early onset schizophrenia

Authors: Sadock, Benjamin James; Sadock, Virginia AlcottTitle: Kaplan & Sadock's Synopsis of Psychiatry: BehavioralSciences/Clinical Psychiatry, 10th Edition

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> Table of Contents > 51 - Early-Onset Schizophrenia

51

Early-Onset Schizophrenia

Childhood-onset schizophrenia (COS) is a rare and severe form ofschizophrenia characterized by an onset of psychotic symptoms by age12 years, believed to represent a subgroup of affected individuals withan increased heritable etiology. Children diagnosed with childhood onsetschizophrenia have high rates of premorbid developmentalabnormalities that appear to be nonspecific markers of severe earlyimpaired neurodevelopment. Recent imaging studies have provided datato suggest that children with COS have decreased anterior cingulatedgyrus (ACG) volumes with age, unlike controls, and an absence of thenormal decreased left to right ACG volume asymmetry. These structuraldifferences are hypothesized to be related to abnormalneurodevelopment influencing attention and emotion regulation, whichare characteristic of some cognitive impairments in psychosis. Thefrequency of COS is reported to be less than 1 case in 10,000 children,whereas among adolescents between the ages of 13 and 18 years, thefrequency of schizophrenia is markedly increased. Schizophrenia withchildhood onset has the same core phenomenological features asschizophrenia in adolescence and adulthood; however, extremely highrates are seen of comorbid psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), depressive disorders, andseparation anxiety disorder in children and adolescents with COS.

Psychosocial stressors are known to influence the course ofschizophrenia, and the same stressors may possibly interact withbiological risk factors in the emergence of the disorder, given thatchildren who are diagnosed with COS have marked neuropsychologicaldeficits in a wide range of brain functions, including attention, workingmemory, and executive functions. Similar defects have beendemonstrated in adolescents and adults with schizophrenia; however,children with schizophrenia have been shown to have more significantdeficits in measures of intelligence quotient (IQ), memory, and tests ofperceptuomotor skills compared with adolescent onset of schizophreniaand adolescents had greater deficits in these areas than adults withschizophrenia. Differences in these cognitive measures of IQ, memory,and perceptuomotor skills in persons with schizophrenia of different

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ages of onset suggests that these deficits may not be a sequelae of thedisorder, but are markers of brain dysfunction even before the onset ofthe illness. Further, the brain dysfunction in schizophrenia occurs on acontinuum with COS, reflecting the most severe neuropsychologicaldeficits. In addition, a study comparing the severity of cognitive deficitsbetween adolescents and adults early in the course of schizophreniaconcluded that, although greater cognitive deficits are seen in earlieronset schizophrenia, a waning may occur of the development of certaincognitive domains influencing working memory and attention followingthe onset of schizophrenia in adolescent patients. The clinicalpresentation of schizophrenia, however, taking into considerationdevelopmental level of the child, remains remarkably similar across theages. Schizophrenia in prepubertal children includes the presence of atleast two of the following: hallucinations, delusions, grosslydisorganized speech or behavior, and severe withdrawal for at least 1month. Social or academic dysfunction must be present, and continuoussigns of the disturbance must persist for at least 6 months. Thediagnostic criteria for schizophrenia in children are identical to thecriteria for the adult form, except that instead of showing deterioratingfunctioning, children may fail to achieve their expected levels of socialand academic functioning.

Before the 1960s, the term childhood psychosis was applied to aheterogeneous group of pervasive developmental disorders withouthallucinations and delusions. In the 1960s and 1970s, children withevidence of a profound psychotic disturbance early in life often wereobserved to be mentally retarded, socially dysfunctional with severecommunication and language impairments, and without a family historyof schizophrenia. In children with psychoses that emerged after the ageof 5, however, auditory hallucinations, delusions, inappropriate affects,thought disorder, and normal intelligence were manifest, and thesechildren often had a family history of schizophrenia; they were viewedas exhibiting schizophrenia, whereas the younger children wereidentified as having an entirely different disorder, either autisticdisorder or a pervasive developmental disorder.

