REVIEW

Early onset : diagnostic dilemmas and treatment challenges

Jennifer Cheng Early onset schizophrenia (EOS), which is defined as onset prior to 18 years of age, is Shannon†1 and associated with significant morbidity, chronicity and psychosocial impairment. EOS appears Jon McClellan2 to be both clinically and neurobiologically continuous with the adult-onset form, although †Author for correspondence 1University of Washington, there are some important differences. Although the treatment literature specifically Department of , addressing juveniles with schizophrenia is sparse, the adult literature appears to apply, Box 356560, Seattle, WA given appropriate developmental considerations. Given the significant morbidity, chronicity 98195, USA Tel.: +1 206 543 6577 and psychosocial impairment associated with EOS, it is imperative that clinicians are familiar [email protected] with the phenomenology, diagnosis, clinical course and treatment of this disorder. This 2Children's Hospital and article provides a brief description of EOS with a focus on treatment modalities, including a Regional Medical Center detailed review of psychopharmacologic and psychotherapeutic interventions. PO Box 5371/M1-1 Seattle, WA 98105, USA Tel.: +1 206-987-2760 [email protected] Early onset schizophrenia (EOS) (defined as onset psychotic disorders. However, other psychopa- prior to age 18 years) is diagnosed using the same thologists, such as Bender and Kanner, placed criteria as for adults and appears to be both clini- it within broader categories defined by devel- cally and neurobiologically continuous with the opmental deficits in language, social relations, adult-onset form. Unfortunately, it is often a more perception and movement. Therefore, child- severe form of the disease and is associated with hood psychoses often included a broader cate- significant morbidity, chronicity and psychosocial gory of neurodevelopmental disorders, impairment. There are also considerable differ- including . It was the work of Kolvin [1] ences between demographic factors, clinical pres- and Rutter [2] who demonstrated that EOS entation and long-term outcome of EOS as was a specific entity, similar to adult schizo- compared with adults. phrenia. In the 1970s, DSM-III revised the The study of EOS is important for several rea- criteria so that EOS was diagnosed using the sons. This subgroup of patients may share a same criteria as those used for adults. higher degree of homogeneity and in as much are an important population in which to study sus- Epidemiology pected etiologic factors. Since the illness disrupts Given the rarity of EOS, few studies have exam- neurodevelopmental processes in the growing ined the incidence rates in the population. child, important information may be gleaned by However, available evidence suggests the preva- examining the onset and progression of the illness lence of schizophrenia in children is signifi- against the backdrop of normal development. cantly lower than in adults, which is estimated Moreover, EOS is often a debilitating disorder at approximately 1% [3]. The onset rate rises that can have a particularly deleterious effect precipitously during the age range of 15 to upon cognitive and social functioning. There- 30 years [3]. Onset prior to the age of 12 years is fore, efforts to improve the impact of therapeutic very rare. In early onset samples, males tend to interventions are critical. It is imperative that cli- predominate [4]. Thomsen found that, in a nicians working with the young are familiar with study of all youths hospitalized for schizophre- Keywords: the phenomenology, diagnosis, clinical course nia in Denmark over a 13-year period (n = atypical , early and treatment of this disorder. This article will 312), only four were under the age of 13 years onset schizophrenia, give a brief description of EOS with an emphasis and only 28 were younger than 15 years of age on treatment modalities. [5]. EOS, especially in those under the age of 13 years, occurs predominantly in males, with Background ratios of approximately 2:1 [1,6–10]. The validity Historically, EOS was originally characterized of the diagnosis in preschoolers is questionable as being similar to schizophrenia in adults, given developmental challenges in discerning Future Drugs Ltd dating back to Kraeplin’s initial descriptions of true psychotic symptoms.

2004 © Future Drugs Ltd ISSN 1475-0708 http://www.future-drugs.com Therapy (2004) 1(1), 131–147 131 REVIEW – Shannon & McClellan

