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 our approach to selecting treatments for schizophrenia in children and adolescents. Pharmacotherapy and psychotherapy for schizophrenia and the epidemiology, pathogenesis, clinical manifestations, course, assessment, diagnosis of schizophrenia in children and adolescents are reviewed separately. The epidemiology, pathogenesis, clinical manifestations, course, assessment, diagnosis, and treatment of schizophrenia in adults (including long-acting injectable antipsychotics, clozapine, and 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".)

●(See "Schizophrenia in adults: Epidemiology and pathogenesis".)

●(See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis".)

●(See "Schizophrenia in adults: Maintenance therapy and side effect management".)

●(See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs".)

●(See "Psychosocial interventions for schizophrenia".)

●(See "Evaluation and management of treatment-resistant schizophrenia".)

●(See "Guidelines for prescribing clozapine in schizophrenia".)

APPROACH TO TREATMENT — To ameliorate symptoms and limit impairments in development and learning [5], prompt diagnosis of schizophrenia and aggressive treatment are necessary. Repeated or prolonged psychotic episodes have deleterious neuropsychological, neurophysiological, and brain structural effects on patients who have been diagnosed with a first psychosis [6-10]. Some evidence suggests that prolonged periods of untreated psychosis may result in increased resistance to conventional treatments [11,12].

Prodromal symptoms — For children/adolescents with prodromal symptoms (ie, disorganized or unusual thought content such as paranoia or suspiciousness, disorganized behavior), we suggest treatment with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine [13], psychosocial interventions, and omega-3 fatty acids (500 to 1000 mg twice daily). The evidence for these treatments is limited.

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 [14,15]. As an example, a clinical trial found omega-3 fatty acids to reduce the rate of transition from sub-diagnostic-threshold psychosis to a psychotic disorder in adolescents [14].

While further trials are needed, particularly in patients with only nonpsychotic, prodromal symptoms, the general health benefits of PUFAs and lack of clinically relevant adverse effects support its use. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Omega-3 fatty acids'.)

SSRIs — A prospective, naturalistic (nonrandomized) study of adolescents with prodromal symptoms found that treatment with an antidepressant was associated with a decreased rate of conversion to a psychotic disorder compared with antipsychotic drug treatment [13]. The study had multiple methodologic limitations. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Antidepressants'.)

Psychosocial interventions — Psychosocial interventions including cognitive-behavioral therapy (CBT), cognitive enhancement therapy, and age-appropriate educational/vocational skills training and support. There are clinical trials supporting their effectiveness for treating schizophrenia in adults, but few trials for schizophrenia in youth and no trials testing their efficacy in preventing or slowing functional deterioration in youth with prodromal symptoms. In our clinical experience, however, skills training and individual psychotherapy can be helpful in slowing the deterioration of cognitive functioning and skill attainment in youth with prodromal symptoms. Cognitive enhancement therapy and CBT for psychosis may also be helpful, if available, but these interventions are most commonly provided in major academic medical centers. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Psychosocial interventions'.)

Other prophylactic medication should be evaluated on a case-by-case basis, including for co-occurring disorders. As an example, a patient with prodromal symptoms that include an anxiety disorder may warrant treatment with an SSRI. An SSRI such as fluoxetine can be prescribed starting at 10 mg daily up to a maximum of 40 mg [13,16]. As a psychotic presentation in childhood could be due to a bipolar diathesis, use of an antidepressant for a major depressive episode should be done with caution. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Prevention' and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)

New patient with schizophrenia — First-line treatment for children and adolescents with schizophrenia is antipsychotic medication with adjunctive psychosocial treatment. Multiple randomized trials have found individual antipsychotics to be efficacious in treating schizophrenia in youth. Clinical trials comparing antipsychotic efficacy [17-22] have found them to have similar effectiveness with the exception of clozapine, which is consistently superior; however, the side effect profile of clozapine limits its use to patients who do not respond to other antipsychotics. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Second-generation antipsychotics'.)

Selecting an antipsychotic medication — Our selection of an initial antipsychotic medication is based on evidence of efficacy in clinical trials in youth with schizophrenia, patient age, and antipsychotic side effect profile.

●Efficacy – We use one of the antipsychotic medications shown in clinical trials to be effective in youth compared with placebo or another antipsychotic. These include several first- and second-generation agents. These are shown on the table (table 1). Further information about these agents can be found elsewhere. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Categories of antipsychotic medications'.)