In the 1980s, schizophrenia with childhood onset was formallyseparated from autistic disorder. This change reflected evidenceaccrued during the 1960s and 1970s that the clinical picture, familyhistory, age of onset, and course of the two disorders differed. After theseparation of the disorders, two controversies ensued. First, a fewresearchers remained of the opinion that a subgroup of autistic childrenwill eventually have schizophrenia, as evidence shows for a small group.The diagnosis of schizophrenia is specifically differentiated from autisticdisorder (see Table 42-1). Many children with early onset schizophreniahave neurodevelopmental abnormalities, some of which are also evidentin children with autistic disorder. Children with autistic disorder areimpaired in multiple areas of adaptive functioning from early life



onward. The onset is almost always before 3 years of age, whereas theonset of childhood schizophrenia occurs before early adolescence butoften is not apparent in children until after the age of 3 years. COS ismore rare than onset in adolescence or young adulthood, and practicallyno reports are found of an onset of schizophrenia before 5 years of age.According to the text revision of the fourth edition of Diagnostic andStatistical Manual of Mental Disorders

(DSM-IV-TR), schizophrenia can be diagnosed in the presence of autisticdisorder.

One of the challenges in applying adult diagnostic criteria COS is thatsome very young children who report hallucinations and apparentthought disorders in conjunction with developmental immaturities inlanguage and in the concepts of differentiating reality from fantasy maybe manifesting phenomena that are better accounted for by immaturitythan psychosis.

EpidemiologySchizophrenia in prepubertal children is exceedingly rare; it isestimated to occur in less than 1 of 10,000 children. In adolescents, theprevalence of schizophrenia is estimated to be 50 times that in youngerchildren, with probable rates of 1 to 2 per 1,000. Boys seem to have aslight preponderance among children diagnosed with schizophrenia, withan estimated ratio of about 1.67 boys to 1 girl. Boys often becomeidentified at a younger age than girls. It has been estimated that 0.1 to1 percent present before age 10 years with 4 percent before 15 years ofage. The rate of onset increases sharply during adolescence.Schizophrenia rarely is diagnosed in children younger than 5 years ofage. Psychotic symptoms usually emerge insidiously, and the diagnosticcriteria are met gradually over time. Occasionally, the onset ofschizophrenia is sudden and occurs in a previously well-functioningchild. Schizophrenia also may be diagnosed in a child who has hadchronic difficulties and then experiences a significant exacerbation. Theprevalence of schizophrenia among the parents of children withschizophrenia is about 8 percent, which is close to twice the prevalencein the parents of patients with adult-onset schizophrenia.

Schizotypal personality disorder is similar to schizophrenia in itsinappropriate affects, excessive magical thinking, odd beliefs, socialisolation, ideas of reference, and unusual perceptual experiences, suchas illusions. Schizotypal personality disorder, however, does not havepsychotic features; still, the disorder seems to aggregate in familieswith adult-onset schizophrenia. Therefore, the relation between the twodisorders is unclear.

Etiology

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The etiology of COS has multiple contributing factors, and estimates ofits heritability are as high as 80 percent. COS is a severe form ofschizophrenia which may increase its likelihood of heritability to amongthe highest of estimates. Genetic studies provide substantial evidencefor a significant genetic basis in the development of schizophrenia. Theprecise mechanisms of transmission of schizophrenia are still not wellunderstood. Schizophrenia is known to be up to eight times moreprevalent among first-degree relatives of those with schizophrenia thanin the general population. Adoption studies of patients with adult -onsetschizophrenia have shown that schizophrenia occurs in the biologicalrelatives, not the adoptive relatives. Additional genetic evidence issupported by higher concordance rates for schizophrenia in monozygotictwins than in dizygotic twins. Higher rates of schizophrenia have beenestablished among relatives of those with childhood-onset schizophreniathan in the relatives of those with adult-onset schizophrenia. A recentcase report identified a rare genetic occurrence in which an offspringreceives two chromosome homologues from the same parent(uniparental isodisomy) of chromosome 5, already implicated in severallinkage studies to be associated with schizophrenia in a child with COS.

