AACAP OFFICIAL ACTION
Practice Parameter for the Assessment and Treatment of Children and Adolescents With Schizophrenia
Jon McClellan, M.D., Saundra Stock, M.D., AND the American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI)
This Practice Parameter reviews the literature on the assessment and treatment of children and adolescents with schizophrenia. Early-onset schizophrenia is diagnosed using the same criteriaas in adults and appears to be continuous with the adult form of the disorder. Clinical standards suggest that effective treatment includes antipsychotic medications combined with psychoeducational, psychotherapeutic, and educational interventions. Since this Practice Parameter was last published in 2001, several controlled trials of atypical antipsychotic agents for early-onset schizophrenia have been conducted. However, studies suggest that many youth with early-onset schizophrenia do not respond adequately to available agents and are vulnerable to adverse events, particularly metabolic side effects. Further research is needed to develop more effective and safer treatments. J. Am. Acad. Child Adolesc. Psychiatry, 2013;52(9):976–990. Key Words: schizophrenia, psychosis
chizophrenia portends substantial morbidity In PubMed, the search strategy from the S and suffering to those afflicted and their Cochrane Review Group on schizophrenia was families. Schizophrenia spectrum disorders used (see below), yielding 282,328 results. This was often first present during adolescence and rarely in refined to reflect treatment studies and reviews childhood. Since the last Practice Parameter for the with limits for ages 0 to 18 years and English Assessment and Treatment of Children and language applied, resulting in 3,662 articles. Search Adolescents with Schizophrenia was published,1 in CINAHL yielded an additional 55 articles, Web knowledge of this topic has increased substan- of Science 214 articles, and PsycInfo 24 articles. Once tially. This revised version of the parameter presents duplicates were removed, there were 3,186 articles. the most up-to-date research findings and clinical The titles and abstracts of these articles were standards regarding the assessment and treatment reviewed. Many studies identified in the search of this disorder. were conducted in a primarily adult population with only a few adolescent subjects. Articles with a METHODOLOGY focus on early-onset schizophrenia (EOS) treatment Earlier versions of this parameter were published (87) were prioritized for inclusion. Additional in 1994 and 2001. The most recent literature search selection criteria were based on the study’sweight covered a 5-year period (January 2004 through in the hierarchy of evidence (e.g., randomized August 2010) using PubMed, PsycInfo (Ovid), controlled trials), attending to the quality of indi- CINAHL (EBSCO), and Web of Science databases. vidual studies and the generalizability to clinical The initial searches were inclusive and sensitive for practice. The search was augmented by review of PubMed using a combination of MeSH headings articles published before 2004, those nominated by and key words. The search was adjusted for expert review, those recently accepted for publica- CINAHL and PsycInfo by “translating,” where tion in peer-reviewed journals, and those pertaining necessary, from the MeSH thesaurus to the to adult-onset schizophrenia treatment. CINAHL and PsycInfo thesauri, and using the Search terms (this search statement was same key words. The Web of Science search also modeled after the Cochrane Review Group on was adjusted because this database responds only Schizophrenia Specialised Register search strate- to key-word searching. gies originally designed for the OVID database,
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY 976 www.jaacap.org VOLUME 52 NUMBER 9 SEPTEMBER 2013 AACAP OFFICIAL ACTION
