EVIDENCE-BASED PRACTICE Assistant Editor: John D. Hamilton, M.D., MSc.

Decision Making About Children With PsychoticSymptoms: Using the Best Evidence

in Choosing a Treatment

PHILIP SHAW, M.D., AND JUDITH L. RAPOPORT, M.D.

A school guidance counselor contacts your officeworried about an ll-year-old boy, Peter, initiallyreferred to her for declining school performance.Along with the counselor you meet with the childand his sole parent, Susan, who is a 34-year-old part­time nursery school teacher. Throughout the interview,Peter appears perplexed and frightened and is extremelyevasive, giving monosyllabic answers to nearly allquestions. His mother tells you he had rather latedevelopmental milestones and little interest in his peers,but was managing at a mainstream school with supportuntil a year ago, when he began to complain that thechildren were "really out to get me," and at times wouldappear terrified when left at the school gates. Twiceduring the past month, he has claimed that he heard agroup of"bad boys" screaming insults at him, althoughthe mother was certain there was no one else present.Despite these changes in Peter, his mother does not feelhe has been unusually sad, and although he lacks drive,he stills retains some of his interest in computer gamesand has been sleeping and eating well. He is in goodhealth and recently had a normal physical examinationby a pediatrician. In addition, the mother gives a history

Acupted May 24, 2006.Dn Shaw and Rapoport a" with the Child Psychiatry Branch. National

Imtitute ofMenial Health. Bethesda. MD.The mearch was Iupported by the Intramural Program of the National

Imtituw ofHealth.The patient dtIcribcd in tht artidt iI not based on any individual. but rathcr

rifkCII tht b"adth ofclinical expcrienu obtained during the mearch programinto childhood omet IChizoph"nia at NIMH ovcr the paIt15 yearl.

Correspondence to Dr. Philip Shaw. Child PIychiatry Branch. NationalImtitute ofMental Health, Bldg. 10, 3N202, Bethesda, MD 20932-1600;t-mail: Ihawp@mail.nih.gov.

0890-8567/06/4511-1381©2006 by the American Academy of Childand Adolescent Psychiatry.

001: 10. J097/0I.chL0000228128.72203.3e

of bipolar affective disorder in her brother and statesthat Peter's biological father had a psychotic episodeshortly before he left the family. What is the likelydifferential diagnosis?

Peter presents with brief self-limited hallucinationsand persecutory ideation (if not frank delusions) on abackground of a gradual deterioration in overallfunctioning. Affective symptoms are not prominent,and there is little to suggest an organic contribution.This raises the possibility that Peter has, or is on theverge of developing, a psychotic disorder, perhapschildhood-onset schizophrenia (COS), defined by thepresence of symptoms before the 13th birthday.Although this must be considered in the differential,it is important to remember that COS is extremely rare.For example, a Canadian study of diagnoses on drugprescriptions indicates that the rate of schirophrenia atan age younger than 15 is 1I50th the rate in adults(Beitchman, 1985). A study of hospital admissions of312 psychotic youth during a 13-year period inDenmark found only 4 patients were younger than13 years (Thomsen, 1996).

The National Institute of Mental Health (NIMH) Cohort

Our experience at the NIMH would indicate that95% of 1,500 children referred because of a high clinicalsuspicion of COS did not meet unmodified DSM-IVcriteria for schizophrenia. By far the most common finaldiagnosis, reached after inpatient observation off allmedication, was a mood disorder. Hallucinations arerelatively common in pediatric bipolar disorder andmajor depression (Chambers et aI., 1982; Varanka et aI.,1988). However, the psychotic symptoms in theseconditions tend to be mood congruent, and follow-upstudies on this population generally suggest a stable

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SHAW AND RAPOPORT

clinical outcome (Garralda, 1984b; McClellan andMcCurry, 1999; McClellan et al., 1999; Ulloa et al.,2000). Such results support the adage that an atypicalpresentation ofa common disorder is more likely than atypical presentation of an extremely rare illness.

Atypical psychosis, usually classified as psychosis nototherwise specified, is another common diagnosis. NIMHresearchers have used the term multidimensionally impairedto capture the mix of stress-related transient episodes ofpsychosis, emotional lability, impaired interpersonal skills,and information-processing deficits that these childrenexhibit (Frazier et al., 1994; Kumra et al., 1998). Pervasivedevelopmental disorders and childhood disintegrativedisorder can often be mistaken for psychosis becausethey show severe impairment in reciprocal communica­tion, social interactions, and odd stereotyped behaviors.Finally, rarely conduct disorder and various otherbehavioral disturbances can be associated with hallucina­tions (Garralda, 1984a, b)

PETER AT RISK

You meet with Peter several times, and his mentalstate remains unchanged over a month. His mother isextremely worried that he is "becoming psychotic likemy brother" and asks your opinion as to how likely it isthat he is developing schizophrenia. She also askswhether there are any medications that might help.

