Childhood Onset Schizophrenia and other Psychotic Disorders, and Substance Abuse Disorder

Childhood Onset Schizophrenia And Other Psychotic DisordersAnne Cristine D. Guevarra, MDChild Psychiatry Rotator

Children and adolescents experience the same range and types of psychotic symptoms as do adults. They can lose the connections between their thoughts (formal thought disorder) and have perceptions without external stimuli (hallucinations).

Psychosis Mental life has been disrupted in its capacities or forms, as a result of a process that generates new forms of psychological experience.McHugh PR, Slavney PR. The perspectives of psychiatry. Baltimore:Johns Hopkins University Press, 1998.The appearance of psychotic symptoms in childhood, albeit rare, is an important clinical entity. This importance extends beyond their clinical prevalence and has begun to influence our understanding of the principal psychotic conditions.What does it mean when a child reports experiencing hallucinations or delusions?When one examines a 5-year old child who claims that he is superman and can fly, the challenge is to determine whether the child has a delusion. Similarly, in a child who complains about hearing a voice telling her to do bad things, one must determine whether she is talking about her conscience or is experiencing auditory hallucinations.From a cognitive and developmental standpoint, certain clinical features in children create diagnostic challenges. One problem is distinguishing true psychotic phenomena in children from nonpsychotic idiosyncratic thinking, perceptions caused by developmental delays, exposure to disturbing and traumatic events, and overactive and vivid imaginations.Organic PsychosesNeurologic ConditionsSeizure DisorderDeteriorative Neurologic DisordersCentral Nervous System LesionsMetabolic and Hormonal DisturbancesToxic Psychoses

Functional PsychosesChildhood Onset SchizophreniaMood DisordersBrief Reactive PsychosisAnxiety DisordersClinician-Rated Dimensions ofPsychosis Symptom Severity

Instead, an eight-symptom Clinician-Rated Dimensions of PsychosisSymptom Severity scale for determining severity of psychosis across many psychotic illnesses is included in Section III of the DSM-5.Symptom domains rated in this scale include the following: hallucinations, delusions, disorganized speech, abnormal psychomotor behavior,negative symptoms (restricted emotional expression or avolition), impaired cognition, depression, and mania.

Scoring and InterpretationEach item on the measure is rated on a 5-point scale (O=none; l=equivocal; 2=present, butmild; 3=present and moderate; and 4=present and severe) with a symptom-specific definitionof each rating level. The clinician may review all of the individual's available informationand, based on clinical judgment, select (by circling) the level that most accuratelydescribes the severity of the individual's condition. The clinician then indicates the scorefor each item in the "Score" column provided.Frequency of UseTo track changes in the individual's symptom severity over time, the measure may becompleted at regular intervals as clinically indicated, depending on the stability of the individual'ssymptoms and treatment status. Consistently high scores on a particular domainmay indicate significant and problematic areas for the individual that might warrantfurther assessment, treatment, and follow-up. Clinical judgment should guide decisionmaking.8Clinician-Rated Dimensions ofPsychosis Symptom Severity

Instead, an eight-symptom Clinician-Rated Dimensions of PsychosisSymptom Severity scale for determining severity of psychosis across many psychotic illnesses is included in Section III of the DSM-5.Symptom domains rated in this scale include the following: hallucinations, delusions, disorganized speech, abnormal psychomotor behavior,negative symptoms (restricted emotional expression or avolition), impaired cognition, depression, and mania.

