Childhood-Onset Schizophrenia Medication

Updated: Mar 25, 2019
  • Author: Marshal E Ash, DO; Chief Editor: Caroly Pataki, MD  more...
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Medication

Medication Summary

Historically, atypical antipsychotics are the first-line therapy for individuals with childhood-onset schizophrenia.

Many second-generation antipsychotics have been approved by the FDA in recent years for adolescents to treat schizophrenia including aripiprazole, lurasidone, olanzapine, quetiapine, paliperidone, and risperidone.

The second-generation antipsychotics iloperidone (Fanapt), asenapine (Saphris), cariprazine (Vraylar), and ziprasidone (Geodon) are approved for adult-onset schizophrenia, but not for pediatric patients.

Non-approved second-generation antipsychotics

These medications are approved for adult-onset schizophrenia, but not for pediatric patients. For discussion purposes, information is included here.

Iloperidone (Fanapt) is approved for adult-onset schizophrenia, but not for pediatric patients. It is structurally similar to risperidone and paliperidone. It was FDA approved for the treatment of adult-onset schizophrenia in 2009. It blocks dopamine D-2 receptors and serotonin 5HT-2A receptors but can block histamine receptors and alpha-adrenergic receptors. Consequently, it can cause sedation, weight gain, dizziness, orthostatic hypotension, and reflex tachycardia. Rarely, it can cause electrocardiogram changes, most specifically, QTC interval prolongation. In addition, higher doses of iloperidone can cause extrapyramidal effects and hyperprolactinemia. It has not received indication for the treatment of childhood- or adolescent-onset schizophrenia. [92]

Asenapine (Saphris) is approved for adult-onset schizophrenia, but not for pediatric patients. It is a dibenzo-oxepino pyrrole medication that blocks D-2 and 5HT-2A receptors and has a high affinity for other dopamine and serotonin receptors, histamine receptors, and alpha-adrenergic receptors, but does not have significant anticholinergic effects. It was approved by the FDA in 2009 for the treatment of adult-onset schizophrenia. It can cause somnolence, dizziness, decreased oral sensation, akathisia, parkinsonian symptoms, and weight gain. It can rarely cause prolongation of the QTC interval and hyperprolactinemia. Asenapine has not been approved for use in children or adolescents with schizophrenia or psychotic symptoms. [92]

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First Generation Antipsychotics (Typical)

Class Summary

Controlled trials of haloperidol and loxapine are available, as are single-blind trials of thioridazine and thiothixene. However, thioridazine is no longer a preferred medication because of its significant cardiac toxicity and risk of death.

Although little difference in the efficacy of individual typical antipsychotics is observed, a difference in the adverse effect profile is noted. High-potency antipsychotics (eg, haloperidol) have an increased risk of extrapyramidal adverse effects, whereas low-potency antipsychotics cause more sedation and orthostatic hypotension. Extrapyramidal adverse effects can occur early, late, or during withdrawal.

Problems that occur early include dystonia, parkinsonism, akathisia, and neuroleptic malignant syndrome (NMS). Dystonia affects adolescent boys more often, but parkinsonism is less common in children. The late-appearing and withdrawal adverse effects include choreiform movements or, less commonly, dystonia. Other adverse effects of antipsychotics include weight gain, [103] photosensitivity, decreased white blood cell count, jaundice, blurred vision, constipation, amenorrhea, and gynecomastia.

Haloperidol (Haldol)

Haloperidol is a high-potency antipsychotic of the butyrophenone class that is available in tablet, solution, and injectable forms.

A study published in 1992 compared the efficacy of haloperidol versus placebo in 16 children diagnosed with very-early-onset schizophrenia ranging in age from 5–11 years. Haloperidol was associated with a significant reduction in positive and negative symptoms when compared with placebo.

Haloperidol decanoate is a depot formulation available for monthly intramuscular (IM) injection.

Thioridazine (Mellaril, Mellaril-S)

Thioridazine is a low-potency neuroleptic that demonstrated effectiveness in reducing symptoms in children with schizophrenia in a controlled trial. This agent is administered orally and is available in tablet, concentrate, and suspension forms. However, significant arrhythmogenic effects limit use of this medication.

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Second Generation Antipsychotics (Atypical)

Class Summary

Generally, second generation antipsychotics are chosen as first-line antipsychotic therapy. As of February 2017, aripiprazole, lurasidone, olanzapine, quetiapine, risperidone, and paliperidone have been FDA approved for treatment of schizophrenia in adolescents.

