Child & Adolescent Psychopharmacology News Volume 16 Number 1, 2011
ROBERT L. FINDLING, M.D., EDITOR
Antipsychotics and Autism: Weight, Metabolism, and Safety
CONTENTS CME Test Article
Jennifer Yen, M.D., Monica Grover, M.D., and Alice Mao, M.D.
In the past two decades, advances in the pharmacological treatment of children and adolescents in psychiatry have resulted in the use of typical (first generation) and atypical (second generation) antipsychotics to target specific symptoms for a variety of DSM-IV TR disorders, including bipolar disorder, schizophrenia, obsessive compulsive disorders, anorexia nervosa, Tourette’s Disorder and pervasive developmental disorders. Psychosis, mania, poor frustration tolerance, impulsivity, aggression, mood instability, etcetera, are among the various symptoms treated with antipsychotics. Since the late 1990s, there has been a transition from the use of typical antipsychotics such as haloperidol, chlorpromazine, and fluphenazine to atypical antipsychotics such as zisprasidone, olanzapine, quetiapine, and aripiprazole in the treatment of these symptoms. The growing trend appears based on evidence that there is an improved side effect profile with atypical antipsychotics compared to typical antipsychotics, specifically with decreased extrapyramidal symptoms (Correll, Leucht, & Kane, 2004; Kane, 2001). With the increase in the use of these drugs there is a heightened awareness of metabolic and endocrine adverse effects that occur in children and adolescents, such as increased appetite, weight gain, hyperglycemia, and hyperprolactinemia.
Educational Objectives Upon completion of this activity, participants should be able to: • Enumerate the types of first and second generation antipsychotics available for treating autism in children and adolescents. • Describe the efficacy for symptoms and side effect profiles in these antipsychotics. Target Audience This CME activity is intended for child and adult psychiatrists, pediatricians and other healthcare professionals with an interest in the psychopharmacology and treatment practices for child and adolescent psychiatric disorders. Physician Accreditation This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medical Education Resources and Guilford Publications. Medical Education Resources is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Medical Education Resources designates this educational activity for a maximum of 1 AMA PRA Category 1 creditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Release Date: 5/11 Expiration Date: 5/12 Disclaimer The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Medical Education Resources or Guilford Publications. The authors have disclosed if any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER or Guilford Publications. Before
Focus •
Antipsychotics and Autism: Weight, Metabolism, and Safety 1
New Research •
Adolescent Depression Resistance to SSRI
12
•
Safety and Efficacy of ABT-089 in Pediatric ADHD
14
• CME Post-Test
13
prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management. Disclosure of Conflicts of Interest Medical Education Resources (MER) insures balance, independence, objectivity and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, planners, managers and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure that all scientific research referred to, reported or used in a CME activity conforms to the generally accepted standards of experimental design, data collection and analysis. MER is committed to providing its learners with high quality CME activities that promote improvements or quality in healthcare and not the business interest of a commercial interest. The faculty reported the following financial relationships with commercial interests: Name of Faculty: Jennifer Yen, M.D., Monica Grover, M.D., and Alice Mao, M.D. Reported Financial Relationship: Dr. Mao has disclosed that she is a paid speaker and consultant for pharmaceutical companies in her area of expertise. Dr. Yen and Dr. Grover have no financial relationships to disclose. The content planners and managers reported the following financial relationships with commercial interests: Name of Planner or Manager: Victoria Smith, M.D. (MER) Reported Financial Relationship: No financial relationships to disclose. Name of Educational Partner Manager: Robert L. Findling, M.D. (Guilford). Dr. Findling has disclosed that his research has been supported in part by the pharmaceutical industry.
