h  i  z  o  p  h  r  e  n  i  a  b  u  l  l  e  t  i  n .  o  x  f  o  r  d j  o  u  r  n  a  l  s .  o  r  g  /   D  o   w  n  l  o  a  d  e  d  f  r  o    m  Table 1.  ContinuedAuthorsDrugs, Mean DailyDose (SD) Duration Participants Effectiveness Adverse Effects LimitationsKumra et al 70 Clozapine, 403.1 mg(201.8); olanzapine,26.2 mg (6.5)12 weeks  N   =  39, mean age(SD): 15.6 (2.1)Clozapine  >  ‘‘high-dose’’olanzapine with respectto improvement innegative symptoms(SANS) for 12 weeks,CGI much/very muchimproved and   30%BPRS reduction: 66%clozapine, 33%olanzapineFive (13%) of 39 patients(3 clozapine, 2olanzapine)gained  > 7% of theirbaseline body weight;high incidence of dyslipidemiaand prediabetes seenwith both drugsShort duration of treatment, smallsample sizeRobb et al, 58 Findling et al 57 Aripiprazole, 10 mg;aripiprazole, 30 mg;PBO6 weeks  N   =  302, mean age:15.5 years (range,13–17)Aripiprazole (10-mgand 30-mg doses)  > PBO in terms of improvement frombaseline to endpoint on the PANSSTotal Score comparedwith placebo (  26.7and   28.6, respectively;placebo, -21.2; LastObservation CarriedForward (LOCF)Mild to moderateseverity of spontaneouslyreported Adverse Events(AEs): extrapyramidaldisorder, somnolence,akathisia; mean changein weight from baselinewas minimal (10 mg, nochange; 30 mg, 0.2 kg)No data available fromdrug-naive subjects toassess whetheraripiprazole is truly‘‘weight neutral’’; highplacebo response rateHaas et al 52 Risperidone, 1–3 mg;risperidone, 4–6 mg;PBO6 weeks  N   =  160, meanage (SD): 15.6years (1.3)Both risperidone groups  > PBO on the PANSSTotal Score (risperidone1- mg:   19.9 andrisperidone 4–6 mg:  20.7, respectively;placebo,   7.8; LOCF)Higher dose risperidonegroup had a greaterincidence of EPS,dizziness, and hypertoniacompared with lowerdose groupShort duration of treatmentKryzhanovskayaet al 50 Olanzapine, 11.1 mg(4.0); PBO6 weeks  N   =  107, mean age(SD): 16.2 years(1.3)Olanzapine  >  PBO interms of improvementfrom baseline to endpoint on the BPRS-C( P   =  .003) and CGI-S( P   =  .004), respectively.Treatment response ratewas not significantlydifferent betweenolanzapine (37.5%) andPBO (25.7%).Mean olanzapine-inducedweight gain (4.3  6  3.3 kg)higher and more severe inyouth compared withadult studiesShort duration of treatment, high placeboresponse rate Note:  EPS, Extrapyramidal side effects; BPRS, Brief Psychiatric Rating Scale; CGI-I, Clinical Global Impression—Improvement Scale; CGI-S, Clinical GlobalImpression—Severity of Illness; BRPS-C, Brief Psychiatric Rating Scale for Children; SAPS, Scale for the Assessment of Positive Symptoms, SANS, Scale for the Assessmentof Negative Symptoms; PBO, placebo; PANSS, Positive and Negative Syndrome Scale.  6    3    E f   f   i    c  a c   y an d  T  ol    e r  a b  i   l   i    t    y of    S  e  c  on d  - G e n e r  a t  i    onAn t  i     p s   y c h   o t  i    c  s     b  y  g  u  e  s  t  o  n   F  e  b  r  u  a  r  y  1  6 ,  2  0  1  6  h  t  t  p :  /  /  s  c  h  i  z  o  p  h  r  e  n  i  a  b  u  l  l  e  t  i  n .  o  x  f  o  r  d j  o  u  r  n  a  l  s .  o  r  g  /   D  o   w  n  l  o  a  d  e  d  f  r  o    m  equivalents), and placebo in 75 adolescents. 30 The thirdstudydirectlycomparedahigh-potencyFGAthiothixene(average daily dose 324 CPZ equivalents,  n  =  13) witha lower potency FGA thioridazine (average daily dose178 CPZ equivalents,  n  =  7) in adolescents. 31 All thesestudiesfoundsignificantextrapyramidal symptomsaffect-ing 70% of those treated with haloperidol or loxitane and50% of those treated with thiothixene. In addition, allstudies reported significant—often intolerable—sedation.The side effect profile of the FGAs, particularly motorside effects and the development of tardive dyskinesia,has led to their decreased utilization among child and ad-olescent psychiatrists. 32 In general, side effects associatedwith FGAsoccur along acontinuum: agentswithlow do-pamine D 2  binding affinity/potency typically producemarked sedation, orthostasis, and moderate weightgain and medications with high dopamine D 2  binding af-finity/potency more frequently cause motor side effectsthat seem partially dose related. There have been nolong-term studies demonstrating the safety of FGAs inchildren, and thus, data must be extrapolated from adultstudies. Casereportsof antipsychotic-related tardivedys-kinesia (TD) have been reported in adults and childrenfor all the available antipsychotics, including theSGAs. 33 In adults, TD is of particular concern, withan incidence of approximately 5% per year of FGA ex-posure and a spontaneous remission rate of 2.5%. 