Scoring and InterpretationEach item on the measure is rated on a 5-point scale (O=none; l=equivocal; 2=present, butmild; 3=present and moderate; and 4=present and severe) with a symptom-specific definitionof each rating level. The clinician may review all of the individual's available informationand, based on clinical judgment, select (by circling) the level that most accuratelydescribes the severity of the individual's condition. The clinician then indicates the scorefor each item in the "Score" column provided.Frequency of UseTo track changes in the individual's symptom severity over time, the measure may becompleted at regular intervals as clinically indicated, depending on the stability of the individual'ssymptoms and treatment status. Consistently high scores on a particular domainmay indicate significant and problematic areas for the individual that might warrantfurther assessment, treatment, and follow-up. Clinical judgment should guide decisionmaking.9Factors to ConsiderMisdiagnosis remain due to symptom overlapAnxiety and stress are probably the most common causes of hallucinations in preschool children with benign prognosisPsychotic phenomena in school age children generally tend to be more persistent, and are more likely to be associated with drug toxicity or significant mental illnessLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionCognitive impairments, particularly impaired concentration and ability to focus, usually accompany psychosis in children.When the psychosis is secondary to an organic origin, there is often accompanying impairment in the sensorium presenting as confusion and disorientation, as is typical of delirium.shyness, and disturbances in adaptive social behavior seem to be the first signs of dysfunctional premorbid developmentEarly language deficits and motor impairmentsDiagnostic ChallengesDistinguishing true psychotic phenomena in children from nonpsychotic: idiosyncratic thinking, perceptions caused by developmental delays, exposure to disturbing and traumatic events, and overactive and vivid imaginationsDifferentiating between the premorbid state and the active psychotic stateDistinguishing true psychotic phenomena in children from nonpsychotic idiosyncratic thinking, perceptions caused by developmental delays, exposure to disturbing and traumatic events, and overactive and vivid imaginations.

12Childhood Psychosis Adult Schizophrenia (?)

Childhood Onset Schizophrenia Adult Schizophrenia

Childhood Onset Schizophrenia = Adult SchizophreniaLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionCOS vs Adult SchizophreniaSimilar to that of poor outcome adult casesPsychosis of COS can usually be distinguished by its severe and pervasive nature and its nonepisodic, unremitting courseChildren show poorer premorbid functioning in social, motor, and language domains, learning disabilities, and disruptive behavior disordersTransient autistic symptoms such as hand flapping and echolalia in toddler years are common, probably reflecting more compromised early brain development.Lewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionHistoryMaudsley first wrote a description of the insanity of early life in his textbook, Physiology and Pathology of Minddevelopmental approachthe mental faculty of children was not organized, and hence the insanity in children must be of the simplest kind, influenced more by reason of bad descent or of baneful influences during uterine life.

15HistoryDe Sanctis may be credited first with setting out childhood schizophrenia as different from mental deficiency and from certain neurologic disorders, such as epilepsy or postinfectious encephalopathyHistoryKraeplin introduced the concept of dementia praecox and noted its onset in late childhood and adolescenceSuggested that 3.5% of patients with schizophrenia had the onset of their illness before the age of 10 years. This led to an increased interest in understanding the developmental aspects of psychosis.HistoryThe term psychosis was used so broadly in children that a spectrum of behavioral disorders and autism were grouped together under the category of childhood schizophrenia.Before the 1960s, the term childhood psychosis was applied to a heterogeneous group of children, many of whom exhibited autism spectrumdisorder symptoms without hallucinations and delusions. In the late 1960s and 1970s, reports of children with evidence of a profoundpsychotic disturbance very early in life included observations of intellectual disabilities, social deficits, and severe communication andlanguage impairments, and no family history of schizophrenia. Children whose psychoses emerged after the age of 5 years, however, moreoften exhibited auditory hallucinations, delusions, inappropriate affect, thought disorder, normal intellectual function, and a positive familyhistory of schizophrenia.18HistoryThe landmark studies of Kolvin first established the clinical distinction between autism and other psychotic disorders of childhood19HistorySchizophrenia with childhood onset was formally separated from autistic disorderIn the 1980s, schizophrenia with childhood onset was formally separated from what was then termed autistic disorder, and currentlytermed autism spectrum disorder.

20Controversy & Confusion after SeparationResearch documented a small group of children with autism spectrum disorder who developed schizophrenia in later childhood or adolescenceMany children with childhood-onset schizophrenia exhibit neurodevelopmental abnormalities, some of which are also evident in children with autism spectrum disorderAccording to the DSM-5, schizophrenia can be diagnosed in the presence of autism spectrum disorder, provided that the diagnosis of schizophrenia is specifically differentiated from autism spectrum disorder.