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EDITORIAL BOARD Robert L. Findling, M.D. Case Western Reserve University School of Medicine, Cleveland, OH Gabrielle Carlson, M.D. Stony Brook University School of Medicine, Stony Brook, NY Normand Carrey, M.D. IWK Health Centre, Halifax, NS Laurence Greenhill, M.D. NYS Psychiatric Institute, New York, NY Joan Luby, M.D. Washington University School of Medicine, St. Louis, MO Bruce Meltzer, M.D. UMass Memorial Medical Center, Westborough, MA Lukas Propper, M.D. IWK Health Centre, Halifax, NS Mark Riddle, M.D. Johns Hopkins University, Baltimore, MD Adelaide Robb, M.D. Children’s National Medical Center, Washington, DC Dara J. Sakolsky, M.D., Ph.D. University of Pittsburgh Medical Center, Pittsburgh, PA Robert Stansbrey, M.D. University Hospital of Cleveland, Cleveland, OH Child & Adolescent Psychopharmacology News (ISSN 1085-0295) is published six times per year (Feb [1], Apr [2], June [3], Aug [4], Oct [5], Dec [6]) by Guilford Publications, 72 Spring Street, New York, NY 10012. SUBSCRIPTION PRICE: Volume 16, 2011 (six issues) Individuals $150.00 ($160.00, Canada and foreign) and Institutions, $265.00 ($280.00, Canada and foreign). Orders by MasterCard, VISA, or American Express can be placed by Phone at 800-365-7006, Fax 212-966-6708, or E-mail news@guilford.com; in New York, 212-431-9800. Payment must be made in U.S. dollars through a U.S. bank. All prices quoted in U.S. dollars. Pro forma invoices issued upon request. Visit our website at www.guilford.com. Guilford’s GST registration number: 137401014. CHANGE OF ADDRESS: Please inform publisher at least six weeks prior to move. Enclose mailing label with change of address. Claims for lost issues cannot be honored four months after mailing date. Duplicate copies cannot be sent to replace issues not delivered because of failure to notify publisher of change of address. Postmaster: Send address changes to Child & Adolescent Psychopharmacology News, Guilford Press, 72 Spring Street, New York, NY 10012. Photocopying of this newsletter is not permitted. Inquire for bulk rates. IMPORTANT NOTICE This publication is intended to provide accurate and authoritative information regarding the subject matter covered. It is sold with the understanding that the publisher is not engaged in rendering medical, psychological, financial, legal, or other professional services. The recommended doses of medications cited in this newsletter are not meant to serve as a guide for prescribing of medications. Physicians, please check the manufacturer’s product information sheet or the PHYSICIAN’S DESK REFERENCE for further information and contraindications.
Antipsychotics and Use in Autism Recently, in children and adolescents with autism, antipsychotic medications have been used more frequently to treat symptoms of irritability, aggression, and self-injury. A recent survey looking specifically at psychotropic drug use in children with pervasive developmental disorders revealed that half of the patients were currently being prescribed a psychotropic drug, and approximately 16.5% were taking an antipsychotic drug in conjunction with behavioral interventions, such as applied behavioral analysis (Aman, Lam, & Van Bourgondien, 2005). Upon review, the antipsychotic medication was, in most cases, used to treat mood and behavioral disturbances such as irritability, aggression, and agitation (Posey et al., 2008). The theory behind the efficacy of antipsychotics in treatment of mood and behavioral symptoms in children and adolescents with autism involves both dopamine and serotonin neurotransmission (Posey & Stigler, 2008). Prior research indicated dopamine is integral to motor and cognitive functioning (Moore & Bloom, 1979), and early trials revealed dopaminergic drugs worsened the symptoms of autism, with dopamine-blocking drugs associated with improvement in the same symptoms (Campbell et al., 1972, 1976). In similar fashion, serotonin, which plays a critical role in the immature brain, directing proliferation and maturation of neurons (Whitaker-Azmitia, 1993), was found in elevated whole blood 5-HT levels in children with autism (Schain & Freedman, 1961). Typical antipsychotics have been found to affect dopamine levels, while atypical antipsychotics affect both dopamine and serotonin levels in the brain and, over the years, researchers have tested their use in the treatment of symptoms of autism. The objectives of this paper are to review the current typical and atypical antipsychotic medications that have been studied in children and adolescents with autism and discuss current clinical perspectives on how to manage metabolic side effects if they occur after initiation of treatment with atypical antipsychotic medications. Only
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two of the medications discussed have received FDA approval for the treatment of irritability and mood instability symptoms in autism. In addition, the available data on metabolic risks associated with each medication will be summarized. Guidelines for monitoring and treatment of children and adolescents treated with antipsychotics for irritability and agitation associated with autism will be reviewed, with focus on clinical considerations for outpatient management.
