Atypical Antipsychotics for Children and Adolescents With Schizophrenia-Spectrum Disorders

Although the onset of psychotic symptoms before the age of 13 years is exceedingly rare, the incidence of schizophrenia rises sharply after the onset of puberty.1 Only 1% of the population has schizophrenia and 30% of these patients experience an onset of psychotic symptoms by age 18 years.2-8 The period that precedes the onset of frank psychotic symptoms (ie, the prodromal phase) has not been well characterized in early-onset schizophrenia-spectrum disorders (EOSS), but retrospective reports have shown that symptoms include high levels of depression and anxiety, emerging cognitive and social deficits, unusual thought content, and (not infrequently) school failure.

 

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Educational Objectives

After reading this article, you will be familiar with:

• Pathogenesis of early-onset schizophrenia-spectrum disorders (EOSS)
• Treatment options for children and adolescents with EOSS
• Benefits versus adverse effects of atypical antipsychotics in children and adolescents with EOSS

Who will benefit from reading this article?
Psychiatrists, pediatric psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing and certification boards.

Although the onset of psychotic symptoms before the age of 13 years is exceedingly rare, the incidence of schizophrenia rises sharply after the onset of puberty.1 Only 1% of the population has schizophrenia and 30% of these patients experience an onset of psychotic symptoms by age 18 years.2-8 The period that precedes the onset of frank psychotic symptoms (ie, the prodromal phase) has not been well characterized in early-onset schizophrenia-spectrum disorders (EOSS), but retrospective reports have shown that symptoms include high levels of depression and anxiety, emerging cognitive and social deficits, unusual thought content, and (not infrequently) school failure.

In the United States, atypical antipsychotics are often prescribed as first-line treatment for children and adolescents with psychotic symptoms. The atypical antipsychotics have lower affinity for dopamine D2 receptors than the typical antipsychotics, and greater affinity for other neuroreceptors-including those for serotonin and norepinephrine.9,10 The superior risk to benefit ratio of an atypical antipsychotic is evident in view of the acute and chronic neurological adverse effects, including extrapyramidal syndrome and tardive dyskinesia that have been associated with conventional antipsychotics.11-13

As illustrated in the case vignette, there are few developmental differences between children and adults in the expression of the core symptoms of schizophrenia (ie, disorganization of thought processes and behavior, distortion of reality manifested by hallucinations and delusions, and negative symptoms).

CASE VIGNETTE

Heidi, 13 years old, was initially seen in our Anxiety Disorder Clinic because of obsessional thoughts with ruminations, high levels of anxiety, and mild depressive symptoms. She was treated with an SSRI at a relatively high dosage without much success. Her symptoms quickly escalated and she became psychotic. She was stabilized with haloperidol, but soon after, she believed she heard the devil telling her to kill herself. The voice was with her constantly.

Haloperidol was gradually cross-tapered with aripiprazole, which was titrated to 30 mg. Akathisia and extrapyramidal symptoms-including dystonias, rigidity, and cogwheeling-developed during aripiprazole therapy. The aripiprazole was stopped and quetiapine was substituted.

Because of the number of her symptoms (eg, suicidal thoughts, obsessionality, anxiety), citalopram was added and titrated to 30 mg/d. Because of the severity of her psychosis, extended-release quetiapine taken orally at bedtime was also added and titrated to 1200 mg. After 4 weeks of treatment, Heidi sufficiently recovered so that she was able to be transitioned to a day hospital program.

After an attempt to decrease the citalopram dosage, Heidi’s depression returned and her obsessions seemed to grow worse. Consequently, the dosage was increased to what it had been. After completing the day hospital program, Heidi returned to school. She has continued to show gradual improvements. She is able to distinguish reality from fantasy and the intensity of her suicidal thoughts has markedly decreased. Because of concerns about weight gain, metformin therapy was initiated and her weight has stabilized.

Pathogenesis

Early-onset schizophrenia is widely thought to be a disorder of brain development. Psychotic symptoms emerge years after brain systems have deviated from normal developmental trajectories for both gray and white matter. Long-term studies indicate that the outcome for EOSS patients is poor.4,14 Most youths require long-term antipsychotic treatment. Successful treatment of an acute psychotic episode, particularly the disorganized behavior associated with positive symptoms, is essential for minimizing the compounding effects of deterioration in social and academic functions.