However, even after the separation of the disorders, controversy and confusion remained as to the distinctiveness in the long-term courses ofthese disorders. First, research documented a small group of children with autism spectrum disorder who developed schizophrenia in laterchildhood or adolescence. Second, many children with childhood-onset schizophrenia exhibit neurodevelopmental abnormalities, some ofwhich are also evident in children with autism spectrum disorder. Children with autism spectrum disorder and those with childhood-onsetschizophrenia are typically impaired in multiple areas of adaptive functioning from relatively early in life. However, in autism spectrumdisorder, the onset is almost always before 3 years of age, whereas the onset of childhood-onset schizophrenia occurs before the age of 13years, but most often is not recognizable in children until after the age of 3 years. Childhood-onset schizophrenia is signicantly less frequentthan adolescent-onset or onset in young adulthood, and few reports document cases of schizophrenia onset before 5 years of age. Accordingto the DSM-5, schizophrenia can be diagnosed in the presence of autism spectrum disorder, provided that the diagnosis of schizophrenia isspecifically differentiated from autism spectrum disorder.21Early-Onset Schizophreniaonset of disease before the age of 18 years, including childhood-onset as well as adolescent-onset schizophreniaassociated with severe clinical course, poor psychosocial functioning, and increased severity of brain abnormalitycurrent evidence supports the efficacy of both psychosocial and pharmacological interventions

Early-onset schizophrenia comprises childhood-onset and adolescent-onset schizophrenia. Childhood-onset schizophrenia is a very rare andvirulent form of schizophrenia now recognized as a progressive neurodevelopmental disorder. Childhood onset is characterized by a morechronic course, with severe social and cognitive consequences and increased negative symptoms compared to adult-onset schizophrenia.Childhood-onset schizophrenia is dened by an onset of psychotic symptoms before the age of 13 years, believed to represent a subgroup ofpatients with schizophrenia with an increased heritable etiology, and evidence of widespread abnormalities in the development of brainstructures including the cerebral cortex, white matter, hippocampus and cerebellum. Children diagnosed with childhood-onset schizophreniahave higher than normal rates of premorbid developmental abnormalities that appear to be nonspecic markers of abnormal braindevelopment. Early-onset schizophrenia is dened as an onset of disease before the age of 18 years, including childhood-onset as well asadolescent-onset schizophrenia. Early-onset schizophrenia is associated with severe clinical course, poor psychosocial functioning, andincreased severity of brain abnormality. Despite the more severe course, current evidence supports the ecacy of both psychosocial andpharmacological interventions in the management of childhood-onset and, particularly, adolescent-onset schizophrenia.22Childhood-Onset Schizophreniaa very rare and virulent form of schizophrenia now recognized as a progressive neurodevelopmental disordermore chronic course, with severe social and cognitive consequences and increased negative symptoms compared to adult-onset schizophrenia.onset of psychotic symptoms before the age of 13 years, increased heritable etiology, and evidence of widespread abnormalities in the development of brain structures including the cerebral cortex, white matter, hippocampus and cerebellum. Have higher than normal rates of premorbid developmental abnormalities nonspecific markers of abnormal brain development.a very rare andvirulent form of schizophrenia now recognized as a progressive neurodevelopmental disorder. Childhood onset is characterized by a morechronic course, with severe social and cognitive consequences and increased negative symptoms compared to adult-onset schizophrenia.Childhood-onset schizophrenia is dened by an onset of psychotic symptoms before the age of 13 years, believed to represent a subgroup ofpatients with schizophrenia with an increased heritable etiology, and evidence of widespread abnormalities in the development of brainstructures including the cerebral cortex, white matter, hippocampus and cerebellum. Children diagnosed with childhood-onset schizophreniahave higher than normal rates of premorbid developmental abnormalities that appear to be nonspecic markers of abnormal braindevelopment.23Childhood-Onset Schizophreniamore significant deficits in measures of intelligence quotient (IQ), memory, and tests of perceptuomotor skills compared with adolescent-onset schizophreniaincreased impairment of cognitive measures such as IQ, working memory, and perceptuomotor skills premorbid markers of illness rather than sequelae, of the disorder. Although cognitive impairments are greater in younger patients with schizophrenia, clinicalpresentation of schizophrenia remains remarkably similar across the agesthe diagnosis of childhood-onset schizophrenia is continuous with that in adolescents and adults, with one exception: In childhood-onset schizophrenia a failure to achieve expected social and academic functioning may replace a deterioration in functioning.24Diagnosis of SchizophreniaActive PhaseAt least one of the following: delusions, hallucinations, disorganized speechAt least one additional symptom present most of the time for a month: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms (i.e. diminished emotional expression or avolition)Symptoms are present for a significant amount of time during a single month AND cause impairment (social, academic, occupational)To meet full criteria for schizophrenia, continuous signs of disturbance must persist for at least 6 months.To meet full criteria for schizophrenia, continuous signs of disturbance must persist for at least 6 months. Social, academic, or occupational impairment must be present. In contrast to previous diagnostic criteria, the subtypes of schizophrenia (paranoid, disorganized, catatonic, undifferentiated, and residual) have been eliminated due to their lack of diagnostic validity and reliability. Instead, an eight-symptom Clinician-Rated Dimensions of PsychosisSymptom Severity scale for determining severity of psychosis across many psychotic illnesses is included in Section III of the DSM-5.Symptom domains rated in this scale include the following: hallucinations, delusions, disorganized speech, abnormal psychomotor behavior,negative symptoms (restricted emotional expression or avolition), impaired cognition, depression, and mania.25EpidemiologyFrequency of COS is less than one case in about 40,000 children, whereas among adolescents between the ages of 13 and 18 years, the frequency of schizophrenia is increased by a factor of at least 50resembles the more severe, chronic, and treatment-refractory adult-onset schizophrenic subgroups, in that the same core phenomenological features are presentCo-morbid disorders: ADHD, depressive disorders, anxiety disorders, speech & language disorders, motor disturbances