Etiology & pathogenesis Approximately 30% of people with this deletion Schizophrenia is currently thought to be a com- develop symptoms of psychosis [16,17]. Although plex disorder with polygenic, multifactorial etiolo- cases of 22q11 deletion are over-represented in a gies. Three primary areas of focus have been study of childhood-onset schizophrenia (COS) identified in the adult literature thus far: genetics; [18], an earlier age of onset was not associated viral exposure; and neurodevelopmental insults. with the deletion in a large screening study [19]. It is important to remember however, that Nicolson and colleagues found that parents of mechanisms may not necessarily have a causal patients with COS had a significantly higher relationship and that schizophrenia continues morbid risk of schizophrenia spectrum disorders to be viewed as a complex syndrome without a than parents of patients with adult-onset schizo- single etiology. Given the lack of research spe- phrenia (AOS) (24.74 vs. 11.35%) [20]. This is cifically focusing on the etiologies of EOS, the consistent with findings by the UCLA-NPI group data presented is what is currently known about [21], which continue to provide convincing evi- schizophrenia in the general population. When dence for the hypothesis that there is a continuous available, studies specifically examining EOS etiology between COS and AOS. will be noted. Despite these promising findings, there is not one single specific gene or chromosomal region Genetics that has been consistently found across studies to There is substantial evidence that genetics play be definitively associated with schizophrenia. an important role as a risk factor for the develop- Given schizophrenia’s heterogeneity, it is likely ment of schizophrenia with a heritability rate of that the genetic component of the disorder is approximately 80% [11]. The lifetime risk of much more complex than identifying a single developing schizophrenia is 5–20 times higher in gene. Moreover, there may be other types of first-degree relatives of affective probands when mechanisms, such as epigenetic influences, yet to compared with the general population [12]. Posi- be identified that relate to the development of tive family histories of schizophrenia are noted in the disorder. youths with EOS, although whether the relative risk is the same as adults has not been well stud- Neurodevelopmental theory ied [4]. Despite this evidence, no single model of The neurodevelopmental hypothesis of schizo- genetic inheritance has yet been identified. The phrenia is based on the idea that early central nerv- phenotype of schizophrenia is heterogeneous ous lesions normal maturational processes. and it is likely that multiple genes are involved. Evidence supporting this theory is partly based on Moreover, the risk conferred may not always be premorbid impairments seen in childhood and expressed as schizophrenia but rather as related adolescence of those who later develop schizophre- traits, such as a schizoid personality. Finally, nia and may represent the neuropathologic mani- many cases are assumed to be sporadic and per- festations of the disorder. Kolvin’s work in the haps due to complicated gene–environment 1970s showed that 87% of 33 children with the interactions. Numerous linkage and candidate equivalent of EOS were premorbidly odd and had genes studies have been completed to date. developmental delays, mostly in speech [1]. Multi- There are several chromosomal regions that at ple recent studies have also replicated delayed least one study has associated with schizophre- motor milestones, speech problems, lower educa- nia, including 1q, 5p, 5q, 6p, 6q, 8p, 10p, 13q, tional test scores and/or poor social adjustment 15q and 22q [13]. Another study identified these before the onset of the disorder [22–25]. A recent genes as well as 18p, although the precise linkage study suggests that these deficits may be more rele- in schizophrenia has yet to be established [14]. vant to those with adolescent onset of the disorder Genes of interest include dybindin (6p22), neu- [26]. In the adult literature, perinatal complica- regulin (8p22) and catechol-O-methyltransferase tions, alterations in brain structure and size, minor (COMT) (22q11) [15]. COMT is of particular physical anomalies and disruption of fetal neural interest because it is found in the commonly development, particularly during the second tri- deleted region of chromosome 22 that is associ- mester of pregnancy, have been correlated with the ated with velo-cardio-facial syndrome (VCFS), illness [27–29]. although there are other genes of interest in this region as well. VCFS is a genetic disorder charac- Infectious processes terized by palatal, facial, cardiac, congenital Viral exposure has been implicated as a risk factor abnormalities and psychiatric conditions. for schizophrenia. Individuals with schizophrenia

132 Therapy (2004) 1(1) Early onset schizophrenia – REVIEW

are more likely to have been born during the subjects in the ongoing National Institute of winter months [30] or soon after an influenza epi- (NIMH) study of COS, progres- demic more often than expected by chance [31]. sive cortical deficits in temporal, frontal and pari- These findings suggest that viral exposure during etal regions have been noted [44–46]. Compared gestation may be a risk factor for the later devel- with controls, subjects with COS had a signifi- opment of schizophrenia. Some research studies cantly accelerated loss of gray matter involving have found that birth cohorts who were in the the frontal eye fields and motor, sensorimotor, second trimester of pregnancy during an influ- parietal and temporal cortices bilaterally over a enza epidemic were shown to have an increased 5 year span. Progressive deficits in the lateral tem- risk of schizophrenia, although this result has not poral and dorsolateral prefrontal cortex were been consistently noted [32]. However, efforts noted on average 3 years after the onset of psy- attempting to directly link viral to the chotic symptoms, suggesting the possibility that development of schizophrenia have been incon- loss of gray matter may in fact occur later in the clusive. Further research is needed to clarify what disease course [46]. Progressive cerebellar volume role, if any, exposure to viral infections have in loss were also noted in this sample [47], consistent the development of schizophrenia. with reports of abnormal cerebellar function in adult schizophrenia [48]. None of the findings are Psychological factors consistent across all subjects and cannot be con- Psychological factors have also been a focus of sidered diagnostic. Although studies tried to con- research and to date have not been directly linked trol for confounding factors, some of the noted to the development of the illness. Chronic inter- findings may have been influenced by personal within the family such as expressed exposure or other environmental factors. emotion, has been found to influence the onset and exacerbation of acute psychotic episodes as Diagnosis & clinical features well as relapse/rehospitalization rates [33]. How- The same criteria are used to diagnosis schizo- ever, this should not be interpreted as a causal phrenia in children as in adults. According to mechanism, since in fact having a family member the DSM-IV-TR [49] at least two of the follow- with schizophrenia often directly increases stress ing are needed for a diagnosis of schizophre- and difficulties with communication. nia, each present for a significant period of time during a 1-month period: • The relationship between schizophrenia and • cannabis use has been known for some time but • Disorganized speech the actual nature of the relationship has remained somewhat unclear. Differing theories • Grossly disorganized or catatonic behavior include self-medication, other drug effects, con- and/or founding factors, predisposed population and • Negative symptoms, such as affective flatten- the etiological hypothesis [34]. Results from five ing, alogia, or recent longitudinal studies imply that cannabis The diagnosis can also be made if only one of the use increases the risk of later schizophrenia [35– following is present: bizarre delusions; hallucina- 39]. In the largest study from Sweden, an odds tions that consist of a voice keeping a running ratio of 2.1–2.5 was found in a sample size of commentary on the child’s behavior or thoughts; over 50,000 subjects [35]. Controversy still exists or two or more voices conversing with each other. regarding whether there is a direct causal link Active psychotic symptoms need to persist for at between cannabis abuse and schizophrenia. least 1 month. Social and functional impairment Nevertheless, the strong association between the are also required, although at times this can be dif- two is an important clinical concern. ficult to establish since most youth have significant premorbid problems. The total duration of illness findings must be at least 6 months; otherwise a diagnosis of Numerous neurobiologic abnormalities have schizophreniform disorder is made. been discovered in EOS, including deficits in Although the diagnostic criteria appear smooth pursuit eye movements, autonomic straightforward, assessing youth for EOS is often a responsivity and neuroimaging findings [40–43]. challenge in clinical settings. Symptoms of EOS These findings are mostly consistent with the overlap with several other psychiatric illnesses, adult literature. In a series of reports examining including mood disorders, organic brain www.future-drugs.com 133 REVIEW – Shannon & McClellan

