Download Medication In ASD - Autism Education Trust

Medication in Autism Spectrum Disorders – What
Works and What Doesn’t
Dr Paramala Santosh, MBBS, MD, DipNB (Psych), FRCPsych, PhD
Head, Centre for Interventional Paediatric Psychopharmacology (CIPP)
Great Ormond Street Hospital for Children, London
Honorary Reader in Child & Adolescent Psychiatry
Institute of Child Health, London
&
Honorary Senior Lecturer in Child & Adolescent Psychiatry
Institute of Psychiatry, London
Centre for Interventional Paediatric
Psychopharmacology (CIPP)
Complex Developmental Neuropsychiatry Clinic: Children or adolescents with
complex neuropsychiatric disorders, especially those with combined
developmental disorders
Childhood Dementias Clinic: Children and adolescents with childhood
dementias in the context of genetic or medical disorders (e.g. metabolic disorders
such as Hurler’s, Hunter’s, Sanfilipo syndrome, Gaucher’s Disease etc.)
Childhood Traumatic Brain Injury Psychopharmacology Clinic: Children and
adolescents with Acquired Brain Injury who have behavioural problems are
assessed and treated.
Complex Paediatric Psychopharmacology Clinic: Children and adolescents
who have developed unusual or serious side-effects.
Research: Clinical and Translational Research
Assessment Process
Referral from Neurology / Paediatrics /
CAMHS Team
Discussed by CIPP
Questionnaires sent to Parent, Child,
Teachers - Analysed
Discussion with MDT and Hypotheses
Emergencies
Pre-morbid Psychopathology Assessment
Current Psychopathology Assessment
Current MEDICAL Re-assessment
Specific Investigations (Neuropsych; MRI;
r/o Medical Illness)
Psychiatric
Diagnoses
TREATMENT
Treatment
Information Sheets for Medication
provided
Medication and lack of
evidence base discussed with
Parents / Child
Parents opt in to treatment
Medication Stabilisation & Monitoring
Reviewed in Clinic and Liaison
Shared Care with local services after
discharge where possible
Emergencies dealt via e-mail and phone
based discussion
Developmental Psychopharmacology
TYPES OF PHARMACOLOGICAL APPROACHES
• Disorder-specific approach
– ADHD, depression, schizophrenia
• Symptom-based approach
– paranoia, agitation, explosive rage, poor sleep, anhedonia, hyperactivity,
inattention, obsessions & rituals, aggression, self-injurious behaviour
Symptom-Based Approach
• Symptoms that are likely to respond to medication
– hyperactivity, inattention, obsessions, tics, psychosis, impulsivity,
labile mood
• Symptoms that need behavioural modification as well
– aggression, rituals, self-injury, depression
• Symptoms that require specific remediation
– deficits in academic, social or sports domain
Drug Action Used To Improve Symptoms
Symptoms
Noradrenaline
Dopamine
Obsessions
+++
++
Hyperactivity
+
+++
Memory
Mood Lability
ACh
+++
Inattention
Depression
Serotonin
++
+
++
++
+++
__
Minimum Effective Dose
Dose with Minimum Adverse Effects
Minimum Effective Dosing Strategy (MEDS) and
Enhancement of Response
•
Functional Analysis of problem behaviour
•
Take underlying cause of symptom into account
•
Start with 1/6 - 1/8 of expected dose and increase by similar increments every 3 to 7 days
depending on pharmacokinetics of drug
•
Regular monitoring for side-effects / response
•
Stop increase as soon as side-effect occurs
•
Wait till it resolves before further increase
•
Increase placebo response and improve concordance of family and child to treatment
using non-pharmacological approaches
Role of Developmental Status on Pharmacological
Intervention
Response to Stimulants in co-morbid
ASD+ADHD, and ADHD
Outcome Measures
ASD and ADHD (n=61)
Pure ADHD (n=113)
“very much improved” and
“much improved”
31 (51%)
71 (63%)
“minimally worse”, “much
worse” and “very much
worse”
7 (11%)
17 (15%)
1.86 +- 1.3
2.27 +- 1.42
Clinical Global Impression
Improvement
Efficacy Index (Mean +- SD)
Santosh PJ et al, 2006
RUPP - MPH Study I
72 subjects with PDD (autistic disorder, Asperger’s disorder, or PDD-NOS) with
moderate to severe hyperactivity
6 excluded due to inability to tolerate MPH, leaving 59 boys and 7 girls
Exclusion of all those with any other comorbid neuropsychiatric disorders that
might require alternative clinical management
3 doses of MPH and placebo trial to chose appropriate dose prior to starting
study
RUPP studies – 0.5 effect size, more side-effects
MPH - RUPP Study II
(Jahromi et al, 2008)
•
33 children (29 boys and 4 girls) with PDD with mental age of
< 9 years, who had data on the observational measures.