Clinical trials in youth and adults have not consistently found any one of the antipsychotics more effective than the others (with the exception of clozapine, which, because of possible adverse effects, is reserved for use in treatment resistance). Hence, our selection among these medications is based on patient age and medication side effect profile.

●Age – We generally follow the age guidelines from the antipsychotic indications approved by the Food and Drug Administration in the United States, which were based on the age of enrollees in the efficacy trials of antipsychotics in youth with schizophrenia or other mental disorders (table 1).

●Side effects – The side effect profiles of individual antipsychotic drugs vary widely. In selecting an initial antipsychotic for children with schizophrenia, we generally follow the following principles, choosing antipsychotics that possibly help and are less likely to exacerbate the patient’s current clinical status:

•We start with a second-generation antipsychotic due to their lower rates of extrapyramidal symptoms and tardive dyskinesia compared with first-generation antipsychotics. We typically use risperidone, but choose an alternative for patients with any gynecomastia or elevated prolactin, and in late-adolescence boys. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Prolactin elevation'.)

•For patients with prominent symptoms of a mood disorder, we use aripiprazole. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics", section on 'Aripiprazole'.)

•For patients with prominent insomnia, we use quetiapine. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Sedation'.)

•For patients in whom weight is a concern, we use lurasidone. When possible, we avoid antipsychotics associated with higher rates of abnormalities seen in metabolic syndrome, such as olanzapine [23]. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Metabolic syndrome'.)

•For patients with significant agitation, we use olanzapine. (See "Assessment and emergency management of the acutely agitated or violent adult", section on 'Second-generation (atypical) antipsychotics'.)

Initiating antipsychotic treatment — Prior to starting the antipsychotic, a complete blood count, fasting glucose, cholesterol, triglycerides, transaminases, HgbA1c, and an electrocardiogram with QTc should be obtained. Most antipsychotics have been shown to cause QTc prolongation in limited studies, with the exception of aripiprazole [24-26]. QTc above 500 ms should prompt a review of all medications being prescribed and consideration of aripiprazole.

The dosing of antipsychotic drugs is based on the child/adolescent’s age, weight, and whether or not the patient is antipsychotic-naïve. There are no published, widely agreed upon recommendations for antipsychotic doses in youth.

In children and adolescents, antipsychotics should generally be started at a low dose and titrated slowly. Doses may need to be given at a greater frequency over the course of the day compared with adults to account for the more rapid metabolism in youth. Younger children (eg, a seven-year-old) should generally be started on a much lower dose compared with a 15-year-old. Antipsychotic-naïve children, regardless of age, should also be started on lower, more frequently divided doses.

A table describes the doses we generally use for antipsychotics with established efficacy in youth, including the initial dose and therapeutic range, for younger and older children (table 1). The table also includes the increment by which we typically increase the medication to a potentially therapeutic dose. Once at that dose, we typically wait three days for evidence of a clinical response in a patient with severe symptoms and as long as two weeks in a patient with less severe symptoms. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Second-generation antipsychotics'.)

As examples of antipsychotic dosing in youth:

●An antipsychotic-naïve seven-year-old, is started on risperidone 0.25 mg and titrated up at 0.25 mg increments over three to five days to 1 to 3 mg in two divided doses.

●A 15-year-old is started on risperidone 0.25 mg twice a day and increased every three to five days by 0.5 mg per day to a potentially therapeutic dose totaling 3 mg/day in two divided doses, up to a maximum total daily dose of 6 mg per day.

Psychosocial treatment — Children/adolescents with schizophrenia should receive psychosocial treatment as an adjunct to antipsychotic medication. The following interventions are generally provided to all children/adolescents with schizophrenia (see "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Psychosocial interventions'):

●Psychoeducation is provided to the patient and family early in treatment

●CBT

●Cognitive enhancement exercises

●Educational/vocational skills training and support

Social skills training and cognitive enhancement training are provided to children with deficits in these areas. The availability of these psychosocial interventions varies widely internationally and in the United States, where they more likely to be available in a metropolitan area with an academic medical center, rather than in rural areas.

Clinical trials testing the efficacy of these interventions in children with schizophrenia are largely absent or limited [27-31]. In our clinical experience, we have found them to be helpful in improving adherence and slowing deterioration. Evidence of effectiveness is more robust in adults with schizophrenia. There are no clinical trials comparing different interventions individually or in different combinations. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Psychosocial interventions' and "Psychosocial interventions for schizophrenia".)