Several studies have been performed investigating the efficacy of atypical antipsychotics in the treatment of childhood-onset schizophrenia. Specifically, A 6-week international, multisite, placebo-controlled trial showed that aripiprazole (10–30 mg), [104] olanzapine (2.5–20 mg), [105] quetiapine (400 mg or 800 mg), [106]  paliperidone (1.5 mg, 3 mg, or 6 mg; 6 mg or 12 mg based on weight), [107] and risperidone (1–3 mg or 4–6 mg) [108] were superior to placebo in improving the Positive and Negative Syndrome scale (PANSS) total score in adolescents aged 13–17 years.

In addition, another study found that risperidone (1.5–6 mg) was superior to a pseudoplacebo of risperidone (0.15–0.6 mg) in treating adolescent-onset schizophrenia. [109] One study found that 279 adolescent schizophrenic patients randomized over an 8-week trial to either low- or high-dose risperidone had significantly lower PANSS in the high-dose than in the low-dose group. [110] In one study, paliperidone did not separate from placebo (at doses of 1.5 mg, 6 mg, or 12 mg), but response rates were significantly superior in both the medium- and high-dose arms. [111] One trial looked at ziprasidone (40–80 mg/d target dose in patients weighing < 45 kg and 80–160 mg in the others) compared with placebo. However, this trial was discontinued when it was determined that the placebo response rate was higher in South America and Asia than in the United States and Europe. [112, 113]

In addition, several head-to-head trials have been conducted comparing the efficacy of several second-generation antipsychotics. Symptom response was not clinically significantly different between olanzapine, risperidone, and haloperidol [114] or between olanzapine and quetiapine [115] in youth with schizophrenia or psychosis. However, one small study demonstrated that clozapine was superior to haloperidol, [116] standard-dose olanzapine, [117] or high-dose (up to 30 mg) olanzapine. [118]  A network meta-analysis studying aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, ziprasidone, and molindone found all antipsychotics to be equally efficacious in treatment of children and adolescents with schizophrenia spectrum disorder, except ziprasidone which was found to be inferior to other antipsychotics. All antipsychotics (except ziprasidone and asenapine) were found to be superior to placebo. Aripiprazole and quetiapine were found to have greatest tolerability (while still having significant adverse side effects.) [119]

In the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study, the efficacy of olanzapine and risperidone was compared with molindone (a first-generation antipsychotic medication) in the treatment of early-onset schizophrenia and schizoaffective disorder in a double-blind multisite trial. No significant difference in response rates on the PANSS was found among treatment groups after 8 weeks of treatment with either olanzapine (2.5–20 mg/day), risperidone (0.5–6 mg/day), or molindone (10–140 mg/day, plus 1 mg/day of benztropine). However, olanzapine and risperidone were associated with greater weight gain, whereas molindone caused more reports of akathisia. [120]

Extrapyramidal adverse effects are less common than those observed with the traditional antipsychotics, although they have been reported with both clozapine and risperidone. Sedation has occurred with all available atypical antipsychotics. Furthermore, studies show that children and adolescents appear to have a higher risk of EPS, akathisia, prolactin elevation, sedation, and metabolic effects of atypical antipsychotics than adults. [121]  A study of adverse outcomes of treatment of early-onset schizophrenia—particularly medication discontinuation and psychiatric hospital admission—found that the choice among risperidone, olanzapine, quetiapine, aripiprazole, or ziprasidone made no difference; there were no statistically significant differences in these two outcomes among these medications. [122]

Weight gain has been a problem with all currently available atypical antipsychotics, although weight gain may be less of a problem with ziprasidone. Pediatric patients with childhood-onset schizophrenia are already at higher risk for obesity and metabolic syndrome. Prescribing second-generation antipsychotics may put these patients at even greater risk for weight-gain and development of metabolic syndrome. It’s suggested clinicians consider the addition of metformin when initiating pediatric patients on second-generation antipsychotics. This is not yet standard of care, but could be considered based on clinical circumstances. [123] In adults, metformin has been shown to reduce the incidence of diabetes by 31% in adults, hence the interest in considering it as a potential metabolic syndrome preventive therapy in the pediatric sphere. [124]

Aripiprazole shown beneficial as maintenance therapy in adolescents, delaying time to exacerbations of psychotic symptoms compared to placebo. [125]

Paliperidone is a major active metabolite of risperidone and the first oral agent that allows once-daily dosing. It is thought to mediate central receptor antagonism of D2 and 5HT2A, and it also elicits antagonist activity at adrenergic alpha1 and alpha2 receptors and histamine-1 receptors. Paliperidone has no affinity for cholinergic, muscarinic, or beta-adrenergic receptors. One case study was found describing the successful use of bromocriptine in mitigating the side effects of paliperidone, hyperprolactinemia and tremor. [126]

