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

• No affiliations to disclose

Disclosures

Outline • Diagnosis• Epidemiology• Etiology• Assessment • Treatment

–Non medication treatments –Medication treatments

Autism Spectrum Disorders

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

• 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 by:

• 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

Consider Evaluation if -

• 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

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

Medical Evaluation

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

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

Potential Target Symptom Domains of

Pharmacotherapy

•Hyperactivity and Inattention

•Repetitive Behaviors

• Irritability

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 ofAripiprazole 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.

• Diagnosis • Assessment• Co-morbidity• Epidemiology• Etiology• Natural History• Treatment

ADHD Outline

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?”

• 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)

Differential Diagnosis of ADHD

APA, DSM-IV TR, 2000

DSM-5 Symptoms for ADHD

Inattention1. Doesn’t attend to details in

schoolwork2. Difficulty sustaining attention

in tasks/play3. Doesn’t listen 4. Doesn’t complete tasks5. Difficulty organizing6. Avoids tasks requiring focus7. Loses things8. Distractible9. Forgetful

Hyperactivity1. Fidgets2. Leaves seat3. Runs about4. Doesn’t play quietly5. “On the go”6. Talks excessively

Impulsivity7. Blurts out answers8. Doesn’t await turn9. 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) interview with parent about developmental history and past academic history

c ) interview with the teend) observing the teen in class e) rating scales completed by teacher and parent

• 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 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.)

• 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

Co-morbidity

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 ? “

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%)

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)

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

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. 2007American 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

1st line1st line 2nd line2nd line 3rd line 3rd 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 XRBiphentin

Concerta

Vyvanse

Adderall XRBiphentin

Concerta

Vyvanse

(CADDRA ,2014)

* Guanfacine 2nd line only for children 6-12yr

(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?

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 ?