Medication in Autism Spectrum Disorders What Works and What Doesn t

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 Parents opt in to treatment Medication and lack of evidence base discussed with Parents / Child Medication Stabilisation & Monitoring Reviewed in Clinic and Liaison Emergencies dealt via e-mail and phone based discussion Shared Care with local services after discharge where possible

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 Serotonin ACh Obsessions +++ Inattention +++ ++ ++ Hyperactivity + +++ Memory + ++ Depression ++ +++ Mood Lability

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) Clinical Global Impression Improvement very much improved and much improved minimally worse, much worse and very much worse 31 (51%) 71 (63%) 7 (11%) 17 (15%) Efficacy Index (Mean +- SD) 1.86 +- 1.3 2.27 +- 1.42 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 20 15 10 5 0 placebo best dose low dose 3 2.5 2 1.5 1 0.5 0 placebo low dose 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.

MPH - RUPP Study II (Jahromi et al, 2008) 20 15 10 5 0 Self-regulation in the Competing Demands task placebo medium dose 14 12 10 8 6 4 2 0 Proportion of Regulated Affect 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 16 subjects (Aut - 7/ Asp-7 PDD NOS - 2) 6-16 years Non verbal IQ>70 1.2-1.4 mg/kg/day 8 weeks 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 16 subjects 5-15 years 7 Aut / 1 Asp / 8 PDD NOS 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 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 et al, 2011 14 boys 7-17 years 10 weeks Upto 1.2 mg/kg BW 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 Change to ATOMOXETINE / RISPERIDONE Dose, compliance Change to CLONIDINE / CBZ / CHOL BT Persistent after treatment? POLYPHARMACY 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 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 Affect recognition / misattribution due to social skills Add Risperidone Competence, suitability Dose, compliance BT with little C Persistent after treatment? POLYPHARMACY 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 IMPULSIVITY- frequently disrupts class, blurts out, shouts INATTENTION distractible, flits from task to task SOCIAL INTERACTION - aloof, little empathy, imaginative play COMMUNICATION - Little social talk, pronominal reversal REPETITIVE/ CIRCUMSCRIBED - maps, capitals of cities, whiz at maths, cognitive rigidity CHALLENGING BEHAVIOUR verbal, property, person, self-injury SLEEP PROBLEM

5 Methylphenidate 30mg 4 Severity 3 2 1 Hyperactivity Inattention Impulsivity Labile Mood Aggression Appetite Cognitive Rigidity Sleep

5 Aripiprazole 2.5mg/day 4 Severity 3 2 1 Hyperactivity Inattention Impulsivity Labile Mood Aggression Appetite Cognitive Rigidity Sleep Sleep

Concordance and Medication Perceived Side-Effects Symptoms child clinician CON parent QoL Brain Damage Therapeutic Effect in Trials = Drug x Therapeutic Alliance x (Placebo action of Drug / Expectancy effect)

CIPP Team CIPP Team Name Dr Paramala Santosh Dr Ruksana Ahmed Dr M. Chiara Colonnelli Dr Otmane El-Mezoued Dr Pushpika Singappuli Dr Laura Roughan Ms Laura McPartlen Mr Michael Woloschin Dr Nagulan Thevarajan Dr Noha Ineusha Ms Nicole Binns Mrs Sandra Poole Position Consultant Child Psychiatrist Consultant Clinical Psychologist Specialty Doctor Specialty Doctor Specialty Doctor Clinical Psychologist Assistant Psychologist Senior Staff Nurse Specialty Registrar Pharmacist Team Administrator and PA 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 SantoP@gosh.nhs.uk