Review of ADHD and Autism Spectrum Disorders Back to Basics Review of ADHD and Autism Spectrum Disorders Dhiraj Aggarwal, MD, FRCP (C ) Child and Youth Psychiatrist, CHEO Assistant Professor, University of Ottawa daggarwal@cheo.on.ca April 9th , 2015

Disclosures No affiliations to disclose

Outline Diagnosis Epidemiology Etiology Assessment Treatment Autism Spectrum Disorders Outline Diagnosis Epidemiology Etiology Assessment Treatment Non medication treatments Medication treatments Back to Basics – Dr. D. Aggarwal

ASD – Diagnostic Criteria DSM 5 A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history: 1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions.

ASD – Diagnostic Criteria 2. Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures: to a total lack of facial expressions and nonverbal communication.

ASD – Diagnostic Criteria 3. Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.

ASD – Diagnostic Criteria B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least 2/4 of the following, currently or by history: 1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases).

ASD – Diagnostic Criteria 2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat same food every day).

ASD – Diagnostic Criteria 3. Highly restricted, fixated interests that are abnormal in intensity or focus (e.g., strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests).

ASD – Diagnostic Criteria 4. Hyper or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement).

C. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life). D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning. E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay.

Etiology Genetic - increased risk in siblings and in twins Twin concordance, monozyg. 60% vs 5% dizygotic ASDs tend to occur more often in people who have certain genetic or chromosomal conditions. About 10% of children with autism are also identified as having Down syndrome, fragile X syndrome, tuberous sclerosis, and other genetic and chromosomal disorders Environmental, toxins, gastrointestinal, immunological factors inconclusive

Unproved Theories Vaccines containing thimerosal are not associated with autism. No association between MMR vaccine and autism

Consider Evaluation if by: 9m: no back-and-forth sharing of sounds, smiles and other facial expressions 12m: No babbling or gesturing (pointing, waving bye- bye) 16m: No single words 24m: No spontaneous 2 word phrases (i.e. not just echolalia or repeating someone else’s words) Any age: any loss of any language or social skills

Consider Evaluation if - Abnormal eye contact Aloofness Not responding to one’s name Not using gestures to point or show Lack of interactive play Lack of interest in other children

Evaluation History - Pregnancy, neonatal and developmental hx, medical hx, family and psychosocial factors Direct interaction and behavioural observations of child Collateral of observations of child in social settings Physical evaluation - identify dysmorphic features, including neurological exam, head circumference, vision, hearing Psychological eval. - Cognitive testing, adaptive skills Speech/language/communication assessment OT evaluation

Shaefer Gen Med 2013; Miller AJHG 2010; Shen Peds 2010 Medical Evaluation Standard of Care for all patients with ASD Chromosomal microarray analysis molecular DNA testing for Fragile-X Tests for selected patients with specific presentations Metabolic testing EEG if clinically observable seizures or history of significant regression in social or communication functioning. MRI Shaefer Gen Med 2013; Miller AJHG 2010; Shen Peds 2010

Goals of treatment In order to optimize outcome, it is important to screen/diagnose early and to initial intensive behavioral therapy. Promote functional conversational language. Promote social interactions while mitigating repetitive, self-stimulatory behaviors, tantrums, aggression and self-injurious behaviors. Unit 3 – Autism Spectrum Disorders – Dr. D. Aggarwal

Intervention Applied Behavior Analysis (ABA): Uses the principles of operant conditioning to teach specific social, communicative, and behavioural skills to children with ASD. It involves teaching new behaviours by explicit reinforcement of these behaviours, problem behaviours are often addressed by carefully analyzing triggers or antecedents of the problem behaviour in order to change the factors in the environment that are contributing to the problems behaviour.