The frequency of childhood-onset schizophrenia is reported to be less than one case in about 40,000 children, whereas among adolescentsbetween the ages of 13 and 18 years, the frequency of schizophrenia is increased by a factor of at least 50. Schizophrenia with childhoodonset resembles the more severe, chronic, and treatment-refractory adult-onset schizophrenic subgroups, in that the same corephenomenological features are present; however, in childhood-onset schizophrenia, extremely high rates of comorbidities are present,including attention-deficit/hyperactivity disorder (ADHD), depressive disorders, anxiety disorders, speech and language disorders, and motordisturbances. 26EpidemiologyIn adolescents, the prevalence of schizophrenia is estimated to be 50 times that in younger children, with probable rates of 1 tom2 per 1,000. Male 1.67: 1 FemaleSchizophrenia rarely is diagnosed in children younger than 5 years of age. The prevalence of schizophrenia among the parents of children with schizophrenia is about 8%, which is about twice the prevalence in the parents of patients with adult-onset schizophrenia.In adolescents, the prevalence of schizophrenia is estimated to be 50 times that in younger children, with probable rates of 1 to2 per 1,000. Boys seem to have a slight preponderance among children diagnosed with schizophrenia, with an estimated ratio of about 1.67boys to 1 girl. Boys often become identified at a younger age than girls do. Schizophrenia rarely is diagnosed in children younger than 5years of age. The prevalence of schizophrenia among the parents of children with schizophrenia is about 8 percent, which is about twice theprevalence in the parents of patients with adult-onset schizophrenia.27Etiologya neurodevelopmental disorder

GENES + ENVIRONMENT Abnormal Early Brain Development

white matter abnormalities and disturbances lead to abnormal connectivityChildhood-onset schizophrenia is a neurodevelopmental disorder in which complex interactions between genes and the environment arepresumed to result in abnormal early brain development. The consequences of the aberrant brain development in schizophrenia may not befully evident until adolescence or early adulthood; however, data support the hypothesis that white matter abnormalities and disturbances inmyelination in childhood, lead to abnormal connectivity between brain regions. The aberrant connectivity in various regions of the brain isbelieved to be an important contributing factor in the psychotic symptoms and cognitive deficits in childhood-onset schizophrenia.28Genetic FactorsHeritability estimates at 80%8x more prevalent among first degree relatives with schizophreniaHigher concordance rates among monozygotic twins than in dizygotic twinsHigher rates among relatives of childhood-onset schizophrenia than in adult-onset schizophreniaNo reliable method can identify persons at the highest risk for schizophrenia in a given family.Estimates of heritability for childhood-onset schizophrenia have been as high as 80 percent. The precise mechanisms of transmission ofschizophrenia are still not well understood. Schizophrenia is known to be up to eight times more prevalent among rst-degree relatives ofthose with schizophrenia than in the general population. Adoption studies of patients with adult-onset schizophrenia have shown thatschizophrenia occurs in the biological relatives, not the adoptive relatives. Additional genetic evidence is supported by higher concordancerates for schizophrenia in monozygotic twins than in dizygotic twins. Higher rates of schizophrenia have been established among relatives ofthose with childhood-onset schizophrenia than in the relatives of those with adult-onset schizophrenia.29

