3 rd Annual AAAP Symposium September 13, 2014 Jan Harold D. Sia, M.D. Developmental-Behavioral Pediatrics Adoption & Foster Care Hospital Affiliations: Makati Medical Center, Manila Doctors Hospital

Outline  DSM-IV-TR and DSM-5  Prevalence of symptoms  Etiological evidence  Symptom expression Neuropsychological/cognitive Behavioral  Impact of comorbid ASD & ADHD  Efficacy of ADHD treatments in ASD  Clinical pathway for evaluation and treatment

 Impairing attention deficits are not improved by standard ASD treatments (Deprey & Ozonoff, 2009)  ADHD symptoms can often be effectively improved with ADHD treatments, including pharmacological treatments (Handen, Johnson, Lubetsky 2000)

DSM-5  ASD & ADHD comorbid diagnoses allowed

Prevalence of symptoms HHigh rate of ADHD symptoms in individuals with ASD 20 – 70% based on recent estimates

 Frazier, et al Rate of ADHD did not differ significantly in PDD and non-PDD children (83% vs 75%) Rate of PDD did not differ significantly in ADHD and non-ADHD children (5% vs 3%)

Prevalence of symptoms  Carlsson, et al % had severe hyperactivity/ADHD

Prevalence of symptoms  Yoshida & Uchiyama % (36) met DSM-IV ADHD criteria ○ 20 – predominantly inattentive ○ 12 – combined type ○ 4 – predominantly hyperactive-impulsive ADHD by PDD subtype ○ Autistic Disorder – 57.6% ○ Asperger’s Disorder/PDD NOS – 85% ADHD by age ○ < 10 years – 78.8% ○ ≥ 11 years – 50%

Prevalence of symptoms  Sinzig, et al % had sufficient ADHD-symptoms to warrant diagnosis based on DSM-IV ○ 46% - inattentive type ○ 32% - combined type ○ 22% - hyperactive/impulsive type ASD+: lower mean age (10.2y vs 13.3y), lower IQ, took medications more often

Prevalence of symptoms  Ryden & Bejerot % - comorbid ADHD ○ 82% - inattentive subtype

Prevalence of symptoms - summary  ADHD symptoms exist among individuals with ASD, from preschool to adulthood  ADHD-Inattentive subtype is the most common presentation  Limitation – use of parental reports, self- reports  Need for evidence from theoretical domains and from neurobiological and neuropsychological studies

Etiological evidence  ADHD symptoms are similar whether occurring alone or comorbid with ASD (Sinzig. 2009)  Genetic studies High rate of ASD and ADHD in persons with 22q11 deletion syndrome (Niklasson, et al. 2009) Children with ADHD and their siblings have higher levels of ASD symptoms compared to typically developing children (Reiersen, et al 2007)

Symptom expression  Both ASD & ADHD are commonly associated with deficits in executive control and difficulty navigating social contexts (Bühler, et al. 2011)  Both are more common in males, have a strong comorbidity with intellectual disability, and are also associated with other specific learning and developmental difficulties (language, reading, and motor problems). (Leitner. 2014)

Symptom expression  Nature of attention problems in ASD may by qualitatively different from attention problems in ADHD (Deprey & Ozonoff 2009) ASD – hypervigilant attention & internal distractibility ADHD – lack of focus & distractibility by external stimuli

Symptom expression  Saulnier & Ventola In ASD, “inattention” to external stimuli may be due to hyper-focused attention on an object or topic of interest “Impulsive” behavior may be due to lack of understanding of the social inappropriateness of the behavior

Symptom expression  Similar high rates of delinquent, aggressive, and other externalizing behaviors for persons with ADHD combined type or ADHD combined type and PDD, but not for children with PDD only (Matsushima, et al. 2008)

Symptom expression – Executive function  ADHD – display difficulties on tasks measuring inhibition and sustained attention, while remaining relatively unaffected on tasks measuring planning or cognitive flexibility.  ASD – appear to display preservation of conscious inhibitory function, but with quite severe problems in planning and shifting attention.