adjusted to work in the PubMed database): aka- depressive illness and dementia praecox.5 Bleu- thisia OR neuroleptic OR neuroleptics OR neuro- ler substituted the term schizophrenia (splitting of leptic* OR parkinsonian* OR psychoses OR the mind) for dementia praecox,6 given the obser- psychotic OR psychosis OR schizoaffective OR vation that the illness was not associated with schizophren* OR tardive OR “childhood onset dementia, but rather with the loss of association schizophrenia” OR “early onset schizophrenia” OR of thought processes and the disruption of ((chronic OR paranoid) AND schizophren*) OR thought, emotions, and behavior.7 “Akathisia, Drug-Induced” [MeSH] OR “Dyski- The original descriptions of the disorder nesia, Drug-Induced” [MeSH] OR “Psychoses, recognized a typical pattern of onset during Substance-Induced” [MeSH] OR (“Antipsychotic adolescence and young adulthood, with reports Agents” [MeSH] OR “Catatonia” [MeSH]) OR of rare cases in children. However, beginning “Neuroleptic Malignant Syndrome” [MeSH] OR with the works of Bender, Kanner, and others,8 “Parkinsonian Disorders” [MeSH] OR “Schizo- the concept of childhood schizophrenia was phrenia and Disorders with Psychotic Features” broadened to include syndromes defined by de- [MeSH] OR “Schizophrenia, Childhood”[MeSH]. velopmental lags in the maturation of language, perception, and motility (which also included 9 DEFINITIONS infantile autism). Hallucinations and delusions were not required criteria. This nosology was EOS is defined as onset before 18 years of age. adopted by the DSM-II. As a result, the childhood Onset before 13 years of age is often described as schizophrenia literature from this period overlaps childhood-onset schizophrenia (COS). The diag- with that of autism and other pervasive devel- nosis of schizophrenia in children and adoles- opmental disorders. cents is made using the same criteria as in adults, Seminal work by Kolvin10 and Rutter11 estab- following the criteria outlined by the DSM-52 or International Classification of Diseases, 10th Revi- lished the distinctiveness of the various child- hood psychoses and the similarity between child sion.3 The DSM-5 requires that two or more and adult schizophrenia. Therefore, beginning characteristic symptoms, i.e., hallucinations, with the DSM-III, the diagnosis of schizophrenia delusions, disorganized speech, disorganized or in youth has been made using the same criteria as catatonic behavior, and/or negative symptoms, for adults, regardless of age of onset. Subsequent must be present for at least 1 month (or shorter if research has generally validated this decision. successfully treated). During this active phase, hallucinations, delusions, or disorganized speech must be present. Evidence of the disorder must be EPIDEMIOLOGY present for at least 6 months and must be asso- The worldwide prevalence of schizophrenia is ciated with a significant decline in social or generally held to be approximately 1%, with occupational functioning. In children and some variation noted across studies and pop- adolescents, decline in function may include the ulations. The male-to-female ratio is approxi- failure to achieve age-appropriate levels of inter- mately 1.4 to 1.12 personal or academic development. The Interna- The prevalence of EOS has not been tional Classification of Diseases, 10th Revision adequately studied. Onset before 13 years of age diagnostic criteria are similar to the DSM-5 appears to be quite rare. The rate of onset then criteria except that the total duration of illness increases during adolescence, with the peak ages required is at least 1 month. of onset for the disorder ranging from 15 to 30 Schizophrenia as defined by the DSM-5 differs years. EOS tends to occur more often in male from the DSM-IV-TR4 by the following: delusions, individuals. As age increases, this ratio tends to hallucinations, or disorganized speech are required even out. The diagnostic validity of schizophrenia for diagnosis and commenting and conversing in young children, e.g., younger than 6 years, has hallucinations and bizarre delusions are no not been established. longer accorded special diagnostic status. CLINICAL PRESENTATION BRIEF HISTORY Psychosis is defined as the severe disruption of Descriptions of madness and insanity date to thought and behavior resulting in the loss of antiquity. In the early 20th century, Kraeplin reality testing. The diagnosis of psychosis is characterized two forms of insanity, manic- based on overt changes in a person’s behavior
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 9 SEPTEMBER 2013 www.jaacap.org 977 AACAP OFFICIAL ACTION
