1. Judith Aronson-Ramos, MD
Medications in ASD

3. Principles of Good Medical Practice (GMP)
Overview
Principles of Good Medical Practice (GMP)
I. Commonly used medications in ASD
II. Nutraceuticals and supplements in ASD
III. Research trends in psychopharmacology for ASD
IV. The role of parents and caregivers in medication management
V. Pharmacogenetic testing
VI. Understanding the evidence
Professional Disclosure – no conflicts of interest

4. Principles of GMP
Start with evidence-based psychosocial treatment (parent training, behavior therapy, etc.)
Parental involvement is essential, with involvement by other caregivers, teachers, therapists as needed
Monitor response to treatment using reliable and valid measures of changes in the target symptoms
In mild cases, attempt a course of at least 12 weeks of psychosocial interventions before considering medication
In moderate to severe cases, a higher level of intervention may be appropriate
Treatment should be individualized

5. GMP continued Initiate and continue with monotherapy when possible
Start low, go slow - continue on lowest effective dose
Continue psychosocial interventions during treatment with medication
Monitor for adverse effects
After 6 to 9 months of stabilization, plan a discontinuation trial to determine whether or not the medication is still needed and effective
Use of psychotherapeutic medication in children under the age of 24 months is not recommended

6. I. Medications in ASD
Medications behavior, cognitive, & social-emotional problems core deficits
All medications used in ASD other than the two FDA approved are used to treat co-existing conditions and various target symptoms/behaviors
Medications include:
Stimulant and non-stimulant medications (methylphenidates, amphetamines, alpha agonists, atomoxetine) - ADHD
SSRI, SNRI and other medications for anxiety, depression, OCD
Antipsychotics – mostly second generation – FDA approved
Mood stabilizers
Anti-epileptics
Benzodiazepines (rare)
Off label use of medications –Fragile X ( Baclofen, Minocycline), Namenda, Amantadine, Naltrexone, Oxytocin, others……

7. FDA approved Medications for ASD
Only two medications are FDA approved for use in ASD: Risperidone (Risperdal) and Aripiprazole (Abilify)
Latest Study (JAACAP ‘16) – 1/6 with ASD, 1/10 ASD and ID on these meds: further study required, psychosocial interventions first, monitor side effects closely (1.)
FDA approval to treat – irritability in ASD as measured on the ABC (Aberrant Behavior Check list*(2.)
Other benefits reduced: aggression, hyperactivity, defiance, stereotyped behaviors
Side effects: weight gain, sedation, extrapyramidal symptoms - (dystonia (spasms/posturing), akathisia (restlessness), tardive dyskinesia (incurable involuntary movements) - and prolactin elevation
Other atypicals used off label: Olanzapine (Zyprexa), Quetiapine(Seroquel), Clozapine (Clozaril), and Ziprasidone (Geodon)
Overall rates of antipsychotic use declining especially 0-5 years (Medicaid studies) keep in mind formal approval is for ages 5/6-17 yrs.

8. *ABC – Aberrant Behavior Checklist
Developed in to assess “… drug and other treatment effects on severely mentally retarded individuals..”
The factors of the Aberrant Behavior Checklist are:
(I) Irritability, Agitation, Crying
(II) Lethargy, Social Withdrawal
(III) Stereotypic Behavior
(IV) Hyperactivity, Noncompliance
(V) Inappropriate Speech
Average subscale scores compared with empirically derived rating scales of childhood psychopathology

9. Issues in Prescribing Medication
How do we know what works?
Outcome measures ?
Broad and non-specific? CGI, ABC
Range of symptoms ?
Researchers continue to seek more objective tools to assess outcome (biomarkers, imaging, EEG, eye tracking, HR, etc.)-
What works for one child with ASD may not be what research supports
Medication management
Treatment guidelines/standard of care
Evidence based studies published in peer reviewed journals
Clinical judgement + prescribers experience
Patient/family feedback
Success=good communication with your physician, informed consent, careful monitoring, realistic expectations and avoiding harmful side effects (short and long term)

10. *CGI- Clinical Global Impression
CGI-Severity (CGI-S). asks the clinician one question: “Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?” rated on 7-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.
CGI-Improvement (CGI-I). Each time the patient is seen after medication has been initiated, the clinician compares the patient's overall clinical condition to the one week period just prior to the initiation of medication (the so-called baseline visit). 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment.”