•
Mean age of 6.93 years (SD = 1.83; Range = 5–13 years).
•
MPH 3 doses and placebo given for 1 week at a time in double blind fashion.
•
Exclusion from RUPP I due to
- lack of observational data (technical difficulty, video camera malfunction,
missed visits, or an uncooperative child).
- 12 had a mental age above the inclusion criteria,
- 2 terminated early due to side effects,
- 1 due to parent declining participation, incomplete data, technical difficulties
with videos, and
- 14 did not schedule videotaping.
MPH - RUPP Study II
(Jahromi et al, 2008)
Frequency of Joint Attention
Initiations
Frequency of Total Responses to
Joint Attention
30
25
3
2.5
20
15
10
5
0
2
1.5
1
0.5
0
placebo
best dose
low dose
placebo
Social Communication Behaviors: Two observers, individually coded the JAMES procedure tapes.
Frequency of Joint Attention Initiations: coordinated looks, points to share, shows, and verbal joint attention initiations
Frequency of Joint Attention Responding Behaviors: following an invitation by the experimenter, and
Frequency of Requesting Behaviors: gives, reaches, points to request, and verbal requests.
low dose
MPH - RUPP Study II
(Jahromi et al, 2008)
Self-regulation in the Competing
Demands task
Proportion of Regulated Affect
14
12
20
10
15
8
6
4
10
5
2
0
0
placebo
medium dose
placebo
medium dose
high dose
Self-Regulation Behaviors
Engaging parent: Attempts to engage the parent in interaction or make bids for attention from the parent
Social referencing: Looking at the parent’s face
Distraction: Prolonged or intense attention to, or manipulation of, an object or toy in the room
Self-soothing: Self-manipulative behaviors such as thumb-sucking, fingering clothing, or twirling hair
Directed fussing: Child expresses distress vocalizations clearly directed at the parent in an attempt to change the parent’s behavior
Passive disengagement: Child withdraws passively, or sits without focus on any particular object
Leave taking: Attempts by the child to leave the room by banging or opening the door, or verbally indicating desire to leave
Atomoxetine in ASD+ADHD
osey et al, 2006
pen label
16 subjects
(Aut - 7/ Asp-7
PDD NOS - 2)
6 - 16 years
Non verbal IQ>70
rnold et al 2006
ouble blind placebo
rossover
16 subjects
5-15 years
7 Aut / 1 Asp / 8 PDD NOS
were on other psychotropics
oo
eineret al, 2011
pen label
14 boys
7-17 years
1.2 - 1.4 mg/kg/day
8 weeks
0.25mg/kg/day and then
increase every 4-5 days by
0.25mg/kg/day
1 week washout in between
crossover
6 week trial
10 weeks
Upto 1.2 mg/kg BW
CGI –I 12 (75%) responders
on hyperactivity (d = 1-1.9) on
hyp on ABC (d = 0.4 - 1.1) on
irritability, social withdrawal,
stereotypy, repetitive speech
13% dropped out
decreased weight
d = 0.9 for hyperactivity / imp;
not inattention
9 responded; 4 responded to
placebo
7 were true responders
1 required hospitalization for
violence
Agitation, mood changes,
decreased appetite, GI
upset, suicidal ideation,
psychosis
1 good responder, 5 moderate
responders in ADHD
symptoms
Nausea and headaches. 2
dropouts due to side-effects
CLONIDINE IN ASD
• Useful in ASD with ADHD / Tourette’s syndrome
• Improvement in - hyperactivity, impulsivity, oppositional behaviour,
socialisation
• Side-effects - sedation, hypotension, tolerance, fatigue
• Especially useful in ASD with insomnia (Ming et al, 2008)
Medication in ADHD+ASD
Poor response to STIMULANT
Dose, compliance
Dose, compliance
Change to ATOMOXETINE /
RISPERIDONE
BT
Change to CLONIDINE / CBZ / CHOL
POLYPHARMACY
Persistent after treatment?
Diagnosis
Co-morbidity?