Subgroups

First-episode psychosis — Emerging data suggest that first-episode psychosis treatment programs are associated with improved clinical outcomes compared with treatment as usual [32-34]. The programs typically include intensive case management, psychiatric medication management, and psychological and peer support. Many of these programs do not include patients under the age of 18. Treatment of first-episode psychosis is reviewed separately.

Co-occurring substance use disorder — Epidemiologic studies have estimated that 61 to 88 percent of youth 13 to 18 years of age with a mental disorder have a co-occurring substance use disorder [35,36]. (See "Schizophrenia in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Co-occurring disorders'.)

Multimodal treatment for children with schizophrenia should include integrated treatment for co-occurring substance use disorders in youth. Components of integrated treatment include [6]:

●Treatment of both disorders (schizophrenia and substance use disorder) by the same clinician or clinical team. (See "Substance use disorder in adolescents: Epidemiology, pathogenesis, clinical manifestations and consequences, course, assessment, and diagnosis", section on 'Co-occurring disorders' and "Psychosocial interventions for substance use disorder in adolescents".)

●Multimodal care generally includes pharmacotherapy and one or more psychosocial interventions. (See "Psychosocial interventions for co-occurring schizophrenia and substance use disorder" and "Pharmacotherapy for co-occurring schizophrenia and substance use disorder".)

●Collaborative goal setting.

●Respectful and empathic treatment of both conditions.

The availability of integrated care varies widely, particularly for children/adolescents. There are no trials of integrated care in children/adolescents with schizophrenia and a substance use disorder; clinical trials comparing integrated and parallel treatment in adults have shown mixed results [7,8]; however, it is supported by a broad consensus among researchers and clinicians with expertise in the area [9,10].

As cannabis use is a potential risk factor for developing or exacerbating psychosis and may exacerbate concurrent schizophrenia, the importance of reducing or stopping cannabis use should be emphasized to the patient and family [37]. (See "Cannabis use disorder in adults" and "Cannabis use: Epidemiology, pharmacology, comorbidities, and adverse effects".)

Co-occurring mental disorder — There is a dearth of clinical trials testing treatments of co-occurring mental disorders in youth with schizophrenia, although we recommend addressing co-occurring disorders concurrently if the symptoms warrant clinical attention. (See "Depression in schizophrenia" and "Anxiety in schizophrenia".)

As an example, any youth with psychotic symptoms or in high-risk states have increased rates of trauma exposure, including physical, emotional, and sexual abuse [38]. Trauma-focused CBT may be helpful for patients diagnosed with schizophrenia that also exhibit symptoms of posttraumatic stress disorder in youth. (See "Psychosocial interventions for posttraumatic stress disorder in children and adolescents", section on 'Individual trauma-focused CBT'.)

Response to initial treatment

Good response — Once an effective clinical response to an antipsychotic is achieved, the medication should be maintained at lowest possible dose for symptom management to reduce risk of adverse effects. There are no controlled studies looking at discontinuation of treatment, as there is no cure for schizophrenia and there are no known ways to recover from the neuronal damage associated with schizophrenia.

Poor or partial response — Approaches to poor or partial responses to an initial second-generation antipsychotic medication include reviewing medication adherence, increasing the antipsychotic dose, or changing to a different antipsychotic. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Medication adjustments'.)

When changing to another antipsychotic after an initial unsuccessful trial, we typically try another second-generation antipsychotic. After two such trials, we would use first-generation antipsychotic, such as haloperidol (table 1).

When discontinuing an initial antipsychotic because of a lack of efficacy or intolerable side effects, the drug should be tapered gradually, eg, reduced by approximately 30 percent per week. Typically, cross tapering off of one antipsychotic while initiating another antipsychotic is most helpful to help prevent the re-emergence of symptoms. (See 'Side effects' below.)

For patients who experience a partial response after a monotherapy trial greater than six weeks at maximum dose, we would add a first-generation antipsychotic like haloperidol or perphenazine.

Side effects — Youth receiving antipsychotic medication should be monitored for side effects, including acute dystonias, metabolic syndrome, extrapyramidal symptoms, akathisia, and tardive dyskinesia. Antipsychotic adverse effects are reviewed in greater detail separately. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Side effects'.)