Potential Target Symptom Domains of Pharmacotherapy Hyperactivity and Inattention Repetitive Behaviors Irritability

RUPP Autism Network, Arch Gen Psychiatry 2005;62:1266-74 RUPP Autism Network: Study of MPH in Children with PDDs + Hyperactivity Subjects: 72 children ( age 5-14 yr) with Autism Asperger’s or PDD-NOS and significant ADHD symptoms using DSM IV criteria 49% (35/72) responded to MPH (ES 0.3 to 0.5) Hyperactivity and impulsive symptoms improved more than inattentive symptoms 18% (13/72) dropped out due to AEs (decreased appetite, insomnia, irritability (most common), dose dependant. RUPP Autism Network, Arch Gen Psychiatry 2005;62:1266-74

Treatment of Aggression and Irritability

RUPP: Acute Risperidone Trial in Autism 8 week, double-blind, parallel groups 101 subjects; Mean age 8.8 y (5-17 y) Mean dose 2.1 mg/d, range 0.5-3.5 mg/d 59% decrease in Irritability score vs 14% decrease in the placebo group CGI-I scale differed by 64% percent for children whose behaviour was much improved or very much improved Mean weight increase: Risperidone = 2.7 kg; Placebo = 0.8 kg RUPP Autism Network. N Engl J Med. 2002;347:314-321.

Placebo-Controlled, Fixed-Dose Study of Aripiprazole in Autism 8 week, double blind, placebo controlled N =218 with autism and significant irritability Age range 6-17yr, mean age 9.7yr Fixed dosing trial, 5mg, 10mg, 15mg/day All Aripiprazole doses better than placebo for irritability No significant difference between doses (5, 10, 15mg vs placebo) Mean weight gain: plc = 0.3kg, Aripiprazole 5mg/10mg =1.3kg; 15mg = 1.5 kg Common side effects leading to discontinuation: sedation, drooling, tremor, akathisia, EPS Marcus, et al. J Am Acad Child Adolesc Psychiatry. 2009;48(11):1110-1119.

Placebo-Controlled Study of Aripiprazole in Autism 8 week, double-blind, placebo controlled N = 98 with autism and significant irritability Age range 6-17yr, mean age 9.3yr Dose range 2 to 15mg/day (mean 8.5mg) Aripiprazole significantly better than placebo for irritability Mean wt gain: placebo = 0.8kg; Aripiprazole =2.0kg Most common AEs: fatigue and somnolence Owen, et al. Pediatrics. 2009;124(6):1533-1540.

Pharmacotherapy- Summary No treatment for core symptoms of social and relationship problems in Autism Risperidone1 (5-16 y) and aripiprazole2,3 (6-17 y) are FDA-approved for irritability/aggression in children and adolescents with autism Stimulants effective in treating ADHD symptoms in ASD patients 1RUPP Autism Network. NEJM. 2002. 2Marcus, et al. JAACAP. 2009. 3Owen, et al. Pediatrics. 2009.

ADHD Outline Diagnosis Assessment Co-morbidity Epidemiology Etiology Natural History Treatment

Case 10 year old boy Joshua presents with difficulty sitting still, distractibility and aggressive behaviour. Mother “The teacher thinks he has ADHD and she told me to put him on Ritalin….I told the school he is just an active boy and the school should be able to manage him…..Dr. what do you think is going on?”

Differential Diagnosis of ADHD Not every inattentive or disruptive child has ADHD A child may be inattentive or act out because of: Learning problems, Mental Retardation Mood (Depression or Bipolar) Anxiety, including OCD Autism Spectrum Disorder Substance related disorder NOS Sleep problems Impaired hearing or vision Personality Change Due to a GMC (ie head injury) Age appropriate behaviours in active child Understimulating environment (gifted child) APA, DSM-IV TR, 2000

DSM-5 Symptoms for ADHD Inattention Hyperactivity Impulsivity Doesn’t attend to details in schoolwork Difficulty sustaining attention in tasks/play Doesn’t listen Doesn’t complete tasks Difficulty organizing Avoids tasks requiring focus Loses things Distractible Forgetful Hyperactivity Fidgets Leaves seat Runs about Doesn’t play quietly “On the go” Talks excessively Impulsivity Blurts out answers Doesn’t await turn Interrupts or intrudes