First-Generation, or Typical, Antipsychotics In the 1970s, several studies were published that examined the effects of different conventional antipsychotics in heterogeneous groups of children that included subjects with autism. Several conventional antipsychotics were studied comparing one active drug with another. Drugs studied included chlorpromazine, trifluoperazine, thiothixene, trifluperidol, fluphenazine, and molindone. Extrapolation of these findings to treatment today is challenging because of lack of consistency in methodology, broad inclusion criteria, and lack of standardized outcome measures. Haloperidol In an early study, young patients with autism treated with haloperidol showed significant improvement in withdrawal and stereotypy, as well as associated acceleration of acquisition of imitative speech when the medication was combined with behavioral interventions (Campbell, 1978). The most common side effect reported was dose-related sedation. Notably, two of the 40 subjects in this study developed acute dystonic reactions. Reports of the development of tardive dyskinesia, including withdrawal dyskinesia, over long-term use of haloperidol resulted in the decline of the use of typical antipsychotics for disruptive behavioral symptoms of autism (Campbell et al., 1997; Perry et al., 1989). As noted earlier, in the early studies of typical antipsychotics there was no consistent methodology for monitoring for metabolic effects, so limited information is available about
Table 1. Major Clinical Trials Involving Metabolic/Endocrine Side Effect Findings for Risperidone Study Authors Pandina et al. (2006)
Study Type*
Length
Age
N**
Dose Range
Appetite Increase
Weight Gain
Avg Weight Gain
Prolactin Change
Prolactin Avg. Change
DB, PC
8 week
5-12 yrs
55
0.5-4.2 mg
11%
3.60%
1.6-3.2 kg
N/A
N/A
RUPP (2002)
DB, R, PC
8 week
5-17 yrs
101
0.5-3.5 mg
24-49%
N/A
2.7 +/- 2.9 kg
N/A
N/A
RUPP (2005)
open-label
16 week
5-17 yrs
63
3.5-4.5 mg
N/A
N/A
5.1 +/- 3.6 kg
N/A
N/A
DB, PC
8 week
5-17 yrs
101
0.5-3.5 mg
32.6-83%
100%
0.5 SD units
N/A
N/A
Anderson et al. (2007)
DB, R, PC
8 week
5-17 yrs
101
0.5-3.5 mg
N/A
N/A
N/A
100%
39.0 +/- 19.2 ng/dL
Martin et al. (2004)
DB, R, PC
8 week
5-17 yrs
63
3.5-4.5 mg
N/A
100%
5.6 +/- 3.9 kg
Aman et al. (2005)
Note. *DB (double-blind), R (randomized), PC (placebo-controlled). **N = number of patients.
weight gain, incidence of hyperglycemia, prolactin elevation, and changes in cholesterol and triglyceride levels.
the medications are utilized to treat the irritability, self-injury, and aggressive behavior in autism.
Other First-Generation Antipsychotics
Risperidone (FDA Approved)
Trials reviewing safety and efficacy of other first-generation antipsychotics, such as trifluoperazine (Fish et al., 1966), fluphenazine (Faretra et al., 1970), chlorpromazine (Tarjan et al., 1957), and pimozide (Naruse et al., 1982) all revealed overall improvement in stereotypy, social withdrawal, irritability, and verbal communication over placebo, with similar side effect profile to haloperidol.
Second-Generation, or Atypical, Antipsychotics In the adult population, multiple randomized controlled trials with various psychiatric diagnoses have been performed with emphasis on safety and adverse events. Clozapine and olanzapine have been consistently found to have the highest risk in adults, with regards to weight gain, risk for diabetes, and worsening lipid profile. Risperidone and quetiapine have moderate weight gain, but have inconsistent data for longterm risk for diabetes and lipid profile. Aripiprazole and zisprasidone have been ranked as having the least risk of causing metabolic profile based on research, with no clear effect on risk for diabetes or lipid profile (ADA, 2004). More recently, trials have also been performed in the child and adolescent population to determine whether the same weight and metabolic trends are present when
In October 2006, risperidone was approved by the U.S. Food and Drug Administration (FDA) for treatment of irritability in children and adolescents with autism from ages 5–16. The approval was based on six short- and longterm studies regarding risperidone’s efficacy and safety in autism (see Table 1 for summary of clinical trials). One of those major studies was conducted by the NIMH funded Research Units on Pediatric Psychopharmacology Autism Network (RUPP, 2006). In an 8-week, randomized controlled study, significant statistical and clinical improvement of symptoms of irritability, as demonstrated by reduction in the Aberrant Behavior Checklist—Irritability subscale, was shown in patients treated with risperidone. A long-term maintenance study conducted by RUPP showed that those patients who continued on risperidone showed a lower rate of relapse compared to those who were maintained on placebo. Risperidone treated subjects had an average weight gain of 2.7 kg, as compared with 0.8 kg with placebo. More recently, a Cochrane review was done of all randomized controlled trials of risperidone versus placebo for patients with autism from 1966 to 2006. Three studies were found to meet criteria for both randomized and doubleblind and were reviewed (McDougle, 1998; RUPP, 2002; Shea, 2004). Re-
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sults revealed evidence of risperidone being beneficial for the treatment of irritability, stereotypy, and social withdrawal in these patients. However, there were reports of adverse events, most commonly involving increased appetite and marked weight gain in children aged 5 to 17 (Jester, ArefAdib, & Coren, 2007). In a review by Malone and Waheed (2009), children and adolescents on risperidone had a mean weight gain of 3–6 kg. In addition, hyperprolactinemia was cited specifically with administration of risperidone, although elevated prolactin levels were not tightly correlated with potential clinical adverse events (Hellings et al., 2005; Masi et al., 2003). Aripiprazole (FDA Approved) Aripiprazole is the only antipsychotic that has partial D2 and 5HT1A receptor antagonist properties, which theoretically reduces dopamine activity in the mesolimbic system and enhances dopamine activity in the mesocortical and nigrostriatal systems, resulting in a decreased propensity to cause weight gain, adverse motor effects and hyperprolactinemia (Malone & Waheed, 2009). The two pivotal studies, performed in 2009 and utilized for FDA approval, were conducted by Owen et al. and Marcus et al. (see Table 2 for summary of clinical trials). In both studies, the authors evaluated the efficacy of aripiprazole in multiple treatment doses versus placebo in the treatment of irritability, tantrums, aggression, and self-injury in children and adolescents with autism. In both studies, by week
Table 2. Clinical Trials Involving Metabolic/Endocrine Side Effect Findings for Aripirazole Study Type*
Length
Age
N**
Dose Range
Appetite Increase
Weight Gain
Avg Weight Gain
Prolactin Change
Prolactin Avg. Change
Marcus et al. (2009)
DB, R, PC
8 weeks
6-17 yrs
218
2-15 mg
5.1-19.2%
1.7-7.7%
1.3-1.6 kg
100%
Decrease of 5.2-5.8 ng/dL
Owen et al. (2009)
DB, R, PC
8 weeks
6-17 yrs
98
2-15 mg
14.90%
N/A
1.9-2.0 kg
97.60%
Decrease of 6.3 ng/dL
Study Authors
Note. *DB (double-blind), R (randomized), PC (placebo-controlled). **N = number of patients.