Currently, no reliable method can identify persons at the highest riskfor schizophrenia in a given family. Neurodevelopmental abnormalitiesand higher-than-expected rates of neurological soft signs andimpairments in sustaining attention and in strategies for informationprocessing appear among children at high risk. Increased rates ofdisturbed communication styles are found in families with a memberwith schizophrenia. Recent reports have documented markedneuropsychological deficits in attention, working memory, andpremorbid IQ among children who develop schizophrenia and itsspectrum disorders. High expressed emotion, characterized by overlycritical responses in families, has been shown to be correlated withincreased relapse rates among patients with schizophrenia.

Recent studies have documented gray matter loss in the brains ofchildren with COS that started in the parietal region and proceededfrontally to dorsolateral prefrontal and temporal cortices, includingsuperior temporal gyri. Magnetic resonance imaging (MRI) studies of 12children with COS at baseline and at follow-up 5 years later werecompared with normal controls. Children with COS showed severebilateral frontal gray matter loss over the 5-year period that occurred ina dorsal-to-ventral pattern across the medial hemispheres. Frontalregions were most affected, whereas cingulated-limbic regions were lessvulnerable, which correlates with the brain areas responsible for thecognitive and metabolic dysfunction typically observed in schizophrenia.Children and adolescents with schizophrenia are more likely to have apremorbid history of social rejection, poor peer relationships, clingywithdrawn behavior, and academic trouble than those with adult -onsetschizophrenia. Some children with schizophrenia first seen in middle



childhood have early histories of motor milestones and delayedlanguage acquisition that are similar to some symptoms of autisticdisorder. The mechanisms of biological vulnerability and environmentalinfluences producing manifestations of schizophrenia remain underinvestigation.

Diagnosis and Clinical FeaturesAll of the symptoms included in adult-onset schizophrenia may bemanifest in children with the disorder. The onset is frequently insidious;after first exhibiting inappropriate affects of unusual behavior, a childmay take months or years to meet all of the diagnostic criteria forschizophrenia. Children who eventually meet the criteria often aresocially rejected and clingy and have limited social skills. They mayhave histories of delayed motor and verbal milestones and do poorly inschool, despite normal intelligence. Although children withschizophrenia and autistic disorder may be similar in their earlyhistories, children with schizophrenia have normal intelligence and donot meet the criteria for a pervasive developmental disorder.

According to DSM-IV-TR, a child with schizophrenia may experiencedeterioration of function, along with the emergence of psychoticsymptoms, or the child may never achieve the expected level offunctioning (see Table 13-4). Auditory hallucinations commonly occur inchildren with schizophrenia. They may hear several voices making anongoing critical commentary, or command hallucinations may tellchildren to kill themselves or others. The voices may be bizarre,identified as â€œa computer

in my head,â€ Martians, or the voice of someone familiar, such as arelative. Visual hallucinations are experienced by a significant numberof children with schizophrenia and often are frightening; the childrenmay see the devil, skeletons, scary faces, or space creatures. Transientphobic visual hallucinations also occur in traumatized children who donot eventually have a major psychotic disorder.

Delusions are present in more than one half of children withschizophrenia; the delusions take various forms, including persecutory,grandiose, and religious. Delusions increase in frequency with increasedage. Blunted or inappropriate affects appear almost universally inchildren with schizophrenia. Children with schizophrenia may giggleinappropriately or cry without being able to explain why. Formalthought disorders, including loosening of associations and thoughtblocking, are common features among children with schizophrenia.Illogical thinking and poverty of thought are also often present. Unlikeadults with schizophrenia, children with schizophrenia do not havepoverty of speech content, but they speak less than other children ofthe same intelligence and are ambiguous in the way they refer topersons, objects, and events. The communication deficits observable in

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children with schizophrenia include unpredictably changing the topic ofconversation without introducing the new topic to the listener (looseassociations). Children with schizophrenia also exhibit illogical thinkingand speaking and tend to underuse self-initiated repair strategies to aidin their communication. When an utterance is unclear or vague, normalchildren attempt to clarify their communication with repetitions,revision, and more detail. Children with schizophrenia, on the otherhand, fail to aid communication with revision, fillers, or starting over.These deficits may be conceptualized as negative symptoms inchildhood schizophrenia.