syndromes and post-traumatic reactions [4]. Differential diagnoses Therefore, it is important to perform a complete The full discussion of the differential diagnoses psychiatric assessment when evaluating a child for of EOS is beyond the scope of this article, how- psychotic symptom. Psychotic symptoms must be ever, important highlights will be discussed. assessed within the developmental context of the EOS is considered a relatively rare disease, espe- child. In general, hallucinations and negative cially in children less than 13years of age. symptoms are the most common presentations in Despite this, it is easily misdiagnosed given an EOS, whereas systematic delusions and extensive differential diagnosis as well as the are rare. In school-aged children with psychosis, lack of trained professionals able to assess psy- the delusional content often revolves around ideas chotic symptoms in the correct context [52]. of reference, somatic preoccupations, or delusions Given extensive overlap of symptomatology of persecution [8]. Compared with psychotic with a wide variety of other psychiatric disor- adults, delusions are less likely to be richly detailed ders, a thorough review of presenting symp- or elaborate. Though it may be counterintuitive, toms, course and premorbid functioning, more elaborate descriptions of suspected psy- adherence to DSM-IV-TR criteria, familiarity chotic phenomena should raise questions as to the with how psychotic symptoms present in this validity of the report. age group and determination of family psychi- Children and adolescents may respond posi- atric history all will help improve the accuracy tively to questions about hallucinations and delu- of diagnosis. Periodic reassessment of the accu- sions for a variety of reasons, including racy of this diagnosis is crucial given the phasic developmental delays, misunderstanding the con- course of this illness. cept being described, overactive imaginations All organic causes of psychosis must be ruled and/or attention seeking [4]. Furthermore, youths out including drug or alcohol intoxication, with histories of child maltreatment are more , CNS lesions, tumors, bacterial or likely to report hallucinations [50]. These issues viral infections, metabolic disorders and seizure add to the diagnostic complexity since the symp- disorders. Certain tests, such as neuroimaging, toms are generally being reported against a back- electroencephalographs and laboratory tests drop of emotional and behavioral difficulties. may be helpful in narrowing the diagnosis may not even be specific, since although are not essential in making a diagnosis disorganized or loose thinking may be simply due of a psychotic disorder. to inattention or impulsiveness [51]. Misdiagnosis The psychiatric history should focus on the of schizophrenia in youth is a significant prob- presenting symptomatology, the longitudinal lem. A substantial number of youths first diag- timeline of symptom development and associ- nosed with schizophrenia have other disorders at ated features and/or confounding factors (e.g., outcome, including bipolar [9] and personality mood disorders, developmental problems and disorders [5]. Moreover, the majority of youths substance abuse). One of the most important referred to a national study of childhood schizo- aspects of obtaining a psychiatric history should phrenia did not have the disorder but instead dis- be to obtain an understanding of the longitudi- played a mixture of developmental delays, mood nal course of the illness given that psychotic dis- lability and subclinical psychotic symptoms [52]. orders have several phases. In collecting this Atypical reports of psychotic symptoms that history, it is important to collect as much collat- suggest a child may not truly have a psychotic eral information from outside sources including illness include: the child’s parents, other caregivers, teachers, • The reports are inconsistent and there is no treatment providers and community support other documented evidence of a psychotic persons such as case workers, probation officers process such as thought disorder or bizarre and peers. disorganized behavior Developmental characteristics must be taken into account. For children, it is often difficult to • The qualitative nature of the reports were not distinguish true psychotic symptoms from other typical of psychotic symptoms, such as, factors, such as an overactive imagination, devel- greatly detailed descriptions or reports more opmental delay, language problem, posttraumatic suggestive of fantasy or imagination phenomenon and/or misperception of the ques- • The reported symptoms only occurred at spe- tions. Furthermore, very young children’s inability cific times, such as, only hearing voices after to apply logical reasoning to their perceptions can an aggressive outburst [53] make it difficult to identify delusions in children

