Piecing the Puzzle Together: Pharmacologic Approaches to Behavioral Management in Autism Spectrum Disorder

Piecing the Puzzle Together: Pharmacologic Approaches to Behavioral Management in Autism Spectrum Disorder Hannah Sauer, PharmD PGY1 Pediatric Pharmacy Resident Mayo Clinic 2015 MFMER slide-1

Objectives Identify challenges associated with medication management in patients with autism spectrum disorder (ASD) Determine appropriate pharmacologic management of behavioral disorders in ASD Recognize the role for novel pharmacologic approaches to behavior management in ASD 2015 MFMER slide-2

Autism Spectrum Disorder (ASD) High functioning autism, Asperger s Autism spectrum conditions Severe or classic autism 2015 MFMER slide-3

Related Disorders Associated Neurological Symptoms Core Symptoms Autism Adapted from Autism Speaks 2015 MFMER slide-4

Related Disorders Associated Neurological Symptoms Core Symptoms Autism Related Disorders OCD ADHD Immune dysfunction GI disorders Hormone dysregulation Associated Symptoms Seizures Sleep deficits Mood and anxiety Hyperactivity and inattention Core Symptoms Social deficits Repetitive behaviors Bauman. Neurotherapeutics 2010; 7:320-327. 2015 MFMER slide-5

Behavioral Manifestations 1. Repetitive, stereotyped behaviors* 2. Irritability and aggression 3. Hyperactivity and inattention 4. Social impairment* *Core Symptoms 2015 MFMER slide-6

Challenges in ASD Training deficits Limited data Available services Limited Resources Polypharmacy Psychotropic medications Hesitation to discontinue Patient Resistance Drug Sensitivity Situational Symptomatic Drug allergies Dose-sensitive Idiosyncratic adverse reactions Vohra, et al. Drugs Real World Outcomes 2016; 3:409-425 2015 MFMER slide-7

The T Word Services Eligibility v. entitlement Guardianship Continuity of care Adaptive functioning Milen, et al. Soc Work Health Care 2017; 56(7):636-648. McConachie, et al. Child Care Health Dev 2011; 37(6):764-766. 2015 MFMER slide-8

Pharmacologic Options Repetitive, stereotyped behaviors Selective serotonin reuptake inhibitors (SSRIs) Irritability and aggression Antipsychotics Valproic acid Propranolol Hyperactivity and inattention Methylphenidate Clonidine Social impairment 2015 MFMER slide-9

Pharmacologic Options Repetitive, stereotyped behaviors Selective serotonin reuptake inhibitors (SSRIs) Irritability and aggression Antipsychotics Valproic acid Propranolol Hyperactivity and inattention Methylphenidate Clonidine Social impairment 2015 MFMER slide-10

SSRIs Used for repetitive, stereotyped behaviors Co-morbid anxiety, depression, OCD Less efficacious and less tolerable in children than adults Primary agents Sertraline Fluoxetine Baribeau et al. Curr Psychiatry Rep 2012; 16:437. Doyle et al. Dialogues Clin Neurosci 2012; 14:263-279. 2015 MFMER slide-11

Pharmacologic Options Repetitive, stereotyped behaviors Selective serotonin reuptake inhibitors (SSRIs) Irritability and aggression Antipsychotics Valproic acid Propranolol Hyperactivity and inattention Methylphenidate Clonidine Social impairment 2015 MFMER slide-12

Antipsychotics Risperidone* Dose-response relationship Target doses based on weight: 1-2.5 mg/day Aripiprazole* No clear dose-response relationship Less efficacious in some adults Titrate to a maximum of 15 mg/day Baribeau et al. Curr Psychiatry Rep 2012; 16:437. Doyle et al. Dialogues Clin Neurosci 2012; 14:263-279. *FDA-Approved in children 2015 MFMER slide-13

Antipsychotics Haloperidol Inferior to risperidone in children and adolescents Unclear efficacy in adults Olanzapine has intermediate efficacy None effective in preventing self-injury Baribeau et al. Curr Psychiatry Rep 2012; 16:437. Doyle et al. Dialogues Clin Neurosci 2012; 14:263-279. *FDA-Approved in children 2015 MFMER slide-14

Valproic acid Used as adjunctive treatment for irritability, aggression, and repetitive behaviors Weak evidence Propranolol Used for irritability in adults and children with developmental disability Weak evidence Baribeau et al. Curr Psychiatry Rep 2012; 16:437. Doyle et al. Dialogues Clin Neurosci 2012; 14:263-279. 2015 MFMER slide-15

Pharmacologic Options Repetitive, stereotyped behaviors Selective serotonin reuptake inhibitors (SSRIs) Irritability and aggression Antipsychotics Valproic acid Propranolol Hyperactivity and inattention Methylphenidate Clonidine Social impairment 2015 MFMER slide-16