MRI Studiesprogressive loss of gray matterdelayed and disrupted white matter growthdecline in cerebellar volumeGray matter abnormalities were normalized over time in the siblings, indicating a protective mechanism in siblings that was not present in those children with childhood-onset schizophrenia. hippocampal volume loss across the age span appears to be static among children with childhood-onset schizophreniaA National Institute of Mental Health (NIMH) prospective study of more than 100 patients with childhood-onset schizophrenia and theirtypically developing siblings has demonstrated progressive loss of gray matter, delayed and disrupted white matter growth, and a decline incerebellar volume in those with childhood-onset schizophrenia. Although siblings of children with childhood-onset schizophrenia alsoshowed some of these brain disruptions, the gray matter abnormalities were normalized over time in the siblings, indicating a protectivemechanism in siblings that was not present in those children with childhood-onset schizophrenia. Furthermore, the hippocampal volumeloss across the age span appears to be static among children with childhood-onset schizophrenia. An MRI NIMH study of more than 100children with childhood-onset schizophrenia and their typically developing siblings, studied for about two decades, documented that inchildhood-onset schizophrenia, progressive brain gray matter loss occurs continuously over time. This gray matter shrinkage occurs withventricular increases, with a pattern of loss originating in the parietal region and proceeding frontally to dorsolateral prefrontal andtemporal cortices, including superior temporal gyri. Studies of childhood-onset schizophrenia at the NIMH provided evidence that early lossof parietal gray matter followed by frontal and parietal gray matter loss is more pronounced in childhood-onset schizophrenia than inschizophrenia with later onset. Other research utilized diusion tensor images from children with childhood-onset schizophrenia versuscontrols and found increased diusivities in the posterior corona radiata in children with childhood-onset schizophrenia, which implicatedabnormal connectivity with the parietal lobes. These results contrasted with ndings among subjects with later onset of schizophrenia inwhom there were more abnormalities in the frontal lobes.34MRI NIMH StudyAn MRI NIMH study of more than 100children with childhood-onset schizophrenia and their typically developing siblings, studied for about two decades, documented that inchildhood-onset schizophrenia, progressive brain gray matter loss occurs continuously over time. This gray matter shrinkage occurs withventricular increases, with a pattern of loss originating in the parietal region and proceeding frontally to dorsolateral prefrontal andtemporal cortices, including superior temporal gyri. Studies of childhood-onset schizophrenia at the NIMH provided evidence that early lossof parietal gray matter followed by frontal and parietal gray matter loss is more pronounced in childhood-onset schizophrenia than inschizophrenia with later onset. Other research utilized diusion tensor images from children with childhood-onset schizophrenia versuscontrols and found increased diusivities in the posterior corona radiata in children with childhood-onset schizophrenia, which implicatedabnormal connectivity with the parietal lobes. These results contrasted with ndings among subjects with later onset of schizophrenia inwhom there were more abnormalities in the frontal lobes.35Phenomenology and Neurobiology of COSPremorbid Developmenthigher rates of early language, social, and motor developmental abnormalities, possibly reflecting greater impairment in early brain developmentLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionPhenomenology and Neurobiology of COSRisk FactorsParental Age and Obstetric Complicationsno correlation with maternal or paternal ageincidence of obstetric complications in COS patients did not differ from that for the healthy sibling control groupEye Trackinggenetic factors underlying eyetracking dysfunction (Smooth pursuit eye movement) may be more salient for COS than AOSFamilial Schizophrenia Spectrum Disordersrate of familial schizophrenia spectrum disorders was higher for COS than AOS, and both were higher than community controlsFamilial Neurocognitive FunctioningCOS siblings had significantly poorer performance than community controls, although the rates of neuropsychological abnormalities for COS were not significantly higher than for AOSLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionPervasive Developmental Disorder and COSPDD in COS may be a nonspecific marker of more severe early abnormal neurodevelopmentLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionNeurocognitive Functioning in COS Probandsperform poorly on tasks involving fine motor coordination, attention, short-term and working memoryEvoked-potential studies show diminished amplitude of brain electrical activity during these tasks, suggesting that allocation of necessary attentional resources is deficient, which is also shared by adults with schizophreniathere was no evidence for a longer term degenerative cognitive process in COS, at least through early adulthood

Lewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionComorbid Disordersdepression (54%)obsessive-compulsive disorder (OCD;21%)generalized anxiety disorder (GAD; 15%)attention deficit hyperactivity disorder (ADHD; 15%)Lewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionBrain Development in COSincreasing ventricular volume and decreasing total cortical, frontal, medial temporal, and parietal gray matter volumes at 2, 4, and 6 years after initial scan

Lewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionWhat is the Pattern of GM Loss in COS and its Relationship with Normal Development?back to front tissue loss, with early parietal gray matter loss followed by frontal and temporal gray matter loss later in adolescencetop-down fashion on the medial surfaceGM loss in COS may reflect an exaggeration of normal maturational process of synaptic/dendritic pruning during adolescenceLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionDoes the Cortical GM Loss in COS EventuallyResemble the Adult Onset Pattern when Subjects Mature?Cortical thickness analyses in adult onset schizophrenia document GM loss mostly in prefrontal and temporal corticesas COS subjects mature, the robust and global GM loss during the adolescent years becomes limited to prefrontal and superior temporal cortices by age 24, thus mimicking a pattern seen in adult patientsLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th Edition

Comparison of the Patterns of Cortical Gray Matter (GM) Loss in Childhood-Onset Schizophrenia (COS) (Between Ages 12 and 16 Years) to That Seen in Normal Cortical Maturation (Between Ages 4 and 22 Years). A. Right lateral view of the dynamic sequences of cortical GM maturation in healthy children between ages 4 and 22 years (n= 13, 54 scans, upper panel) rescanned every 2 years. Scale bar shows GM amount at each of the 65 536 cortical points across the entire cortex represented using a color scale (red to pinkmore GM, blueGM Loss). Cortical GM maturation appears to progress in a "back-to-front" (parietotemporal) manner.[49]B. Right lateral view of the dynamic sequence of cortical GM maturation in COS between ages 12 and 16 years compared with age- and sex-matched healthy controls (n= 12, 36 scans in each group), where children are rescanned every 2 years. Dynamic maps representPvalues for the difference in GM amount between COS and controls at each of the 65 536 cortical points, andPvalues are represented using a color scale (eg, pink,P< .00002). Cortical GM loss in COS also appears to follow in a "back-to-front" direction on the lateral surface, thus suggesting that the COS pattern is an exaggeration of the normal GM maturation.[50]Asterisk represents data on childhood schizophrenia only age 1216 years. Adapted fromProc Natl Acad Sci USA2004;101:8178 andProc Natl Acad Sci USA2001;98:11652.44

Progression of Cortical Gray Matter (GM) Loss in Childhood-Onset Schizophrenia (COS) (n= 70, 162 scans) Relative to Age-, Sex-, and Scan IntervalMatched Healthy Controls (n= 72, 168 Scans) From Adolescence to Young Adulthood (age 1224 years). Analyses were done using mixed model regression statistics and covaried from mean cortical thickness. Side bar showststatistic with threshold to control for multiple comparisons using the false discovery rate procedure withq= 0.05. Differences are from mixed model regression with age centered at approximate 3-year intervals for middle 80% of the age range, and colors represent areas of statistically significant thinning in COS.81 Adapted fromJ Child Psychol Psychiatry2006;47:1007.45

Cortical Gray Matter (GM) Thickness in Healthy Childhood-Onset Schizophrenia (COS) Siblings (n= 52, 110 scans) Compared With Age-, Sex-, and Scan IntervalMatched Healthy Controls (n= 52, 108 scans) Between Ages 8 Through 28 Years. Healthy COS siblings show significant GM deficits in left prefrontal and bilateral temporal cortices and smaller deficits in right prefrontal and inferior parietal cortices. These deficits in healthy siblings normalize with age with no abnormalities remaining by age 20 years. Side bar showststatistic with threshold to control for multiple comparisons using the false discovery rate procedure withq= 0.05. Differences are from mixed model regression with age centered at approximate 3-year intervals for middle 80% of the age range, and colors represent areas of statistically significant thinning in COS siblings.Adapted from Arch Gen Psychiatry. 2007;64:774.46