134 Therapy (2004) 1(1) Early onset schizophrenia – REVIEW

younger than 5 years of age. However, language noted that many youth with atypical presenta- problems may be greater in childhood onset cases, tions, or psychosis not otherwise specified (NOS) therefore the presence of a does have traumatic histories, including physical, sexual not rule out the possibility of schizophrenia [54]. and/or emotional abuse [60]. These youths may Adolescents have mental status features more like describe symptoms suggestive of auditory or visual adults. Confounding factors, such as substance hallucinations and/or paranoid delusions, yet the abuse, may confuse the clinical picture. In general, reports are generally either brief or atypical in children and adolescents may not report halluci- nature and the child does not demonstrate the nations since they are frightened or confused other hallmark symptoms of schizophrenia. Fur- and/or they recognize the implications of ther, some children with abuse histories may report acknowledging ‘being crazy’. psychotic symptoms in the context of reinforce- Another factor that often complicates the diag- ment that occurs in a chaotic environment. There- nostic picture is that 10–20% of youths with EOS fore, potential environmental reinforcers of having IQ’s in the borderline to mentally retarded psychotic behaviors should be assessed. Although range [4]. Learning and language disorders are also some youth characterized with psychosis nos even- common. Although youths with schizophrenia are tually develop definable psychotic disorders, many at risk for cognitive deficits, the presence of devel- do not [60,61]. opmental delays also creates diagnostic difficulties. Children with pervasive development disor- In these cases, reported psychotic symptoms may ders (PDDs) may be suspected as having schizo- simply represent misunderstanding of the concepts phrenia based on their potentially odd behaviors. and/or misinterpreted normal sensory phenomena. By definition, youths with PDD will have prob- Furthermore, it is also common for youths with lems with social relatedness, language difficulties EOS to have either other comorbid or premorbid and idiosyncratic behaviors, thus raising the psychiatric disturbances, such as attention deficit question of negative symptoms or disorganized hyperactivity disorder (ADHD), conduct prob- behaviors. However, unless they develop overt lems, anxiety and/or substance abuse, all of which hallucinations or delusions the diagnosis of schiz- may complicate diagnosis and/or treatment. ophrenia should not be used [4]. Conversely, the The first step in the differential is deciding prodromal phase of schizophrenia may resemble whether the child or adolescent is truly psy- Aspergers Disorder and cannot be differentiated chotic. Once psychotic symptoms are docu- until the psychotic symptoms fully present. mented and other medical causes are ruled out, the differential includes schizophrenia, psychotic Differential diagnosis. mood disorders or schizo-affective disorder. Both schizophrenia and psychotic mood disorders (especially ) present with a vari- Psychiatric – Psychotic disorder due to a general medical ety of affective and psychotic symptoms [9,55–57]. condition In children and adolescents with schizophrenia, – Bipolar disorder negative symptoms may be mistaken for depres- – Major depressive episode with psychotic sion. Alternatively, in teenagers often features – presents with florid psychosis, including hallucina- – Psychotic disorder NOS tions, delusions and thought disorder [58]. The – overlap between mood and psychotic symptoms – Posttraumatic stress disorder – Obsessive compulsive disorder increases the likelihood of misdiagnosis at the time – Pervasive of onset. Longitudinal reassessment is needed to – ensure accuracy of diagnosis. Family psychiatric – Evolving borderline history may also be a helpful differentiating factor. Psychosocial There are children with complex developmental – Abuse – Traumatic stress problems, including disturbances in affect modu- – Chaotic family environment lation, social relatedness and thinking, whose Medical symptoms do not fit well within the current crite- – ria for schizophrenia. Kumra and colleagues, have – Delirium characterized a group of children with deficits in – Brain tumor – Head injury attention, impulse control, affect regulation and – Seizure disorder transient or subclinical psychotic symptoms as – Meningitis multidimensionally impaired [59]. Others have www.future-drugs.com 135 REVIEW – Shannon & McClellan

Longitudinal course completed in adults with schizophrenia is EOS is a phasic disorder, consisting of a prodro- approximately 10% [4]. mal, acute, recuperative/recovery and residual In comparison with other early onset psy- phase. The prodromal phase varies in time from chotic illnesses, those with schizophrenia gener- an acute change lasting days to weeks to a chronic ally fare worse than those with psychotic mood impairment lasting months to years. Prodromal disorders [60,69]. Predictors of outcome are less features may include deteriorating function, social well studied in EOS as compared with adult- isolation and increasingly odd or bizarre behavior. onset but onset below the age of 10 years, nega- Cornblatt and colleagues have identified three tive symptoms, low IQ and level of premorbid clinical high-risk groups including: functioning have been associated with a worse • Negative and nonspecific symptoms, such as prognosis [65]. social isolation which is the earliest Treatment • Moderate intensity positive symptoms A multimodal approach should be utilized in the (attenuated) treatment of EOS incorporating psychopharma- • Severe-attenuated positive symptoms which cology and psychosocial interventions. The treat- are considered the closest to psychosis ment plan should be tailored to each patient based With regards to EOS, children in the prodromal on the developmental characteristics of the phase of illness may also exhibit increased behav- patient, the phase of the disorder and needs of the ioral problems, such as aggression, deceitfulness family. Given the lack of both psychopharmaco- and/or substance abuse that may represent a sig- logic and psychosocial research in the area of nificant change from baseline functioning or a EOS, treatment recommendations are generally worsening of premorbid personality characteris- based on the adult literature. Since EOS appears tics. Children with EOS tend to have more to be continuous with the adult-onset form, this insidious onsets [62]. practice seems justified as long as developmental The acute phase usually lasts 1–6 months and considerations are taken into consideration. is one in which positive symptoms predominate and cause significant deterioration of function. A Psychopharmacology gradual shift from positive to negative symptoms agents are the cornerstones of may occur during the course of treatment. Treat- treatment for psychotic disorders in the adult ment response often determines the length of population. The atypical antipsychotics are a this phase. The recuperative/recovery phase major advance and add to the therapeutic occurs as the acute psychosis resolves and is most armamentarium of drugs available for the often characterized by ongoing negative symp- treatment of schizophrenia. However, at this toms that cause a significant degree of impair- time there are only five randomized controlled ment. The residual phase can last prolonged trials examining the efficacy and safety of periods of time (several months or more) and is a antipsychotics in youths with EOS, only two period during which youths with EOS do not of which examined an atypical agent. Control- have active positive symptoms. A small propor- led trials using traditional agents in children tion of patients may go into remission. Few stud- and adolescents with schizophrenia: thiothix- ies have examined long-term outcome in EOS ene and thioridazine (Mellaril®, Novartis and most are retrospective. Generally, these stud- Pharma) [70], haloperidol (Haldol®, Janssen ies have found that 75–90% of subjects with Cilag) [71] and loxitane® (loxapine, Apotex) [72] EOS are moderately to severely impaired at fol- suggested a similar response rate and side low-up (ranging from 2–42 years) [63–65], effect profile to that found in adults. However, although not all studies have found such a poor in clinical practice, traditional agents are usu- prognosis [66]. The outcome for patients with ally relegated to second-line treatments. The EOS is generally thought to be poor and has agents have become the been reported to possibly be worse than that of agents of first choice based upon a more favo- AOS with regards to multiple domains of func- rable side effect profile, greater efficacy for tion including educational achievement, negative symptoms and mood stabilization employment, and social relationships. A mortal- properties in adults. Table 1 summarizes the ity rate of approximately 5% for EOS due to sui- published data to date with these agents for cide, or accidental death related to psychosis has EOS. We will discuss each of the atypical been reported [9,67,68]. This reported risk for antipsychotics in greater detail below.