and functioning, with evidence of disrupted working memory, attention, and processing thinking evident on mental status examination.13 speed.27 Cognitive decline typically occurs at the Although psychotic symptoms are characteristic time of onset of illness. Once established, intel- of schizophrenia, psychosis may present with lectual deficits appear to be stable over time other illnesses, including mood disorders, neu- without continued deterioration.28 These findings rologic conditions, and acute intoxication. are consistent with those in the adult literature. The diagnostic assessment of schizophrenia in youth presents unique developmental concerns. Premorbid Functioning Misdiagnosis is common, particularly at time of Premorbid abnormalities are evident in most 14-17 onset. Conditions often misdiagnosed as youth who develop schizophrenia, especially schizophrenia in youth include bipolar disorder those with COS.29 Common premorbid difficul- 17,18 and other psychotic mood disorders, person- ties include social withdrawal and isolation, 19 20 ality disorders, obsessive-compulsive disorder, disruptive behavior disorders, academic difficul- 16 and developmental syndromes. Comprehensive ties, speech and language problems, and cogni- diagnostic assessments, which reconcile mental tive delays. Because schizophrenia in youth often fi status ndings with the rigorous application of has an insidious onset, the gradual development 14,21 diagnostic criteria, help improve accuracy. of psychotic symptoms in a child with premorbid Most children who report hallucinations do language delays and social withdrawal can be not meet criteria for schizophrenia, and many do difficult to recognize. 22,23 not have a psychotic illness. Normative child- Predicting which youth with premorbid char- hood experiences, including overactive imagina- acteristics of schizophrenia will eventually de- tions and vivid fantasies, can be misinterpreted as velop the disorder remains a challenge. Factors in psychosis. Distinguishing formal thought disorder high-risk youth that predict progression into the from developmental disorders that impair speech illness include familial risk for schizophrenia plus 24 and language function can be a challenge. a recent deterioration in functioning; unusual, Expertise in childhood psychopathology and suspicious, or paranoid thought content; greater experience in assessing reports of psychotic social impairment; and/or a history of substance symptoms in youth are important prerequisite abuse.30 skills for clinicians evaluating youth for possible psychosis. ETIOLOGY Symptomatology Schizophrenia is a heterogeneous disorder with Schizophrenia is characterized by positive and multiple etiologies. To date, no single set of causes fi negative symptoms. Positive symptoms refer to has been identi ed. Current evidence suggests hallucinations, delusions, and thought disorder. that a multifactorial neurodevelopmental model Negative symptoms are those of deficits, i.e., flat best explains the development of schizophrenia, affect, anergy, and paucity of speech or thought. with multiple genetic and environmental expo- 31 Disorganized behavior may represent an inde- sures playing roles. Neurobiological research pendent third domain, including disorganized suggests that EOS and adult-onset schizophrenia speech (e.g., incoherence, looseness of associa- share etiologic factors, although EOS may be 32,33 tions), bizarre behavior, and poor attention.4 a more severe form. Hallucinations, thought disorder, and flattened affect have been consistently found in EOS, Genetic Factors whereas systematic delusions and catatonic Family, twin, and adoption studies support symptoms occur less frequently.25 Developmental a strong genetic component for schizophrenia. variation in language and cognition may affect the The lifetime risk of developing the illness is 5 to range and quality of symptom presentation. 20 times higher in first-degree relatives of affected probands compared with the general population. Cognitive Delays The rate of concordance between monozygotic Cognitive delays are common with EOS.26 Defi- twins is approximately 40% to 60%. Concordance cits in memory, executive functioning, attention, rates in dizygotic twins and other siblings are and global impairments are generally noted. 5% to 15%.34 Genomewide association studies, Children who later develop schizophrenia often using large collaborative international cohorts, have premorbid problems with verbal reasoning, have published findings implicating different
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY 978 www.jaacap.org VOLUME 52 NUMBER 9 SEPTEMBER 2013 AACAP OFFICIAL ACTION
