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Georgina Garcia, MD*

There has been a growth in the knowledge about  autism and autism spectrum disorders (ASD) in the United States and worldwide. As the prevalence  rates have grown, so has the awareness of the need to develop effective and safe treatments  for children with ASD. In addition to the behavioral interventions such as applied behavioral  analysis, parent training, and adaptive skills training, there has been an increase in the  use of medications for the treatment of ASD symptoms. At this time, there are two antipsychotics  approved by the FDA for the use in children with ASD, risperidone and aripiprazol.  Generally, the use of this classification has been more recently associated with changes  in metabolic function in children. The purpose of this article is to review briefly the use  of psychotropic medications, focusing on antipsychotics, and discuss the metabolic risks and  risk factors associated with their use within children with autism. 

Key Words:autism, autism  spectrum disorders (ASD), antipsychotics, autism, autism spectrum disorders (ASD),  antipsychotics, metabolic syndrome, treatment and management of autism

INTRODUCTION 

Autism and autism spectrum disorders (ASD) are  neurodevelopmental disorders that cause impairments in social interactions and communication.  In addition, ASD can manifests with symptoms of irritability, cognitive rigidity,  stereotyped/restricted patterns of behavior, and often aggression. Although symptoms are  usually present from the age of 3, there is increasing evidence that there is a wide range  of impairments within children and adolescents leading to wide variation in the long-term  impact of ASD on quality of life. 

Since 1943, when Kanner originally described  and coined the term “autism”, there have been huge advancements in autism research and the  awareness of ASD.¹ A recent study published by the Autism Developmental Disabilities Monitoring Network in the US estimated the prevalence across 14 sites to be 11.3 per 1,000 (1/88).² Additionally, a 2012 report on the global prevalence of autism and ASD reported a lower  prevalence rate of 62 per 10,000 and stated, “while existing estimates are variable,  the evidence reviewed does not support differences in PDD prevalence by geographic region  nor a strong impact of ethnic/cultural or socioeconomic factors”.³ Regardless, there have been great advancements in the development of diagnostic tools to  identify and distinguish children with ASD, allowing us to further our understanding about  the disorder and develop ways to treat and manage symptoms related to ASD. 

Given the increased awareness of ASD and its  worldwide prevalence, there have been amplified efforts and research into treatments to reduce  the impact of the disorder and improve the quality of life for these children. Home based  and school based behavioral interventions to improve social interactions and improve communication  skills have been developed. Children with ASD are now able to have social skills training,  adaptive skills training, applied behavioral analysis (ABA), and other cognitive therapies based on their needs. Of the behavioral interventions, ABA therapy has been the most successful  and been found effective in several hundred evidence based trials and indicating improvements  in intellectual functioning, language development, development of activities of daily living  skills, and social functioning.^4,5,6

In addition to the behavioral interventions,  psychopharmacological interventions have also been developed for children with ASD.  Unfortunately, medications are often reserved for children with more severe impairments in  functioning and target symptoms of irritability, aggression, hyperactivity, inattention,  and stereotyped/repetitive behaviors/or cognitions. Due to difficulties with attention,  children with ASD are often impulsive in their actions resulting in an increased risk of  harm to themselves or others. Specifically, medications are sometimes used to reduce self-injurious  behavior (SIB) and aggression that can occur in children with ASD.^7,8

Current estimates of the use of antipsychotics  in ASD in the United States range from 30 to 60%.⁷ Of those on medications, it is estimated that almost half of the children with ASD who are  prescribed antipsychotic medications are on two or more medications.^8,9 As our medication usage in this population increases, so has our awareness of the risk of  serious side effects that can impact children treated with antipsychotic medications.  The focus of this article is to briefly review the psychopharmacological treatment of ASD  with antipsychotics and their risk of metabolic derangements in children and adolescents. 

Table 1. Antipsychotic Medication Trials used in Autism Spectrum Disorder (ASD).

Table 2. Metabolic Syndrome Criteria as defined by the International
Diabetes Federation for Children (16 yrs).

PSYCHOPHARMACOLOGICAL TREATMENT OF AUTISM SPECTRUM  DISORDERS 

The use of medications in ASD has been a very  complex process due to the heterogeneous nature of the disorder and clinical presentations.  In reviewing the literature, some barriers to interpreting the published findings include:  controversy as to the reliability and validity of the current diagnostic criteria of ASD;  difficulties in screening, identifying, and targeting ASD behaviors as opposed to symptoms  of co-morbid psychiatric disorders; systemic difficulties in the recruitment of homogeneous  ASD participants in randomized controlled trials; and the lack of the consistent use of standardized  and validated measures for monitoring target behavior/outcomes in response to medication treatment. 

