Atypical Antipsychotics for Children and Adolescents With Schizophrenia-Spectrum Disorders

 

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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

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