Peter thus certainly fits the profile of a child atultrahigh risk of developing psychosis, and this raisesthe difficult question of how to manage and possiblytreat him. Treatment may be justified because theprodromal or prepsychotic state is itself problematic forPeter, and interfering with his progress at school. Inaddition, there is the hope that treatment at this stagemay avert psychosis entirely; the evidence of this isconsidered below. Weighed against intervention areseveral ethical and pragmatic concerns. First, even thebest current criteria of ultrahigh risk are far from perfectand carry a high rate of false positives. Thus, manysubjects will be potentially exposed to medications orother treatments without any clear evidence that theywould have developed psychosis ifleft untreated. Second,intervention entails contact with psychiatric services andthe label of being at risk of developing psychosis, both ofwhich are likely to carry some social stigma.

To evaluate the evidence that treatment at this stagecan avert psychosis entirely, you decide to look at theliterature. You do a search on the open-access database

PubMed using the terms "high risk AND psychosis" andlimit the search to randomized, controlled trials. You get17 hits and find rwo papers that look relevant (McGorryet al., 2002; Morrison et al., 2004). You are puzzled atfinding so few reports and so search again with the terms"prodrome AND schizophrenia," again limiting thesearch to randomized, controlled trials. This gives youone more clearly relevant study (Woods et al., 2003).Final searches using other combinations of your keyterms (psychosis, schizophrenia, high risk, prodrome)yield no more trials except a descriptive summary of anongoing trial in Germany, but the reponing is notcomplete (Ruhrmann et al., 2005). Also, there are reportsfrom the New York High Risk Project and HillsideRecognition and Prevention Program that you haveheard a lot about (Cornblatt, 2002), but the pharmaco­logical studies are not controlled.

You decide to start with the randomized, controlledtrials as the evidence with the least bias. You summarizethe studies (Table 1) and prepare to discuss the evidencewith Peter and his mother: There is good evidence fromthe available studies that low-dose antipsychotics andcognitive therapy may reduce the intensity of theprodromal psychotic symptoms. Whether the interven­tions also decrease the risk ofprogression to full psychosisis less clear. On the basis ofthe raw figures, there seem tobe striking reductions in the rate of transition topsychosis. Yet, given the small numbers in the trials,these results often do not reach significance. Also, it is notclear how long benefits are sustained, and side effects, likeweight gain with the olanzapine group, need to beconsidered. You also mention to Peter's mother that fewof these studies have included patients as young as Peter.

CHOOSING PETER'S TREATMENT

You and his mother, with Peter's assent, decidetogether that medication is not the best choice andchoose to monitor his mental state closely whilearranging additional support at school. He remainsabout the same with this plan for many months, butthen shows a rapid decline in mental state shortly beforehis 13th birthday: Peter describes a constant voice of aboy insulting him and increasingly complex delusionsabout persecution from other children orchestrated byteachers at his school. There is now little doubt thatPeter has a psychotic illness and would meet criteria fora schizophreniform disorder (and may well eventuallymeet criteria for schizophrenia).

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EVIDENCE-BASED PRACTICE

Evidence of treatment of first-episode psychosis inchildren includes only one randomized, double-blindtrial comparing outcomes in children treated witholanzapine, risperidone, and haloperidol (Sikich et al.,2004). This 8-week study included 75 children andadolescents with psychotic symptoms stemming from awide range of underlying diagnoses. All three treatmentswere associated with significant reductions in the totalsymptom scores at baseline (using the Brief PsychiatricRating Scale for Children) of 50% for risperidone, 44%for olanzapine, and 67% for haloperidol. The categoricalresponse rates, like most outcome measures, did not

differ significantly, but there was a trend to betterresponse for the atypicals: 74% (14/19) with risperidone,88% (14/16) with olanzapine, and 53% (8/15) withhaloperidol. The findings of the study are congruent withthose of an 8-week, open-label, unrandomized compar­ison of olanzapine, risperidone, and haloperidol in 43adolescents with schizophrenia that found all three agentswere equally efficacious (Gothelf et al., 2003).