Is the GM Loss in COS a Medication Effect?The GM findings in COS appeared to be due to schizophrenia and not due to medicationsIs the GM Loss in COS Diagnostically Specific?The GM findings in COS appeared to be due to schizophrenia and not due to medicationsLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionNATURE VS. NURTURE NATURE & NURTURE

Deficits in measures of IQ, memory, and tests of perceptuomotor skills

Children > Adolescents > Adults

Suggests that these deficits are NOT sequelae of the disorder, but are MARKERS of brain dysfunction even before the onset of illnessPsychosocial stressors are known to influence the course of schizophrenia, and the same stressors may possibly interact with biological risk factors in the emergence of the disorder, given that children who are diagnosed with COS have marked neuropsychological deficits in a wide range of brain functions, including attention, working memory, and executive functions. Similar defects have been demonstrated in adolescents and adults with schizophrenia; however, children with schizophrenia have been shown to have more significant deficits in measures of intelligence quotient (IQ), memory, and tests of perceptuomotor skills compared with adolescent onset of schizophrenia and adolescents had greater deficits in these areas than adults with schizophrenia. Differences in these cognitive measures of IQ, memory, and perceptuomotor skills in persons with schizophrenia of different ages of onset suggests that these deficits may not be a sequelae of the disorder, but are markers of brain dysfunction even before the onset of the illness.52Vulnerability Factorsshyness, and disturbances in adaptive social behaviorearly language deficits and motor impairmentsIntellectual delays

a socially odd child is not usually schizophrenicDiagnosis & Clinical Featurespremorbid history of social rejection, poor peer relationships, clingy withdrawn behavior, and academic trouble, delayed motor milestones and language acquisitionOnset is insidious, starting with inappropriate affect or unusual behaviorAuditory hallucinationsVisual hallucinations associated with lower IQ and earlier age at onsetVisual, tactile, and olfactory hallucinations may be a marker of more severe psychosisDiagnosis & Clinical FeaturesDelusions increase in frequency with increased ageBlunted or inappropriate affectInappropriate giggling and cryingFormal thought disorders, including loosening of associations and thought blockingIllogical thinking and poverty of thoughtdo not have poverty of speech content, but they speak less than other children and ambiguous in the way they refer to persons, objects, and eventsDiagnosis & Clinical FeaturesCommunication deficits: unpredictably changing the topic of conversation without introducing the new topic to the listener (loose associations)illogical thinking and speaking and tend to underuse self-initiated repair strategies to aid in their communicationfail to aid communication with revision, fillers, or starting over NEGATIVE SYMPTOMSDiagnosis & Clinical FeaturesThe clinical presentation of schizophrenia remains remarkably similar across the ageSchizophrenia in prepubertal children includes the presence of at least two of the following: hallucinationsdelusionsgrossly disorganized speech or behaviorsevere withdrawal for at least 1 monthsocial or academic dysfunction must be presentcontinuous signs of the disturbance must persist for at least 6 monthsThe diagnostic criteria for schizophrenia in children are identical to the criteria for the adult form, except that instead of showing deteriorating functioning, children may fail to achieve their expected levels of social and academic functioning.The clinical presentation of schizophrenia, however, taking into consideration developmental level of the child, remains remarkably similar across the ages. Schizophrenia in prepubertal children includes the presence of at least two of the following: hallucinations, delusions, grossly disorganized speech or behavior, and severe withdrawal for at least 1 month. Social or academic dysfunction must be present, and continuous signs of the disturbance must persist for at least 6 months. The diagnostic criteria for schizophrenia in children are identical to the criteria for the adult form, except that instead of showing deteriorating functioning, children may fail to achieve their expected levels of social and academic functioning.57DifferentialsLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionDifferentialsLewiss Child & Adolescent Psychiatry: A Comprehensive Textbook 4th EditionCourse and PrognosisImportant predictors of course and outcome:childs premorbid level of functioningthe age of onsetIQresponse to psychosocial and pharmacological interventionsdegree of remission after the first psychotic episodedegree of family supportLess treatment responsive:Early age at onsetwith comorbid developmental delayslearning disorderslower IQpremorbid behavioral disorders, such as ADHD and conduct disorderCourse and PrognosisPredictors of a poorer course:family history of schizophreniayoung age and insidious onsetdevelopmental delayslower level of premorbid functionchronic or length of first psychotic episodeAn important factor in outcome is the accuracy and stability of the diagnosis of schizophrenia.Management & TreatmentStage 1 (prodromal phase): The child may experience some period of deteriorating function, which may include social isolation, idiosyncratic preoccupations and behaviors, and academic difficulties.