A schedule for routine monitoring for the metabolic effects of antipsychotic drugs is recommended (table 2). More frequent measurements may be necessary for some patients (eg, more frequent assessment of lipids and glucose in patients with significant weight gain) or for patients on specific antipsychotics.

The Abnormal Involuntary Movement Scale should be administered at six-month intervals to youth treated with antipsychotics to assess for tardive dyskinesia (form 1).

Some side effects of antipsychotic medications may be responsive to lower doses or changes to alternative antipsychotics. Medications used to treat specific side effects should be adjusted for weight of the child.

Poor adherence — Long-acting injectable antipsychotics, used for schizophrenia in adults unable to adhere to daily oral administration, have not been sufficiently studied in younger children to recommend their use. Older adolescents (≥16 years) with poor adherence are sometimes treated with them at adult doses (table 3). (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs".)

Treatment resistant — Childhood-onset schizophrenia and early-onset schizophrenia are often resistant to treatment. The Treatment of Early-Onset Schizophrenia Spectrum Disorders study found that more than half of participants did not respond to antipsychotic medication adequately after eight weeks of treatment, regardless of the specific antipsychotic [17].

For patients with a clear diagnosis of schizophrenia who experience an inadequate response to two or more adequate trials of other antipsychotics (either residual symptoms or intolerable side effects), we suggest treatment with clozapine. An adequate trial is considered to be six to eight weeks in length at the maximum tolerated dose.

Obtaining a baseline clozapine level in youth can be useful to evaluate whether subsequent deterioration may stem from low plasma levels due to increased metabolism or nonadherence. A six-week study of clozapine plasma levels in 11 youth with schizophrenia found that clinical improvement in symptoms was directly correlated to plasma concentration and increased as concentration increased [39].

The efficacy and side effects of clozapine in youth are described separately. (See "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Clozapine'.)

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".)

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

●For youth with prodromal symptoms (ie, disorganized or unusual thought content such as paranoia or suspiciousness, disorganized behavior), we suggest treatment with a selective serotonin reuptake inhibitor such as fluoxetine rather than an antipsychotic medication with the aim of delaying conversion to schizophrenia (Grade 2C). We additionally treat these patients with omega-3 fatty acids and psychosocial interventions to the extent they are available. (See 'Prodromal symptoms' above and "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Prevention'.)

●We suggest first-line treatment of schizophrenia in youth with an antipsychotic rather than other medications (table 1) (Grade 1B). We favor initially using a second-generation antipsychotic with lower sedation and fewer problems with metabolic syndrome. Individual patient characteristics can influence drug choice. (See 'New patient with schizophrenia' above and "Pharmacotherapy and psychosocial interventions for schizophrenia in children and adolescents", section on 'Antipsychotic medication'.)

●Antipsychotic dosing is based on the patient’s age, weight, and whether or not the patient is antipsychotic naïve (table 1). We generally follow the age guidelines from the indications approved by the Food and Drug Administration in the United States, which were based on the age of enrollees in the efficacy trials of antipsychotics in youth with schizophrenia or other mental disorders. (See 'Initiating antipsychotic treatment' above.)

●Prior to starting the antipsychotic, a complete blood count, fasting glucose, cholesterol, triglycerides, transaminases, HgbA1c, and an electrocardiogram with QTc should be obtained. (See 'Initiating antipsychotic treatment' above.)

●For antipsychotic-treated youth with schizophrenia, we suggest adjunctive psychosocial treatment that includes psychoeducation, cognitive-behavioral therapy, cognitive enhancement, and age-appropriate vocational skills training and support rather than other psychosocial interventions (Grade 2C). Cognitive remediation and social skills training should be provided to patients with deficits in these areas. (See 'Psychosocial treatment' above.)

●Strategies for patients who experience a poor or partial response to antipsychotic treatment of schizophrenia include dose adjustments and changes to another antipsychotic (eg, a first-generation antipsychotic). (See 'Poor or partial response' above.)

●For patients who experience insufficient improvement from two or more adequate trials of other antipsychotics, we suggest treatment with clozapine rather than another antipsychotic (Grade 2B). An adequate trial is considered to be six to eight weeks in length at the maximum tolerated dose. (See 'Treatment resistant' above and "Guidelines for prescribing clozapine in schizophrenia".)