136 Therapy (2004) 1(1) Early onset schizophrenia – REVIEW

Table 1. Atypical antipsychotic trials in early onset schizophrenia . Trial Subjects Study type Dosage Outcome Efficacy measures Ref. (age) Clozapine Siefen et al. n = 21 Open 352 17/21 positive response NA [74] (1986) (18.1) Schmidt et al. n = 57 Retrospective 285 67% significantly improved NA [111] (1989) (9–21) review >50%

schizophrenia Birmaher et al. n=3 Case series 300 3/3 positive response NA [112] (1992) (17–18) Blanz et al. n=57 Open 285 50/57 positive response (67% NA [76] (1993) (10–21) significant improvement, Majority TR 21% partially improved) schizophrenia Frazier et al. n = 11 Open 370 > 50% positive response in Brief Psychiatric Rating [75] (1994) (12–17) Brief Psychiatric Rating Scale Scale, Children’s Global Scale for Assessment of Positive and Negative Symptoms Remschmidt n=36 Chart review 330 27/36 with some degree of Scale for Assessment of [113] et al. (1994) (18) clinical improvement, less Positive and Negative effective in negative Symptoms symptoms Levkovitch et al. n=13 Open 240 10/13 more than 50% Brief Psychiatric Rating [114] (1994) (14–17) decline of Brief Psychiatric Scale Rating Scale Mozes et al. n=4 Case series 150–300 4/4 substantial improvement, Brief Psychiatric Rating [115] (1994) (10–12) remission of symptoms in Scale, Clinical Global daily functioning, social Impression interaction, academics Piscitelli et al n = 11 Clozapine vs. 5.99 mg/kg/d Linear relationship between NA [116] (1994) (14.1) haloperidol vs. 0.24 clozapine concentration and plasma levels mg/kg/d efficacy, not observed with and efficacy haloperidol Levkovitch et al. n = 2 Case series 450–500 2/2 significant improvement Brief Psychiatric Rating [117] (1995) TD of , 30% Scale, Tardive reduction in Brief Psychiatric dyskinetic rating scale Rating Scale Kowatch n=5 Case series 75–225 5/5 had 42% decrease in Clinical Global [118]

et al.(1995) (TR (6–15) Clinical Global Impression- Impression, Children’s schizophrenia severity of illness Global Assessment and bipolar disorder) Kumra et al. n = 21 Double- 176 Clozapine > Brief Psychiatric Rating [77] (1996) (14.4) blind/ haloperidol on all measures of Scale, Clinical Global TR schizophrenia haloperidol psychosis Impression, Bunney- Hamburg Psychosis Scale, Positive and Negative Symptom Scale

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Table 1. Atypical antipsychotic trials in early onset schizophrenia (Continued). Schulz et al. n=40 Open: 324/465 Higher serotonin levels NA [119] (1996) (14–22) clozapine vs. associated with fewer typical negative symptoms, higher neuroleptic MHPG with less Turetz et al. n=11 Open 220 11/11 had > 50% reduction Brief Psychiatric Rating [120] (1997) (9–13) in all scales Scale, Positive and TR schizophrenia Negative Symptom Scale, Clinical Global Impression Chalasani et al. n=6 Chart review NA Improved social interaction, NA [121] (2001) decrease in violence, SI/HI schizophrenia or schizoaffective Zan et al. (2001) n = 43 Open 100–450 50% reduction in Clinical Clinical Global [122] (12–18) Global Impression Impression, Global Assessment Functioning Scale Frazier et al. n=6 Open 3.4 mg/kg NA NA [78] (2003) (9–16) (pharmacokineti cs) Risperidone Cozza et al. n=2 Case series 2 2/2 had significant NA [123] (1994) (15) improvement in positive and negative symptoms Quintana et al. n=4 Case series 4–5 3/4 marked improvement in Clinical Global [124] (1995) (12-17) negative symptoms Impression, Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale Lykes et al. n=2 Case series 2.5/5.5 1 moderately and 1 markedly Global Clinical [125] (1996) (7, 11) improved Judgment Scale Grcevich et al. n = 16 Chart review 2–10 15/16 Brief Psychiatric Rating [126] (1996) Scale, Clinical Global Impression Armenteros et al n = 10 Open 6.6 6/10 significant reduction in Positive and Negative [127] (1997) (15.1) Positive and Negative Symptom Scale, Symptom Scale Clinical Global Impression, Brief Psychiatric Rating Scale Calhoun et al. n=191 Chart review 1.8 164/191 had target symptom NA [128] (1999) (13–17) improvement Psychotic symptoms Zalsman et al. n=11 Open 3.14 10/11 had 20% reduction in Positive and Negative [129] (2003) (15–20) Positive and Negative Syndrome Scale, Syndrome Scale, not effective Clinical Global for negative signs and Impression, Brief symptoms Psychiatric Rating Scale

