Description of the condition
The autism spectrum is a group of developmental disorders described in the Diagnostic and Statistical Manual of Mental Disorders (DSM) DSM-IV-TR as autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) (Wing 1997; AAP 2001). DSM-V uses the diagnosis of autism spectrum disorder (ASD) for individuals with a DSM-IV diagnosis of autistic disorder, Asperger's disorder or pervasive developmental disorder not otherwise specified (Hyman 2013). ASD encompasses disorders previously referred to as early infantile autism, childhood autism, Kanner’s autism, high-functioning autism, atypical autism, pervasive developmental disorder not otherwise specified, childhood disintegrative disorder, and Asperger’s disorder (Hyman 2013). The 10th revision of the International Classification of Diseases (ICD-10) classifies childhood autism as a disorder of psychological development, defined by 1) the presence of abnormal or impaired development that is manifest before three years of age, and 2) the characteristic type of abnormal functioning in all three areas of psychopathology: reciprocal social interaction, communication, and restricted, stereotyped, repetitive behaviour (WHO 2007).
DSM-IV describes three characteristic manifestations of ASDs: 1) impaired social interaction; 2) impairment communication; and 3) restricted repetitive and stereotyped patterns of behaviour (Wing 1997; Filipek 1999). DSM-V uses five diagnostic criteria for the diagnosis of ASD: 1) persistent deficits in social communication and social interaction across multiple contexts; 2) restricted, repetitive patterns of behaviour, interests, or activities; 3) symptoms are present in the early developmental period; 4) symptoms cause clinically significant impairment; and 5) these disturbances are not better explained by intellectual disability or global developmental delay (Hyman 2013). The studies that will be reviewed use the DSM-IV or DSM-IV-TR Diagnostic Criteria, where they refer to the DSM, as the DSM-V was only published in May 2013.
A systematic review of prevalence studies (Williams 2006) calculated an overall prevalence estimate of 7.1 per 10,000 (95% CI 1.6 to 30.6) for typical autism and a prevalence of 20.0 (95% CI 4.9 to 82.1) for ASD. The estimated prevalence of ASD in Australia is 62.5 per 10,000 for children aged six to 12 years (AABASD 2007). In recent years, reported frequencies for ASD across the US and other countries have approached 1% of the population, with similar estimates in child and adult samples (Brugha et al. 2011). Some of the variation in prevalence of ASD quoted in studies is likely to be due to the use of different diagnostic criteria and the age of children in the sample.
Since the early observations of autism by Kanner in 1943 (Kanner 1943), the autism spectrum is recognised as a heterogenous group of disorders with varying clinical presentations and severities (AAP 2001; NICHD 2014). The onset is typically before three years of age (APA 1994), although the diagnosis is often not made until two or three years after symptoms are evident (Filipek 2000). Children commonly present with speech delay, poor eye contact, social impairment, unusual or repetitive play, need for routine, difficulty coping with change, and obsessions. A significant proportion have intellectual impairment, but many have an intelligence quotient in the normal range. All groups may also present with abnormal movements or stereotypies, heightened levels of anxiety, and self injurious or aggressive behaviour. In addition to specific diagnostic features, common non-specific problems include phobias, sleeping and eating disturbances, temper tantrums, and (self directed) aggression (WHO 2007). Abnormalities of attention (overly focused or easily distracted) are common in individuals with ASD, as is hyperactivity, and many meet the DSM criteria for attention deficit hyperactivity disorder (ADHD) (Handen 2000; Hyman 2013). Hyperactivity and inattention can lead to poor school performance and academic underachievement, further social impairment due to inappropriate and impulsive behaviours, and can place the child at risk of harm. These behaviours are not only a significant impairment for the child, but also affect the parents, carers, and siblings. There is often emotional and psychological stress, along with financial strain due to the time needed for supervision of the child, medical appointments, and therapy.
Parr 2008 reports that "About 15 percent of adults with autism live independent lives, whereas 15 to 20 percent live alone with community support." For the ASD population "...verbal and overall cognitive capacities seem to be the most important predictors of an ability to live independently as an adult" (p.760).