Although the study by Sikich and colleagues providesperhaps the best evidence of the treatment of psychosisin adolescents. two factors limit its applicability to Peter.First, the study included a diagnostically heterogeneous

TABLE 1Randomized Trials of Interventions for Patients at High Risk of Developing Psychosis

Srudy Interventions NOutcome Is this relevant ro Perer?Measures Results Is this imporrant for Peter?

10/29 placebo vs. 5/31olanzapine developedpsychosis: significant groupdifference at 8 wk using linearmixed-models analyses (detecrsdifference in rate of change)

2/35 in CT developed psychosisvs. 5/23 in TAU: low overallrate of transition to psychosis(12%); 96% reduction in oddsof making a rransition copsychotic in CT group (afreradjustment for potentialmoderating variables)

Developmentof psychosis(using Scaleof ProdromalSympcoms)

Developmentof definitepsychoticsympcoms(based onPANSS)

Development 10/28 in NBI developed psychosis at Outcome was any form ofof definite 6 mo vs. 3/31 in SNI: patienrs who psychosis, nor just sehizo-psychotic were fully adherent co risperidone phrenia: subjects were oldersymptoms had lower rare of developmenr of than Peter (14-30 yr); only(based on psychosis (2/14 vs. 7/17); difference 14 participants were fullyPANSS) not susrained at 12 mo adherent to antipsychotic

rreatment, so numbets arcsmall; no teporting on ad­verse side effects; unclearwhether it was medication,CBT, or both that wereeffective in me shoH term;unclear what the CBTinvolved; 74% of subjectsenrolled in rrial did notrransirion co psychosis

Ourcome was any form ofpsychosis not just schizo­phrenia; excluded subjects<16 yr; unclear whichcomponent of CBT wastherapeuric; CI for thereducrion in odds are large,so there may nor be muchreduction at all; 88% ofsubjeclS enrolled in rrial didnot rransition co psychosis

Outcome was any form ofpsychosis not just schizo­phrenia: included subjects> 12 yr; no data on ourcomeafter 8 wk; marked weighrgain in olanzapinewing (10 Ib)

58

60

59

Placebo vs.olanzapine(double blind)

TAU vs. cr(single blind)

Needs based interventionvs. specific preventiveintervention (risperidone1.3 mg/day and CBT;single blind)

Morrison et aI.,2004

Woods et aI.,2003

McGorry et aI.,2002

Nott: CBT =cognitive behavioral therapy; PANSS =positive and negative syndrome scale; SNI =specific needs intervention; NBI =needsbased intervention: TAU =treatment as usual: CT =cognitive therapy.

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SHAW AND RAPOPORT

group, and only half of the subjects had a diagnosis of aschizophrenia specrrum disorder. Second, a large propor­tion of youths in the study were receiving other psy­chotropic medications and may have had some degree oftreatment resistance. Despite these caveats, it is likely thatthe atypical antipsychotics olanzapine and risperidone areat least as effective as typicals, such as haloperidol, and areappropriate as first-line agents in the trearrnent of COS.

As you try a wide range of medications with Peter,there are problems. Haloperidol is oversedating;olanzapine is excellent in abating symptoms but hegains 8 kg and refuses co continue taking the drug; andrisperidone, quetiapine, and low-dose perphenazine areineffective despite more than adequate trials over aperiod of 3 months each. What are the remainingtreatment options? Given the malignant course of veryearly onset schizophrenia, such a scenario is sadly notunusual. In adult-onset schizophrenia, most but not allmeta-analyses suggest that dozapine is more efficaciousthan typical and possibly mOSt atypical antipsychoticsin the short-term treatment of patients who aretreatment resistant (Davis ct al., 2003; Geddes et al.,2000; Leucht et aI., 2003; Moncrieff, 2003). Is this truefor very early onset schizophrenia also?

You do a literature search again using PubMed andentering the terms "childhood schizophrenia ANDdozapine' with the limit of "randomized controlledtrial." This gives you three hits, and the first refers to adouble-blind comparison of haloperidol and dozapine(Kumra et al., 1996). This NIMH study randomized 21children fot 6 weeks of treatment and found dozapine to

0.8+---

0.6+--­Effect size

0.4 +---

0.2+---

be markedly superior on all components of the BriefPsychiatric Symptom Scale and overall ratings ofdinicalimprovement, a striking finding given the small sampleand the severity of illness at baseline. The mean dose ofhaloperidol used was 16.8 mg/day, which is at the upperend of the contemporary treatment range. This studydid not find a significant increase from baseline in eitherarm in the rates of extrapyramidal side effects, whereasmost other studies find rates of between 58% and 80%in patients with COS treated with typical antipsychoticssuch as haloperidol (Engelhardt et aI., 1973; Pool et al.,1976; Spencer et al., 1992).