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Table 1. Atypical antipsychotic trials in early onset schizophrenia (Continued). Olanzapine Kumra et al. n=8 Open Olanzapine: 53% of clozapine treated met Brief Psychiatric Rating [89] (1998) (olanzapine) comparison 17.5 mg responder criteria vs. 0% of 8 Scale, Scale for n = 15 to clozapine Clozapine: treated with olanzapine at Assessment of Positive (clozapine) 317 mg +/- week 6, at week 8, 5/8 and Negative 147 mg olanzapine treated had Symptoms, Clinical minimal to much Global Impression improvement on the Clinical Global Impression Dittman et al. n= 24 Chart review 16.8 18/24 moderate Similar to Clinical [130] (1999) (13–19.5) significant improvement Global Improvement Scale Junghanss et al. n=24 Chart review 16.8 2 very much improved, 18 Similar to Clinical [131] (1999) (17.2) much improved Global Improvement Scale Sholevar et al. n=15 Open 2.5–5 5/15 moderate improvement NA [132] (2000) (6–13) Grothe et al. n=8 Open 20 NA NA [133] (2000) (10–18) (pharmacokinetics) Findling et al. n = 16 Open 12.4 11/16 much improved Positive and Negative [134] (2003b) Symptom Scale, Clinical Global Impression, Children’s Global Assessment Scale Dittman et al. N=96 Open 16.7 60/96 responders at 6 weeks Brief Psychiatric Rating [135] (2003) (12–21) Scale, Clinical Global Impression Ross et al. (2003) N = 20 Open 10.4 74% responders at 1 year Brief Psychiatric Rating [136] (6–15) Scale-child version, Scale for Assessment of Positive and Negative Symptoms Mozes et al. n=9 Open 8/9 sustained improvement at [90] (2003) 1 year (population treatment refractory to 2 or more prior antipsychotics) Quetiapine McConville et al. n = 10 Open 400 bid 10/10 significant decreases in Brief Psychiatric Rating [92] (2000) (12.3–15.9) all measures Scale, Clinical Global Impression Shaw et al. n = 15 Open 467 13/15 moderate to significant Brief Psychiatric Rating [91] (2001) (13–17) improvement Scale, Clinical Global Impression, Positive and Negative Symptom Scale, Young Mania Rating Scale

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Table 1. Atypical antipsychotic trials in early onset schizophrenia (Continued). Grcevich et al. n=14 Open 308.9 11/14 positive response Brief Psychiatric Rating [137] (2001) (11.6) Scale, Clinical Global Impression, Global Assessment of Functioning McConville et al. n=10 Open 300–800 Significant improvement in Brief Psychiatric Rating [138] (2003) (12.3–15.9) positive and negative Scale, Clinical Global symptoms Impression, Scale for Assessment of Negative Symptoms Ziprasidone NA Aripiprazole NA Combined Sikich et al. n=50 DB/flexible 5mg vs. 53% met response criteria [79] (2004) (8–19) dose of 4mg vs. with haloperidol, 74% with (schizophrenia haloperidol 12.3 mg risperidone, 88% with spectrum vs. risperdal (mean olanzapine disorders, MDD vs. dosage at with psychotic olanzapine end of study) features) Case reports included. Positive response based on study’s primary and secondary efficacy measures. MDD: Major depressive disorder; MHPG: Methoxyhydroxyphenylglycol.

Clozapine 14.0 ± 2.3 years) with COS. However, while on Kane and colleagues [73] noted that schizophrenic clozapine, five youths developed significant neu- adolescents and adults with chronicity and poor tropenia (this resolved spontaneously in three of response to standard neuroleptics had positive subjects) and two had seizures. Such high rates of responses to clozapine. This marked the begin- neutropenia have not been observed in other ning of several studies examining the use of cloza- large case studies and it is difficult to infer the pine in this population. Open trials supported its overall risk based on a small sample size. Never- efficacy in this age group. Siefen and Remschmidt theless, although potentially more efficacious, completed an open-label trial of clozapine in 21 clozapine’s apparent increased risk for adverse in-patients (average age 18 years) who had either reactions in youth raises caution. At this time, been treatment resistant or had not tolerated a although clozapine may be effective for treat- typical neuroleptic [74]. Overall clozapine was well ment resistant cases, it is not recommended as a tolerated (mean dose of 352 mg). Marked first line agent based on its side effect profile. improvement or complete remission of psychotic Clozapine pharmacokinetics was studied com- symptoms was seen in 52% of subjects. Frazier pleted in 6 youths (aged 9–16 years) with schizo- and colleagues found clozapine to be helpful in a phrenia [78]. Serum was collected after 6 weeks sample of subjects with treatment-resistant child- treatment prior to and 30 mins* following a hood schizophrenia [75]. Blanz and Schmidt morning dose of 3.4 mg/kg. The metabolite nor- reviewed the records of 57 in-patients (9–21 years clozapine was found to exceed clozapine in its of age) treated with mean dosage of 285 mg of concentration in contrast to adults in whom the clozapine [76]. Significant improvement was seen opposite is true. Dose-normalized concentra- in 67% of patients. tions of clozapine did not vary with age and were There has only been one randomized, control- similar to adults. led study examining the use of clozapine in EOS [77]. In the NIMH study, clozapine (mean dose Risperidone 176 ± 149 mg/day) was superior to haloperidol There are no placebo-controlled studies of risp- (16±8mg/day) for treating both positive and eridone in EOS, although several open studies negative symptoms in 21 youth (mean age and case reports suggest that many patients