Neurological correlates of early-onset psychosis center on changes within the dopamine system in the prefrontal cortex during mid to late adolescence.15 These include decreased density of dopamine cells and peak basal dopamine levels.16,17 Dopamine turnover and dopaminergic prefrontal cor-tex input are affected.18-20 There are also changes in dopamine (D1 and D2) receptor concentrations in the striatum (caudate and putamen).21,22

Variations in dopamine metabolism and in noradrenergic and serotonergic regulation during brain development may explain differences in adverse-effect profiles of atypical antipsychotics. These drugs differ in their interactions with the dopamine D2 receptor.23,24 Children and adolescents who are treated with atypical antipsychotics appear to be more sensitive than adults to adverse effects, including weight gain and metabolic problems associated with these agents.25-30 Weight and metabolic problems were a notable problem in the most recent study of olanzapine.31 About 46% of adolescents gained an average of 4.3 kg over a 6-month period. Risperidone may cause prolactin elevations and extrapyramidal symptoms have also been seen with aripiprazole.27,32-36

Treatment with atypical antipsychotics

Recently, there have been placebo-controlled trials of 4 different atypical antipsychotics as well as some head-to-head comparison studies. The placebo-controlled studies included 2 doses of risperidone (1-3 mg and 4-6 mg), 2 doses of aripiprazole (10 mg and 30 mg), 2 doses of quetiapine (400 mg and 800 mg), and a flexible-dose study of olanzapine (2.5-20 mg/d).31,37-39

A comparison of the general efficacy of these medications is presented in Figure 1. Results of the acute-phase placebo-controlled studies show an equivalent therapeutic effect. The Tablesummarizes the major clinical take-home points that can be derived from these trials.

Preliminary data demonstrate that the atypical antipsychotic medications may also target the depressive symptoms that children and adolescents with EOSS frequently experience. Figure 2 shows the decrease in Calgary Depression Scores from a 12-week open-label comparison study of risperidone, olanzapine, and quetiapine.40

Benefits versus adverse effects

In the decision to treat children, there is also a major question about metabolic syndrome and weight gain. Perhaps the most well-documented problems with weight gain were observed in the Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS) study.41 In this 8-week study, there were 3 arms: risperidone, olanzapine, and molindone. The children treated with olanzapine gained an average of 6.1 kg and increased their body mass index (BMI) by an average of 2.2 kg/m2. This dramatic weight change prompted the Data Safety Monitoring Board to stop the assignment of additional patients to the olanzapine arm, after an interim analysis.

Similar changes in weight gain were also observed in the placebo-controlled study of olanzapine.31 At the end of week 6, the BMI for olanzapine was up 1.4 kg/m2 and weight had gone up 4.3 kg. Both of these increases were significantly different from those associated with placebo (P < .001).

Weight gain associated with olanzapine appears to continue beyond the short-term phase of treatment. In a 1-year study, a small cohort of 20 children in the open-label olanzapine group demonstrated some of the major problems with long-term use.42 (Figure 3 shows BMI and percentage of study participants who were either overweight or obese.) Before olanzapine treatment, 46% of the 20 children had either elevated BMI or obesity. By the end of the year, all 20 children had either elevated BMI or obesity. Each of the atypical antipsychotics appears to have problems associated with weight change, with the possible exception of aripiprazole. Findling and colleagues38 found that at day 42, patients treated with 400-mg quetiapine had gained 2.2 kg and those treated with 800-mg quetiapine had gained 1.8 kg. These data suggest that weight gain associated with quetiapine treatment is not a dose-related adverse effect. Approximately 20% of the adolescents had a weight increase of more than 7% over baseline.

Weight gain with risperidone therapy has also been noted. After 6 months of taking risperidone, patients gained 4.2 kg on average and BMI had increased by 1.2 kg/m2.37 Finally, in the aripiprazole treatment group, the weight change from baseline was either unchanged in the 10-mg group or only up 0.2 kg in 6 weeks in the 30-mg group.39

There are fewer systematic data available regarding treatment-emergent abnormalities. Increases in levels of triglycerides and lipids, as well as glucose, may predispose patients to metabolic syndrome. Quetiapine was associated with significant elevations in fasting triglycerides in 10% of the study population in a placebo-controlled short-term trial. Adolescents treated with olanzapine had increases in fasting triglycerides, glucose, total cholesterol, and high-density lipoprotein cholesterol; however, these increases were not statistically significant.