12. ASD & ADHD Medications
ADHD is extremely common as a co-existing diagnosis in ASD
2012 study from AS-ATN of 3,ooo patients with ASD 2-18 yrs., >50% with ADHD untx
2013 DSM 5 dual diagnosis of ADHD and ASD hopefully improved identification and tx
ADHD medications include: stimulants and non-stimulants
Stimulants: methylphenidates (Ritalin) and amphetamines (Adderall) – numerous preparations and forms
Stimulants have a long history of safe and effective use in ADHD
Stimulants primarily work on the dopaminergic and norepinephrine systems in the brain primarily PFC
ADHD medications may allow some children with ASD
1. To function in less restrictive settings
2. Make gains academically
3. Show improved self regulation
4.Reduced impulsivity and hyperactivity
5.Better socialization
Negative effects: anxiety, increased repetitive behaviors, disrupted sleep, aggression, more self stims, decreased appetite

13. Evidence -Stimulant Medications in ASD
Stimulants show "moderate strength” of evidence (very low-low- moderate-high) in ASD
Largest RCT studies show more side effects in children with ADHD + ASD than in children with ADHD alone
Best studies show ~49% report “much” or “very much improved” with a ~30% symptom reduction
~18% discontinued due to side effects – most commonly irritability (3.)
Individual responses to different ADHD medications will vary based on genetics, metabolism, and other variables

14. ADHD - Stimulants
Methylphenidate – Concerta, Ritalin, Ritalin LA, Metadate CD, Daytrana, Aptensio XR, Quillivant XR, Quillichew
Dexmethylphenidate – Focalin, Focalin XR
Amphetamine – Adderall, Adderall XR, Evekeo, Zenzedi, Adzenys, Dyanvel
Lisdexamphetamine – Vyvanse
Most of the new medications are reformulations of Ritalin and Adderall in novel delivery systems
Choosing a medication: age, delivery, duration, insurance, prescriber experience, prior medication trials, and PGX testing, family history, parent preference

15. Non-Stimulants
Atomoxetine (Strattera) –mixed results- two well powered studies moderate strength (21-48% improvement) less benefit than stimulants but fewer side effects
Alpha Agonists – emerging data not yet conclusive
Guanfacine ER (Intuniv)
Clonidine ER (Kapvay)
Very young respond well to short acting non-stimulants (Guanfacine/Tenex)
In my experience - high response rate with alpha agonists and ASD
Non-stimulants can be used as monotherapy or combination therapy
Why use a non-stimulant? Tics, anxiety, side effects, synergy, duration of action (all day)

17. Summary: ADHD MEDICATION & ASD
At some point over 50 % of children with ASD will try a medication for ADHD
Response can vary with age, co-existing problems, and unique psychopharmacological effects
Younger children more side effects
Amphetamines more anxiety than methylphenidates
Side effects most difficult to manage – sleep, decreased appetite, increased levels of anxiety, hyper focus resulting in more perseveration, self stims, rebound or wear off
Non-stimulants – constipation, fatigue, weight gain, moody

19. Anxiety, OCD, & Depression in ASD
Mood disorders are very common in ASD
11-42% have one or more anxiety disorders
7-26% have depression more in adults
Some symptoms of anxiety and OCD behaviors are central to core deficits in ASD – fine line
Degree of anxiety and OCD are what drive medication management not the presence of anxiety and OCD
Medication is not always indicated
Quality data is sparse for SSRI, SNRI, and atypical antidepressant use but these medications are widely used
Less common tricyclics, benzodiazepines, mood stabilizers

20. Medications for Mood Disorders
SSRIs–Fluoxetine (Prozac), Escitalopram (Lexapro), Citalopram (Celexa), Sertraline (Zoloft) and SNRI – Duloxetine (Cymbalta) are commonly used in ASD for coexisting depression, anxiety, and ocd
Safe and well tolerated, start low go slow
“Activation”- moody, aggressive, irritable, manic - more common in ASD
Atypicals – Bupropion (Wellbutrin), Mirtazapine (Remeron), Trazodone
Tricyclics – rarely used, sometimes refractory OCD, serious side effects
Anti-Epileptics – Lamotrigine (Lamictal), Oxcarbazepine(Trileptal), Carbamazepine (Tegretol), Topirimate (Topamax), Divalproex Sodium (Depakote)
Mood Stabilizers –Lithium, Gabapentin (Neurontin)
Virtually every psychotropic medication has been tried for someone with ASD somewhere at sometime – few + studies

