INTRODUCTION — Schizophrenia in children and adolescents is a syndrome consisting of positive and negative symptoms of psychosis that impact development and cognitive functioning. The etiology of this syndrome is poorly understood, but early diagnosis and treatment are critical to limit the morbidity of the disorder.

Childhood-onset schizophrenia usually represents a more severe form of the disorder with more prominent prepsychotic developmental disorders, structural brain abnormalities, and genetic risk factors [1-4].

This topic reviews pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents. The epidemiology, pathogenesis, clinical manifestations, course, assessment, diagnosis of schizophrenia in children are reviewed separately. The epidemiology, pathogenesis, clinical manifestations, course, assessment, diagnosis, and treatment of schizophrenia in adults (including long-acting injectable antipsychotics, clozapine, medication to treat side effects, and the evaluation and management of treatment-resistant schizophrenia) are also reviewed separately. (See "Schizophrenia in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Schizophrenia in adults: Epidemiology and pathogenesis" and "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Schizophrenia in adults: Maintenance therapy and side effect management" and "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs" and "Psychosocial interventions for schizophrenia" and "Evaluation and management of treatment-resistant schizophrenia" and "Guidelines for prescribing clozapine in schizophrenia".)

APPROACH TO TREATMENT — Our approach to treating schizophrenia in children and adolescents is described separately. (See "Approach to treating schizophrenia in children and adolescents".)

ANTIPSYCHOTIC MEDICATION — Antipsychotic medication is the cornerstone of treatment for schizophrenia in youth, augmented by psychosocial treatment. Choice of antipsychotic and initial dosing in the pediatric population are reviewed separately and in a table (table 1). (See "Approach to treating schizophrenia in children and adolescents".)

Categories of antipsychotic medications

Second-generation antipsychotics — Randomized clinical trials have shown several second-generation antipsychotics (with the exception of ziprasidone [5]) to reduce positive and negative symptoms of schizophrenia in youth in comparison with placebo:

●Olanzapine [6]

●Aripiprazole [7-9]

●Quetiapine [10]

●Risperidone [11]

●Lurasidone [12]

As an example, a 2017 clinical trial randomly assigned 146 patients age 13 to 17 with schizophrenia to receive either aripiprazole or placebo for a 52-week maintenance period [9]. Over the course of the study, patients assigned to receive aripiprazole experienced a longer mean time to exacerbation of psychotic symptoms/impending relapse compared with placebo (hazard ratio 0.46, 95% CI 0.24-0.88). Aripiprazole had lower rates of treatment-emergent adverse events compared with placebo (3.1 versus 12.5 percent). Rates of weight gain, extrapyramidal symptoms, and somnolence in the aripiprazole group were similar or lower compared with the placebo group.

Comparative clinical trials in youth with schizophrenia have shown greater efficacy for clozapine in comparison to haloperidol and olanzapine [13,14]. Due to its more severe side effect profile compared with other antipsychotics, clozapine’s use is generally restricted to patients who fail to respond to other antipsychotics; its efficacy is reviewed in further detail below. (See 'Clozapine' below.)

However, comparative clinical trials have not shown greater efficacy for paliperidone in comparison to aripiprazole in the treatment of schizophrenia in children and adolescents [15,16].

Clozapine — Clozapine has demonstrated superior efficacy for treatment-resistant schizophrenia in three randomized clinical trials in youth in comparison with haloperidol [13], olanzapine [14], and high-dose olanzapine [17]. As an example, a trial of 39 youths found that the group randomly assigned to receive clozapine had a higher rate of response (ie, a decrease of 30 percent or more on the Brief Psychiatric Rating Scale) compared with high-dose olanzapine (66 versus 33 percent) [17]. These trials enrolled patients as young as seven [13,14].

Due to its more severe side effect profile, the use of clozapine is generally restricted to patients that have not responded to other antipsychotics. (See 'Clozapine' below and "Approach to treating schizophrenia in children and adolescents", section on 'Treatment resistant'.)

Guidelines for prescribing clozapine, including information about pretreatment assessment, administration, treatment monitoring/reporting, and adverse effects in adults, are reviewed separately. (See "Guidelines for prescribing clozapine in schizophrenia".)

First-generation antipsychotics — Few first-generation antipsychotics currently in clinical use have directly been shown to be efficacious for symptoms of schizophrenia in youth. Those that have been shown to be efficacious in clinical trials are listed below:

●Chlorpromazine [18]

●Loxapine [19]

●Haloperidol [19,20]

Perphenazine, while not tested in clinical trials of youths with schizophrenia, is also used in this population based on our and other clinicians’ experience in youth as well as results from efficacy studies in adults.