8, all aripiprazole dose groups produced significantly greater improvement than placebo in aberrant behaviors, with the most common side effect leading to discontinuation being sedation. When evaluated for metabolic concerns, weight gain on aripiprazole was around 1–2 kg, compared to placebo, which was between 0.5–1 kg, and dose dependent. There was mild elevation in triglyceride levels compared to placebo in one of the two studies, but both studies revealed statistically significant decreases in prolactin levels when compared to placebo (Owen, Marcus et al., 2009). In addition, other studies have evaluated metabolic parameters with aripiprazole, such as cholesterol, fasting glucose, and triglyceride levels, and found no significant changes during treatment with aripiprazole from baseline and in comparison to placebo (Biederman et al., 2007; Findling et al., 2008; Owen et al., 2008; Stigler et al., 2009; Werner et al., 2008). Olanzapine There is limited research in the use of olanzapine to treat symptoms in children and adolescents with autism, but both open label and double-blind studies have been conducted. Malone et al. (2007) found that when olanzapine was compared with haloperidol in treating children from age 5–12 years with autism, both patient groups showed improvement in the symptoms of irritability and social withdrawal. In the first double-blind, placebo-controlled olanzapine study of 11 subjects with PDD, there was noted to be a significant linear trend on the Clinical Global Impressions-Improvement (CGI–I) scale, with 50% on olanzapine versus 20% on placebo responding to treatment. Olanzapine may be a promising treatment for improving global function-
ing for PDD, but the risk of significant weight gain remains a concern. Hollander (2006) found that olanzapine was associated with significant weight gain (3.4 +/- 2.2 kg vs. 0.7 +/- 0.7 kg on placebo). In other studies with olanzapine, the major side effects reported were increased appetite, weight gain between 2–3.5 kg, with a long-term study planned to evaluate risk for metabolic syndrome, diabetes, and dyslipidaemias (Kemner et al., 2002; Malone et al., 2007). Again, the weight gain in children and adolescents were marked when compared to adults treated with olanzapine, as well as when compared to risperidone or haloperidol (Fremaux, 2007). Zisprasidone The mechanism of action of ziprasidone is unique in that it blocks reuptake of norepinephrine and serotonin, as well as acts as a 5-HT2 and D2 receptor antagonist (Reilly & Kirk, 2007). Consideration of zisprasidone for use in children and adolescents with autism stemmed from the lack of significant weight gain with its administration. With regards to evaluation of potential metabolic issues, several studies were reviewed to determine the risk of weight gain, endocrine abnormalities, and metabolic syndrome. In an open-label study, McDougle et al. (2002) reported a 50% response to treatment with ziprasidone, with transient sedation as the most common side effect when evaluating its use in youths aged 8–20 years with autism. There was actually weight loss overall, postulated to be lost from weight gain due to previous treatment (McDougle, 2002). Similar results were obtained by Malone et al. (2007), in which they found 75% response with the use of ziprasidone in adolescents aged 12–18 years with autism to address
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hyperactivity, aggression, self-abusive behavior, temper tantrums, irritability, and lability of mood. Other than a significant average increase of 14.7 msec on the QTc interval, there was a slight increase in overall BMI that was not statistically significant, and an overall drop in cholesterol from a mean of 171 to 161 mg/dL by the end of the study. No change in prolactin level was detected (Malone et al., 2007). Clozapine There are few open-label case reports on the use of clozapine in the treatment of autism symptoms. This is likely due to the increased risk of serious adverse events such as agranulocytosis, and with it, the need for frequent blood monitoring (Malone & Waheed, 2009). Zuddas et al. (1996) documented three cases of children diagnosed with autism with marked hyperactivity, fidgetiness, and aggressiveness that had minimal effect utilizing other antipsychotics. Clozapine was administered with 40% improvement in all symptom arenas after 3 months of treatment, although one patient relapsed shortly after. The most common side effects reported in those three cases were sedation and enuresis (Zuddas et al., 1996). In another case report, a 13 year old girl who had not responded to risperidone or haloperidol for aggression, social withdrawal, and communication issues exhibited improvement within two weeks of maintenance dose clozapine, with good tolerance and no issues with changes in blood cell counts during close monitoring (Lambrey et al., 2010). No reports of metabolic issues were given but previous research on adult populations has documented significant weight gain and risk for diabetes and hyperlipidemia (ADA, 2004).