21. Summary
NOT every child or individual with ASD will benefit from medication
A large % of individuals with ASD will trial medication at some point in their lifetime
Pharmacotherapy should never be considered the first line treatment in ASD – medication management is driven more by treating symptoms than disorders
Polypharmacy should be avoided when possible
Published medical evidence of good quality is limited – strength of evidence is summarized below
Risperidone and Aripiprazole – HIGH
Stimulants – MODERATE
Alpha agonists - ? EMERGING
SSRI, Mood Stabilizers, Anti-Epileptics –INSUFFICENT

22. SLEEP No data for use of any sleep aide in children under two years
Older children Melatonin 1-10 mg at bedtime (typical dose is 3 mg)
Administer minutes prior to bedtime
Recommend the use of pharmaceutical grade melatonin
Differences in response may occur due to lack of uniformity in manufacture of over-the-counter (OTC) brands
Better response if combined with behavioral interventions
Most helpful for sleep onset; may not help for sleep maintenance
There is no specific sleep medication recommended
In severe cases of insomnia – Trazadone, Clonidine/Kapvay, Remeron and other medications have been used

24. II. Nutraceuticals & Supplements
Growing field - limited studies of good quality to result in evidence based treatment recommendations (4., 5.)
Therapeutics with emerging data – Omega 3, Vitamin D, Probiotics (6.), Multi- vitamin/Multi-mineral products, Glutathione, NAC, ? Mito cocktail (CoQ 10, creatine, L-carnitine, L-arginine, folinic acid) –(7.)
Without evidence – digestive enzymes, high dose multivitamins, B12 shots, hyperbaric O2, chelation, IVIG
Evidence is encouraging for some supplements - larger well designed studies are necessary to make strong recommendations
Many families choose to try things on their own – consulting with your physician or a nutritionist regarding safety is always a good idea
Lack of regulation of OTC products, potential dismantling of FDA
Theories lacking scientific validation: opioid excess, leaky gut, fungal overgrowth
Gaining evidence – oxidative stress, inflammation, detoxification, biome
Recent publication of data about high levels of heavy metals in GFCF diet (8.) positive effects on ADHD with Mediterranean diet
Standard recommendation in my practice: omega, probiotic, multivitamin, eat clean

26. III. Research Trends
Big pharma investment in psychiatric drugs has decreased 70% since the introduction of Prozac and other SSRIs in the late 80’s early 90’s (8.)
Expiring patents, complexity of researching psychiatric drugs, and increasing popularity of generics have made this area less lucrative
Private/Public foundations and universities: MIT McGovern Institute, ATN/AS, UC MIND, ASF, Duke, NIH/NIMH, CDC
FDA changes may have significant implications for medications in ASD
Dysfunction in the GABA system – inhibitory control – sensory processing
Endocannabinoid receptors- unknown if ASD would be improved or worsened
CNS network modification – functional connectivity & default mode network
Importance of GI microbiome and autistic behaviors – studies in mice
Oxidative stress – free radicals in blood stream (schizophrenia, autism)
Use of apps, video games, and virtual reality to augment drug effects
Hallucinogens combined with psychotherapy – ketamine, MDMA, etc.
Oxytocin – continues to attract researchers
Cord Blood –Duke University Study
Fragile X

28. IV. Role of Parents & Caregivers
Observation at home, therapies, leisure activities
Communicate with teachers and therapists to get well rounded view of how child is doing
Keep track of side effects
Be open and detailed with your physician including use of supplements and nutritional interventions
Have clear expectations of target symptoms
Be patient, follow directions, don’t make changes without informing your physician
Know what your health plan covers
Understand what a plan exclusion means

30. V. Pharmacogenetic Testing
Pharmacogenetic testing is a relatively new field offering individualized medication management
PGX tests look at how your child’s unique genetic profile interacts with different medications
Studies have shown decreased adverse events, quicker time to a therapeutic response, greater patient satisfaction
Downside – cost , ? risk of misuse
Useful in hard to treat cases, significant side effects, bad family history, parent preference
Results can lead to different medication choices that may not be typical for a physician in the same clinical context

31. PGX and Oxytocin
Predicting treatment response with Oxytocin (the natural hormone) and ASD
Why has Oxytocin shown mixed results in improving different aspects of autism-related behavior, including face recognition, social behavior, and empathy
Oxytocin improves connectivity between areas of the brain involved in reward and perception of social cues
There are different types of mutations of the oxytocin receptor which lead to different patterns of connectivity and facial recognition ability
These different mutations also predict the behavioral response to oxytocin and whether or not it produces improvements in social abilities
The studies of Oxytocin show how PGX can improve autism treatment - particular types of genetic differences will respond better to specific treatments