genomic loci and genes, including the major similar to the adult regional pattern.56,57 Structural histocompatibility complex (6p21.1), MIR137, and brain findings found in EOS are theorized to stem ZNF804a.35,36 For EOS, positive associations have from the disruption of neurodevelopmental pro- been reported for several candidate genes, in- cesses emerging during adolescence.58 In the cluding those reported in the adult literature.37 National Institute of Mental Health COS cohort, Emerging evidence shows that rare deletions unaffected siblings of patients shared similar and duplications are enriched in individuals with patterns of cortical deficits, suggesting these are schizophrenia.38-42 Structural mutations arising at familial traits with variable impact on disease genomic “hotspots,” including 1q21.1, 15q13.3, risk.59,60 and 22q11.2, may be responsible for 0.5% to 1.0% of cases. EOS appears to be associated with Psychological and Social Factors a higher rate of large cytogenetic abnormalities 37 There is no evidence that psychological or social and rare structural variants than reported in factors cause schizophrenia. Rather, environ- adults with the illness. These include 22q11.2 43 mental factors may potentially interact with bio- deletion syndrome (velocardiofacial syndrome), logic risk factors to mediate the timing of onset, which is associated with substantial rates of course, and severity of the disorder.61 Psychoso- behavioral, cognitive, and psychiatric problems, cial factors, including expressed emotion within including psychosis. Most rare copy number the family setting, influence the onset and/or errors detected in affected persons are found at exacerbation of acute episodes and relapse rates. different genetic loci, and many are unique to one These interactions are complex and bidirectional. individual or family. Thus, the emerging research Being raised in a healthy home environment may suggests that most affected persons have a be protective for children with a familial risk for different genetic cause, which has important schizophrenia.62 Alternatively, the presence of implications for intervention and translational fi 44 dif cult family interactions may not be causal, research. but rather a reaction to the collection of difficul- ties the patient brings to the family setting. Environmental Exposures Genetic and environmental factors interact to shape neurodevelopmental processes, affecting COURSE AND OUTCOME disease risk and progression.45 Environmental The course of schizophrenia varies across indi- exposures may mediate disease risk by different viduals. There are hallmark phases that are mechanisms, including direct neurologic damage, important to recognize when making diagnostic gene-by-environment interactions, epigenetic ef- and therapeutic decisions. fects, and/or de novo mutations.46 Numerous Prodrome. Most patients experience some environmental factors have been hypothesized to degree of functional deterioration before the contribute to the development of schizophrenia, onset of psychotic symptoms, including social including in utero exposure to maternal famine, withdrawal and isolation, idiosyncratic or bizarre paternal age, prenatal infections, obstetric com- preoccupations, unusual behaviors, academic plications, marijuana use, and immigration.47 failure, deteriorating self-care skills, and/or dysphoria. These changes may be associated with Neuroanatomic Abnormalities depression, anxiety, aggressive behaviors, or Structural brain aberrations most consistently re- other conduct problems, including substance ported in adults with schizophrenia include abuse, which often confuse the diagnostic picture. increased lateral ventricle volumes and decreases The prodromal phase may vary from an acute in hippocampus, thalamus, and frontal lobe marked change in behavior to a chronic insidious volumes.48 EOS is associated with similar abnor- deterioration. malities,49,50 with limbic structures appearing to Acute Phase. The acute phase is marked by play a particularly important role.51 Youth with prominent positive symptoms (i.e., hallucinations, EOS exhibit significant decreases in gray matter delusions, disorganized speech and behavior) and volumes52,53 and decreased cortical folding.54 asignificant deterioration in functioning. This Cortical abnormalities appear to be most pro- phase may last several months depending in part found in COS.55 Follow-up longitudinal studies on the response to treatment. have shown that cortical thinning in COS may Recuperative/Recovery Phase. After the acute plateau in early adulthood, when it becomes phase, with the remission of the acute psychosis,
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 9 SEPTEMBER 2013 www.jaacap.org 979 AACAP OFFICIAL ACTION
