Atypical Antipsychotics for Treatment of Schizophrenia Spectrum Disorders

The number of prescriptions for antipsychotic treatment of teenagers has increased sharply in office-based medical practice.¹ Adolescents with psychotic symptoms frequently present for clinical evaluation, and early-onset schizophrenia spectrum disorders (onset of psychotic symptoms before the age of 18 years) represent an important consideration in the differential diagnosis in these youths. The onset of schizophrenia occurs by the age of 19 in nearly 40% of male patients and 23% of female patients.² Although childhood-onset schizophrenia (onset of psychotic symptoms before age 13) is rare,³ the incidence of schizophrenia rises sharply and steadily after the onset of puberty.⁴ Since a longer duration of untreated psychosis may be a predictor of poor outcomes in first-episode psychosis, early and appropriate treatment is crucial.⁵

The goals of antipsychotic treatment for psychotic episodes are amelioration of acute symptoms; main- tenance of treatment effect; and functional recovery in terms of academics, peer relations, and family life. Although antipsychotic medications remain the cornerstone of treatment for early-onset schizophrenia spectrum disorders, most teenagers require multiple treatment strategies to facilitate rehabilitation, including individual supportive therapy, family psychoeducation, and special classroom placement. These interventions help prevent relapse, enhance treatment adherence, and address deficits in social skills. In addition, once acute psychotic symptoms have resolved, comorbid conditions (eg, substance use) must be addressed, as well as other psychosocial factors that contribute to psychiatric morbidity.⁶

The atypical antipsychotics, which differ from typical antipsychotics because of a decrease in associated extrapyramidal symptoms (EPS), have now become the standard treatment for youth with early-onset schizophrenia spectrum disorders.⁷ For years now, these medications have been given to younger people without specific FDA approval for pediatric populations, and clinicians have provided off-label prescriptions drawing from clinical experience using these medications successfully in adults. However, 3 recently completed double-blind, randomized controlled clin- ical trials reporting the use of risperidone(Drug information on risperidone), olanzapine, and aripiprazole(Drug information on aripiprazole) for early-onset schizophrenia spectrum disorders in teenagers have demonstrated effectiveness relative to placebo.^8-10 As a result of these studies, risperidone and aripiprazole now have a formal indication for the treatment of psychotic symptoms in adolescents with schizophrenia. Several important adverse effects are common with the use of atypical antipsychotics including sedation, metabolic abnormalities, elevated prolactin levels, and movement disorders.

This article reviews the available efficacy and safety data for each atypical antipsychotic. A discussion of the considerations involved in choosing an atypical antipsychotic for this population follows (Table).

The first atypical antipsychotic to be approved by the FDA, clozapine(Drug information on clozapine) is known for its exceptional efficacy and for its considerable associated adverse effects. Although clozapine is not approved for use in pediatric patients, early studies of this medication in youths with early-onset schizophrenia spectrum disorders suggested that it is effective in that group.^11,12 Because it is associated with risks of neutropenia and agranulocytosis, treatment with clozapine is reserved for children and adolescents with treatment-resistant schizophrenia.¹³ Two initial open-label trials of clozapine treatment in youths demonstrated efficacy with mean dosages of 370 mg/d¹⁴ and 227 mg/d.¹⁵

The first randomized controlled trial of clozapine in pediatric patients compared clozapine with haloperidol(Drug information on haloperidol) in adolescent inpatients with treatment-refractory schizophrenia.¹⁶ In this study, initial dosages were based on weight and ranged from 6.25 to 25 mg/d, and were titrated every 3 days by 1 or 2 times the initial dose. The final mean dosage was 176 mg/d. The investigators reported that although clozapine was superior in efficacy to haloperidol, it was associated with adverse effects including neutropenia, which required 1 patient to discontinue the study. Other notable adverse effects observed in patients taking clozapine included hypotension and dizziness, sialorrhea, seizures, and myocarditis.

Risperidone was the first atypical antipsychotic to be released as a first-line agent in the United States and will soon be available in generic form. The most frequently prescribed antipsychotic agent for children and adolescents, risperidone has now been approved by the FDA for the treatment of schizophrenia in adolescents as well as for autistic spectrum disorders in children. After it was introduced in the United States in 1993, early studies using this medication in children and adolescents with early-onset schizophrenia spectrum disorders suggested that risperidone is effective in reducing psychotic symptoms in this group but that it is associated with adverse effects including moderate weight gain, mild sedation, and dose-related EPS.^17-19 In the study by Armenteros and colleagues,¹⁷ 10 adolescents with schizophrenia were treated for 6 weeks beginning with 1 mg bid and increasing by 1 mg to a maximum daily dose of 10 mg. Six of the patients showed significant reduction of symptoms overall, and although adverse motor effects developed in 5 patients, the medication was thought to be generally well-tolerated.