Symptom expression  Additive effect? More impairment in daily functioning in ASD+ADHD vs when they occur alone (Goldstein & Schweback. 2004) Less severe symptoms of ASD+ADHD = better social skills (Matson, et al. 2010) Combined ASD & ADHD was associated with more severe ASD symptoms than persons with ASD only (Ames & White. 2011)

Symptom expression  Additive effect? Individuals with ASD+ADHD had greater impairments in verbal and spatial working memory, response inhibition, and global executive functioning than children with ASD only or typically developing children (Yerys, et al. 2009)

Etiology for co-occurrence?  Rommelse, et al The two are independent disorders occurring together by association with a third independent factor Alternatively, ASD & ADHD share a common underlying etiology, a common genetic basis ○ Family and twin studies – about 50 – 72% of the contributing genetic factors in both disorders show overlap. ○ These shared genetic and neurobiological underpinnings form an explanation why both disorders occur so frequently within the same patient and family.

Impact of comorbidity  There is preliminary evidence that when ADHD is comorbid with ASD, the risk for increased severity of psychosocial problems increases (Gadow et al. 2004; Yerys et al. 2009)  Co-occurring symptoms are associated with greater impairment than a single diagnosis.

Impact of comorbidity  Children with ADHD and ASD experience more difficulty in daily life as reported by parents and teacher (Rao & Landa. 2013)  These co-occurring conditions may be less responsive to standard treatments for either disorder.  Children with comorbid ASD & ADHD show lower cognitive functioning, more severe social impairment, and greater delays in adaptive functioning than children with ASD-only as reported by their parents

Impact of comorbidity  St. Pourçain, et al Autistic symptoms were more stable than ADHD behaviors, which showed more variability

Impact of comorbidity  St. Pourçain, et al Trajectories for both traits were strongly, but not reciprocally interlinked, such that the majority of children with a persistent hyperactive-inattentive symptomatology also showed persistent social-communication deficits, but not vice versa.

ADHD Treatments in ASD  General conclusions from clinical trials: IQ and gender are not a determinant of stimulant efficacy Effect sizes for the ASD population are somewhat smaller than the non-ASD population Fewer individuals in the studies are classified as ‘responders’ than in the non- ASD population (preschool to adolescents) Side effects are more common in the ASD population.

ADHD Treatments in ASD  Aman ○ Stimulants – highly variable responses (significant improvement through to more problematic behavior), but would still be a reasonable first choice for previously untreated children with PDD and uncomplicated ADHD ○ Noradrenergic reuptake inhibitor - atomoxetine

ADHD Treatments in ASD  Aman Evidence for positive effects: ○ Atypical antipsychotics – risperidone, quetiapine, ziprasidone, aripiprazole ○ Alpha-2 adrenergic agonists – clonidine, guanfacine Weak evidence for: ○ Antidepressants – TCA, SSRI ○ Anxiolytics – benzodiazepines ○ Antiepileptic mood stabilizers – divalproex sodium, carbamazepine, topiramate

ADHD Treatments in ASD  Psychopharmacological treatment of ADHD symptoms in individuals with autism should be carefully considered.  These individuals should not be treated identically to those with ADHD only (Gargaro. 2011).

ADHD Treatments in ASD  Psychosocial interventions ??? No known psychosocial interventions that target co-occurring ASD & ADHD (Davis & Kollins 2012)

ADHD Treatments in ASD  Psychosocial interventions ??? Similarities across approaches to treat both disorders (Davis & Kollins 2012) ○ Use of conditioning procedures ○ Behaviorally oriented parenting intervention but different conceptualization For ADHD, “parent training” typically involves manual, group based programs designed to teach parents strategies to manage the behaviors of their children (eg, reduce impulsive behavior, increase focus on tasks)

ADHD Treatments in ASD  Psychosocial interventions ??? Similarities across approaches to treat both disorders (Davis & Kollins 2012) ○ Behaviorally oriented parenting intervention but different conceptualization For ASD, “parent education” places more emphasis on individualized treatments that provide parents with tools to promote child skills development (eg, improve social engagement, increase communication attempts).

 The picture that is emerging on the comorbidity of ASD & ADHD is one of common neurodevelopmental pathways, overlapping symptoms, and co-occurring disorders (Lindblad, Gillberg, & Fernell, 2011; Samyn, Roeyers, & Bijttebier, 2011).