Diagnosis of ASD includes history from parents and teachers, clinical observation, psychological and often speech language assessment. Numerous behaviour rating scales have been developed both to aid the assessment of ASD as well as monitor response to therapy. Examples of commonly used rating scales include the Autism Diagnostic Observation Schedule - generic (ADOS) (Lord 2000) and the Autism Diagnostic Interview, Revised (ADI-R) (Scahill 2005; Bertoglio 2009). Other scales are used in the context of screening, including the Childhood Autism Rating Scale (CARS) (Handen 2000; AAP 2001; Scahill 2005; Scahill 2006; Bertoglio 2009); the Children's Global Assessment Scale (CGAS) or a modified version known as the Developmental Disabilities-CGAS (for children under 18 years of age with pervasive developmental disorder) (Wagner 2007); the Australian Scale for Asperger's Syndrome (ASAS) (Filipek 1999); and the Autism Behaviour Checklist (ABC) (AAP 2001; Scahill 2005; Bertoglio 2009). There is much variability between the rating scales with no clear consensus regarding which measure provides the most reliable results to aid diagnosis. Some tools, such as ASAS, are targeted at primary school-aged children with possible Asperger's. There are also a number of generic rating scales, such as the C-GAS and the CBCL (Achenbach 1991), that can be used to monitor behaviour in individuals with ASD.
Description of the intervention
The mainstays of treatment for ASD are therapeutic, with pharmacological treatments targeted at specific behaviours. The SIGN 2007 guideline summarises the evidence for non-pharmacological interventions and suggests that behavioural interventions should be considered to address a wide range of specific behaviours. There is also some evidence for tailored social communication and communication interventions (such as the use of visual augmentation) (SIGN 2007). Pharmacological therapy, including atypical antipsychotics and antidepressants, target specific behaviours and aim to achieve a global improvement. Pharmacological treatments have been widely used and, to date, much of the evidence has been from small randomised controlled trials (RCTs). NICE 2013 does not support the use of antipsychotics, antidepressants, and anticonvulsants. Recently, Cochrane reviews have looked into the use of selective serotonin reuptake inhibitors (SSRIs) in children with ASD and concluded that there is no evidence to support the use of SSRIs to reduce core features of ASD and anxiety in these children (Williams 2010). Another Cochrane review has looked into the use of risperidone in targeting behavioural problems in ASD and concludes that there is a limited role for risperidone, perhaps only short term and targeted at specific behaviours (Jesner 2007).
Psychostimulants are commonly prescribed to target ADHD behaviours (inattention, distractibility, and impulsivity) in children with ASD. Of the psychostimulants (that is, methylphenidate, dexamphetamine, pemoline, and modafenil), methylphenidate is by far the most widely used in the treatment of ADHD to improve concentration and reduce the symptoms of impulsivity and hyperactivity. In this review, therefore, we will focus on methylphenidate. Another Cochrane review has studied the effect of dexamphetamine in adults with ADHD (Castells 2011) and the other stimulants are much less commonly used in clinical practice.
Methylphenidate primarily acts as a dopamine-noradrenaline reuptake inhibitor. Its effect on adrenaline is much weaker than its effect on dopamine. It acts by inhibiting dopamine-noradrenaline reuptake transporters. Treatment with immediate-release formulations should be initiated at 5 mg once or twice daily, up to a maximum of 60 mg per day. Treatment with modified-release formulations of methylphenidate should be initiated at a dose of 18 mg once daily (in the morning), and increased, if necessary, up to a maximum of 54 mg once daily. (NICE 2013). Methylphenidate is also available in some countries as an extended-release form, transdermal patch (Mayo Clinic 2014). Short-release systems of methylphenidate are absorbed rapidly within 30 minutes and their effects last up to four to six hours. Long-acting or modified-release forms contain immediate and delayed-release mechanisms, and are taken once daily (in the morning). They are available in eight-hour and 12-hour preparations. The advantages of these controlled-release products include the possible decrease in likelihood and severity of rebound symptoms (Szymansk 2001), and increase in compliance in children due to reduced dosing frequency and fewer tablets.