Prolactin elevations are a concern for various reasons, including a possible decrease in future fertility.33 Prolactin elevations have been seen in patients treated with risperidone and olanzapine. Results from a 6-month study show that 9% of the patients treated with risperidone had galactorrhea and prolactin-related adverse effects.37 Kryzhanovskaya and colleagues31 found that compared with baseline, 81% of 72 patients given olanzapine had significantly higher prolactin levels. In contrast, the opposite was seen in patients treated with aripiprazole. Study results showed a mean decrease in prolactin levels of 212 ng/mL in the 10-mg group and 217 ng/mL in the 30-mg group.39 In a study of quetiapine, prolactin levels were decreased in both the active medication and placebo groups.38

The side-effect profile for akathisia and extrapyramidal syndrome is another major issue. The degree of akathisia that is experienced can be seen in the TEOSS study, in which benztropine was given prophylactically to the molindone (typical antipsychotic) group. Despite this intervention, scores on the Barnes akathisia scale increased significantly in the molindone group: 18% of the participants experienced moderate to severe akathisia; 39% required additional benztropine (vs 41% for risperidone and 20% for olanzapine).

In the placebo-controlled studies of aripiprazole, the scores on the Simpson Angus Scale (for extrapyramidal symptoms) were statistically significantly higher for groups receiving 10 mg and 30 mg of this agent.

Parkinsonism occurred twice as often in the group treated with 10-mg aripiprazole as in the placebo group and 4 times as often with 30-mg aripiprazole. There were no differences in the incidence of akathisia or in extrapyramidal symptoms in the group treated with olanzapine compared with the placebo group. In the quetiapine studies, somnolence was a major adverse effect. In the group treated with 400-mg quetiapine, fewer than 5% had increased appetite or dry mouth, and in the 800-mg group, fewer than 10% had those symptoms.

Clozapine

A big question is when to use clozapine. Clozapine was found to be superior to haloperidol in treating both positive and negative symptoms of schizophrenia.27 Clozapine was also more effective than standard-dose olanzapine (up to 20 mg/d).43 After a medication-free washout phase, both olanzapine and clozapine were effective in treatment-resistant children (ages 7 to 16 years). However, clozapine was superior to olanzapine in reducing negative symptoms when compared with the patients’ admission status when taking their baseline antipsychotic.

Last year a study demonstrated that children with schizophrenia had more success with clozapine than with high-dose olanzapine (up to 30 mg/d): 66% of those treated with clozapine responded favorably compared with 33% of those treated with olanzapine.44 Clozapine, as in the previously mentioned study by Shaw and Rapaport,43 was also found to be more effective in reducing negative symptoms than olanzapine.

However, because of the increased risks with clozapine, 4- to 6-week trials of 2 or 3 of the available atypical antipsychotics at therapeutic doses are needed before a change is made to clozapine. In the haloperidol/clozapine study by Kumra and colleagues,27 treatment was discontinued in approximately one-third of the patients treated with clozapine because of neutropenia or recurrent seizures. Finally, substantial weight gain was seen in recipients of clozapine and olanzapine in acute-phase treatment.

Summary

The choice of medication is up to the treating clinician. There are clear advantages to the atypical antipsychotics compared with placebo. The atypical antipsychotics are roughly equivalent in efficacy. However, adverse-effect profiles are markedly different. In the case vignette, for example, severe extrapyramidal symptoms were triggered by 30 mg of aripiprazole, which necessitated a switch to quetiapine.

Adolescent patients with schizophrenia begin to show improvement by the second week of treatment that can be differentiated from improvement seen with placebo. Positive symptoms respond fairly quickly, but dramatic improvements may take a month or more. Improvements in the negative symptoms, cognitive function and anxiety, may take longer than 6 weeks.

In the studies with quetiapine, aripiprazole, and risperidone, improvement was seen more quickly with higher doses than with lower doses in the first several weeks. However, by the end of the 6 weeks, responses to higher and lower doses were approximately equivalent. Using higher doses in an attempt to achieve more rapid results must be balanced against the increased risks of adverse effects. This was especially seen with the aripiprazole study: 10 mg may be the preferable target dose for adolescent patients.

Weight gain and metabolic factors are yet another consideration. Especially for olanzapine and to some extent for risperidone and quetiapine, careful monitoring is needed to prevent weight gain from becoming a significant problem. Preliminary data suggest that metformin may be a safe and effective way of stopping weight gain, increasing insulin sensitivity, and thereby protecting patients, especially patients who are being treated with olanzapine.45

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