Stage 2(acute phase): This is usually the time when the child comes to the attention of a mental health professional, when the clinical picture is dominated by frank delusions and hallucinations and other positive symptoms such as a formal thought disorder or strange and idiosyncratic behaviors.

Management & TreatmentStage 3 (recovery phase): The symptoms usually begin to remit and dissipate. However, often there may still be the presence of some psychotic symptoms, although they are less disturbing to the child. In this phase, the child may continue to experience some levels of confusion, disorganization, or lability in mood.

Stage 4 (residual phase): The positive symptoms continue to subside, but the child continues to experience apathy, lack of motivation, withdrawal, and restricted or flat affect.

Pathology & Laboratory ExaminationsNo specific laboratory tests are diagnostically specific for childhood-onset schizophreniaAlthough data exist to suggest that hypoprolinemia is associated with the risk of schizoaffective disorder due to an alteration on chromosome 22q11, no association of hyperprolinemia with childhood-onset schizophrenia has been identified.Management & TreatmentIntegrated Psychological Interventions:Cognitive behavioral therapygroup skills trainingcognitive remediation therapymultifamily psychoeducationsupportive counseling on the prevention of psychosisMore effective than standard treatments in delaying the onset of psychosis over a 2-year follow-up periodChildren may have less robust responses to antipsychotic medications than adolescents and adultManagement & TreatmentPharmacotherapy is instituted in an attempt to treat the underlying cause of the psychosis, or for symptom control, in those children who have psychotic symptoms secondary to a known origin.

Informed consent from the parents or guardian should be obtained before treatment with psychopharmacologic agents is instituted.Pharmacotherapysome efficacy:Risperidone up to 3 mg per dayOlanzapinerandomized 6-week controlled trial of olanzapine in adolescents with schizophrenia found that it was more efficacious than placebo.AripiprazoleAt two fixed doses, superior to placebo in the treatment of positive symptoms of adolescent schizophrenia; however, more than 40 percent of subjects in the active medication group did not achieve remission.Clozapinemore effective than haloperidol in improving both positive and negative symptoms in treatment resistant schizophrenia in youthPharmacotherapyClozapine vs high dose Olanzapineresponse rates were about twice as great for clozapine as olanzapine (66% vs. 33%)clozapine was found to be associated with a significant reduction in all outcome measures, whereas olanzapine showed improvement on some measures but not on allclozapine was superior to olanzapine in alleviating negative symptomsClozapine was associated with more adverse events, such as lipid abnormalities and a seizure in one patient.

Management & TreatmentPsychosocial interventions should include working with both the parents and the child.Improving family functioning, problem solving, communication skills, and relapse prevention have been shown to decrease relapse rates in adultsSocial skills training and may require specialized educational programs, academic adjustments, and support at schoolOngoing illness teaching and medication education, are important to promote compliance with treatment and to help in coping with the daily and sometimes long-term implications of the childs illness.Psychosicial InterventionsPsychotherapists who work with children with schizophrenia must take into account a childs developmental level in order to support the childs reality testing and be sensitive to the childs sense of self. Long-term supportive family interventions and cognitive behavioral and remediation interventions combined with pharmacotherapy are likely to be the most effective approach to early-onset schizophrenia.Management & TreatmentTreatment strategies need to focus on the clinical symptoms and morbidity of the underlying disorder, while also addressing any comorbid disorders or biopsychosocial stressors.The assessment of the child with psychotic symptoms should include a careful, comprehensive, and thoughtful evaluation