Quetiapine There are no published controlled studies evaluating quetiapine use in the treatment of aberrant symptoms of autism in children and adolescents. However, there are a few open-label studies and case reports, with small sample sizes. A retrospective study done by Hardan, Jou, and Handen (2005) with 10 children found improvements in the conduct, inattention, and hyperactivity symptoms of PDD, with reports of sedation being the most common adverse event reported. Review of a case report and open-label, prospective study revealed only minimal improvements in irritability, overactivity, tantrums, and social withdrawal, with significant issues with dose-related sedation and weight gain of 0.9 to 8.2 kg in these patients (Martin et al., 1999; Findling et al., 2004). Paliperidone Recently, paliperidone was approved by the FDA to treat adults with schizophrenia. It is the major active metabolite of risperidone, and uses an osmotic controlled release system (OROS), providing controlled drug delivery (Karlsson et al., 2005). Unlike risperidone, paliperidone elimination through the cytochrome P450 system, specifically the CYP2D6 variant, is limited. Most of the drug is excreted unchanged in the urine (Vermeir et al., 2005). Since risperidone had shown efficacy in the treatment of symptoms of mood lability and disruptive behavior in children and adolescents with autism, Stigler et al. (2010) reviewed a pooled analysis of three randomized, double-blind, placebo-controlled, parallel-group, dose-response studies in adults evaluating paliperidone that showed improvements on the Positive and Negative Syndrome Scale (PANSS) total score from baseline to end point. It was also noted in the pooled analysis that weight gain, glucose measures, and lipid measures were comparable to placebo in all three studies (Meltzer et al., 2008). They were then able to utilize these previous results as a basis for formulating a hypothesis about potential efficacy and tolerability to paliperidone
in the autism population. In their case samples, subjects had co-morbid autism and mental retardation, with reported issues of irritability with aggression, self-injury, and tantrums. There was clinically significant reduction in the irritability domain at therapeutic doses, with good tolerance of medication results in the adult population (Davidson et al., 2007; Kane et al., 2007; Marder et al., 2007). In addition, there were no clinically significant differences in weight gain, glucose measures, and lipid measures, in any of the subjects. Although there was a slight median increase in prolactin levels in adult studies, the female adolescent in this sample had no hyperprolactinemia; in fact, both samples had reduction in weight from baseline (Stigler et al., 2010). Iloperidone Iloperidone has recently been introduced into the market with FDA approved indication for treatment of schizophrenia in adult populations. There currently no pediatric trials published on use of iloperidone to treat disruptive behaviors associated with autism. Of note, research performed on iloperidone in the adult schizophrenic population has shown that in the four placebo-controlled, 4- or 6-week, fixedor flexible-dose studies, the proportions of patients having a weight gain of ≥ 7% body weight was 12% for iloperidone at 10–16 mg/day, 18% for iloperidone 20–24 mg/day, and 13% for iloperidone (combined doses) versus 4% for placebo (Potkin, 2008). Across all shortand long-term studies, the overall mean change from baseline at endpoint was 2.1 kg for weight. Further, long-term studies need to be done to determine iloperidone’s effects on blood glucose and risk for diabetes mellitus. As for concerns about risk of hyperprolactinemia, in a short-term placebo-controlled trial (4 weeks), the mean change from baseline to endpoint in plasma prolactin levels for the iloperidone 24 mg/daytreated group was an increase of 2.6 ng/ mL compared to a decrease of 6.3 ng/ mL in the placebo-group. In this trial, elevated plasma prolactin levels were observed in 26% of adults treated with
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iloperidone compared to 12% in the placebo group (Potkin, 2008). No significant differences were noted for lipid levels when the adults with schizophrenia were treated with iloperidone. Asenapine Asenapine is FDA approved for treatment of schizophrenia and bipolar disorder in adult populations. It does not currently have a child or adolescent indication, and there are no published studies of the use of asenapine in children and adolescents with autism. It is important, however, to be aware that in short-term, placebo-controlled adult trials, the mean weight gain was 1.1–1.3 kg for asenapine treated patients compared to 0.1–0.2 kg for placebo. The proportion of patients with a ≥7% increase in body weight was 4.9–5.8% for patients on asenapine versus 0.5–2% for placebo (Potkin et al., 2007). In clinical trials, the incidences of adverse events related to abnormal, elevated prolactin levels were 0.4% versus 0% for placebo. When