Patients treated with olanzapine had higher BMI compared to patients treated with other antipsychotics at six months, but no longer significantly higher at twelve and twenty-four months. [90]

Patients treated with risperidone had worse neurological side effects compared to other antipsychotics at six months, but no longer statistically significantly worse at twelve and twenty-four months. [90]

In a systematic review and Network Meta-Analysis, ziprasidone was found to have “limited or no effect on decreasing total and positive symptoms” in the treatment of schizophrenia in patients less than nineteen years old. [119]

Clozapine is available as a tablet or oral-disintegrating tablet. Though plasma concentrations vary, therapeutic monitoring (checking plasma clozapine levels) should be considered to monitor for medication adherence and assessing for dose adjustment needs. [127]

One small retrospective chart review found clozapine to be safe in the use of treatment for childhood onset schizophrenia; this study noted only three cases (out of 17) of transient neutropenia, and no agranulocytosis or severe infections. They did find more tachycardia on discharge in the clozapine treatment group compared to the control group. [128]  One study found younger age, male sex, and African American ethnicity to be risk factors for developing neutropenia in children and adolescents being treated with clozapine. Overall rates of neutropenia were found to be higher in children and adolescents compared to adults treated with clozapine. [129]

Despite these risks and concerns, clozapine is generally safe and effective in the treatment of refractory early onset schizophrenia. [130]  And, the general tolerability of clozapine is comparable to that of other atypical antipsychotics. [90]  Not only that, but treatment of early onset schizophrenia with clozapine was associated with less discontinuation and greater occupational outcomes at twenty years old compared to non-clozapine use. [131]

Aripiprazole (Abilify)

Aripiprazole improves positive and negative schizophrenic symptoms and is indicated for treatment in adults with schizophrenia and acute manic and mixed episodes associated with bipolar disorder. It is also approved by the FDA to treat schizophrenia in adolescents. Aripiprazole shown beneficial as maintenance therapy in adolescents, delaying time to exacerbations of psychotic symptoms compared to placebo. This agent is hypothesized to work differently than other antipsychotics; it is thought to be a partial dopamine (D2) and serotonin (5HT1A) agonist that antagonizes serotonin (5HT2A). Aripiprazole is available as a tablet, oral disintegrating tablet, oral solution, or intramuscular injection. Injection is indicated for the treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed.

Paliperidone (Invega)

Paliperidone is indicated in adults for the acute and maintenance treatment of schizophrenia. It is also approved by the FDA to treat schizophrenia in adolescents. This agent is a major active metabolite of risperidone and the first oral agent that allows once-daily dosing. It is thought to mediate central receptor antagonism of D2 and 5HT2A, and it also elicits antagonist activity at adrenergic alpha1 and alpha2 receptors and histamine-1 receptors. Paliperidone has no affinity for cholinergic, muscarinic, or beta-adrenergic receptors. One case study was found describing the successful use of bromocriptine in mitigating the side effects of paliperidone, hyperprolactinemia and tremor. This agent is available as an extended-release delivery system via osmotic pressure.

Olanzapine (Zyprexa)

Olanzapine is indicated in adults for treatment of schizophrenia and acute mixed or manic episodes associated with bipolar disorder. It is also approved by the FDA to treat schizophrenia in adolescents. It may inhibit serotonin, muscarinic, and dopamine effects. The efficacy of this agent in schizophrenia is mediated through a combination of dopamine and 5HT2A antagonism, and it also antagonizes muscarinic M1-5, histamine H1, and adrenergic alpha-1 receptors. Olanzapine is available as a tablet, oral-disintegrating tablet, or intramuscular (IM) injection. IM injection is indicated for the treatment of agitation associated with schizophrenia and bipolar I mania.

Patients treated with olanzapine had higher BMI compared to patients treated with other antipsychotics at six months, but no longer significantly higher at twelve and twenty-four months.

Quetiapine (Seroquel)

Quetiapine is an antipsychotic medication used for long-term management of schizophrenia and is indicated in adults for the treatment of schizophrenia, depressive episodes associated with bipolar disorder, and acute manic episodes associated with bipolar I disorder as either monotherapy or adjunct therapy to lithium or divalproex. It is also approved by the FDA to treat schizophrenia in adolescents. This agent is available in tablet form and may act by antagonizing dopamine and serotonin effects. Quetiapine's improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, Parkinsonism, and tardive dyskinesia.