Stimulants Used for hyperactivity, inattention FDA-approved for co-morbid ADHD Controversial in patients with severe intellectual disability Methylphenidate Typical doses poorly tolerated ~50% response rate Limited data in adults Baribeau et al. Curr Psychiatry Rep 2012; 16:437. Doyle et al. Dialogues Clin Neurosci 2012; 14:263-279. 2015 MFMER slide-17

Clonidine Used as second-line for hyperactivity or adjunctive treatment for irritability and aggression Benefit in children with co-morbid sleep disturbances Oral or transdermal Baribeau et al. Curr Psychiatry Rep 2012; 16:437. Doyle et al. Dialogues Clin Neurosci 2012; 14:263-279. 2015 MFMER slide-18

AB is a 8 year-old (25 kg) male with high-functioning ASD presenting with what mom reports as more frequent and severe tantrums. His irritability is currently maintained with appropriate behavioral intervention in addition to risperidone 1 mg daily. What is the most appropriate next step for AB? A. Increase risperidone to the recommended maximum dose for his age (2.5 mg daily) B. Up-titrate risperidone dose slowly every 2 weeks C. Discontinue risperidone due to treatment failure and initiate aripiprazole D. Initiate propranolol as adjunctive treatment 2015 MFMER slide-19

The Missing Pieces Repetitive, stereotyped behaviors Selective serotonin reuptake inhibitors (SSRIs) Irritability and aggression Antipsychotics Valproic acid Propranolol Hyperactivity and inattention Methylphenidate Clonidine Social impairment 2015 MFMER slide-20

The Missing Pieces Repetitive, stereotyped behaviors Selective serotonin reuptake inhibitors (SSRIs) Irritability and aggression Antipsychotics Valproic acid Propranolol Hyperactivity and inattention Methylphenidate Clonidine Social impairment 2015 MFMER slide-21

Augmentative Therapy Postmortem analyses Animal studies Clinical trials 2015 MFMER slide-22

Augmentative Research Series: Tehran University Study design Randomized, double-blind placebo-controlled trials Population Children with DSM-IV diagnosed autism Inclusion Criteria Exclusion Criteria Age 4-12 years ABC-C score 12 Comorbid psychiatric conditions Severe mental disability History of drug or alcohol abuse History of tardive dyskinesia *Abberant Behavior Checklist-Community 2015 MFMER slide-23

Augmentative Research Series: Tehran University Intervention Efficacy Outcomes 10 weeks risperidone + intervention drug* 10 weeks risperidone + placebo Mean decrease in ABC-C scores: 1. Irritability # 2. Lethargy/social withdrawal 3. Stereotypical behavior 4. Hyperactivity 5. Inappropriate speech Safety Outcomes Rates of adverse effects *Memantine, galantamine, or N-acetylcysteine # Primary outcome 2015 MFMER slide-24

Ghaleiha, et al., 2013 Memantine (n=20) Placebo (n=20) F-Value P-Value Irritability 18.25 8.90 17.65 12.75 21.48 <0.01 Lethargy/social withdrawal Stereotypical behavior 16.55 11.65 16.85 13.85 2.56 0.10 8.83 3.30 8.26 6.99 30.42 <0.01 Hyperactivity 23.0 8.25 22.45 13.85 153.5 <0.01 Inappropriate speech 6.0 4.50 5.85 4.69 2.04 0.13 Ghaleiha, et al. 2013 Int J. Neuropsychopharmacol; 16:783-789. 2015 MFMER slide-25

Ghaleiha, et al., 2014 Galantamine (n=20) Placebo (n=20) Mean Difference P- Value Irritability 15.59 5.3 14.95 8.8 3.3 0.018 Lethargy/social withdrawal Stereotypical behavior 11.1 5.6 10.4 8.35 3.45 0.005 6.1 3.95 5.8 4.5 0.85 0.4 Hyperactivity 20.85 10.85 22.3 16.05 3.75 0.14 Inappropriate speech 3.5 2.15 3.25 2.8 0.9 0.29 Ghaleiha, et al. 2014 J. Psychopharmacol; 28(7):677-685. 2015 MFMER slide-26

Nikoo, et al., 2015 N-acetylcysteine (n=20) Placebo (n=20) Mean Difference P-Value Irritability 21.2 11.95 19.7 14.35 3.90 0.02 Lethargy/social withdrawal Stereotypical behavior 21.1 17.15 20.65 17.95 1.25 0.37 10.55 7.75 10.05 8.7 1.45 0.12 Hyperactivity 27.65 21.45 25.1 23.05 4.15 0.01 Inappropriate speech 5.7 4.95 4.75 4.8 0.44 0.08 Nikoo, et al. 2015 Clinical Neuropharmacol; 38(1):11-17. 2015 MFMER slide-27

Augmentative Research Series: Tehran University Strengths Doses of risperidone reflect clinical practice ABC-C rating scale Limitations Wash-out period Exclusion of patients with co-morbid conditions Adverse effects 2015 MFMER slide-28