Long-acting injectable formulations — Although less commonly used in youth than in adults, long-acting injectable (LAI) antipsychotics are used in patients with schizophrenia who have difficultly adhering to daily oral dosing. There has been little rigorous testing of LAI antipsychotics in this population, though published research supports the safety and efficacy of the formulation:

●A randomized clinical trial in 113 adolescents (ages 12 to 17 years) with schizophrenia randomly assigned to paliperidone extended release or oral aripiprazole for eight weeks [15]. Both groups improved over the course of the trial; no difference was seen in response rates between the two drugs (67.9 versus 76.3 percent). Risk of extrapyramidal symptoms was slightly higher in paliperidone extended release over aripiprazole.

●Open trials and case reports have described the use of LAI antipsychotics in 36 children (mean age of 12 years) with bipolar or schizophrenia spectrum disorders [21]. Twenty-four subjects received LAI risperidone and eight received paliperidone palmitate. Fluphenazine decanoate, aripiprazole extended-release injectable, zuclopenthixol decanoate, and olanzapine extended release were each used in one patient case reports. Most cases reported clinical improvement and the majority of individuals were reported to tolerate the medication well.

Optimal dosing of LAI antipsychotics for pediatric schizophrenia is not known. In our clinical experience, older adolescents (16 years and older) are treated with LAI antipsychotics using adult dosing with results similar to those seen in adults (table 2).

Treatment of schizophrenia in adults with LAI antipsychotics is reviewed separately. (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs".)

Side effects

Second-generation antipsychotics — Adverse effects associated with second-generation antipsychotics include metabolic side effects (weight gain, diabetes, hyperlipidemia) QT interval prolongation, akathisia, and tardive dyskinesia. Some of these medications also cause extrapyramidal side effects but generally at rates lower than first-generation agents. Second-generation antipsychotic use in adults is reviewed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

Clozapine — More severe adverse effects of clozapine, particularly agranulocytosis, have generally limited the medication’s use to treatment-resistant cases. (See "Approach to treating schizophrenia in children and adolescents", section on 'Treatment resistant'.)

A 2014 systematic review of 16 trials of clozapine in youth found that sedation and hypersalivation occurred in over 90 percent of patients [22]. Other common side effects were enuresis, constipation, weight gain, and nonspecific electroencephalogram changes (10 to 60 percent).

Neutropenia was seen in 6 to 15 percent of cases. Neutropenia has been found to be more frequent in clozapine-treated children and adolescents compared with adults. As an example, in an eight-month study of 172 youth (mean age, 18 years), 13 percent developed neutropenia [23]; however, the cumulative risk of agranulocytosis was only 0.8 percent over the first year of treatment. Some of the risk may be mitigated by concurrent treatment with lithium to raise the white blood cell count [24,25].

Under the Clozapine Risk Evaluation and Mitigation Strategy program in the United States, the risk of agranulocytosis with clozapine is managed through regular monitoring and registry reporting of neutrophil counts. Clozapine is stopped in cases of moderate and severe neutropenia; the medication can be restarted in some patients [23,25].

Children may be at greater risk for seizure when taking clozapine compared with the adult population. A baseline electroencephalogram should be completed in cases with focal deficits on neurological exam, evidence of neurodevelopmental delay, or other concern of neurological abnormalities including focal neurologic deficits or neurodevelopmental delay. A repeat electroencephalogram is indicated during dose titration or treatment if there are behavioral changes that could be consistent with seizure [26].

Comparative studies in youth have shown that clozapine can result in increased tachycardia or mean blood pressure compared with olanzapine [14]. Weight gain with clozapine (0.9 to 9.5 kg in a study of 97 youths) was less than olanzapine (3.8 to 16.2 kg in 353 youths) in a review of randomized, cohort, and pharmacoepidemiologic studies [14,27]. (See "Guidelines for prescribing clozapine in schizophrenia", section on 'Cardiovascular'.)

First-generation antipsychotics — Common adverse effects of first-generation antipsychotics include extrapyramidal side effects (tremor, bradykinesia, shuffling gait, akathisia), acute dystonic reactions, tardive dyskinesia, and hyperprolactinemia. First-generation antipsychotic use in adults is reviewed separately. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".)

Pimozide, thioridazine and intravenous haloperidol prolong the QT interval, particularly at higher doses. These medications should be avoided in patients with cardiac disease, a family history of sudden death, and in conjunction with other medications that prolong the QT interval such as antiarrhythmics and erythromycin.