ADHD Diagnostic Criteria (DSM-5) Inattentive symptoms (≥6/9), AND/OR hyperactive-impulsive symptoms (≥6/9) (for age 17 and older at least 5 symptoms are required) Several symptoms must have been present <12 y.o. Several symptoms must be present ≥2 settings (home, school, work, friends, other activities) Clear interference in functioning (school, social, family, work) Symptoms not better explained by another mental health disorder or medical condition

What part of the assessment is the least helpful in making the dx of ADHD in a 15year old teen? a) Parent interview b) Teen interview c) Teen mental status d) Rating scale completed by parent e) Rating Scales completed by teacher

c ) interview with the teen d) observing the teen in class What part of the assessment is the most helpful in making the dx of ADHD in a 15year old teen? case conference with teachers and parents to get a better understanding of the teens behaviour at school b) interview with parent about developmental history and past academic history c ) interview with the teen d) observing the teen in class e) rating scales completed by teacher and parent

Assessment in Children and Adolescents Parent interview including developmental history Child/adolescent interview Information from teachers and other sources Rating Scales -useful to support clinical evaluation and monitor progress, but should not be used on their own to make a diagnosis Conners Rating Scale-Revised (Parent/Teacher) SNAP-IV Teacher/Parent Rating Scale (available at www.caddra.ca)

Assessment (cont.) Medical evaluation: History and physical examination Hearing and vision tests Laboratory and imaging tests only if indicated by the clinical evaluation Consider a psychoeducational evaluation, including both cognitive and academic testing, to assess for learning problems

Co-morbidity Children with ADHD have high rates of co-morbid psychiatric disorders Almost 70% of children with ADHD had at least one co-morbid condition Disorders that are frequently co-morbid with ADHD: Learning disorders Anxiety & depressive disorders Oppositional defiant disorder & conduct disorder Substance use disorders Tic disorders Pliszka et al., 2007; Spencer et al., 2007; Spencer et al., 1999; MTA Cooperative Group, 1999

Father “How common is ADHD. What causes ADHD. Will Joshua outgrow ADHD

ADHD presentations in children: (Polanczyk et al., 2007) Prevalence of ADHD School age children: 6-9% (Wolraich et al., 1998; CDC, 2010; Ontario Child Health Study, 1989) Gender differences: 9.0% in boys (4-16 yrs old) and 3.3% in girls (OCHS, 1989) Adult : 4.4% (NCS-R, 2006) ADHD accounts for 30-50 % of mental health referrals (MTA Cooperative Group, 1999) ADHD presentations in children: (Polanczyk et al., 2007) Combined (50-75%) Inattentive (20-40%) Hyperactive-impulsive (<5-15%)

Genetics accounts for ~0.76 of the variance in ADHD Neurobiology of ADHD Genetics accounts for ~0.76 of the variance in ADHD Non-genetic factors > low birth weight/prematurity, maternal smoking or drinking alcohol in pregnancy, psychosocial adversity Parenting is not a cause of ADHD, but parenting influences the outcome of ADHD Polygenic Disorder (many genes involved) Catecholamine dysfunction (Norepinephrine and Dopamine)

–Have secondary effects on inhibiting DA reuptake Pharmacodynamics Methylphenidate: –Blocks DA and NE transporters in the presynaptic neuron, thus inhibiting reuptake and resulting in increased synaptic concentrations of these neurotransmitters •Amphetamines: –Stimulate release of DA and, to a lesser extent, NE, from presynapticsites –Have secondary effects on inhibiting DA reuptake

Not just a Disorder of Executive functioning / supplementary motor cortex (Stahl's Essential Psychopharmacology, 2008)

Father “I think my wife has ADHD. I made a video to show you Father “I think my wife has ADHD. I made a video to show you. what do you think ?”