140 Therapy (2004) 1(1) Early onset schizophrenia – REVIEW

demonstrate measurable improvement. Sikich well-tolerated with weight gain being the most and colleagues compared responses with risperi- common side effect. Average weight gain of done (1–6 mg/d), haloperidol (2–8 mg/d) and 6.10 ± 3.25 kg was observed. At 1-year follow- olanzapine (Zyprexa®, Eli Lilly & Co.) (5– up, improvement in psychiatric symptoms 20 mg/d) in 50 children (aged 8–19 years) with continued in eight children. more broadly defined psychosis. Subjects maintained treatment on olanzapine signifi- Quetiapine cantly longer than the other two agents, with a There are no pediatric double-blind/controlled positive response noted in 74% of those treated studies of quetiapine monotherapy. Multiple with risperidone, 88% with olanzapine and case reports and open-label studies have 53% with haloperidol. In this pilot study, described quetiapine’s efficacy in the treatment improvement was noted for all agents, without of EOS. In one open-label study, Shaw and col- significant differences between the individual leagues studied the efficacy and tolerability of . The rates of extrapyramidal side quetiapine in 15 psychotic adolescents with a effects (EPS) and weight gain for children mean dosage of 467 mg/day. Quetiapine was treated with atypical antipsychotics were higher found to have a positive effect with improvement than typically reported in adults [79]. in psychotic and manic symptoms. Most com- Reports vary as to whether children and ado- mon side effects included somnolence, agitation lescents are at a higher risk for EPS with risp- and drowsiness [91]. Decreased thyroxine (T4) eridone [80–83]. Case reports describe the levels have been reported with quetiapine use development of withdrawal dyskinesias and suggesting that clinical monitoring to signs of tardive dyskinesia [84–86] and risperidone- is warranted [92]. related neuroleptic malignant syndrome (NMS) [87]. Comparative risks for these unto- Ziprasidone & aripiprazole ward effects with adult patients are unknown. To our knowledge, no studies have yet been pub- Compared with other atypicals, risperidone has lished examining the use of ziprasidone in EOS. It been more often associated with elevated prol- is being used in clinical settings and offers promise actin levels. Prolactin levels in children treated given the advantage of not being associated with with risperidone were reviewed examining data significant weight gain. Cardiac monitoring is from five studies [88]. There was a modest early needed since the agent may cause prolongation of increase in mean serum prolactin levels that QT intervals. In addition, there is one report of an decreased after eight weeks of risperidone ther- adolescent with schizophrenia developing mania apy. Levels were above baseline but within associated with ziprasidone therapy [93]. normal limits by the end of 1 year. The newest agent on the market, aripipra- zole (Abilify®, Bristol Myers Squibb) has been Olanzapine shown to be more efficacious than placebo and There are no pediatric double-blind/controlled as efficacious as conventional antipsychotics in studies of olanzapine in EOS. In an open label the treatment of adult schizophrenia [94–96]. To study, olanzapine was efficacious (defined as our knowledge, no studies have yet been pub- more than 28% improvement in Brief Psychi- lished regarding the use of aripiprazole in EOS. atric Rating Scale [BPRS] scores) in two out of An early report described short-term safety and eight children with treatment refractory COS. tolerability of aripiprazole in which initial In this sample, olanzapine was inferior to cloz- doses of 1 mg/kg/day were titrated to a maxi- apine given 53% of clozapine versus 0% of mum of 15 mg/day and well-tolerated [97]. olanzapine subjects had responded at 6 weeks. Nausea and vomiting were the most common Increased appetite, constipation, somnolence, side effects and no other adverse events, , tachycardia and transient increases including negative cardiovascular outcomes, in liver function tests were the main side effects were reported. observed in the olanzapine-treated group [89]. Given the dearth of data regarding use of Mozes and colleagues used olanzapine in nine atypical antipsychotics in this population, fur- children hospitalized for schizophrenia who ther trials need to focus on safety and effective- had been treatment resistant to two previous ness of these agents for EOS using randomized antipsychotics [90]. At 12 weeks, a reduction in controlled designs and adequate sample sizes. all scores was observed com- There are such studies underway nationally at pared with baseline. Overall, olanzapine was this time. www.future-drugs.com 141 REVIEW – Shannon & McClellan

Safety monitoring Treatment guidelines Youths appear to have the same spectrum of side Treatment varies depending on the phase of effects with typical antipsychotics as those the illness and the patient’s history of medica- described in adults, including: extrapyramidal tion response and side effects. The American symptoms, sedation, tardive dyskinesia and neu- Academy of Child and Adolescent Psychiatry roleptic malignant syndrome [84,86,98,99]. provides the following general guidelines for Although they are often viewed as more benign, the psychopharmacological management of atypical antipsychotics are associated with signifi- schizophrenia [4]. cant adverse events, including weight gain and Antipsychotics are the front-line treatment for endocrine abnormalities, cardiovascular changes EOS with atypical antipsychotics generally being and sedation. There have been concerns that these the first choice (Table 2). With regards to choice occur at even higher rates than those reported in of antipsychotic, this should be made based on adults, with weight gain being a particular con- the agent’s relative potency, potential side effects cern [79,100]. A 12-week naturalistic study of olan- and the patient’s history of medication response. zapine, risperidone and quetiapine in juveniles demonstrated significant weight gain, increased Acute phase triglycerides and insulin resistance for all com- In the acute phase, a trial of an adequate dosage of pounds (n = 134) [101]. EPS is also a concern for antipsychotic should last no less than 4 to 6 weeks this age group. In a report of 34 patients with before any conclusions regarding efficacy are EOS being treated with either clozapine, haloperi- made. Although children usually require lower dol, or olanzapine, 50% of patients were noted to dosages of drugs, it should be kept in mind that have either withdrawal dyskinesias or tardive dys- the drug metabolism of antipsychotics in children kinesia at some point during the trial [102]. Finally, tends to be higher and therefore children usually there may be the potential for long-term risks for require approximately adult dosages. If no which there are currently no studies. For example, improvement is seen at 4 to 6 weeks, then a decreased mineral bone density has been observed change in antipsychotic should be made. with risperidone use in adults [103]. The relation- ship between hyperprolactinemia and osteoporo- Recuperative phase sis is a theoretical risk but to date has not been Although improvements in positive symptoms examined in the pediatric population. are observed in the recuperative phase, it is It is recommended that youths are monitored important to maintain medication given addi- for side effects in a systematic fashion. Baseline tional recovery may be obtained over the next 6– assessments should include a full physical exam- 12 months. If side effects were elicited with ination and review of systems, with special higher dosages in attempts to control the acute attention to seizures, pre-treatment extrapyrami- phase, gradual decreases in the dosage may be dal signs, cardiac symptoms and prolactin-asso- attempted. However, any reductions in dosage ciated phenomena, such as galactorrhea or consequently increase risk for relapse, therefore amenorrhea. Once on the agent, routing moni- close monitoring is required. toring of weight, metabolic functioning and examininations for the presence of abnormal Recovery phase movements is needed. The US Food and Drug During this period, a medication free trial may Administration (FDA) recently asked manufac- be attempted in those youth who have been turers of all six atypical antipsychotic drugs to symptom free for 6–12 months. However, sta- include a warning statement in their inserts tistics are grim and without maintenance thera- regarding the increased risk of developing high pies, approximately 65% of adult patients have blood sugar levels and diabetes associated with been shown to relapse within 1 year [3] and a these drugs. Consistent with recent FDA guide- striking 80% relapse at least once over 5 years lines, weight, fasting glucose and lipid levels [105]. Physicians should be meeting frequently, should be assessed every 3 to 6 months for all at least monthly, to monitor symptoms, side atypical antipsychotics. Specific agents may need effects and medication adherence. other additional tests, for example, cardiac mon- itoring with ziprasidone [104]. It is important to Nonresponders remember that almost all uses of atypical antip- For the minority of patients who do not respond sychotics in children are off-label and that the to a first trial of antipsychotic, the etiology may effects of long-term treatment are unknown. be a misdiagnosis or side effects of the medication