Differences in youth — Children and adolescents, compared with adults, are at higher risk of many of the side effects associated with antipsychotic use, including extrapyramidal side effects, withdrawal dyskinesias, elevated prolactin, weight gain, and metabolic abnormalities [28-32]. (See "Metabolic syndrome in patients with severe mental illness: Epidemiology, contributing factors, pathogenesis, and clinical implications" and "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Metabolic dysregulation'.)

Tardive dyskinesias are less common in youth compared with adult and older-adult populations (0.4 versus 6.8 percent) [28-33]. The risk of tardive dyskinesia in children appears to be greatest with first-generation antipsychotics with minimal or no risk seen with second-generation antipsychotics, although some of these data are extrapolated from adult studies [28]. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis".)

Other adverse effects — Nausea and sedation are common side effects of antipsychotic treatment in all patients but often remit over time and should not be considered reasons to terminate treatment [34]. Neuroleptic malignant syndrome, agranulocytosis, myocarditis, cardiomyopathy, and severe allergic reactions are also possible with antipsychotic medications and are a reason to terminate that medication immediately and provide appropriate medical care and support.

Management of side effects associated with antipsychotic medications is reviewed separately. (See "Tardive dyskinesia: Prevention, treatment, and prognosis" and "Metabolic syndrome in patients with severe mental illness: Epidemiology, contributing factors, pathogenesis, and clinical implications" and "Schizophrenia in adults: Maintenance therapy and side effect management".)

PSYCHOSOCIAL INTERVENTIONS — Psychosocial interventions for children/adolescents with schizophrenia, in our clinical experience, are important adjuncts to treatment with antipsychotic medication. There have been few clinical trials of these interventions in youth; however, they are widely used clinically. Most were originally developed for adults; use in children requires customization to fit the patient’s age, development, social setting, family, and risk factors.

The availability of psychosocial treatments for children with schizophrenia varies widely internationally. In the United States, they are more likely to be available in major metropolitan areas with large academic medical centers rather than in smaller cities or more rural areas. Psychosocial treatment programs may be more likely to incorporate principles and techniques from modalities we describe rather than to deliver a series of specific, discrete interventions.

Psychoeducation — Psychoeducation, best provided early in treatment and frequently reviewed, provides children and their parents/support persons information about the illness, medications, and other interventions. It is highly useful to have family members integrated into the treatment team and educated in order to support the youth effectively and to enhance compliance.

There are no clinical trials evaluating the efficacy of psychoeducational interventions for children/adolescents with schizophrenia and their families; however, in our clinical experience, developmentally appropriate psychoeducation is a critical component of care. Psychoeducation and family interventions for schizophrenia in adults are reviewed separately. (See "Psychosocial interventions for schizophrenia", section on 'Family-based Interventions'.)

Individual and family therapy — Individual and/or family therapy for children/adolescents with schizophrenia varies in content but typically includes some combination of education, support, and/or principles of problem solving therapy or cognitive-behavioral therapy (CBT).

Cognitive-behavioral therapy — CBT for children/adolescents with schizophrenia (and in some cases family members) consists of:

●Cognitive approaches to address maladaptive and delusional beliefs.

●Behavioral approaches, including social and vocational skills training. (See 'Skills training' below.)

Treatment goals of CBT include reducing the intensity of delusions and hallucinations (and related distress), improving social functioning, and promoting the active engagement of children and families in treatment.

Clinical trials have found mixed evidence for the efficacy of CBT in children/adolescents with schizophrenia [35-37]. As an example, a clinical trial randomly assigned 62 participants age 15 to 25 years with a first episode of psychosis to receive either CBT or a control condition [36]. After 14 weeks, both groups had reductions in positive and negative symptoms, but no difference was seen between them in symptomatic or functional improvement.

CBT is used in adult schizophrenia to treat patients with symptoms resistant to antipsychotic medication. In contrast, in our clinical experience, all children with schizophrenia could benefit from CBT.

CBT for schizophrenia in adults is reviewed separately. (See "Psychosocial interventions for schizophrenia", section on 'Cognitive-behavioral therapy'.)

Skills training — Social and vocational skills training are important components of psychosocial treatment for children. Surveys of patients consistently show positive functional outcomes as being equally, if not more, important to the patients than remission of symptoms [38]. Social skills training is aimed at children with observed deficits such as problems with attention and working memory (eg, poor affect regulation). All adolescents should receive age-appropriate vocational skills training, which may also include help with placement and support during employment.

