The past 5 five years have seen major advances in the diagnosis and treatment of schizophrenia in children and adolescents. This article, reviews the clinical and diagnostic characteristics of schizophrenia in youth with an eye toward recent findings. This article also provides a more extensive review and update of the psychopharmacology of early-onset schizophrenia.
The past 5 years have seen major advances in the diagnosis and treatment of schizophrenia in children and adolescents. This article reviews the clinical and diagnostic characteristics of schizophrenia in youth with an eye toward recent findings. This article also provides a more extensive review and update of the psychopharmacology of early-onset schizophrenia (EOS).
Definitions
Schizophrenia
Schizophrenia is a chronic debilitating disorder associated with deficits in affect, cognition, and the ability to relate socially with others. Symptoms are traditionally described as positive, which include delusions, hallucinations, disorganized speech, and disorganized behavior (including catatonia) or negative, which include flattened affect, paucity of thought, and diminished and/or slowed speech.
EOS
EOS is defined as schizophrenia with onset of psychotic symptoms before 18 years of age. It is typically a chronic condition associated with elevated rates of premorbid abnormalities, significant long-term morbidity, and poor outcome.
Childhood-Onset Schizophrenia
Childhood-onset schizophrenia (COS) is defined as schizophrenia that develops before 13 years of age.
Historical perspective
Kraepelin viewed COS as a rare form of the more typical adult-onset disorder. Over time, however, COS was characterized as part of a general category of childhood developmental syndromes that included infantile autism. When the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM), Second Edition was published in 1968, this opinion still held. Thus, research from this time reflects a broad rubric of pervasive developmental problems.
EOS was eventually recognized as distinct from autism and continuous with the adult-onset disorder. The DSM Third Edition modified the diagnostic criteria for schizophrenia in childhood, using the same criteria as adults regardless of the age of onset. This convention has been maintained with subsequent revisions of both the DSM current edition DSM Fourth Edition (IV) Text Revision (TR) and the International Classification of Diseases (ICD). The evidence to date suggests that results from research on adult-onset schizophrenia can be reasonably extrapolated to children and adolescents, provided developmental differences are taken into account.
Historical perspective
Kraepelin viewed COS as a rare form of the more typical adult-onset disorder. Over time, however, COS was characterized as part of a general category of childhood developmental syndromes that included infantile autism. When the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM), Second Edition was published in 1968, this opinion still held. Thus, research from this time reflects a broad rubric of pervasive developmental problems.
EOS was eventually recognized as distinct from autism and continuous with the adult-onset disorder. The DSM Third Edition modified the diagnostic criteria for schizophrenia in childhood, using the same criteria as adults regardless of the age of onset. This convention has been maintained with subsequent revisions of both the DSM current edition DSM Fourth Edition (IV) Text Revision (TR) and the International Classification of Diseases (ICD). The evidence to date suggests that results from research on adult-onset schizophrenia can be reasonably extrapolated to children and adolescents, provided developmental differences are taken into account.
Epidemiology
The prevalence of EOS is not known. COS is extremely rare, with an estimated prevalence of 1 in 10000. The rate of onset increases during adolescence, with the prime ages of onset for schizophrenia ranging from 15 to 30 years. EOS, particularly COS, presents more often in males. As the age increases, the gender ratio tends to even out.
Clinical features
The diagnostic criteria for schizophrenia as delineated in DSM-IV-TR are age-independent. These criteria are briefly summarized. To make a diagnosis of EOS, the DSM-IV-TR or ICD criteria should be followed. It is important to stress that, despite the historical ambiguity, a consensus has emerged that schizophrenia does develop in childhood, albeit rarely, and can be diagnosed using the DSM criteria.
Overview of Diagnostic Criteria and Characteristic Symptoms
Schizophrenia characteristically presents with positive and negative symptoms. The former include hallucinations, especially auditory, delusions, and disordered behavior and/or speech. Negative symptoms include a generalized loss of energy, apathy, and flattening of affect. At least 2 positive symptoms or 1 positive and 1 negative symptom must be present for a 1 month in order to diagnose EOS, unless the symptoms are treated successfully within that time. An exception to this rule exists wherein this portion of the criteria can be fulfilled by hallucinations or delusions that are particularly florid and/or continuous. The remaining criteria essentially involve evidence of at least 6 months of deterioration in some area of social functioning and exclusion of other disorders (see discussion later).
Diagnostic Challenges and Differential Diagnosis
Although the criteria for diagnosing EOS in children are identical to those for adults, the younger age group presents some specific diagnostic challenges, which is especially true for COS. The main issues are with differentiating psychotic mood disorders, posttraumatic phenomena, and symptom reports suggestive of psychosis when taken out of developmental context. Immature responses of normal children can occasionally be confused with psychotic symptoms; it has been reported that 10% of children from the community may report experiences suggestive of hallucinations or delusions, yet do not have a true psychotic illness.