evaluating the changes to blood glucose levels, it was determined that there was an average increase of 3.2 mg/dL to fasting levels, but it was statically nonsignificant. Similar results were gathered when evaluating fasting cholesterol and triglyceride levels on asenapine, with studies reporting a small increase of fasting cholesterol of 0.1–1.10 mg/dL and triglyceride of 3.5–3.8 mg/dL (Potkin et al., 2007). Lurasidone Lurasidone is one of the newest atypical antipsychotics, FDA approved for use in schizophrenia in adult populations. It is also currently pending approval for treatment of bipolar disorder in adult populations. There are currently no published pediatric trials evaluating lurasidone and treatment of mood and behavioral symptoms of autism in children and adolescents. It is hypothesized to be effective due to a combination of central D2 and 5HT2 receptor antagonism, with minimal histaminic or muscarinic affinity. The FDA reviewed more than 40 clinical trials involving lurasidone, but efficacy and safety was based on four 6-week, placebo-controlled trials in
adult patients with schizophrenia (Nakamura et al., 2010; Sunovion Pharmaceuticals, 2010). In evaluating weight gain, the four studies revealed mean weight gain of 0.75 kg compared to 0.26 kg with placebo; however, the openlabel extension studies showed mean decrease in weight of between -0.38 to 0.71 kg by week 52. Pooled data from the four adult studies revealed a mean change in blood glucose of 2.5 mg/dL on 40 mg and 120 mg per day dose over the 6 weeks. In uncontrolled longer studies, the mean average change in glucose was between 0.3–1.6 mg/dL between 24 and 52 weeks out. In evaluating lipid changes, the pooled data revealed a decrease in overall cholesterol and triglycerides in all dose groups, which was reflected also in the uncontrolled, longer-term studies, showing a mean change between -1.9 mg/dL and -6.5 mg/dL. Incidence of hyperprolactinemia was noted with lurasidone, with a short-term median change of 1.1 ng/mL versus -0.6 ng/mL in placebo.
Monitoring and Treatment Monitoring It is clear that although both typical and atypical antipsychotics are useful in the treatment of irritability, aggression, self-injury, and tantrums in children and adolescents with autism, serious consideration should be taken in regards to the cardiometabolic side effects of these medications—weight gain, hyperglycemia, hypertension and dyslipidemia. It is well documented that there are inherent characteristics of children taking antipsychotics that can contribute to a 1.5 to 2.0 times higher prevalence of obesity and diabetes when compared that the general population (ADA, 2004). These include sedentary behavior, lower socioeconomic status, problems obtaining access to healthcare, and poor diet. Recent post hoc analyses have shown that children with autism taking aripiprazole have higher incidence of metabolic side effects and weight gain then children and adolescents with bipolar disorder or schizophrenia (Robb et al., 2009). This prompts the thought pro-
voking question, are children with autism inherently at higher risk for developing obesity and therefore at greater risk for diabetes and other metabolic adverse events prior to initiation of atypical antipsychotic medication? A recent analysis of data from the National Survey of Children’s Health revealed that children with autism may be at greater risk for weight gain, with the prevalence of obesity in autistic children to be 30.4% compared to 23.6% in non-autistic children (Curtin et al., 2010). Rimmer et al. (2010) have demonstrated not only that those with ASD have a higher prevalence of being overweight and developing obesity than normally developing children, but also that obese children with ASD and other cognitive disabilities suffer from higher rates of diabetes and high cholesterol compared to autistic children of normal weight. These results may be explained by difficulties with physical activity due to poor gross and fine motor performance (Dewey et al., 2006), as well as preference for starches and foods with a high caloric content found in children with autism (Schreck et al., 2006). Given that previous studies have shown atherosclerotic plaques, for which obesity and dyslipidemias are risk factors, present in autopsy studies of children (Berenson et al., 1998), the decision to initiate and continue an antipsychotic should take into account the future cardiovascular implications for the patient. Ideally, the prescribing physician would work closely with dieticians, psychologists, pediatricians and specialists to choose the most appropriate treatment for the child. Continual and consistent monitoring of side effects is critical while undergoing treatment. Any abnormality merits a reevaluation of the medication in which the clinician may consider the following options: • Lower the dosage of the atypical antipsychotic medications to decrease side effects. • Switch to an alternative atypical antipsychotic medication with potentially fewer side effects.