Knowing that the NIMH is studying childhoodschizophrenia and thinking Peter may benefit from andcontribute to the study, you quickly find their Internetsite and call. While talking about Peter with the intakeresearch social worker, you discover the NIMH grouphas recently completed a direct comparison of olanza­pine, one of the most widely used atypical agents, withdozapine. In a double-blind randomized, controlled,8-week trial, 25 patients with COS were randomized(12 to dozapine and 13 co olanzapine). Using intent-co­treat analyses, dozapine was associated with a significantreduction in all outcome measures, with olanzapineshowing a rather less impressive improvement, as shownin Figure 1 (Shaw et al., 2006).

A direct comparison of rrearrnent efficacy showed thatfor most measures there was no significant difference be­tween the groups. The only exception was in the alle­viation of negative symptoms of schizophrenia, withdozapine producing a 45% greater reduction in the

SANS CGl-S SAPS BPRS­24

Outcome measureFig. 1 A visual summary ofdata comp<lring dozapine to olanzapine in reducing symptoms in childhood-onset schiwphrenia ftom an antipsychotic-free baseline.

The effect size is calculated by comparing the change scores in each oUtcome measute associated with dozapine and olanzapine. An effect size of~.8 indicates that the

supetiority ofdozapine over olanzapine is large; an effect size between 0.5 and 0.8 indicates moderue superiority fordozapine. and between 0.2 and 0.5. a minimalsuperiority for dozapine. Olanzapine W<lS not associated with greater improvement in any of these outcome measures. SANS =Scale of Negalive Symptoms; CGI-S =Oinical Global Impressions-Severity score; SAPS = Scale of Positive Symptoms; BPRS-24 = Brief Psychiatric Symptom Scale. 24-item version.

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Scale for the Assessment ofNegative Symptoms from anantipsychotic-free baseline (p = .04; effect size, 0.89).The size of the differential effect on negative symptomsis thus large and stands in marked contrast to studies ofadults with schizophrenia that report no significantdifference between olanzapine and clozapine in treatingnegative symptoms, despite a larger sample size andpower to detect smaller effects (Bitter et al., 2004;Tollefson et al., 2001; Volavka et al., 2002). Unfortu­nately, clozapine was also associated with significantlymore overall side effects including hypertension, tachy­cardia, and enuresis. Both treatments were associatedwith substantial weight gain of 4 kg. The double-blindstudies are complemented by uncontrolled studiesshowing good clinical response to clozapine in youthwith COS who have not responded to other anti­psychotics (Frazier et al., 1994; Turetz et aI., 1997).

Overall, the evidence from the NIMH studiescertainly suggests clozapine is superior to haloperidolfor patients like Peter who have either failed otherantipsychotics or developed intolerable side effects.There is evidence for superiority of clozapine overolanzapine with a general pattern of superior clinicalresponse for clozapine, which needs to be balancedagainst its increased side effects.

Attention to psychosocial factors that may contributeto his lack of response to treatment is also important,especially the level of expressed emotion within thefamily (indexed by degree of criticism, hostility, andoverinvolvement). Behavioral family therapy is oftenhighly effective in reducing the level of such expressedemotion and in adult-onset schizophrenia has been foundto reduce the rates of relapse (Pharoah et aI., 2003).

Given these data, you and his mother choose treatmentwith clozapine. Peter has an excellent response, withresolution of his positive symptoms and a markedincrease in his level ofmotivation. Unfortunately, he alsodevelops a range of side effects, including drooling and amarked weight gain of6 kg. On a positive note, Peter hasnot developed some of the other side effects associatedwith clozapine such as neutropenia or seizures, problemswith glucose regulation, including diabetes mellitus, ormyocarditis. You manage his hypersalivation with a lowdose of an anticholinergic. You find that there is someevidence for managing weight gain associated withclozapine through behavioral techniques, and refer Peterto a dietician and physical therapist who has experiencein this area (Faulkner et al., 2003).

EVIDENCE-BASED PRACTICE

Such a severe and complex disorder as childhoodschizophrenia is well served by an approach based onevidence with the least bias. Although patients such asPeter present complex treatment issues, in our experi­ence, a multidisciplinary team approach, which matchesoptimal pharmacotherapy with attention to educationalneeds and the family environment, is a highly effectiveintervention that can ameliorate the course of thisdevastating illness.

Disclosure: The authors have no financial relationships to disclose.

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