Efficacy of risperidone for the treatment of schizophrenia in adolescents has now been established. Haas and colleagues⁸ studied 160 adolescents with schizophrenia (aged 13 to 17 years) who were randomized to either 6 weeks of treatment with risperidone (1 to 3 mg/d or 4 to 6 mg/d) or placebo. At the end of the study, improvements in treatment outcomes (eg, Positive and Negative Syndrome Scale [PANSS] total, positive and negative symptom subscale scores) were significantly greater in both risperidone groups than in those who received placebo, and there were few observed differences in efficacy between the active treatment groups. However, the higher-dose group had a greater incidence of EPS and dizziness than the lower-dose group.

Overall, the findings indicate that risperidone is effective in the treatment of early-onset schizophrenia spectrum disorders in adolescents, although it is associated with risks of adverse effects such as movement disorders (possibly at an increased rate compared with adults),²⁰ prolactin elevation,²¹ and significant weight gain. Although prolactin elevation has been repeatedly described for youths treated with risperidone, the available data do not suggest that these changes interfere with development in puberty.²²

The next atypical antipsychotic introduced in the United States was olanzapine(Drug information on olanzapine). Pharmacokinetic data for olanzapine use in adolescents suggest that its effect on metabolism is similar to that in adults.²³ Initial studies assessing the use of olanzapine in youth focused on treatment-resistant schizophrenia. In addition, a growing body of research, including case series,²⁴ chart reviews,²⁵ and open-label prospective trials,²⁶ has investigated the use of olanzapine as a first-line treatment option for youth with early-onset schizophrenia spectrum dis- orders. The findings suggest that olanzapine is effective in reducing symptoms in adolescents with these disorders and that it is associated with a low incidence of adverse motor effects.

In a recently completed 6-week, randomized placebo-controlled trial of adolescents with schizophrenia (N = 107), Kryzhanovskaya and colleagues⁹ found olanzapine to be superior to placebo in reducing symptom ratings (ie, overall psychopathology, positive and negative symptoms). In this study, olanzapine was started at 2.5 or 5 mg/d. The titration schedule was flexible, with a final mean dosage of 11.1 mg/d achieved between 4 and 6 weeks. However, patients gained an average of 4.3 kg during this short-term trial, and continued weight gain was observed in patients who enrolled in the 6-month, open-label extension phase. Indeed, among the atypical antipsychotics, olanzapine seems to be associated with a greater risk of weight gain, which limits its practical use. For example, the NIMH Data Safety Monitoring Board stopped enrollment in the olanzapine arm of the Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS) study after an interim analysis revealed alarming levels of weight gain and metabolic changes in children treated with olanzapine.²⁷ Although the findings of a recent study indicated that orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets, the weight gain still remained in excess of what was seen for youth treated with risperidone.²⁸

After quetiapine(Drug information on quetiapine) received its initial indication from the FDA for treatment of schizophrenia in 1997, several stud- ies assessing its use in pediatric populations have been conducted. Early data suggested that it is a helpful and well-tolerated medication for children and adolescents with a variety of psychiatric disorders.²⁹ In the first open-label study that assessed the use of quetiapine in adolescents with psychotic disorders, McConville and colleagues³⁰ demonstrated efficacy and tolerability in a 23-day trial in which 10 adolescents with psychotic disorders were given quetiapine 25 mg bid, with upward titration to 400 mg bid by day 20. The investigators found the drug to be well-tolerated and reported an average mean weight gain of 1.5 kg. Pharmacokinetic studies were also undertaken and showed that adolescents and adults have similar metabolism of this medication.

In an open-label extension of this trial, patients were treated with a physician's choice flexible dose titration, with ending dosages ranging from 300 to 800 mg/d. The investigators reported a significant decrease in psychotic symptoms, as well as a nonsignificant increase in weight after 6 weeks.³¹

Shaw and colleagues³² conducted an open-label, 6-week trial using quetiapine to treat psychotic disorders in children and adolescents with an average final treatment dosage of 467 mg/d. They found the drug to be well-tolerated, with the exception of weight gain of 4.1 kg on average.

Randomized controlled data supporting the use of quetiapine in teenagers with schizophrenia are not yet available. Other adverse effects noted in the use of quetiapine include sedation, hypotension, and dizziness. Studies have suggested that the incidence of treatment-emergent movement disorders in adult patients given a daily dose ranging from 50 to 750 mg does not differ from that seen with placebo.³³

Ziprasidone was approved for use in the United States in 2001 for the treatment of schizophrenia in adults; it now also has an indication for adult bipolar mania. Efficacy and tolerability have been demonstrated in pediatric patients with Tourette syndrome³⁴ and autistic disorders,³⁵ but there are few data regarding its use in children and adolescents with early-onset schizophrenia spectrum disorders. Single-dose pharmacokinetics and the safety of ziprasidone(Drug information on ziprasidone) in children and adolescents have been examined in an open-label study that reported findings that were comparable to those in adults.³⁶ Prompted by concerns about QT prolongation from the adult trials, prospective data have been generated in children and adolescents, which suggested that long-term treatment with low-dose (40 mg) ziprasidone led to prolongation of the QT interval by 28 ± 28 milliseconds.³⁷ Cardiac monitoring according to guidelines recommended by the American Heart Association is advised.³⁸