The use of second generation antipsychotics in children and adolescents with bipolar disorder and schizophrenia: A summary of the AHRQ comparative effectiveness review

BACKGROUND

One of the greatest problems with second generation antipsychotics (SGAs), also known as atypical antipsychotics, in children and adolescents, is the lack of labeled indications in this population. Currently, only five agents in the SGA class are approved for use in pediatrics including: risperidone, olanzapine, quetiapine, aripiprazole, and paliperidone. However, children and adolescents suffer from disease states that warrant the use of SGAs, and their use in this population is increasing. SGAs can be effective in treating pediatric patients, but also present with a risk of serious adverse events that can be detrimental to growth and development in young patients.

METHODS

Recently, the Agency for Healthcare Research and Quality (AHRQ), an agency within the Department of Health and Human Services, released a comparative effectiveness review which included an evaluation of the use of SGAs in pediatric patients.¹ The review included results from 81 studies from 1987 to 2011 in which the patient population was less than 25 years old with diagnoses of bipolar disorder or schizophrenia. The statistical results have been included when available in the AHRQ review.¹ This article will summarize the comprehensive review with a focus on bipolar disorder and schizophrenia. Of note, clozapine was not included in this review due to the uniqueness of the drug compared to other SGAs.

BIPOLAR DISORDER

Bipolar disorder is characterized by extreme mood changes. Although considered rare in adults, in children with bipolar disorder, manic and depressive episodes can occur in a single day. It is often difficult to diagnose children with bipolar disorder, because it may be normal in childhood development to have lows and highs in daily behavior. The standard treatment for mania in bipolar I disorder in children includes the use of SGAs. There has been a trend in using SGAs as monotherapy to treat bipolar disorder in children.² Currently, risperidone, olanzapine, quetiapine, and aripiprazole are FDA approved for the treatment of bipolar disorder in pediatric patients (see Table 1).³ Although there are very limited evidence based data on the use of SGAs in autism, labeled agents are included in Table 1 for reference.

Table 1. FDA labeled pediatric indications of second-generation antipsychotics³

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The majority of the studies conducted comparing SGAs in bipolar disorder were comprised of patients that had bipolar type I disorder. The Young Mania Rating Scale (YMRS) is commonly used to evaluate mania symptoms in pediatric patients with bipolar disorder. In two randomized controlled trials (RCTs), patients treated with risperidone had a significant decrease in mania symptoms on the YMRS when compared to olanzapine (95% CI, 1.97 to 11.69).⁴⁵ Risperidone was also shown to decrease mania symptoms on the YMRS when compared to ziprasidone. There was not a significant difference in YMRS scores between other SGAs.⁵ Therefore, based upon efficacy as evidenced by reduction in YMRS scores, risperidone may be the treatment of choice in young patients with bipolar disorder.

SCHIZOPHRENIA

The occurrence of childhood-onset schizophrenia is rare. Only 1 in 10,000 children develop early-onset schizophrenia. Patients with early-onset schizophrenia have a greater risk of substance abuse, suicide, psychosis, and undergo a more severe course of disease than those with late-onset conditions.⁶ SGAs are generally considered first line treatment for decreasing psychotic symptoms associated with schizophrenia.² Risperidone, olanzapine, quetiapine, aripiprazole, and paliperidone have FDA labeled indications for the treatment of schizophrenia in pediatric patients.¹

When comparing SGAs in the treatment of schizophrenia, patients rated olanzapine over quetiapine when compared using a behavioral screening tool called the Strengths and Difficulties Questionnaire (p=0.03).⁵ There was no significant difference between olanzapine and risperidone (5 RCTs) for symptoms of schizophrenia.^7–11

ADVERSE EFFECTS

SGAs are accompanied by substantial side effects including weight gain, dyslipidemia, increased prolactin levels, sedation, and neuromotor events. Children and adolescents are often more prone to SGA side effects than adult patients. Side effects associated with SGA treatment can have detrimental effects on childhood growth and development. Therefore, it is essential that side effects are monitored carefully, and the side effects associated with SGA therapy are understood before initiating therapy. Measures should be taken to choose the appropriate therapy with the lowest side effect profile.

