Medications in ASD Judith Aronson-Ramos, MD - PowerPoint Presentation

1. Medications in ASDJudith Aronson-Ramos, MD

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3. OverviewPrinciples of Good Medical Practice (GMP)I. Commonly used medications in ASD II. Nutraceuticals and supplements in ASDIII. Research trends in psychopharmacology for ASDIV. The role of parents and caregivers in medication managementV. Pharmacogenetic testingVI. Understanding the evidenceProfessional Disclosure – no conflicts of interest

4. Principles of GMPStart 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 continuedInitiate and continue with monotherapy when possibleStart low, go slow - continue on lowest effective doseContinue 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 http://www.medicaidmentalhealth.org

6. I. Medications in ASDMedications 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/behaviorsMedications include:Stimulant and non-stimulant medications (methylphenidates, amphetamines, alpha agonists, atomoxetine) - ADHD SSRI, SNRI and other medications for anxiety, depression, OCDAntipsychotics – mostly second generation – FDA approvedMood stabilizersAnti-epilepticsBenzodiazepines (rare)Off label use of medications –Fragile X ( Baclofen, Minocycline), Namenda, Amantadine, Naltrexone, Oxytocin, others……

7. FDA approved Medications for ASDOnly 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 ChecklistDeveloped in 1985 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 SpeechAverage subscale scores compared with empirically derived rating scales of childhood psychopathology

9. Issues in Prescribing MedicationHow do we know what works? Outcome measures ? Broad and non-specific? CGI, ABCRange 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 supportsMedication management Treatment guidelines/standard of careEvidence based studies published in peer reviewed journalsClinical judgement + prescribers experience Patient/family feedbackSuccess=good communication with your physician, informed consent, careful monitoring, realistic expectations and avoiding harmful side effects (short and long term)

10. *CGI- Clinical Global ImpressionCGI-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.”

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12. ASD & ADHD Medications ADHD is extremely common as a co-existing diagnosis in ASD2012 study from AS-ATN of 3,ooo patients with ASD 2-18 yrs., >50% with ADHD untx2013 DSM 5 dual diagnosis of ADHD and ASD hopefully improved identification and txADHD medications include: stimulants and non-stimulantsStimulants: methylphenidates (Ritalin) and amphetamines (Adderall) – numerous preparations and formsStimulants have a long history of safe and effective use in ADHD Stimulants primarily work on the dopaminergic and norepinephrine systems in the brain primarily PFCADHD medications may allow some children with ASD 1. To function in less restrictive settings 2. Make gains academically3. Show improved self regulation4.Reduced impulsivity and hyperactivity 5.Better socializationNegative effects: anxiety, increased repetitive behaviors, disrupted sleep, aggression, more self stims, decreased appetite

13. Evidence -Stimulant Medications in ASDStimulants show "moderate strength” of evidence (very low-low- moderate-high) in ASDLargest RCT studies show more side effects in children with ADHD + ASD than in children with ADHD aloneBest 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 - StimulantsMethylphenidate – Concerta, Ritalin, Ritalin LA, Metadate CD, Daytrana, Aptensio XR, Quillivant XR, QuillichewDexmethylphenidate – Focalin, Focalin XRAmphetamine – Adderall, Adderall XR, Evekeo, Zenzedi, Adzenys, DyanvelLisdexamphetamine – VyvanseMost of the new medications are reformulations of Ritalin and Adderall in novel delivery systemsChoosing a medication: age, delivery, duration, insurance, prescriber experience, prior medication trials, and PGX testing, family history, parent preference

15. Non-StimulantsAtomoxetine (Strattera) –mixed results- two well powered studies moderate strength (21-48% improvement) less benefit than stimulants but fewer side effectsAlpha Agonists – emerging data not yet conclusiveGuanfacine 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 ASDNon-stimulants can be used as monotherapy or combination therapy Why use a non-stimulant? Tics, anxiety, side effects, synergy, duration of action (all day)

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17. Summary: ADHD MEDICATION & ASDAt 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 effectsYounger children more side effectsAmphetamines more anxiety than methylphenidatesSide effects most difficult to manage – sleep, decreased appetite, increased levels of anxiety, hyper focus resulting in more perseveration, self stims, rebound or wear offNon-stimulants – constipation, fatigue, weight gain, moody

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19. Anxiety, OCD, & Depression in ASDMood disorders are very common in ASD11-42% have one or more anxiety disorders7-26% have depression more in adultsSome symptoms of anxiety and OCD behaviors are central to core deficits in ASD – fine lineDegree of anxiety and OCD are what drive medication management not the presence of anxiety and OCDMedication is not always indicatedQuality data is sparse for SSRI, SNRI, and atypical antidepressant use but these medications are widely usedLess 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 ASDAtypicals – Bupropion (Wellbutrin), Mirtazapine (Remeron), TrazodoneTricyclics – rarely used, sometimes refractory OCD, serious side effectsAnti-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. SummaryNOT every child or individual with ASD will benefit from medicationA large % of individuals with ASD will trial medication at some point in their lifetimePharmacotherapy should never be considered the first line treatment in ASD – medication management is driven more by treating symptoms than disordersPolypharmacy should be avoided when possiblePublished medical evidence of good quality is limited – strength of evidence is summarized belowRisperidone and Aripiprazole – HIGHStimulants – MODERATEAlpha agonists - ? EMERGINGSSRI, Mood Stabilizers, Anti-Epileptics –INSUFFICENT