Clinical course of EOS
Before the onset of schizophrenia, most patients experience prodromal symptoms associated with deteriorating social and intellectual functioning. During this time, children may appear depressed and anxious, while also developing unusual or bizarre behaviors. In teenagers, substance abuse is common, which confounds the diagnostic presentation. In addition, patients who develop EOS, particularly COS, have high rates of premorbid conditions, including early language abnormalities, cognitive disabilities, social withdrawal, and delayed motor development. Patients diagnosed with COS generally have an insidious onset, whereas some adolescents experience an acute onset of the illness.
The onset of positive symptoms (ie, hallucinations, delusions, and disorganized speech and behavior) marks the acute phase of the illness. This phase generally lasts anywhere from 1 to 6 months. Once the acute symptoms are controlled, the patient typically remains impaired, with a predominance of negative symptoms (eg, flat affect, loss of energy, social withdrawal). Patients may also develop a postschizophrenic depression and flat affect. Acute symptoms may recur at varying intervals, and long-term impairment from the negative symptoms is, unfortunately, common.
Prognosis
Follow-up studies of EOS suggest moderate to severe impairment across the lifespan. Poor long-term outcome is predicted by low premorbid functioning, insidious onset, higher rates of negative symptoms, childhood onset, and low intellectual functioning. When followed up into adulthood, youth with EOS demonstrated greater social deficits, lower levels of employment, and a lesser likelihood of living independently relative to those with other psychiatric disorders.
Suicidal behavior is higher in adolescents with first-episode psychosis. In follow-up studies, at least 5% of individuals with EOS die by completed suicide or by accidental death directly because of behaviors influenced by psychotic thinking. Individuals with schizophrenia are also at a higher risk of other morbidities, such as heart disease, obesity, human immunodeficiency virus infection, hepatitis, and diabetes.
Assessment of EOS
The effective treatment of EOS relies on an accurate diagnosis and a thorough assessment to identify any other contributing medical or psychiatric condition and/or psychosocial stressors. Fig. 1 lists the differential diagnosis for EOS.
Psychiatric Assessment
To screen for psychosis, the clinician can ask the child age-appropriate questions, such as “Do you hear voices talking to you when you are alone?” or “You know how you have dreams at night, do you sometimes feel like you have dreams when you are awake in the day?” Youth are sometimes responsive to direct questions about having “trouble thinking” or having their “thoughts now being more confused.” When interviewing intellectually disabled children and children younger than 12 years, the clinicians must ensure that the child truly understands the question. Parents are important sources of information when trying to determine whether a child has difficulty with thinking or perceptions. Changes in behavior and signs of responding to internal stimuli are most easily described by those who know the child best.
Children who do not have true psychotic illnesses sometimes report symptoms suggestive of psychosis. This reporting is particularly true for youth with trauma histories and for those with other types of emotional and conduct problems. Schizophrenia is defined by overt psychotic symptoms and observable mental status changes rather than solely by positive responses to a checklist of questions. Atypical psychotic symptom reports differ qualitatively from those associated with true psychosis. Reports of hallucinations are often much more detailed and organized, with content related to traumatic experiences, anxiety, or demonstrative imaginations. Atypical psychotic symptoms are also more likely to be situationally specific, for example, children who describe hallucinations only when adults are setting limits or telling them “no.”
The diagnosis of schizophrenia should be reassessed as the symptoms evolve over the natural course of the disorder. It is not uncommon that the clinical presentation will change over time. Reevaluation and/or a second opinion becomes more critical when the clinical presentation is atypical and/or the symptoms appear treatment refractory. Structured diagnostic interviews developed for use in pediatric populations with modules specific to psychotic disorders, such as Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS), may help improve the diagnostic accuracy.
Pharmacologic management of EOS
Introduction
This section focuses on the medication management of EOS. It is important to recognize that effective management of EOS requires both psychosocial interventions and medication. Because EOS encompasses a pediatric population, psychosocial interventions should include developmentally appropriate treatment strategies and address family issues.
Antipsychotic medications are the foundation of treatment of EOS ( Table 1 ). Because of a paucity of controlled clinical studies in children and adolescents, medication treatment of EOS has been guided primarily by extrapolation from adult literature and clinical experience.
| FDA Indication for Adults | FDA Indication for Adolescents 13–17 Years | Positive-Controlled Trials in Pediatric Population | |
|---|---|---|---|
| First-Generation Antipsychotics | |||
| Haloperidol | ✓ | ✓ | ✓ |
| Perphenazine | ✓ | — | — |
| Chlorpromazine | ✓ | ✓ | — |
| Molindone a | ✓ | ✓ | ✓ |
| Loxapine | ✓ | — | ✓ |
| Thioridazine | ✓ | ✓ | ✓ |
| Thiothixene | ✓ | ✓ | ✓ |
| Second-Generation Antipsychotics | |||
| Risperidone | ✓ | ✓ | ✓ |
| Olanzapine | ✓ | ✓ | ✓ |
| Quetiapine | ✓ | ✓ | ✓ |
| Aripiprazole | ✓ | ✓ | ✓ |
| Ziprasidone | ✓ | — | — |
| Asenapine | ✓ | — | — |
| Paliperidone | ✓ | — | — |
| Clozapine | ✓ | — | ✓ |
| Iloperidone | ✓ | — | — |
a Molindone is no longer available for sale as of June 2010.