A clinical trial supports the use of vocational skills training in this population [38]. Forty-one patients in the United Kingdom ages 15 to 25 years with schizophrenia were randomly assigned to receive individual placement and support or a control condition; patients assigned to the active intervention had higher rates of employment, earnings, and duration of employment compared with control group [39].

Social skills training for adults with schizophrenia is described separately. (See "Psychosocial interventions for schizophrenia", section on 'Social skills training'.)

Therapeutic schools — Therapeutic schools are used to educate children who struggle accessing the curriculum in a typical school setting due to mental illness or other emotional, behavioral, or psychological conditions. These schools vary but may offer academic assistance, counseling, behavior modification, individual and group therapy, as well as developmentally appropriate skill building to support these youth. Children or adolescents with schizophrenia who are treatment-resistant or who have associated cognitive/emotional challenges can benefit from therapeutic schools.

There are no clinical trials of the efficacy of therapeutic schools in youth with schizophrenia.

Cognitive enhancement/remediation — All youth with schizophrenia should receive cognitive enhancement therapy (or the similar cognitive remediation), if available, which consist of:

●Computer-based exercises aimed at slowing deterioration in attention, memory, language, and executive functioning.

●Social-cognitive group sessions for experiential learning and interpersonal interactions.

Clinical trials suggest that cognitive enhancement therapy or remediation may be superior to other psychotherapies:

●A two-year clinical trial randomly assigned 58 youth with early onset psychosis to receive either cognitive enhancement therapy or to enriched supportive therapy, finding that cognitive enhancement therapy led to superior results on social cognition, social adjustment, and symptomatology for cognition [40].

●A three-month trial of cognitive remediation therapy in 40 adolescents with schizophrenia was found to be superior for cognitive flexibility (as evidenced by the Wisconsin Card Sort Test) in comparison to standard therapy [41].

Although the availability of cognitive enhancement therapy, like other psychosocial interventions for youth with schizophrenia, is limited geographically, their availability is expanding to include online resources that can be done by the youth at home, which may provide benefit. Standardized definitions of cognitive remediation/enhancement components have not been well defined; further study is needed.

Cognitive remediation for adults with schizophrenia is described separately. (See "Psychosocial interventions for schizophrenia", section on 'Cognitive remediation'.)

PREVENTION — Psychosocial and pharmacotherapeutic treatments have been tested for their ability to prevent or delay the onset of psychotic disorders in children at high (or “ultra-high”) clinical risk of developing a psychotic disorder. The criteria for these high risk states vary, ranging from prodromal symptoms (ie, disorganized or unusual thought content such as paranoia or suspiciousness, disorganized behavior) to the presence of psychotic symptoms below the threshold of a psychotic disorder.

Psychosocial interventions — A clinical trial randomly assigned 51 youth/young adults (age range 14 to 30) at “ultra-high” risk for psychosis to receive either cognitive behavioral therapy or supportive therapy [42]. No differences were found between groups at 6- or 12-month follow-up, though both groups showed improvement from baseline in attenuated positive symptoms, anxiety, and depression.

The findings are consistent with our clinical experience in suggesting that all youth with these high risk symptoms would benefit from supportive or cognitive-behavioral therapy as well as close clinical monitoring for conversion to psychosis.

Medications — Medications that have been tested, some in combination with psychosocial treatment, in youth at high risk for psychosis include:

Omega-3 fatty acids — Clinical trials are mixed for the effect of long-chain omega-3 polyunsaturated fatty acids (PUFAs; 500 to 1000 mg twice daily) on the rate of transition to a psychotic disorder among youth/young adults with subthreshold psychotic symptoms:

●A trial randomly assigned 81 youth age 15 to 25 years with subthreshold psychosis to receive omega-3 PUFAs (1 gram twice daily) or placebo for 12 weeks [43]. Both groups were offered a nine-session psychosocial intervention. After 12 months, subjects assigned to receive omega-3 PUFAs were less likely to transition to a psychotic disorder compared with the placebo group (4.9 versus 27.5 percent). Omega-3 PUFAs also led to reduced positive, negative and general symptoms, and improved functioning compared with placebo. The incidence of adverse effects did not differ between the treatment groups.

●A trial randomly assigned 304 youth/young adults (mean age 19 years) at ultrahigh risk for psychosis to receive dietary supplementation with long-chain omega-3 PUFAs (1.4 grams daily) in combination with cognitive behavioral case management or placebo plus the psychosocial intervention [44]. After six months, there was no difference between groups in the rate of transition to psychosis (6.7 versus 5.1 percent).