22. SLEEPNo 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 30 - 60 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 maintenanceThere is no specific sleep medication recommendedIn severe cases of insomnia – Trazadone, Clonidine/Kapvay, Remeron and other medications have been used

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24. II. Nutraceuticals & SupplementsGrowing 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, IVIGEvidence is encouraging for some supplements - larger well designed studies are necessary to make strong recommendationsMany families choose to try things on their own – consulting with your physician or a nutritionist regarding safety is always a good ideaLack of regulation of OTC products, potential dismantling of FDATheories lacking scientific validation: opioid excess, leaky gut, fungal overgrowth Gaining evidence – oxidative stress, inflammation, detoxification, biomeRecent publication of data about high levels of heavy metals in GFCF diet (8.) positive effects on ADHD with Mediterranean dietStandard recommendation in my practice: omega, probiotic, multivitamin, eat clean

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26. III. Research TrendsBig 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 lucrativePrivate/Public foundations and universities: MIT McGovern Institute, ATN/AS, UC MIND, ASF, Duke, NIH/NIMH, CDCFDA changes may have significant implications for medications in ASDDysfunction in the GABA system – inhibitory control – sensory processingEndocannabinoid receptors- unknown if ASD would be improved or worsenedCNS network modification – functional connectivity & default mode networkImportance of GI microbiome and autistic behaviors – studies in miceOxidative stress – free radicals in blood stream (schizophrenia, autism)Use of apps, video games, and virtual reality to augment drug effectsHallucinogens combined with psychotherapy – ketamine, MDMA, etc.Oxytocin – continues to attract researchersCord Blood –Duke University Study Fragile X

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28. IV. Role of Parents & CaregiversObservation at home, therapies, leisure activitiesCommunicate with teachers and therapists to get well rounded view of how child is doingKeep track of side effectsBe open and detailed with your physician including use of supplements and nutritional interventionsHave clear expectations of target symptoms Be patient, follow directions, don’t make changes without informing your physicianKnow what your health plan coversUnderstand what a plan exclusion means

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

31. PGX and OxytocinPredicting treatment response with Oxytocin (the natural hormone) and ASDWhy 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 abilityThese 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

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33. VI. Understanding the EvidenceParents 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 ASDwww.sfari.orgnewsletters@spectrumnews.orgNIMH, CDC, UC Mind Institute, Autism Science FoundationKey terms to understand about quality research: Randomized designDouble blind placebo controlledStudy sizeFunding, 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 flowimproved 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 anxietyHippotherapy , 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 WorkCareful and conservative use of medication, supplements, and nutritionRegular exercise Sleep Stress reduction – children and caregiversLeisure activities – finding outlets for your child other than screensNatureEvidence based therapies : ABA, ST, OT, PT, ESDM, PRT, Social Skills, CBT, hippotherapy, supported classrooms, visual schedulesDon’t waste time and resources- travel, money, fatigue

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37. Bibliography1 . Park et al (2016), Antipsychotic use Trends in ASD. JAACAP, Vol 55, No. 6, p. 456-4672. Aman MG (2012) Aberrant Behavior Checklist: Current Identity and Future Developments. Clin Exp Pharmacol 2:e114. doi:10.4172/2161-1459.1000e1143. 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 0972-5997 Volume 8, Issue 4; Oct - Dec 20095.Saudi Pharmaceutical Journal (2013) 21, 233–2436. Cell 155, December 19, 2013 ª2013 Elsevier Inc. 14477. 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 Society8. Pediatric News, Feb 2017, Deepak Chitnis, Gluten Free Diets Related to High Levels of Arsenic, Mercury8. https://www.theguardian.com/society/2016/jan/27/prozac-next-psychiatric-wonder-drug-research-medicine-mental-illness9. 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’dJ Can Acad Child Adolesc Psychiatry. 2013 Feb; 22(1): 55–60. Amantadine: A Review of Use in Child and Adolescent PsychiatryOoi, 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. 35054.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, 2016. 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 InformationAUTISM AND HEALTH: A SPECIAL REPORT BY AUTISM SPEAKS Advances in Understanding and Treating the Health Conditions that Frequently Accompany Autism 2017 https://www.autismspeaks.org/sites/default/files/docs/facts_and_figures_report_final_v3.pdf 2017 Best Practices Guideline for Psychopharmacology for ASD and ID http://www.medicaidmentalhealth.org/_assets/file/Guidelines/17-ASD%20&%20ID%20Guidelines%20(w%20references)%20%206.5%20x%209.5.pdf