Risperidone (Risperdal, Risperdal Consta)

In children and adolescents, risperidone is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. In adults, this agent is indicated for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and schizophrenia. It is also approved by the FDA to treat schizophrenia in adolescents. Patients treated with risperidone had worse neurological side effects compared to other antipsychotics at six months, but no longer statistically significantly worse at twelve and twenty-four months.

Risperidone is an atypical antipsychotic with potent effects on serotonergic system by binding to dopamine D2-receptor with 20 times lower affinity than for 5HT2-receptor affinity. Open-label studies suggest its effectiveness in the treatment of childhood-onset schizophrenia. Risperidone is available as a tablet, oral-disintegrating tablet, oral solution, or long-acting intramuscular injection

Lurasidone (Latuda)

Benzoisothiazol derivative medication that is structurally related to buspirone. It blocks D-2 and 5HT-2A receptors. It has a high affinity for serotonin 5HT-7 receptors and moderate affinity for alpha-2-adrenergic receptors. It does not have significant anticholinergic or antihistaminic effects. It is a partial agonist at 5HT-1 receptors. Adverse effects include akathisia, parkinsonian symptoms, nausea, agitation, and somnolence. It was approved by the FDA in 2010 for the treatment of adult-onset schizophrenia and now it is indicated for schizophrenia in adults and adolescents (aged 13–17 y).

Ziprasidone (Geodon)

Ziprasidone is indicated in adults for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features, and schizophrenia; intramuscular (IM) injection is indicated for the treatment of acute agitation in adults with schizophrenia in whom treatment with ziprasidone is appropriate and who need IM antipsychotic medication for rapid control of the agitation.

This agent antagonizes dopamine D2, D3, 5HT2A, 5HT2C, 5HT1A, 5HT1D, is alpha1adrenergic, and has a moderate antagonistic effect for histamine H1. Ziprasidone moderately inhibits reuptake of serotonin and norepinephrine. This medication is available as a tablet and IM injection.

Clozapine (Clozaril, Fazaclo)

Clozapine is indicated in adults for management of severely ill patients with schizophrenia who fail to respond adequately to standard pharmacological treatment and for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior based on history and recent clinical state.

Clozapine has been demonstrated to be: (1) effective for childhood-onset schizophrenia in double-blind studies as well as (2) superior to haloperidol in treatment of children with schizophrenia. However, this agent remains second-line because of its major adverse effects. Start clozapine only after failure of medication trials using 2-3 antipsychotics from different classes. This agent is available as a tablet or oral-disintegrating tablet. 

 

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Benzodiazepines

Class Summary

Benzodiazepines have been used in combination with antipsychotic agents early in the treatment of acute psychosis when sedation is needed.

Lorazepam (Ativan)

Lorazepam has been used acutely in agitated children with schizophrenia and may also be helpful in reducing akathisia. This agent is available for oral and parenteral use.

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Antiparkinsonian Agents

Class Summary

Anticholinergic medications have been used to prevent and treat acute dystonia, Parkinsonism, and neuroleptic malignant syndrome. These agents have also been used for tardive dyskinesia.

Benztropine (Cogentin)

Benztropine can be started concurrently with antipsychotic medications to prevent or control extrapyramidal reactions that occur as adverse effects of neuroleptic agents.

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Antihistamines

Class Summary

Antihistamines are possibly useful for the treatment of extrapyramidal adverse effects of antipsychotic agents (eg, dystonia, akathisia). They have also been used for sedation and as mild hypnotics.

Diphenhydramine (Benadryl, Anti-Hist, Diphenhist)

Diphenhydramine can be administered acutely for dystonic reactions or long term for medication-induced Parkinsonism and akathisia.

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Beta-adrenergic Blockers

Class Summary

Beta-adrenergic blockers have been used to treat akathisia, tremor, anxiety, and aggression.

Propranolol (Inderal)

Propranolol may be helpful in treating akathisia.

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Dopamine Agonist

Class Summary

Neuroleptic malignant syndrome (NMS) is an adverse effect of antipsychotic agents and is characterized by fever, muscle rigidity, and autonomic dysfunction. NMS has been treated with dopamine agonists (eg, bromocriptine, amantadine). Other medications used include dantrolene sodium, benztropine, and diphenhydramine.

Bromocriptine (Parlodel)

Bromocriptine is a dopamine agonist that reduces the mortality rate of neuroleptic malignant syndrome.

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