there is generally a several-month period when rare in youth, especially in children younger than the patient continues to experience a significant 12 years. The accurate diagnosis of schizophrenia degree of impairment. Negative symptoms (flat and other psychotic illnesses should be based affect, anergia, social withdrawal) predominate, on characteristic patterns of illness and overt although some positive symptoms may persist. In signs on the mental status examination. Clinical addition, some patients will develop a post- features that help confirm a diagnosis of schizo- psychosis depression characterized by dysphoria. phrenia include deteriorating function, thought Residual Phase. Youth with EOS may have pro- disorder, and bizarre behavior. There are several longed periods (several months or more) between important diagnoses to rule out when assessing acute phases when they do not experience signifi- a youth for schizophrenia. cant positive symptoms. However, most patients will continue to be at least somewhat impaired Medical Conditions owing to negative symptoms. Unfortunately, The list of medical conditions that can result in some affected individuals never progress to psychosis is exhaustive, including central nervous residual symptoms and remain chronically system infections, delirium, neoplasms, endocrine symptomatic despite adequate treatment. disorders, genetic syndromes (e.g., velocardiofacial [22q11] syndrome), autoimmune disorders, and Outcome toxic exposures. Follow-up studies of EOS, spanning periods up to Drugs of abuse that can result in psychotic several decades, have suggested moderate to symptoms include dextromethorphan, lysergic severe impairment across the lifespan.25 Poor acid diethylamide, hallucinogenic mushrooms, long-term outcome is predicted by low premorbid psilocybin, peyote, cannabis, stimulants, and functioning, insidious onset, higher rates of inhalants. Prescription drugs associated with negative symptoms, childhood onset, and low psychosis, especially when used inappropriately, intellectual functioning.15,63-67 When followed include corticosteroids, anesthetics, anticholiner- into adulthood, youth with EOS have shown gics, antihistamines, and amphetamines. Typi- greater social deficits, lower levels of employment, cally, acute psychosis secondary to intoxication and a lower likelihood to live independently resolves within days to weeks once the offending compared with those with other childhood-onset drug is discontinued. 67,68 Adolescents with EOS appear to be at substan- psychotic disorders. 72 Suicidality is prevalent in youth with schizo- tial risk for comorbid substance abuse. Cannabis 69 use in teenagers is associated with a higher risk of phrenia spectrum disorders. In follow-up stud- 73 ies, at least 5% of individuals with EOS died by eventually developing psychosis. When drug completed suicide or by accidental death directly abuse precedes the development of schizophrenia, fi because of behaviors influenced by psychotic it is dif cult to gauge whether the psychosis thinking.17,70 As adults, individuals with schizo- represents independent drug effects or the phrenia are at higher risk of other morbidities, such unmasking of the underlying illness in an indi- as heart disease, obesity, human immunodefi- vidual with other neurobiological vulnerabilities. ciency virus, hepatitis, and diabetes.71 Schizoaffective Disorder By definition, schizoaffective disorder requires DIFFERENTIAL DIAGNOSIS the presence of psychotic symptoms plus prom- The effective treatment of schizophrenia relies on inent mood episodes (meeting full criteria for an accurate diagnosis and a thorough assessment mania or depression) that are present for to identify any other contributing medical or a substantial duration of the illness. The DSM-5 psychiatric conditions and/or psychosocial emphasizes the requirement of a full mood stressors. The proper assessment of psychosis in episode, which should be present for the majority youth requires the gauging of potential symptom of the total duration of the active and residual reports in the context of normal development. portions of the illness. These are important The mere fact that a child responds affirmatively distinctions because mood symptoms, such as to questions regarding hallucinations or delu- dysphoria, irritability, or grandiosity, are com- sions does not ipso facto mean the child is mon in individuals with schizophrenia, and the psychotic. Psychotic symptoms occur in the reliability of the diagnosis of schizoaffective context of an illness, and psychotic illnesses are disorder in clinical settings has been poor.