The core phenomena for schizophrenia seem to be the same amongvarious age groups, but a child's developmental level influences thepresentation of the symptoms. Delusions of young children are lesscomplex, therefore, than those of older children. Age-appropriatecontent, such as animal imagery and monsters, is likely to be a sourceof delusional fear in children. Other features that seem to occurfrequently in children with schizophrenia are poor motor functioning,visuospatial impairments, and attention deficits.

In the DSM-IV-TR are delineated five types of schizophrenia: paranoid,disorganized, catatonic, undifferentiated, and residual.

A 12-year-old boy developed concerns that his parents might bepoisoning his food. Over the next year, his symptoms progressed withincreased fearfulness, preoccupation with food, and beliefs that Satanand voices from the radio and television were sending him badthoughts. During this time, his parents also observed bizarre behaviors,including talking and yelling to himself, perseverating about devils anddemons, assaulting family members because he thought they were evil,and attempting to hurt himself because he believed it would pleaseGod. No predominant mood symptoms or any history of substanceabuse were found.

Developmentally, he was the product of a full -term pregnancycomplicated by a difficult labor and forceps delivery. His early motorand speech milestones were normal. As a younger child, he tended tobe quiet and socially awkward. His intelligence was felt to be in thenormal range, but academic testing was consistently below grade level.

He has had no significant medical problems. An organic work-upincluded normal serum chemistries, thyroid functions, toxicologyscreen, ceruloplasmin, and brain MRI. His family psychiatric history wassignificant for depression in a maternal aunt and a completed suicide ina maternal great-grandparent. His symptoms have not significantlyimproved in the 5 years subsequent to the onset of his illness. He hasbeen hospitalized nine times, including placement in a long-termresidential program. He has been on numerous antipsychoticmedications, both traditional neuroleptics and atypical agents, andnumerous other agents, including selective serotonin reuptake



inhibitors (SSRIs) and mood stabilizers. His mental status examinationcontinued to display tangential and disorganized thinking, paranoiddelusions, loose associations, perseverative speech patterns, and a flat,at times inappropriate, affect. His time has generally been spent pacingand muttering to himself, with no social interaction with others unlessinitiated by adults. Some improvement was finally noted with clozapine(Clozaril) therapy, although he remained symptomatic. (Courtesy of JonM. McClellan, M.D.)

Pathology and Laboratory ExaminationsNo specific laboratory tests are diagnostically specific for COS. Althoughneuroimaging studies are converging to suggest that children with COShave decreased ACG volumes with age, and an absence of the normaldecreased left-to-right ACG volume asymmetry, this research cannot beused as an index for diagnosis. High incidences of pregnancy and birthcomplications have been reported in the histories of children withschizophrenia, but presently, no specificity has been found in theserisks for childhood schizophrenia. Electroencephalogram (EEG) studieshave not been helpful in distinguishing children with schizophrenia fromother children. Although data exist to suggest that hypoprolinemia isassociated with the risk of schizoaffective disorder because of analteration on chromosome 22q11, no association has been found ofhyperporlinemia with childhood onset schizophrenia.

Differential DiagnosisThe differential diagnosis of COS includes autistic disorder, bipolardisorders, depressive psychotic disorders, multicomplex developmentalsyndromes, Asberger's syndrome, drug-induced psychosis, andpsychotic states caused by organic disorders. Children with COS havebeen shown to have multiple frequently occurring concurrent disorders,including ADHD, oppositional defiant disorder, and depression. Childrenwith schizotypal personality disorder have some traits in common withchildren who meet diagnostic criteria for schizophrenia. Blunted affect,social isolation, eccentric thoughts, ideas of reference, and bizarrebehavior can be seen in both disorders; however, in schizophrenia,overt psychotic symptoms, such as hallucinations, delusions, andincoherence, must be present at some point. When they are present,they exclude a diagnosis of schizotypal personality disorder.Hallucinations alone, however, are not evidence of schizophrenia;patients must show either a deterioration of function or an inability tomeet an expected developmental level to warrant the diagnosis ofschizophrenia. Auditory and visual hallucinations can appear as self -limited events in nonpsychotic

young children who are faced with extreme psychosocial stressors, suchas the breakup of their parents, and in children experiencing a major

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loss or significant change in lifestyle.