Second-generation antipsychotic agents (SGAs) (with the exception of clozapine) have generally been considered the first-line treatment of EOS, and until recently were widely thought to be safer and more effective than first-generation agents. However, several large adult trials, including the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia (CutLASS) study, and the European First Episode Schizophrenia Trial (EUFEST) study failed to demonstrate the superiority of SGAs over first-generation (typical) antipsychotics. Furthermore, regardless of the medication choice, many patients discontinue their treatment because of lack of efficacy, side effects, or noncompliance.
Efficacy of Antipsychotics in Children and Adolescents
There have been 11 published randomized controlled trials of antipsychotics in children and adolescents ( Table 2 ). Positive findings are noted for several agents, including both first-generation medications (loxapine, haloperidol, thiothixene, thioridazine, and molindone) and second-generation medications (risperidone, olanzapine, and clozapine). Although molindone would seem to be a useful agent for EOS, it has been taken off the market and is no longer available.
| Study | Design | N | Age (y) | Drug | Mean Dose (mg/d) | NNT | Outcome | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Weeks | DB-RPCT | DB-RCT | SB-RCT | Ave Mean | Range | Measure | Findings | |||||
| Pool et al, 1976 | 4 | ✓ | — | — | 75 | 15.5 | 13–18 | LOX HAL PBO | 87.5 9.8 — | — | BPRS CGI-S | Both medications superior to PBO; ns between LOX and HAL; EPS & sedation problematic |
| Realmuto et al, 1984 | 4–6 | — | — | ✓ | 21 | 15.6 | 11–18 | THIX THIO | 0.26 2.57 | — | BPRS | Both medications significantly reduced symptoms |
| Spencer et al, 1992 | 8 | ✓ | — | — | 12 | 8.8 | 5–12 | HAL PBO | 2.02 — | — | CGI-S CGI-I | HAL superior PBO; sedation problematic |
| Kumra et al, 1996 | 6 | — | ✓ | — | 21 | 14.0 | — | CLO HAL | 176 16 | — | BPRS-C | CLO superior to all measures; however, neutropenia and seizures lead to one-third of the patients discontinuing on CLO |
| Sikich et al, 2004 | 8 | — | ✓ | — | 50 | 14.8 | 8–19 | RIS OLA HAL | 4.0 12.3 5.0 | 5 3 — | BPRS-C | Significant improvement with RIS, OLA, HAL; ns between medications; EPS and weight gain higher in youth compared with reports in adults |
| Shaw et al, 2006 | 8 | — | ✓ | — | 25 | 12.2 | 7–16 | CLO OLA | 403.1 26.2 | 6 — | CGI-S/SANS SAPS | Significant improvement with CLO & OLA; ns between medications; marked weight gain in both groups |
| Haas et al, 2007 | 6 | ✓ | — | — | 160 | 15.6 | 13–17 | RIS RIS PBO | 2.6 5.3 — | 6 5 — | PANSS | RIS 1–3 mg & RIS 4–6 mg superior to PBO; higher dose had greater incidence of EPS |
| Findling et al, 2008 | 6 | ✓ | — | — | 302 | 15.5 | 13–17 | ARI ARI PBO | 9.5 27.8 — | 8 6 — | PANSS | ARI 10 mg & ARI 30 mg superior to PBO |
| Kumra et al, 2008 | 12 | — | ✓ | — | 39 | 15.6 | 10–18 | CLO OLA | 403.1 26.2 | 3 — | BPRS-C | CLO & OLA caused significant improvement; ns between medications; 13% (3 patients on CLO, 2 patients on OLA) gained more than 7% of baseline body weight |
| Sikich et al, 2008 | 8 | — | ✓ | — | 119 | — | 8–19 | OLA RIS MOL a | 11.4 2.8 59.9 | — | CGI-I PANSS | OLA, RIS, & MOL significant improvement; ns between medications; OLA & RIS greater weight gain; OLA greatest risk of weight gain and increased levels of cholesterol; MOL a most reports of akathisia |
| Kryzhanovskaya et al, 2009 | 6 | ✓ | — | — | 107 | 16.2 | 13–17 | OLA PBO | 11.1 — | 6 — | BPRS-C PANSS/CGI-S | OLA superior to PBO; 46% vs 15% PBO; patients on OLA gained ≥7% of body weight (higher and more severe in youth compared with reports in adults) |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