The optimal dose of methylphenidate is based on observations of clinical response by the individual, as individual responses are variable and not dose predictable. The dose is initially titrated by increasing the daily dose every week until the effects are observable, or until adverse effects warrant dose reduction or cessation. In children with ADHD, the ability to attend and focus, particularly in busy environments, such as the classroom, indicates clinical effect. In short-acting forms, the maximum recommended dose is 1.5 mg/kg/day or 60 mg in two to three divided doses (TGL 2012). This can be given as a once-daily dose in the combination forms. Most side effects of methylphenidate are dose dependent (Rossi 2010). Common side effects include headaches, loss of appetite, abdominal discomfort, nausea, anxiety, and insomnia (Rossi 2010). These effects could lead to reduced tolerance of the drug. Methylphenidate also increases blood pressure and heart rate, so consultation with a cardiologist is required before starting the drug in children with cardiac abnormalities. It also has the potential to infrequently cause serious conditions, such as growth restriction, psychosis, liver dysfunction, and neuroleptic malignant syndrome, for which monitoring is needed (Medsafe 2010).
Clinical studies assessing the impact of treatments for hyperactivity symptoms in children with ASD are important to guide clinicians (Nicolson 2000; Siegel 2012). However, the variability of presentations and diagnostic criteria used in trials is high and it remains challenging to identify subgroups of children who will benefit most from treatment (Siegel 2012). In this review, we wish to assess the overall effectiveness of methylphenidate in these children, by evaluating the evidence both for changes in ADHD symptoms and also for changes in the core symptoms of ASD. This is because we cannot exclude a priori the possibility that the effect of methylphenidate on one of these sets of symptoms is in a different direction from its effect on the other set, which might negate any overall clinical benefit.
How the intervention might work
Methylphenidate blocks the dopamine and noradrenaline transporter, thereby increasing extracellular dopamine levels (Volkow 2001). In children with ADHD this has been shown to reduce impulsivity and increase their ability to concentrate. The mechanism of action has not been clearly defined but may be due to the role of dopamine in task-specific signalling or in the motivation and reward pathway (Volkow 2001). The possible mechanisms underpinning the effect of methylphenidate in children with ASD, who display behaviours similar to those in ADHD (for example, impulsivity and overactivity), have not yet been established.
Why it is important to do this review
The use of psychostimulants, and methylphenidate in particular, for ASD has been controversial. Psychiatrists and paediatricians have questioned its efficacy and expressed concerns that the drug could worsen symptoms. Recently, a number of small trials have suggested that methylphenidate may have a role in the management of core symptoms as well as ADHD-like symptoms in children with ASD (Santosh 2006). A review of the literature concludes that psychostimulants are effective in the treatment of ADHD-like symptoms in individuals (children, adolescents, and adults) with ASD (Cortese 2012), however they did not investigate the effect on core symptoms of ASD.
Not only does ASD affect the individual, but there is also a significant impact on the family. A study evaluating the coping strategies of families who have children with ASD reports that "...the parents of children with ASD have somewhat lower marital happiness and family cohesion.." (Higgins 2005 P. 125). In addition, another study reports that "..siblings [are faced with] precocious responsibility whilst they also have a greater risk of developing internalising behaviour problems" (Benderix 2007 P. 416). Furthermore, the financial cost of caring for a child with ASD is twice that of caring for a child without ASD (Croen 2006).
There is considerable recognition of the role of attention deficits in ASD and how such deficits might impact a range of behaviours and impairments associated with the disorders (Burack 1997; RUPP Autism Network 2005). Studies have shown that up to 12% of children with autism are prescribed stimulant medications to treat these secondary features of impaired concentration, impulsivity, and hyperactivity (Handen 2000), indicating that behaviours typically seen in ADHD are frequently treated in this population. But if children with ASD respond to traditional pharmacological treatments for ADHD-like symptoms at rates similar to typically developing children, there is little available data to support such an assumption or to guide clinicians (Handen 2000). Since psychostimulants are frequently used, it is important to determine their effectiveness.
In this review, we aim to explore whether methylphenidate has an impact on core ASD features of communication skills, social interactions, and stereotypical or repetitive behaviours, and on global function, concentration, the ADHD-like behaviours, and the rate of adverse effects. It is important to determine the rate of side effects experienced by the participants and whether this outweighs any significant benefit or influences treatment compliance.