Mother “ How do you treat ADHD Mother “ How do you treat ADHD? Are there any side effects with medications? Are there any long-term side effects of medications?

Behavioural Management vs. Medication for ADHD

Non-Medication Interventions For Children Psychoeducation Explain the rationale for the diagnosis Explain that ADHD is mainly a genetically and neurobiological based disorder Review the natural course of ADHD Provide a sense of hope since ADHD is one of the most treatable psychiatric conditions Behavioural Parent Management Training Behavioural School and Academic Intervention AACAP ADHD Practice parameter. JAACAP. 2007 American Academy of Pediatrics. Pediatrics. 2011

Stimulants Duration of Action (hours) Methylphenidate • Ritalin 4 (3-4) • Biphentin 8-10 • Concerta 12 (8-14) Amphetamines • Dexedrine 4 (3-6) • Adderall XR 10-12 • Lisdexamfetamine (Vyvanse) 12-13

Stimulant Side Effects Initial insomnia Decreased appetite, weight loss Small increases in HR and BP Stomachaches Headache Thirst, Palpitations

• Anxiety • Social withdrawal, decreased spontaneity • Increased activity, aggression, irritability, dsyphoria • Tics • Risk of growth suppression

Current Recommendations Before initiating a stimulant Personal history of cardiac symptoms including syncope, palpitations, chest pain, shortness of breath or seizures during exercise of cardiac disease including a clinically significant murmur (not functional) Family history of premature (sudden/unexpected) death in family members <40 years old of cardiac history including hypertrophic cardiomyopathy, clinically important arrhythmias including long QT syndrome (LQTS), Marfan syndrome (Hammerness et al., 2011)

Contraindications to Stimulants Advanced arteriosclerosis Moderate to severe hypertension Untreated hyperthyroidism Glaucoma Hypersensitivity to the drug During treatment with MAO inhibitors, and for up to 14 days after discontinuation (hypertensive crises may result) Pregnancy Stimulants are not contraindicated in individuals with seizure disorders, autism spectrum disorders, or Tourette syndrome, but their use should be cautious in these populations

Atomoxetine (non stimulant) Selective norepinephrine (NE) reuptake inhibitor (NRI) 24 hour coverage, OD dosing Effect size =0.6 (stimulants effect size = 1) Small benefit for anxiety symptoms

Monitoring for Stimulants and Atomoxetine Height and weight on growth charts HR and BP at baseline, with dose changes and periodically thereafter Use parent and teacher rating scales to monitor response and side effects at different doses

Guanfacine XR (Intuniv XR) selective alpha 2A-adrenergic receptor agonist Similar to clonidine, but less sedation & hypotension four doses (1, 2, 3 and 4mg), OD dosing 2nd line treatment: Health Canada approval for the treatment of ADHD in children aged 6-12 with sub-optimal response to psychostimulants either as an adjunctive therapy to psychostimulants monotherapy

2014 CADDRA Guidelines Medical Treatment of ADHD 1st line 2nd line 3rd line Adderall XR Biphentin Concerta Vyvanse Atomoxetine Guanfacine XR * Short Acting Stimulants Dexedrine Dexedrine spansules Ritalin IR Ritalin SR Off label   Imipramine Modafinil Bupropion * Guanfacine 2nd line only for children 6-12yr (CADDRA ,2014) 57

(CADDRA, 2011)

(CADDRA, 2011)

Are There Side Effects of Not Treating? Side effects of the ADHD meds are well know but are the consequences of not treating ADHD as well appreciated?

Impairments Poor Health/Injury Academic/ Occupational Domains of Impairment Poor Health/Injury Academic/ Occupational Impairments Smoking and Substance Abuse Low self-esteem Risky Sexual Behaviour Relationships Legal difficulties Traffic Violations and Motor Vehicle Accidents

Questions ?