Potential side effects/adverse effects of omega-3 fatty acids include bleeding and heartburn. The medications also have cardiovascular protective effects.

Antidepressants — Two naturalistic studies, one prospective and the other retrospective, found that treatment with antidepressants but not with antipsychotic drugs was associated with reduced rates of progression to a psychotic disorder of adolescents with prodromal symptoms or at other states of high risk for schizophrenia [45,46].

As an example, the prospective observational study of 152 adolescents with prodromal symptoms included 20 subjects treated with selective serotonin reuptake inhibitor antidepressants and 28 treated with second-generation antipsychotics [46]. Polypharmacy was common. The treatment groups did not differ in baseline symptom profiles, with the exception of disorganized thinking, which was more severe in second-generation antipsychotic-treated adolescents. Twelve of the 48 adolescents (25 percent) developed a psychotic disorder, with all converters having been prescribed second-generation antipsychotics. There were no conversions among antidepressant-treated adolescents. Eleven of the 12 converters were nonadherent, with nonadherence more common with second-generation antipsychotics compared with antidepressants (61 versus 20 percent).

Antipsychotics — The use of antipsychotic medication in prodromal or high risk patients with the aim of delaying or preventing conversion to psychosis is controversial and not supported by clinical trials [47,48].

As an example, a clinical trial randomly assigned 60 patients to receive olanzapine (5 to 15 mg/day) or placebo for one year, followed by a one-year period of no treatment. Over the course of the treatment year, in a near-significant finding, a smaller proportion of olanzapine patients compared with placebo patients experienced a conversion to psychosis (17 versus 40 percent). The conversion rate did not differ between groups during the subsequent year without treatment. The olanzapine patients experienced an average 9 kg weight gain compared with the placebo-treated patients.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psychotic disorders".)

SUMMARY AND RECOMMENDATIONS — Schizophrenia in children and adolescents is a syndrome consisting of positive and negative symptoms of psychosis that impact development and cognitive functioning. The etiology of this syndrome is poorly understood, but early diagnosis and treatment are critical to limit the morbidity of the disorder.

●Our approach to selecting treatments for schizophrenia in children and adolescents is described separately. (See "Approach to treating schizophrenia in children and adolescents".)

●Antipsychotic medication is the cornerstone of treatment for schizophrenia in youth, augmented by psychosocial treatment. Multiple first- and second-generation antipsychotic medications have been found to reduce schizophrenia symptoms in children and adolescents. (See 'Antipsychotic medication' above and 'Second-generation antipsychotics' above.)

●Children and adolescents, compared with adults, are at higher risk of many of the side effects associated with antipsychotic use, including extrapyramidal side effects, withdrawal dyskinesias, elevated prolactin, weight gain, and metabolic abnormalities. Tardive dyskinesias are less common in youth compared with adult and older-adult populations than in youth. (See 'Differences in youth' above.)

●Neuroleptic malignant syndrome, agranulocytosis, myocarditis, cardiomyopathy, and severe allergic reactions are possible with antipsychotic medications and are a reason to terminate that medication immediately and provide appropriate medical care and support. (See 'Other adverse effects' above.)

●Psychosocial interventions are important adjuncts to antipsychotic treatment for children/adolescents with schizophrenia, but have received little study in clinical trials.

•Psychoeducation gives children and their parents/support persons information about the illness, medications, and other interventions. (See 'Psychoeducation' above.)

•Age-appropriate training in vocational skills and social skills aims to prevent deterioration in vocational and interpersonal functioning. (See 'Skills training' above.)

•Cognitive remediation therapy consists of computer-based exercises aimed at slowing deterioration in attention, memory, language, and executive functioning. (See 'Cognitive enhancement/remediation' above.)

•Individual and/or family therapy for children/adolescents with schizophrenia varies in content but typically includes some combination of education, support, and/or principles of problem solving therapy or cognitive-behavioral therapy. (See 'Individual and family therapy' above.)

●Several medications aimed at delaying or reversing progression to a psychotic disorder among adolescents with prodromal symptoms or at states of high risk for schizophrenia have been tested in clinical trials. Trials of omega-3 fatty acids have shown mixed results. Selective serotonin reuptake inhibitor antidepressants have been shown to be helpful in a naturalistic study, but have not been tested in a clinical trial. Clinical trials have not found antipsychotics to be efficacious. (See 'Prevention' above.)