Medication treatment of ASD is challenging because  most of the medications being used were originally designed to target different symptoms (e. g. depression, anxiety, mood stability) as opposed to ASD symptoms. As result, medications  are often prescribed off-label in children with ASD. The majority of medication studies in  ASD target symptoms such as hyperactivity, irritability, stereotypy, social withdrawal,  inappropriate speech, and repetitive and restrictive behaviors.¹⁰ Several intervention studies use the Aberrant Behavior Checklist (ABC) in their studies  to monitor for symptoms of irritability, aggression, and self-injurious behavior.¹¹ Reviews of the published literature indicates that atypical antipsychotics are the first  line of treatment of the symptoms of ASD.^12,13

Generally, the classifications of medications  used in ASDtrials include alpha 2 agonists, antipsychotics, mood stabilizers, norepinephrine  reuptake inhibitors, serotonin reuptake inhibitors, and stimulants. A recent systematic review  of psychotropic medications used for children 18 years and younger with ASD used the Reichow  methodology for evaluating autism evidence based practices found; only aripiprazole,  haloperidol, and risperidone had “established evidence” for irritability, behavioral symptoms,  hyperactivity, and stereotypy.¹⁰ Although other classifications of medications such as mood stabilizers, stimulants, and antidepressants are regularly used in patients with ASD, none of them has been classified  as having sufficient evidence for their use.¹⁰ Of these medications, only aripiprazole (2009) and risperidone (2006) are FDA approved for  the treatment of irritability associated with ASD (FDA reference) (Table 1). Of note,  none of the studies published in recent reviews provided information on the use of more than  one antipsychotic in children with ASD.^10,13

METABOLIC SYNDROME AND ANTIPSYCHOTICS 

Children with ASD can suffer from sensory integration  difficulties, food aversions, and restrictive patterns of behavior/or eating that can put  that am an increased risk for weight gain and poor nutritional habits.^4,6 The impact on children with ASD can be compounded by the use of antipsychotics,  which although useful in the treatment of ASD, has been found to have a significant impact  medically on weight gain and metabolic functioning. Metabolic Syndrome, also as referred to  in the literature as Syndrome X, insulin resistance syndrome, or dysmetabolic syndrome,  was first identified nearly 50 years ago when it was described by the World Health Organization  and the United States Cholesterol Education Program (NECAP) Adult Treatment Panel (ATP).  The National Health and Nutritional Examination Survey (NHANES) from 1999-2002 has reported  that the rate of metabolic syndrome in adolescents in the US varies from 2% to > 9% depending  on the diagnostic criteria applied.²⁵ The key components of metabolic syndrome include: obesity, blood pressure, cholesterol,  and glucose intolerance (Table 2). 

There is a complex relationship between metabolic  syndrome and obesity indicating that it may be a bidirectional relationship with significant  impact on cardiovascular morbidity and mortality.²⁶-²⁸ Additionally, children with ASD often suffer from restrictive patterns of eating and sensory  integration difficulties that can contribute to their weight gain. Due to the complex spectrum  of ASD and their related behaviors, it is difficult to quantify their impact on the development  of metabolic syndrome and obesity. Weight gain and obesity have been associated with an increase  in elevated blood pressure, coronary artery disease, dyslipidemia, colorectal cancer,  insulin resistance, type 2 diabetes, and inflammatory responses.^28,29 Although the specific mechanisms are unknown, a growing body of evidence supports the impact  of histaminic receptor antagonism contribution towards weight gain and indirectly to insulin  resistance.^27,30 Some evidence comes from studies indicating that there is a dose dependent risk of developing  diabetes mellitus in medications with the higher histamine receptor affinity.^30,31 At this time, one specific receptor or target causing insulin resistance remains unclear,  and it is likely that the etiology of insulin resistance is a complex interplay between neurotransmitters  within the brain neuroendocrine receptors and transmitters peripherally and at specific organ sites.^32,33 On review of the weight gain and metabolic risks associated with antipsychotic use,  it is concerning that children in general are at an increased risk weight gain when using  antipsychotic medication in comparison to adults.²⁷ It has also been identified that younger children with ASD who possibly had less exposure  to antipsychotic use were at an increased risk of weight gain.²⁷ Children treated with antipsychotics, independent of ASD diagnosis, have been found to have  a significantly higher risk of weight gain (Odds ration [OR], 2.28), type 2 diabetes (OR,  2.36), and dyslipidemia (OR, 5.26).³⁵ Given that antipsychotics have been found to be effective in the treatment of psychiatric  disorders, it is of critical importance that practitioners understand the metabolic risks  of treatment and monitor patients carefully for metabolic syndrome. 