Weight gain is a major adverse effect that pediatric patients may experience while on SGA therapy. Weight gain is related to eating disorders, depression, and other medical comorbidities. Risperidone and olanzapine are associated with causing a significant increase in weight and other metabolic changes. However, children receiving risperidone were shown to have less weight gain, lower fat mass, lower body mass index (BMI), and lower BMI percentiles than those taking olanzapine. Again, when compared to olanzapine, risperidone had significantly lower mean total cholesterol and mean triglycerides. Risperidone appears to be the less problematic of the two drugs in this area. Also, risperidone had less patients shift from a normal baseline weight to obese when compared to quetiapine. Therefore, with regards to effect on weight or other metabolic measures, risperidone appears to be the preferred agent compared to olanzapine with regard to SGAs approved in this patient population.

Olanzapine consistently had more weight gain and dyslipidemia side effects than other SGAs. When compared to both aripiprazole and quetiapine, pediatric patients taking olanzapine were shown to have a significantly greater increase in weight gain, BMI, fat mass, and waist circumference. The review also showed patients receiving olanzapine to have a significant weight increase when compared to those on ziprasidone. An increase in dyslipidemia also occurred more frequently in patients taking olanzapine when compared to aripiprazole and quetiapine. Since weight gain is a major adverse effect in children and adolescent patients on SGA therapy, regular exercise and balanced nutrition should be included as a part of the treatment plan in these patients. Consequently, olanzapine would not be a first choice if weight or other metabolic measures are of concern.

Patients on SGA therapy may also experience hyperprolactinemia, which can affect the development of a growing body. Post-pubertal patients are expected to present with more hyperprolactinemia signs and symptoms than pre-pubertal patients, as pre-pubertal children may not present with side effects related to the reproductive system. SGAs differ in ability to cause hyperprolactinemia, with risperidone being the worst offender. It was shown in patients treated with risperidone, prolactin levels were higher than those treated with olanzapine or quetiapine. Additionally, prolactin levels in pediatric patients were higher when receiving olanzapine compared to quetiapine or ziprasidone. Therefore, in patients where elevations in prolactin are of concern, risperidone should not be the first choice.

Sedation is also a prevalent side effect related to SGA therapy. Pediatric patients need to be alert during the school day to allow for educational progress. In one study, risperidone caused more somnolence than olanzapine in young adults.¹¹ The review also showed that patients receiving ziprasidone withdrew because of adverse events, such as sedation, more frequently than those receiving aripiprazole. Although most agents resulted in some level of somnolence, patients usually develop tolerance to the sedation symptoms in a short amount of time.

Although extrapyramidal symptoms are generally seen in first generation antipsychotics, these symptoms are still a concern for patients on SGA therapy as well. Risperidone is usually considered the most problematic in causing neuromotor symptoms. However, in one small study, dyskinesia was shown more frequently in patients receiving quetiapine than those receiving risperidone or olanzapine.¹² There was not a discussion about movement disorders such as akathisia, dystonia, or pseudoparkinsonism in the comprehensive review. Nevertheless, knowing that children are often more sensitive to side effects in general, clinicians should be observant for any signs and symptoms of movement disorders.

SUMMARY

SGAs play an important role in the treatment of psychiatric disorders in the pediatric population. However, there are limited data for SGA use in children and adolescents. SGAs are accompanied by a broad range of adverse effects. When treating children and adolescents, it is important to select an SGA with a limited side effect profile. For example, aripiprazole and ziprasidone are generally thought to have the smallest possibility of severe side effects. Olanzapine's side effect profile includes weight and metabolic parameters, and needs to be monitored closely. Ziprasidone and quetiapine need to be studied more thoroughly in children and adolescents, but seem to have a lower risk for adverse events when compared to risperidone and olanzapine. Taking all the above into account, the newest member of the SGA class included in the AHRQ review, aripiprazole, may soon become the treatment of choice for symptoms of schizophrenia and bipolar disorder in pediatric patients, as it displays relatively good efficacy and tolerability in younger patients. Overall, SGAs need to be studied more extensively to expand FDA labeled indications for use in the pediatric population in order to treat younger patients more effectively.