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• Discontinue atypical medication and consider alternative medications to target problematic symptoms. • Continue the atypical medication and refer to specialist to treat the problematic symptoms (e.g., pediatric endocrinologist for metabolic syndrome and/or glucose control). In regards to recommendations for monitoring frequency, although there are no current practice parameters discussing the management of children and adolescents on antipsychotics, Correll (2008) proposes the following protocol: • Weight, height and BMI at baseline, and at each visit • Blood pressure at baseline, at three months, then every six months • Fasting lipids and glucose at baseline, at three months, then every six months • TSH baseline, then yearly • Prolactin level only if symptomatic Diagnosis and Management For cases in which antipsychotics are deemed therapeutically necessary, a review of the pediatric literature offers some valuable insights into the diagnosis and management of overweight, obesity and their co-morbidities. An assessment begins with a thorough history involving past history of obesity and related morbidities, smoking and alcohol abuse, and family history, particularly heart attacks in persons age 55 or younger (NCEP, 1992). Special attention should be given to patients diagnosed with diabetes, lupus, HIV, renal disease, congenital heart disease or to those with a history of cancer (McCredie et al., 2007). Regular laboratory evaluation is necessary for screening for side effects of antipsychotics and for obesity comorbidities, such as dyslipidemias, diabetes, and hypertension. Table 3 summarizes abnormal lab values for obesity and its related diseases in the pediatric population and their currently recommended treatments.
Table 3. Abnormal Lab Values For Obesity Obesity
Abnormal Values/Cut off Points
Management
Overweight
Diet/Lifestyle counseling
BMI ≥ 85th and <95th percentile
BMI curves: http://www.cdc.gov/growthcharts/clinical_charts.htm#Set1)
Obese
Aggressive diet/lifestyle changes,
BMI ≥ 95th percentile Hypertriglyceridemia
Fasting Triglycerides:
+/- Pharmacotherapy, +/-Surgery Diet/Lifestyle changes
≥150 mg/dl Hyper/hypocholesterolemia
Fasting: LDL ≥130 mg/dl and < 160 mg/dl
Diet/Lifestyle changes +Pharmacotherapy with diabetes
≥160 mg/dl and <190 mg/dl
Diet/Lifestyle changes +Pharmacotherapy with risk factorsa
≥190
Diet/Lifestyle changes +Pharmacotherapy
HDL ≤35
Diet/Lifestyle changes
Total Cholesterol ≥200 Pre-Diabetes
Diet/Lifestyle changes
Fasting plasma glucose >100 mg/dl or
Diet/Lifestyle changes therapy
+/- Pharmaco-
2 hr glucose >140 mg/dl but <200 mg/dl (on oral glucose tolerance test (OGTT)) Diabetes
Fasting plasma glucose >126 mg/dL, or Random glucose >200 mg/dL
Diet/Lifestyle changes +Pharmacotherapy
or OGTT: 2 hr glucose >200 mg/dl) (If asymptomatic, must have abnormal values on 2 separate occasions) Hypertension
(Use tables for percentiles standardized for height, age, sex. Diagnosis made with abnormal values on 3 separate occasions)
(tables: http://www.nhlbi.nih.gov/guidelines/hypertension/ child_tbl.htm)
Prehypyertension BP >90th percentile (recheck in 6 mos.)
Weight loss
Stage 1 BP 95th–99th percentile plus 5 mm Hg (recheck in 1 wk)
Weight Loss/possible +Pharmacotherapy for risk factors
Stage 2 BP >99th percentile plus 5 mm Hg – (refer within 1 wk or immediately if symptomatic)
Weight loss +Pharmacotherapy
Note. Table compiled primarily from Gilbert AP, et al. 2008 or two or more other CVD risk factors: low HDL cholesterol (<35 mg/dL), cigarette smoking, high blood pressure, obesity, or diabetes, after vigorous attempts have been made to control these risk factors.
Obesity Body Mass Index (BMI), defined as weight (in kilograms) divided by height squared (in meters), is recommended as a valuable initial screen for identifying children with a high percentage of body fat, a significant risk factor for cardiovascular disease in adulthood. As height and weight distribution change depending on age and sex, so do BMI percentiles; thus growth charts, such as
those provided by the Centers for Disease Control (CDC) employed to track percentiles. Consensus guidelines by both the Endocrine Society Task Force on Obesity and the American Medical Association (AMA) advise defining “overweight” as BMI ≥ 85th percentile and < 95th percentile; those with BMI ≥ 95th percentile are termed “obese” (Gilbert et al., 2008).