33. VI. Understanding the Evidence
Parents need to evaluate information and avoid an anything goes mentality - “Trying Everything and Anything for Autism” (10. NY Times, 2010)
Every biomedical intervention.. “is supported by anecdotes and personal testimonies: it is understandable that parents want to share their experience that their child has made progress, and it is equally understandable that other parents are impressed by success stories.” “When parents have invested money, time, energy and, above all, hope into a particular treatment, it is natural to seek to attribute any improvement to that treatment.”
Good websites for keeping informed of latest quality research about ASD
NIMH, CDC, UC Mind Institute, Autism Science Foundation
Key terms to understand about quality research:
Randomized design
Double blind placebo controlled
Study size
Funding, self interest – peer reviewed journals

34. Some Evidence & No Harm
Mindfulness Meditation – child and caregivers – neurobiological changes, emerging body of robust research – evidence based for ADHD, Anxiety, Depression – currently data to support use in HF ASD – Mindful Kids Miami and MBSR (Jon Kabat Zinn)
MBSR – changes in biochemistry, connectivity, blood flow
improved cognitive control and regulation, reduced sensory and emotional reactions
reduced connections between the right amygdala and part of the anterior cingulate cortex that helps regulate emotion, mood, and anxiety
Hippotherapy , Aqua therapy, Pet Therapy, Aromatherapy etc.- if you have time, resources, and there is no harm - trying alternative therapies can be reasonable

35. Treatments that Work
Careful and conservative use of medication, supplements, and nutrition
Regular exercise
Sleep
Stress reduction – children and caregivers
Leisure activities – finding outlets for your child other than screens
Nature
Evidence based therapies : ABA, ST, OT, PT, ESDM, PRT, Social Skills, CBT, hippotherapy, supported classrooms, visual schedules
Don’t waste time and resources- travel, money, fatigue

37. Bibliography
1 . Park et al (2016), Antipsychotic use Trends in ASD. JAACAP, Vol 55, No. 6, p
2. Aman MG (2012) Aberrant Behavior Checklist: Current Identity and Future Developments. Clin Exp Pharmacol 2:e114. doi: / e114
3. McPheeters, et. Al , Pediatrics 2011
4. Online Journal of Health and Allied Sciences Peer Reviewed, Open Access, Free Online Journal Published Quarterly : Mangalore, South India : ISSN Volume 8, Issue 4; Oct - Dec 2009
5.Saudi Pharmaceutical Journal (2013) 21, 233–243
6. Cell 155, December 19, 2013 ª2013 Elsevier Inc. 1447
7. A Modern Approach to the Treatment of Mitochondrial Disease Sumit Parikh, MD, Russell Saneto, DO, PhD, Marni J. Falk, MD, Irina Anselm, MD, Bruce H. Cohen, MD, Richard Haas, MB, BChir, MRCP, and The Mitochondrial Medicine Society
8. Pediatric News, Feb 2017, Deepak Chitnis, Gluten Free Diets Related to High Levels of Arsenic, Mercury
8. research-medicine-mental-illness
9. Watanabe, T., et al., Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism. Soc Cogn Affect Neurosci, 2016.
10. NY Times, Jan 20, 2009, Jane Brody, Trying Anything and Everything for Autism

38. Bibliography cont’d
J Can Acad Child Adolesc Psychiatry Feb; 22(1): 55–60.
Amantadine: A Review of Use in Child and Adolescent Psychiatry
Ooi, Y.P., et al., Oxytocin and Autism Spectrum Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pharmacopsychiatry, 2016.
Gordon, I., et al., Intranasal Oxytocin Enhances Connectivity in the Neural Circuitry Supporting Social Motivation and Social Perception in Children with Autism. Sci Rep, 2016. 6: p
Hernandez, L.M., et al., Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism. Mol Psychiatry, 2016.
Westberg, L., et al., Variation in the Oxytocin Receptor Gene Is Associated with Face Recognition and its Neural Correlates. Front Behav Neurosci,  10: p. 178.
Watanabe, T., et al., Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism. Soc Cogn Affect Neurosci, 2016.

39. Additional Information
AUTISM AND HEALTH: A SPECIAL REPORT BY AUTISM SPEAKS Advances in Understanding and Treating the Health Conditions that Frequently Accompany Autism gures_report_final_v3.pdf
2017 Best Practices Guideline for Psychopharmacology for ASD and ID ASD%20&%20ID%20Guidelines%20(w%20references)%20%206.5 %20x%209.5.pdf