Mahajan R, et al. Pediatrics

Pathway 1: Symptom Evaluation  Key points Accurate ASD diagnosis should be made using existing ASD diagnostic guidelines (including language and cognitive testing) Educational, speech & language, and behavioral supports should be optimized ADHD-focused clinical interview if ADHD symptoms continue despite initial steps; supplemented by ADHD-focused questionnaires (Conners Scale, Vanderbilt)

Pathway 1: Symptom Evaluation  Key points Need for information from school, home and community Systemic medical evaluation to rule out any undiagnosed medical problem that may contribute to the ADHD symptoms Optimize medical, mental health, and educational/behavioral interventions Reevaluate to assess need for medication trial Simultaneous evaluation and treatment across multiple steps

Pathway 2: Medication Choice  Key points Methylphenidate preparations are generally the first choice ○ Preferable to start with short-acting formulation to gauge side effects

Pathway 2: Medication Choice  Key points 2 nd line medications ○ Amphetamine salts ○ Atomoxetine ○ Alpha-2 adrenergic agonists: Clonidine, Guanfacine ○ Atypical antipsychotics: Risperidone, Aripiprazole Most evidence for efficacy in the context of irritability and aggression

Clinical practice  Involve the family in the decision-making process to discuss: Evidence Target symptoms that may improve and when to expect improvement Potential side effects or adverse events Explore beliefs and values about medication for ADHD symptoms  More than 1 clinic visit/appointment may be necessary to discuss pros and cons of a given treatment plan

Clinical practice  Careful documentation and analysis of this potential overlap between ASD and ADHD should be a mandatory component in assessment. (Geurts, et al. 2008)

Five-year view  There may be an increase in the research base on the comorbid state  Future research based on the framework adopted by Biederman et al (1991) The comorbid disorders are the expression of phenotypic variability of the same DSM-5 disorder Each disorder is a separate DSM-5 disorder ADHD and ASD possess common vulnerabilities

Five-year view  Future research based on framework adopted by Biederman et al (1991) The comorbid ADHD and ASD state represents a homogeneous subgroup with the ADHD (or ASD) population One condition is a developmental precursor to the other condition One disorder increases the risk for the second disorder

Five-year view  Other research topics Assessment strategies Treatment with mixed amphetamine salts Treatment using combined behavioral and medication management Focus on family level variables (eg, parenting efficacy, parenting stress, parent mental health, etc.) as either independent or dependent variables.

Final thought….  This new attitude will not only allow for more efficient clinical management of these children, but will also clear the way for a more precise scientific understanding of the overlap of these two disorders. (Leitner. 2014)

Summary  A majority of children with ASD have significant symptoms of ADHD but not all children with ASD have these symptoms  Family and twin studies suggest a common genetic etiology for both disorders  ADHD and ASD are associated with executive dysfunction but in different domains

Summary  There is evidence for using MPH in treating ADHD in ASD  Dual diagnosis may be essential to implementation of effective treatments. (Holtmann, et al. 2007)

References Matson JL. Rieske RD, Williams LW. The relationship between autism spectrum disorders and attention-deficit/hyperactivity disorders: an overview. Res Dev Disabil. 2013;34. Gargaro BA, Rinehart NJ, Bradshaw JL, Tonge BJ, Sheppard DM. Autism and ADHD: how far have we come in the comorbidity debate? Neuroscience and Biobehavioral Reviews. 2011; 35. Sinzig J, Walter D, Doepfner M. Attention-deficit/hyperactivity disorder in chidlren with autism spectrum disorder: symptom or syndrome? Journal of Attention Disorders Leitner Y. The co-occurrence of autism and attention-deficit hyperactivity disorder in children – what do we know? Frontiers in Human Neuroscience. 2014; 8. Davis NO & Kollins SH. Treatment of co-occurring attention-deficit/hyperactivity disorder and autism spectrum disorder. Neurotherapeutics. 2012; 9. Antshel KM, Zhang-James Y, Faraone SV. The comorbidity of ADHD and autism spectrum disorder. Expert Rev. Neurother. 2013; 13(10). Mahajan R, et al. Clinical practice pathways for evaluation and medication choice for attention-deficit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics. 2012; 130(Supp 2).