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Both prevention and management of overweight and obesity center on healthy diet and exercise starting at an early age; diet and lifestyle counseling by clinicians, including psychiatrists, is critical in particular for patients taking antipsychotics, even when they are of normal weight. Expert guidelines make the following recommendations for preventing obesity:
• Limiting consumption of sugarsweetened beverages • Limiting television and screen time to two hours a day • Eating breakfast daily • A high fiber diet • Restricting portion size • Limiting eating out, especially at fast food restaurants • Encouraging moderate to vigorous physical activity for at least 60 minutes each day.
mg/dl) or high blood pressure (NCEP, 1992). The AMA recommends defining hypertriglyceridemia as ≥150 mg/ dl and HDL ≤ 35 mg/dl. (Kavey et al., 2003) No pharmacologic therapy is currently indicated for increased total cholesterol, low HDL, or high triglycerides, unless in extreme elevations of ≥350 mg/dl which may help to prevent pancreatitis (McCrindle et al., 2007).
According to AMA recommendations, overweight children with risk factors or obese children will require a more aggressive strategy if simple counseling has failed to result in a decrease in weight after 3–6 months of a trial of diet and exercise. A dietician or physician specialized in weight management should implement a structured plan with specific goals that includes a specialized eating regimen, planned activity, and regular weight monitoring (Barlow, 2007). Pharmacotherapy has been suggested for obese children failing other forms of therapy. In a open label trial of 11 children and adolescents on antipsychotics, the mean weight loss of those taking metformin was -2.82 kg (Shin et al., 2009). A study by Klein et al. (2006) of 39 children on atypical antipsychotics revealed that metformin prevented further weight gain, while those receiving placebo gained an average 0.31 kg/week. These studies indicate a future role for metformin in restricting weight gain in patients taking antipsychotic medications.
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) recommends a simple fasting glucose to diagnose type 2 diabetes (>126 mg/dl fasting or >200 mg/dl non-fasting on two separate occasions, if asymptomatic). It is particularly important to recognize pre-diabetes (fasting glucose >100 mg/dl), which should be managed through intensive weight loss; emerging evidence also provides promising results using metformin in pre-diabetes as prophylaxis against type 2 diabetes (Freemark, 2003). Patients that have developed diabetes should be referred to a diabetes self-management education program and to an endocrinologist experienced in treating pediatric onset diabetes.
Lipids The National Cholesterol Education Program defines hypercholesterolemia as LDL ≥ 130 mg/dl or total cholesterol ≥200 mg/dl. Patients with hypercholesterolemia should begin diet and lifestyle modifications as recommended with obesity. Studies have also shown positive results with drugs such as statins and cholesterol absorption inhibitors like ezetimibe in cases with LDL levels ≥ 190 mg/dl. Lower cut off points for LDL are used for those with cardiovascular disease (CVD) risk factors: family history of CVD before age 55, cigarette smoking, obesity, low HDL (≤ 35
Glucose
Blood Pressure Though not regularly measured in psychiatric private practice, it is useful to follow blood pressure in the overweight and obese, as hypertension puts patients/ further at risk for cardiovascular disease. For a diagnosis of hypertension, the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) advises that elevations in blood pressure must be present on three separate occasions based on percentiles standardized for height, sex and gender.1 As with other diseases associated with excessive body fat, weight loss is the standard of care for stage 1 hypertension, while medications are utilized in stage 2, as well as in certain at-risk populations in stage 1. Any diagnosis of hypertension warrants referral to a pediatrician or specialist.
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Conclusion As the field of child and adolescent psychiatry continues to expand and explore new treatment options for patients with autism, clinicians need to carefully weigh the potential benefits and risks of each potential therapeutic intervention. Atypical antipsychotic medications such as risperidone and aripiprazole have been shown to be effective in reducing irritability, mood instability and self-injurious behaviors in children and adolescents with autism. However, since many factors increase the risk for weight gain in children with autism independent of medication intervention, clinicians need to be mindful of the metabolic risks of antipsychotics in this population. Careful selection of an atypical antipsychotic that can potentially reduce side effect burden is important because many will need long-term maintenance on medication to manage their symptomatology. Better tolerability will improve compliance to treatment. Psychiatrists will need to work closely with their patients, families and pediatricians to assess response to treatment and monitor for potential metabolic side effects with the goal of improving overall quality of life for patients and their families. Jennifer Yen, M.D., Baylor College of Medicine, Depelchin Children’s Center, Asian American Family Services, 6655 Travis, Suite 700, Houston, TX 77030; E-mail: jyen@bcm.tmc.edu. Monica Grover, M.D., Depelchin Children’s Center, 1703 Randon’s Pt. Dr., Sugar Land, TX 77478. Alice R. Mao, M.D., Associate Professor of Psychiatry, Menninger Department of Psychiatry and Neurology, Baylor College of Medicine.
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