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 April 7 th, 2016

No affiliations to disclose Disclosures

 Which Statements are True Regarding Autism Spectrum Disorders?  There is a female predominance.  The approximate prevalence is 0.1%.  There is no evidence of a genetic etiology to these conditions.  The pharmacological agent with the most evidence to support effectiveness is risperidone. Unit 3 – Autism Spectrum Disorders – Dr. D. Aggarwal

 The triad of social impairment for individuals with autism spectrum disorder includes all of the following EXCEPT  A)a restrictive behavioral repertoire.  B)difficulty communicating with others.  C)difficulty interacting with others.  D)mobility difficulties. Unit 3 – Autism Spectrum Disorders – Dr. D. Aggarwal

 Which of the following medications have randomized control trials demonstrating effectiveness in treating symptoms associated with Autism  Risperidone ?  Olanzapine ?  Aripriprazole (Abilify) ?  Methylphenidate (Ritalin)? Unit 3 – Autism Spectrum Disorders – Dr. D. Aggarwal

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

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. 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.Intervention

Etiology Genetics - increased risk in siblings and in twins:Twin concordance, monozyg. 90% vs 20% dizygotic Known genetic syndromes, defined mutations, and de novo copy number variations (CNVs) are reported to account for almost 20% of ASD About 10% of children with autism are also identified as having Down syndrome, fragile X syndrome, tuberous sclerosis, and other genetic and chromosomal disorders Recurrence rates for ASD within families : 20% for dx of ASD and 20% for ASD traits in siblings

Early Red Flags Social communication Little social smiling Limited social eye contact Little comfort seeking Little separation anxiety Limited greeting Impaired joint attention

Important indicator of autism is the failure to develop joint attention which refers to the child’s ability to share interests, pleasurable experiences, or requests by using gestures or verbal communication in combination with eye contact with another person Important indicator of autism is the failure to develop joint attention which refers to the child’s ability to share interests, pleasurable experiences, or requests by using gestures or verbal communication in combination with eye contact with another person Joint Attention

DSM-5 Symptoms for ADHD Inattention 1.Doesn’t attend to details in schoolwork 2.Difficulty sustaining attention in tasks/play 3.Doesn’t listen 4.Doesn’t complete tasks 5.Difficulty organizing 6.Avoids tasks requiring focus 7.Loses things 8.Distractible 9.Forgetful Hyperactivity 1.Fidgets 2.Leaves seat 3.Runs about 4.Doesn’t play quietly 5.“On the go” 6.Talks excessively Impulsivity 7.Blurts out answers 8.Doesn’t await turn 9.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

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

If parent has ADHD the Probability that child will have ADHD? A) 10% B) 25% C) 40% D) 50%

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 Assessment in Children and Adolescents

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 Assessment (cont.)

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 % 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%)

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)

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 (Stahl's Essential Psychopharmacology, 2008) / supplementary motor cortex (executive functioning)

Behavioural Management vs. Medication for ADHD

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 (ES 0.55) – improved compliance with parental commands; improved parental understanding of behavioral principles; high levels of parental satisfaction with treatment) Behavioural School and Academic Intervention (ES 0.61) – improved compliance with classroom rules; decreased disruptive behavior; improved work productivity) American Academy of Pediatrics. Pediatrics Non-Medication Interventions For Children

Non-Medication Interventions for Adults Psychoeducation Behavioural Intervention and Goal Setting – Assistive and Organizational Technologies – Work place or academic accommodations (CADDRA, 2011)

Psychotherapy for ADHD in Adults CBT in combination with medication (Safren SA et al., 2005; Stevenson CS et al., 2002; Safren SA et al., 2010) Meta-cognitive therapy (Solanto M et al., 2010) – a group-administered, cognitive-behavioral principles and training in executive self- management skills. Other psychotherapies – Individual psychotherapy – Marital therapy

Stimulants Duration of Action (hours) Methylphenidate Ritalin 4 (3-4) Biphentin8-10 Concerta12 (8-14) Amphetamines Dexedrine4 (3-6) Adderall XR10-12 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)

Current Recommendations Assessment of heart rate and blood pressure per gender/age/height norms. If screen negative, no additional screening including an ECG is required If abnormal findings in above screen consider ECG and consultation with primary care physician or cardiologist (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 Children: Effect size =0.6 (stimulants effect size = 1) Adults : Effect Size = 0.3 to 0.4 (Cunill et al., 2013 [meta-analysis])

Atomoxetine Monitoring Response and adverse effects using rating scales HR and BP at baseline and periodically thereafter Suicidal ideation Height and weight Baseline LFTs are not necessary, but LFTs should be done at the first symptom or sign of liver dysfunction

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 2 nd line treatment: Health Canada approval for the treatment of ADHD in children aged 6-17 with sub- optimal response to psychostimulants either as – an adjunctive therapy to psychostimulants – monotherapy

1 st line 2 nd line 3 rd line 2014 CADDRA Guidelines Medical Treatment of ADHD Off label Imipramine Modafinil Bupropion Off label Imipramine Modafinil Bupropion Atomoxetine Guanfacine XR * Short Acting Stimulants Dexedrine Dexedrine spansules Ritalin IR Ritalin SR Atomoxetine Guanfacine XR * Short Acting Stimulants Dexedrine Dexedrine spansules Ritalin IR Ritalin SR Adderall XR Biphentin Concerta Vyvanse Adderall XR Biphentin Concerta Vyvanse (CADDRA,2014) * Guanfacine 2 nd line only for children 6-17yr

Suggested Pharmacological Algorithm for ADHD 1.Stimulants (try methylphenidate and at least one amphetamine before moving on) 2.Atomoxetine or Guanfacine XR 3.Bupropion 4.Tricyclic antidepressants, Modafinil, other medications and medication combinations

(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?

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

Questions ?