Memantine Galantamine NAC MOA: NMDA receptor antagonist Mean dose 16.8 mg/day Additional efficacy in: Stereotypic behaviors Hyperactivity Variable response MOA: cholinesterase inhibitor Dosed 10 or 20 mg/day Additional efficacy in: Social withdrawal MOA: restores glutathione, free radical scavenger Use in pediatrics Dosed 500 mg/day Additional efficacy in: Hyperactivity Conflicting results Rossignol, et al. Front Pediatr 2014; 2:87. Stutzman, et al. AJHP 2015; 72(22). 2015 MFMER slide-29

The Missing Pieces Repetitive, stereotyped behaviors Selective serotonin reuptake inhibitors (SSRIs) Irritability and aggression Antipsychotics Valproic acid Propranolol Hyperactivity and inattention Methylphenidate Clonidine Social impairment 2015 MFMER slide-30

Based on the augmentative therapy studies presented, which of the following patients with ASD may benefit from treatment with memantine? A. 6 year old male on appropriately dosed risperidone with continued disruptive behaviors B. 20 year old male with increased outbursts in the setting of a group home transition C. 3 year old female with significant tantrums resulting in self-injury D. 9 year old male with co-morbid schizophrenia and ADHD with chief complaint of worsening irritability 2015 MFMER slide-31

Intranasal Oxytocin 2015 MFMER slide-32

Fear reduction Oxytocin Perceptual selectivity Affiliative motivation 2015 MFMER slide-33

Parker, et al., 2017 Study design Randomized, double-blind, placebo-controlled, parallel trial Population Children 6-12 years old with ASD Inclusion Criteria Exclusion Criteria 4 weeks of stable medications Medically healthy IQ >40 Psychiatric disorder Nasal obstruction or regular nosebleeds Hearing or vision impairment Habitual consumption of large volumes of water Parker, et al. 2017 Proc Natl Acad Sci USA; 114(30):8119-8124. 2015 MFMER slide-34

Parker, et al., 2017 Intervention Intranasal oxytocin 24 IU OR Placebo Administered twice daily for 4 weeks Primary Outcome 1. Social abilities measured by the Social Responsiveness Scale (SRS) Secondary Outcomes 1. Efficacy of oxytocin for core versus associated symptoms 2. Tolerability Parker, et al. 2017 Proc Natl Acad Sci USA; 114(30):8119-8124. 2015 MFMER slide-35

Results 12 Improvement in SRS Total Score 10 8 6 P=0.0275 4 2 0 Oxytocin Placebo Parker, et al. 2017 Proc Natl Acad Sci USA; 114(30):8119-8124. 2015 MFMER slide-36

Results Associated Symptoms Anxiety Spence Score Trend toward improvement Repetitive behaviors RBS-R Score* No difference Tolerability Increased blood pressure in oxytocin group Nasal congestion No significant difference in adverse effects Parker, et al. 2017 Proc Natl Acad Sci USA; 114(30):8119-8124. *RBS-R=Repetitive Behaviors Scale-Revised 2015 MFMER slide-37

Interpretation Limitations Gender: 84% male subjects Parent reporting of symptoms Unanswered questions Sub-populations Confounding endogenous oxytocin Parker, et al. 2017 Proc Natl Acad Sci USA; 114(30):8119-8124. 2015 MFMER slide-38

Oxytocin: The Bottom Line Several studies in last 2 years Adults and children Mixed results May be effective in improving social interactions in some patients. At the very least, does not worsen symptoms. 2015 MFMER slide-39

Pharmacologic Options Repetitive, stereotyped behaviors Irritability and aggression Hyperactivity and inattention Selective serotonin reuptake inhibitors (SSRIs) Augmentative therapy Antipsychotics Augmentative therapy Valproic acid Propranolol Methylphenidate Clonidine Social impairment Augmentative therapy Oxytocin 2015 MFMER slide-40

The Pharmacist s Approach Start low, go slow Limit multiple medication changes Review frequently Assess for indications and adverse reactions Identify complicating co-morbidities Stop drugs that don t work (taper) Anticipate challenges and facilitate continuity 2015 MFMER slide-41

LM is an 18 year old with ASD (non-verbal) and history of seizure presenting with new-onset repetitive chest tapping accompanied by increased irritability. His current medications include: risperidone 3 mg daily, Depakote 500 mg twice daily, sertraline 100 mg daily, methylphenidate 20 mg twice daily, and lorazepam 1 mg as needed for agitation. Which of the following should be on your differential when assessing LM s new symptoms? A. A new medical diagnosis presenting through behavioral symptoms B. Medication side effects C. Medication adherence D. Recent changes in home or social environment E. All of the above 2015 MFMER slide-42

Summary Patients with ASD face many challenges in their healthcare that warrant special attention from a pharmacist s perspective A evidence-based approach should be taken when managing behaviors associated with ASD Studies of novel agents for ASD suggest that the approach to treatment in these patients should be highly individualized 2015 MFMER slide-43

Questions & Discussion 2015 MFMER slide-44