33 In2 large adult studies, the incidence of TD over 5 yearswas 20%–25%. 34–36 In addition, adult data suggest thatFGAs appear to have minimal benefit for neurocognitivesymptomsincomparisontoSGAs. 37 However,itremainsunclear to what extent the improvements in cognitiondemonstrated for SGAs in adult studies reflect normali-zation of cognitive deficits, practice effects, lack of inclu-sion of a healthy control group in some studies, orreduced burden of EPS. Second-Generation Antipsychotics The current published practice parameter for the assess-ment and treatment of children and adolescents withschizophrenia 38 does not address the question of whichantipsychotic to prescribe as a first-line agent for patientsbased on phase of illness, severity of clinical symptoms,and side effectrisk. Concerns aboutthe safety and lack of efficacy of the FGAs prompted a search for more effec-tive agents with better tolerability. As a class, SGAs haveaffinity for both dopamine D 2  receptors as well as forserotonin5-hydroxytryptamine(5-HT) 2 andincludecloza-pine, risperidone (and its active metabolite paliperidone),olanzapine,quetiapine,andziprasidone. 39 Inaddition,ari-piprazole, another novel antipsychotic that is a partial do-pamine agonist, is often classified as an SGA. The SGAshave become the standard treatment for EOSS disorder. 38 As a class, these agents have a reduced propensity tocause adverse motor side effects and prolactin elevationswhen compared with FGAs of similar potency. However,as with FGA agents, each of the SGAs tends to be moreprone to certain adverse effects that exist along a spec-trum. 40 These side effects appear directly related to theunique receptor-binding profiles of each of the SGAs.For example, some SGAs (eg, quetiapine, clozapine) rap-idly dissociate from the dopamine D 2  receptor 41 possiblyallowing normal surges in dopamine to overcome recep-tor blockade in the nigrostriatal and tuberoinfundibularpathways.In contrast,aripiprazole actsasaselective par-tial agonist at the dopamine D 2  receptor. 42 These uniquefeaturesmayresult inthelower EPSliability andminimaleffects on prolactin levels of clozapine, quetiapine, andaripiprazole compared with other SGAs such as risperi-done in children. 43–47 Whether the improved tolerabilityofthe SGAswill enhancetreatmentadherenceinchildrenand adolescents with EOSS disorder remains an impor-tant, but unanswered question.Nonadherence to treatment is a widespread phenome-non among youth with schizophrenia, due to such factorsas impaired cognition, lack of insight, and side effects as-sociated with antipsychotic treatment. Also, the qualityof relationships with clinicians during acute admissionappears to be an important determinant of patients’and families’ attitudes toward treatment. Enhancingsuchrelationshipsmayyieldimportantclinicalbenefits. 48 To date, there has been little systematic research exam-ining the benefits of psychological interventions aimedat promoting medication adherence in children/adoles-cents. Although there are no data available regardingthe use of risperidone microspheres (Risperdal Consta)in children and adolescents, injectables and long-actingformulations of antipsychotics may also offer benefitsin terms of ensuring treatment adherence in selectpatients. Placebo-Controlled Studies As of the writing to this article, several US pharmaceu-tical manufacturers have short-term, placebo-controlledstudiesthatarecurrentlyunderwayand/orthathavebeenrecently completed. It is possible that the patients in-cluded in these trials may not be ‘‘real-world’’ patientsbecause they and their families must be willing to partic-ipate in a placebo-controlled trial. Also, while the care-fully supervised conditions of a clinical trial allowschildren and adolescents with schizophrenia-spectrumdisorders to be closely monitored, there remains someethical concerns about withholding medications in chil-dren with EOSS disorder, particularly those who are se-verely ill, because it could be argued that participation inthesetrialsmayexposethemtosubstantialrisks. 49 Toourknowledge, the results from 3 short-term placebo-controlled studies that have now confirmed the efficacyand tolerability of SGAs (risperidone, olanzapine, aripi-prazole) relative to placebo in EOSS disorder have beenpresented at national meetings and the manuscripts forthese data are currently under review. 64 S. Kumra  et al  .   b  y g u e  s  t   onF  e  b r  u a r  y1  6  ,2  0 1  6 h  t   t   p :  /   /   s  c h i  z  o ph r  e ni   a  b  ul  l   e  t  i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om 
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