Receptor Activity of the Newer Antipsychotics
RUPP Risperidone Trial in ASD
•
Open label risperidone responders
•
8 week DBPCT (101) : 1.5mg/day; aggression, self injury, severe tantrums better,
(sedation, weight gain)
Effect size ‘d’ was
CGI improvement - 1.4
Irritability - 1.2
Self-injury - 2.11
Tantrums - 1.95
•
4 months open label risperidone (63) : improvement continued – on Ritvo-Freeman Real
Life Rating Scale,
decreased sensory motor behaviours,
affectual reactions,
sensory symptoms,
obsessive and ritualistic behaviour,
maladaptive behaviour.
No change in social relatedness and communication.
(12.32+8.58 lbs wt gain). Leptin did not predict weight gain.
•
Double blinded discontinuation 8 weeks (n=32) : 62.5% versus 12.5% relapse.
(McKrecken et al, 2002; Arnold et al, 2003; RUPP 2005; Martin et al, 2005; Vitiello et al, 2005; McDougle et al,
2005)
Parent Training + Risperidone
•
•
•
•
•
•
•
•
•
Risperidone and parent training (COMB) Vs Risperidone alone (MED) in severe behavioral
problems in ASD.
24-week, randomized, parallel-groups clinical trial (n= 124 children, aged 4 through 13
years).
The children were randomized 3:2 to COMB (n = 75) or MED (n = 49).
Received Risperidone monotherapy from 0.5 to 3.5 mg/day (with switch to aripiprazole if
risperidone was ineffective).
Parents in the COMB group (n = 75; 60.5%) received a mean of 10.9 PT sessions.
Primary Outcome: COMB was superior to MED on Home Situations Questionnaire (HSQ)
[effect size = 0.34].
Secondary Outcome: groups did not differ on CGI-I scores at endpoint; COMB showed
significantly more reductions on ABC - Irritability, Stereotypic Behavior, and
Hyperactivity/Noncompliance subscales.
Final mean dose for MED was 2.26 mg/day (0.071 mg/kg), compared with 1.98 mg/day for
COMB (0.066 mg/kg).
Medication plus PT resulted in greater reduction of serious maladaptive behavior than
MED in children with ASDs, with a lower risperidone dose.
(Aman et al, 2009)
Aripiprazole in ASD
wen et al, 2009
week DBRPCT
arcus et al 2009
week DBRPCT
98 subjects Autism and
irritability (tantrums,
aggression, selfinjurious behavior, or a
combination of these).
Flexibly dosed aripiprazole
(target dosage: 5, 10, or 15
mg/day) or placebo.
Aripiprazole
demonstrated significantly
greater global
improvements than
placebo, from week 1
through week 8.
Discontinuation rates - 10.6% for
aripiprazole, 5.9% for placebo.
Extrapyramidal symptoms - 14.9%
for aripiprazole and 8.0% for
placebo.
Weight gain - 2.0 kg aripiprazole, 0.8
kg placebo at week 8.
N=218, Autism with
irritability (tantrums,
aggression, selfinjurious behavior, or a
combination of these).
Randomized 1:1:1:1 to
aripiprazole (5, 10, or 15
mg/day) or placebo.
All aripiprazole doses
produced greater
improvement than
placebo in mean CGI
improvement and mean
ABC Irritability subscale
scores.
Discontinuation rates : placebo 7.7%,
aripiprazole 9.4% to 13.6%.
Two serious adverse events:
presyncope (5 mg/day) and
aggression (10 mg/day).
At week 8, mean weight change was
: placebo +0.3 kg, aripiprazole +1.3
to 1.5 kg. Sedation was common.
Metabolic Syndrome
• Weight gain, hyperlipidemia, hyperglycaemia, insulin resistance,
hypertension
• Weight Gain
• High risk - clozapine, olanzapine, risperidone
• Moderate risk – quetiapine
• Low risk - amisulpiride, ziprasidone, aripiprazole
• Baseline and follow-up fasting cholesterol, lipids, glucose, insulin, LFT,
TFT, U&Es, prolactin, FBC is warranted
ASD + ODD
Modified CBT - Parent training with
modification
Competence, suitability
Affect recognition / misattribution due to
social skills
Dose, compliance
Add Risperidone
BT with little C
POLYPHARMACY
Persistent after treatment?
Diagnosis
Co-morbidity?