Psychotic phenomena are common among children with majordepressive disorder, in which both hallucinations and, less commonly,delusions may occur. The congruence of mood with psychotic features ismost pronounced in depressed children, although children withschizophrenia may also seem sad. The hallucinations and delusions ofschizophrenia are more likely to have a bizarre quality than those ofchildren with depressive disorders. In children and adolescents withbipolar I disorder, it often is difficult to distinguish a first episode ofmania with psychotic features from schizophrenia if the child has nohistory of previous depressions. Grandiose delusions and hallucinationsare typical of manic episodes, but clinicians often must follow thenatural history of the disorder to confirm the presence of a mooddisorder. Pervasive developmental disorders, including autistic disorderwith normal intelligence, often share some features with schizophrenia.Most notably, difficulty with social relationships, an early history ofdelayed language acquisition, and ongoing communication devianceoccur in both disorders; however, hallucinations, delusions, and formalthought disorder are core features of schizophrenia and are notexpected features of pervasive developmental disorders. Pervasivedevelopmental disorders usually are diagnosed by 3 years of age, butschizophrenia with childhood onset can rarely be diagnosed before 5years of age.

Alcohol and other substance abuse sometimes can result in adeterioration of function, psychotic symptoms, and paranoid delusions.Amphetamines, lysergic acid diethylamide (LSD), and phencyclidine(PCP) may lead to a psychotic state. A sudden, flagrant onset ofparanoid psychosis is more suggestive of substance-induced psychoticdisorder than an insidious onset. Medical conditions that can inducepsychotic features include thyroid disease, systemic lupuserythematosus, and temporal lobe disease.

Course and PrognosisImportant predictors of the course and outcome of early-onsetschizophrenia include the child's level of functioning before the onset ofschizophrenia, the age of onset, IQ, response to pharmacologicinterventions, how much functioning the child regained after the firstepisode, and the amount of support available from the family. Childrenwith developmental delays, learning disorders, lower IQ, and premorbidbehavioral disorders, such as ADHD and conduct disorder, seem torespond less well to medication treatment of schizophrenia and arelikely to have the most guarded prognoses. In a long-term outcomestudy of patients with schizophrenia with onset before 14 years of age,the worst prognoses occurred in children with schizophrenia that wasdiagnosed before they were 10 years of age and who had preexisting



personality disorders.

An additional issue in outcome studies is the stability of the diagnosisof schizophrenia. In one study, one third of children who received adiagnosis of schizophrenia were diagnosed with bipolar disorder inadolescence. Children and adolescents with bipolar I disorder may havea better long-term prognosis than children and adolescents withschizophrenia. In adult-onset schizophrenia, family interactions, such ashigh expressed emotion, may be associated with increased relapserates. No clear-cut data are available regarding childhoodschizophrenia, but the degree of supportiveness, as opposed to criticaland overinvolved family responses, probably influences the prognosis.

Childhood-onset schizophrenia appears to be a more malignant type ofschizophrenia which presents a greater challenge to treat withpharmacology and psychosocial interventions. It seems to respond lessto medication than schizophrenia with adult onset or adolescent onset,and the prognosis may be poorer. Positive symptomsâ€”that is,hallucinations and delusionsâ€”are likely to be more responsive tomedication than negative symptoms such as withdrawal. In a recentreport of 38 children with schizophrenia who had been hospitalized, twothirds required placement in residential facilities, and only one thirdimproved sufficiently to return home.