METABOLIC MONITORING OF ASD PATIENTS RECEIVING  ANTIPSYCHOTICS TREATMENT 

At this time, there are no consensus guidelines  around the monitoring of antipsychotic medications in children with or without ASD.  Practitioners working with children with ASD should carefully weigh the risk of weight gain,  dyslipidemia, diabetes, and metabolic syndrome against the possibly benefit of reduced irritability,  aggression, and improved social/emotional functioning when considering the use of medication  treatment of children with ASD. Treatment and management of children and adolescents with  antipsychotics should include the following key components: review and identification of risk  factors, regular monitoring of metabolic markers, and identification of potential modifiers  to the development of metabolic syndrome (i.e. lifestyle, polypharmacy). Easily identifiable  risk factors to review include: patient history of weight gain, familial obesity,  familial diabetes, family history of hypercholesterolemia, and family history of cardiovascular  disease and/or events. Given the risk factors, prescribers can tailor the treatment regimen  using the evidence-based research. For example, patients with a history of weight gain and/or  diabetes may avoid medications known to increase the risk of these side effects such as risperidone  and olanzapine.^27,31 Certain cardiovascular risk factors (QTc prolongation, diabetes, and weight gain) also appear  to have dose dependent side effect profiles that may require monitoring at dose changes.^31,35,36

Several groups such as the International Diabetes  Association, World Health Organization, American Diabetes Association, and others have attempted  to create guidelines for the monitoring and management of metabolic side effects with antipsychotics. Unfortunately, most of the guidelines are difficult to translate to the pediatric population  due to discrepancies in measuring and determining cut offs of variables such as insulin insensitivity,  weight gain, and lipids. Additionally, pediatric measurements have to take into consideration  modifying factors such as growth velocity, genetic predisposition, pubertal onset,  and other physiological developmental differences between and among children and adolescents.  Given these difficulties it seems prudent to measure certain metabolic variables prior to  initiation of antipsychotic treatment and at intervals such as dose changes, medication changes,  or time from medication initiation (Table 3).

Table 3. Proposed Metabolic Screening Measures for Children and Adolescents on Antipsychotics.

CONCLUSION 

There has been a growth in the use of atypical  antipsychotics in the treatment of children with autism and ASD. At this time, there is a  growing body of data on the usage patterns, side effects, and monitoring of the use of antipsychotics  in children in general. Given that children with ASD appear to be at an increased risk of  weight gain, insulin resistance, the metabolic syndrome, and type 2 diabetes, as well as possibly  other metabolic derangement, it seems prudent for providers to be aware of the side effect potentials and begin monitoring children prior to initiation of the medications.  There also are studies indicating that some medications can be used to protect or counteract  the impact the metabolic effects of antipsychotics. There are some indications that omega-3  may be used in children with ASD against cardiovascular abnormalities and metformin has been  used in pediatric and adult populations to address weight gain and glucose metabolism.^37,38 Unfortunately, there is limited data on the use of omega-3 in ASD and metformin in children,  often necessitating consultation with subspecialists in child psychiatry and/or endocrinology.  There appears to be a great need for further discussions and guidelines to be developed and  provided so that prescribers can best prescribe medication interventions for children with  ASD in the future. 

Georgina Garcia, MD* 

Children’s Hospital Boston, Instructor in Psychiatry  Harvard Medical School, Boston, MA 

*Corresponding Author: Department  of Psychiatry, Children’s Hospital Boston, 300 Longwood Avenue, Hun 129, Boston,  MA 02115. Tel: 617 355-7989. (Email: georgina.garcia@childrens.harvard.edu )

CONFLICT OF INTEREST 

Georgina Garcia, MD is an employee at Children’s Hospital Boston. Dr. Garcia does not receive any funding from any funding sources  related to the content of this article, nor does she have any conflict of interest. 

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