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY 980 www.jaacap.org VOLUME 52 NUMBER 9 SEPTEMBER 2013 AACAP OFFICIAL ACTION
Youth with schizoaffective disorder present Pervasive Developmental Disorders/Autism with the same severity of psychotic symptoms Autism and pervasive developmental disorders and functional impairment as those with schizo- are distinguished from schizophrenia by the phrenia.74 The stability of early-onset schizo- absence of psychotic symptoms and by the affective disorder as a diagnosis appears to vary predominance of the characteristic deviant over time and can be difficult to distinguish from language patterns, aberrant social relatedness, or schizophrenia.15,21 repetitive behaviors. The younger age of onset and the absence of a normal period of develop- Affective Psychosis ment are also indicative. The premorbid abnor- Psychotic mood disorders (especially bipolar malities in EOS tend to be less pervasive and disorder) can present with different affective and severe than those with autism.10,11 psychotic symptoms. Full-blown mania in teen- Youth with schizophrenia often have pre- agers often presents with florid psychosis, in- morbid and/or comorbid problems with social cluding hallucinations, delusions, and thought oddities and aloofness, which may be character- disorder.75 Psychotic depression may present ized as autism spectrum disorders.85 These with mood congruent or incongruent hallucina- symptoms are likely nonspecific markers of dis- tions or delusions.76 rupted brain development86 and may reflect Alternatively, symptoms of schizophrenia, potential shared etiologic mechanisms that are such as negative symptoms, may be confused common to both syndromes.85 Once psychotic with a mood disorder. The overlap in symptoms symptoms become apparent, the diagnosis of increases the likelihood of misdiagnosis. Longi- schizophrenia takes precedence. tudinal reassessment is needed to ensure diag- nostic accuracy. EVIDENCE BASE FOR PRACTICE Atypical Reports of Psychotic Symptoms PARAMETERS Many children and adolescents report symptoms In this parameter, recommendations for best suggestive of hallucinations and delusions, yet do assessment and treatment practices are stated in not present with overt evidence of psychosis.22,23,77 accordance with the strength of the underlying In an epidemiologic survey, questions regarding empirical and/or clinical support. possible psychotic symptoms had a high rate of false-positive results.78 Reports suggestive of Clinical Standard [CS] is applied to recom- psychosis in children may stem from overactive mendations that are based on rigorous empir- imaginations, cognitive limitations, or simply ical evidence (e.g., meta-analyses, systematic misunderstanding the question. reviews, individual randomized controlled Youth diagnosed with posttraumatic stress trials) and/or overwhelming clinical consensus disorder, conduct problems, and/or depression Clinical Guideline [CG] is applied to recom- have been found to report significantly higher rates mendations that are based on strong empirical of psychotic-like symptoms than controls.22,23,77 evidence (e.g., nonrandomized controlled trials, Maltreated youth are particularly vulnerable to cohort studies, case-control studies) and/or report such symptoms, which may represent strong clinical consensus dissociation and/or anxiety, including intrusive Clinical Option [OP] is applied to recommen- thoughts/worries, derealization, or depersonal- dations that are based on emerging empirical ization.15,79-81 Individuals with childhood abuse evidence (e.g., uncontrolled trials or case histories are at greater risk for being diagnosed series/reports) or clinical opinion, but lack with psychotic illnesses as adults.82,83 Of course, strong empirical evidence and/or strong clin- individuals with schizophrenia may have signifi- ical consensus cant histories of trauma. A trauma history neither Not Endorsed [NE] is applied to practices that establishes nor rules out a schizophrenia spectrum are known to be ineffective or contraindicated disorder. The clinical task is to determine the The strength of the empirical evidence is rated nature of symptom reports to make an accurate in descending order as follows: diagnostic assessment. Differentiating trauma- related symptoms from true psychosis can be Randomized, Controlled Trial [rct] is applied to particularly challenging, yet has important impli- studies in which subjects are randomly as- cations for treatment and diagnostic specificity.84 signed to two or more treatment conditions
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 52 NUMBER 9 SEPTEMBER 2013 www.jaacap.org 981 AACAP OFFICIAL ACTION