TreatmentThe treatment of COS requires a multimodal approach, includingpharmacologic interventions, family education, social skillsinterventions, and appropriate educational placement. Current researchsuggests that, in adolescents and young adults, early interventionsduring the prodrome of schizophrenia with atypical antipsychotics andpsychosocial support may improve symptoms and delay or preventprogression to full blown schizophrenia. Investigation is needed on therecognition of prodromal states of COS to assess the benefits of veryearly interventions. Current treatments for COS are based on verylimited data. Antipsychotic medications are indicated, given the degreeof impairment in both social relationships and academic functionexhibited by children with schizophrenia. Children with COS may haveless robust responses to antipsychotic medications than adolescents andadults with the same disorder. Family education and ongoing familyinterventions are critical to maximize the level of support that thefamily can give the patient. The proper educational setting for the childis also important, because social skills deficits, attention deficits, andacademic difficulties often accompany childhood schizophrenia.

PharmacotherapyAtypical antipsychotics, serotonin-dopamine antagonists are currentfirst-line treatment for children and adolescents with schizophrenia,



having replaced the dopamine receptor antagonists because of theirmore favorable side effect profiles. The serotonin-dopamine agonists,including risperidone (Risperdal), olanzapine (Zyprexa), and clozapine(Clozaril) differ from the conventional antipsychotics in that they act asserotonin receptor antagonists with some dopamine (D2) activity, butwithout a predominance of D2 receptor antagonism. They arehypothesized to be more effective in reducing positive and negativesymptoms of schizophrenia, and incur less risk of causingextrapyramidal adverse effects. Additional atypical antipsychotics, suchas quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole(Abilify), are also serotonin-dopamine antagonists that are used inclinical practice for children and adolescents with psychotic disorderswho do not respond to other atypical antipsychotics. A limited evidencebase exists to inform the treatment of COS with the atypicalantipsychotics and a need is seen for randomized clinical trials in thispatient population.

A recent double-blind, randomized 8-week controlled trial compared theefficacy and safety of olanzapine to clozapine in COS. Children with COSwho were resistant to at least two previous treatments withantipsychotics were randomized to treatment for 8 weeks with eitherolanzapine or clozapine followed by a 2-year open-label follow-up. Usingthe Clinical Global Impression of Severity of Symptoms Scale andSchedule for the Assessment of Negative/Positive Symptoms, clozapinewas found to be associated with a significant reduction in all outcomemeasures, whereas olanzapine showed improvement on some measuresbut not on all. The only statistically significant measure in whichclozapine was superior to olanzapine was in alleviating negativesymptoms, compared with baseline. Clozapine was associated with moreadverse events, such as lipid abnormalities and a seizure in one patient.

Several recent studies have provided evidence that risperidone, abenzisoxazole derivative, is as effective as the older high-potencyconventional antipsychotics, such as haloperidol (Haldol), and causesless frequent severe side effects, in the treatment of schizophrenia inolder adolescents and adults. Published case reports and limited largercontrolled studies have supported the efficacy of risperidone in thetreatment of psychosis in children and adolescents. Risperidone hasbeen reported to cause weight gain and dystonic reactions and otherextrapyramidal adverse effects in children and adolescents. Olanzapineis generally well tolerated with respect to extrapyramidal adverseeffects compared with conventional antipsychotics and risperidone butis associated with moderate sedation and significant weight gain.

High-potency conventional antipsychotics, such as haloperidol andtrifluoperazine (Stelazine), are available as second-line treatments;however, lower potency antipsychotics, such as chlorpromazine(Thorazine) may be preferable for young children because of their

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decreased risk of dystonic reaction. Acute dystonic reactions do occur inchildren, and 1 to 2 mg a day of benztropine (Cogentin) usually issufficient to treat the extrapyramidal adverse effects.

Children and adolescents who are treated with antipsychoticmedications are at risk for withdrawal dyskinesis when the medication iswithdrawn. The long-term adverse effects, including tardive dyskinesia,are perpetual risks for any patients treated with an antipsychoticmedication.

PsychotherapyPsychosocial interventions aimed at family education, and patient andfamily support are recognized as critical component of the treatmentplan for COS. Psychotherapists who work with children withschizophrenia must take into account a child's developmental level.They must continually support the child's good reality testing and besensitive to the child's sense of self. Long-term intensive andsupportive psychotherapy combined with pharmacotherapy is the mosteffective approach to this disorder.

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