Serotonergic Drugs in ASD
• Tryptophan depletion in ASD – symptoms worsened
• Fluvoxamine improved mood, speech, social relatedness, repetitive behaviours,
aggression, stereotypies
(McDougle et al, 1996)
• SSRIs no better than placebo for repetitive behaviour in ASD (Williams et al, 2010)
• Fluoxetine in severe depression
• Sertraline / fluoxetine in severe Anxiety and OCD
• Behavioural activation common
Mood Stabilizers in ASD
Possible Indications: Labile Affect, Bipolar Disorder, Explosive Rage, Epilepsy, ? EEG
abnormality
SODIUM VALPROATE:
• The effect of divalproex sodium for irritability/aggression in ASD. N=55, (mean age
9.46+/-2.46, mean nonverbal IQ 63.3+/-23.9).
• 12-week DBRPCT, efficacy measures were obtained by an independent evaluator
blinded to randomization condition and side effects.
• 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGIirritability OR: 16.7) and the ABC-Irritability subscale.
• There was a trend for responders to have higher valproate blood levels compared
with nonresponders. Larger sample follow-up studies are warranted.
LAMOTRIGINE, CARBAMAZEPINE
ATYPICAL ANTIPSYCHOTICS
NALTREXONE IN ASD
• Initial open trials showed some positive results
• Double-blind placebo controlled trials show it is no better than placebo
• Possible improvements in - self-injury and hyperactivity
• Side-effects - mild / transient, stereotypies worse
Oxytocin in ASD
• Deficits in the ability to recognize the emotions of others are central to
ASD.
• In a double-blind, randomized, placebo-controlled, crossover design,
oxytocin nasal spray (18 or 24 IU) or a placebo was administered to 16
male youth aged 12 to 19 who were diagnosed with Autistic or Asperger's
Disorder.
• Participants then completed the Reading the Mind in the Eyes Task, a
widely used and reliable test of emotion recognition.
•
• In comparison with placebo, oxytocin administration (low and high doses)
improved performance on the Reading the Mind in the Eyes Task.
• This study provides the first evidence that oxytocin nasal spray may
improve emotion recognition in young people diagnosed with autism
spectrum disorders.
(Guastella et al, 2009)
Pharmacological Preparation for Medical or
Surgical Interventions in ASD / LD
• Subjects with ASD find medical investigations (eg.MRI), minor surgical procedures
difficult.
• May necessitate a General Anaesthetic.
• Often leads to late intervention
• Mild - Oral Midazolam
• Moderate to severely affected - Oral Ketamine
• Routine IV fluids, antiemesis prophylaxis, and removal of IV cannula before return
to ward also help.
Case with ASD + Comorbidity
HYPERACTIVITY – restless, fidgity, on the go
SOCIAL INTERACTION - aloof, little empathy, imaginative
play
IMPULSIVITY- frequently disrupts class, blurts out,
shouts
COMMUNICATION - Little social talk, pronominal reversal
INATTENTION – distractible, flits from task to task
REPETITIVE/ CIRCUMSCRIBED - maps, capitals of cities,
whiz at maths, cognitive rigidity
CHALLENGING BEHAVIOUR – verbal, property, person, self-injury
SLEEP PROBLEM
3
Severity
EEDBACK IN REAL TIME AND ONLINE
Methylphenidate 30mg
5
4
1
Sleep
Hyperactivity
Inattention
Impulsivity
Labile Mood
Aggression
Appetite
Cognitive Rigidity
2
3
Severity
Aripiprazole 2.5mg/day
5
4
2
Sleep
Sleep
Cognitive Rigidity
Appetite
Aggression
Labile Mood
Impulsivity
Inattention
Hyperactivity
1
Concordance and Medication
Perceived Side-Effects
clinician
QoL
Symptoms
CON
child
parent
Brain Damage
Therapeutic Effect in Trials = Drug x Therapeutic Alliance x (Placebo action of Drug / Expectancy effect)
CIPP Team
Team
CIPP
Name
Position
Dr Paramala Santosh
Consultant Child Psychiatrist
Dr Ruksana Ahmed
Consultant Clinical Psychologist
Dr M. Chiara Colonnelli
Specialty Doctor
Dr Otmane El-Mezoued
Specialty Doctor
Dr Pushpika Singappuli
Specialty Doctor
Dr Laura Roughan
Clinical Psychologist
Ms Laura McPartlen
Assistant Psychologist
Mr Michael Woloschin
Senior Staff Nurse
Dr Nagulan Thevarajan
Specialty Registrar
Dr Noha Ineusha
Pharmacist
Ms Nicole Binns
Team Administrator and PA
Mrs Sandra Poole
Team Administrator
Contact Details
Dr. Paramala J Santosh
Centre for Interventional Paediatric Psychopharmacology (CIPP)
Level 4, Frontage Building,
Great Ormond Street Hospital for Children,
London WC1N 3JH
[email protected]