142 Therapy (2004) 1(1) Early onset schizophrenia – REVIEW

Table 2. Psychotropics used for psychosis in children and of early transition to psychosis and this study sug- adolescents. gests that it may be possible to at least delay the progression to psychosis [107]. Atypical Typical Considered when As would be expected, psychotherapy alone antipsychotics antipsychotics other medications fail has not been proven to be an effective treat- Olanzapine Haloperidol Clozapine ment for schizophrenia. However, adjunctive Risperidone Thiothixene Electroconvulsive therapy psychosocial treatments including psychoedu- (ECT) cation [108], behaviorally based family therapy Quetiapine Chlorpromazine [109,110] and cognitive behavioral therapy [106] Aripiprazole Trifluoperazine have been shown to reduce relapse rates and Ziprasidone Molindone improve positive and negative symptoms in schizophrenic patients. Therapeutic resources, such as in-patient/par- clouding the clinical presentation. Therefore, a tial hospitalization programs, case management, medication-free trial may be attempted if diag- vocational and rehabilitative assistance, or special nostic questions exist. Clozapine is a proven drug education programs may also be incorporated. of choice for nonresponders and is reserved for Unfortunately, these resources are often unavaila- those who are truly treatment resistant which is ble or difficult to obtain secondary to lack of defined by failure of at least two therapeutic trials resources. The gross lack of mental health services of other neuroleptics (at least one of which is an for this population has fueled the impetus for leg- atypical agent). islation, such as the Child Healthcare Relief Crisis Act which aims to address the national shortage of Psychosocial interventions children‘s mental health professionals, including Psychological interventions include education, child and adolescent . family and individual therapy. Psychoeducation for the patient should include ongoing education Expert opinion about the illness, treatment options, social skills EOS, although a relatively rare disorder, has training, relapse prevention, basic life skills train- significant importance given its morbidity, ing and problem-solving strategies. Psychoedu- chronicity and psychosocial impairment. cation for the family include education about the Although the same DSM-IV criteria are used, illness, treatment options and short- and long- clinicians should be aware of differences that term prognosis. There should be a focus on help- exist between schizophrenia in youths and ful coping strategies to deal with their child’s adults as well as the greater diagnostic chal- symptoms and behavioral manifestations of the lenges of truly identifying psychotic symptoms disorder. It is important that the patient and in children. Treatment should be based on the family are told that its course is unpredictable phase of illness as well as tailored to each indi- and different for each child. vidual child and family’s characteristics and Cognitive behavioral therapy (CBT) has been needs. Psychopharmacology is best combined gaining more attention as an important compo- with different types of psychotherapy, including nent of schizophrenia treatment. In schizophre- psychoeducational and cognitive behavioral nia, CBT focuses on challenging thoughts and therapies, to optimize outcomes. Antipsychotic beliefs that surround psychotic symptoms such as agents are considered front-line therapy, with hallucinations and delusions, problem solving atypical antipsychotics being preferred over skills and increasing compliance. In adults, typical neuroleptics given their reported supe- adjunctive CBT has been found to produce large rior side effect profile in adults. However, these clinical effects on both positive and negative agents bring their own set of concerns includ- symptoms of schizophrenia [106]. In children, ing weight gain and metabolic disturbances. there have been no studies examining the out- Children and adolescents may be at even higher comes of CBT in EOS. McGorry and colleagues risk for these problems. The current treatment conducted a randomized controlled trial compar- literature for EOS is sparse, and most treatment ing risperidone and CBT against needs-based guidelines are based on adult literature. Further intervention (supportive psychotherapy, no randomized controlled trials need to be con- antipsychotic medication) in 59 patients at risk of ducted before firm conclusions regarding the progression to first-episode psychosis [107]. The efficacy and safety of antipsychotic agents in medication and CBT group showed lower rates this population can be made. www.future-drugs.com 143 REVIEW – Shannon & McClellan

Highlights Outlook The neurobiological underpinnings of EOS are • Early onset schizophrenia (EOS) has significant importance given its likely to be unraveled as the understanding of neu- morbidity, chronicity and psychosocial impairment. rodevelopment and genetics advance. EOS may be • Although the same DSM-IV criteria are used for diagnosis, several a more homogenous form of the disorder. Thus diagnostic considerations should be made within a developmental context etiologic mechanisms underlying earlier-onset when evaluating psychotic symptoms in a child. cases may be more readily identified, with discov- • Treatment should involve a multidimensional approach, including both psychopharmacology and psychotherapy, that is tailored to the phase of eries paving the way for future endeavors within illness and individual needs of child and family. other realms of . Of course, neuro- • Antipsychotic agents are considered first line agents in the treatment of biological mechanisms are only one piece of the EOS, with atypical antipsychotics preferred over typical antipsychotics puzzle and the current biopsychosocial approach given their favorable side-effect profile. However, only a few randomized will continue to be emphasized. With the sparse controlled trials have been conducted and current treatment literature is treatment data available, randomized controlled sparse in this population. trials are needed to examine the safety and efficacy of medications and psychosocial interventions in this population.

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