1. The Important Questions to Ask Before Considering Medications Michael J. Murray, M.D. Penn State College of Medicine Milton S. Hershey Medical Center

2. Today’s Goals Questions to consider when thinking about adding medication to the treatment plan Guidelines for interpreting the research on medication A basic understanding of commonly used medications for ASD

3. Beyond the Diagnosis Medication Management Diagnosis of Comorbidities Periodic Reassessment Consultation with Other Treatment Providers Therapy for the Individual Therapy for the Family Advocating for Best Practices

4. “Typical” Treatment team may include… Primary Care Physician Neurologist Psychiatrist Special Education Teacher Behavior Analyst Speech Therapist Physical Therapist Occupational Therapist Behavior Specialist Therapeutic Staff Support Personal Care Aides Recreational Therapist Parents, Self-Advocates and Other Family Members

5. Things to Consider What are the potential risks? How will potential adverse outcomes affect the individual and the family? Has the treatment been validated scientifically? Are the assessment methods specified ?

6. Things to Consider How will the treatment be integrated into the individual’s other treatment interventions? Do not overvalue a given treatment such that functional curriculum, vocational life, and social skills are ignored.

7. Things to Consider Most importantly, need to gauge the social validity of the proposed intervention with the individual and family as appropriate

8. Social Validity Essentially asks, “How valuable is this?” Needs to be assessed before and intermittently throughout the intervention

9. Interpreting Research Results Not all research is created equal The design of the study significantly contributes to the strength of the research findings or observations The stronger the research design, the more reliable the outcome

10. Case Report A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Also referred to as anecdotal report Of limited benefit aside from justifying pilot studies

11. Case Series A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information on diagnosis, treatment, response to treatment, and follow-up after treatment. Not hypothesis driven or controlled

12. Open Label Study A type of study in which both the health providers and the patients are aware of the drug or treatment being given. Used frequently as they are easier to conduct than randomized studies and avoid ethical issues of withholding treatment.

13. Randomized controlled trials The randomized, double-blinded, controlled clinical trial is the gold standard of study design This design provides protection from allocation bias by the investigator and from bias in assessment of outcomes by both the investigator and the patient.

14. Non-Randomized Clinical Trials This category includes trials in which treatment allocation was made by a strategy that would make the allocation known to the investigator before informed consent is obtained from the patient. An imbalance can occur in treatment allocation under such circumstances.

15. Other things to consider… The larger the “N” the better The more variables matched the better The longer the treatment phase the better The longer the follow-up the better The more assessment measures the better The smaller the “p” the better

16. Medication

17. There Is No Magic Bullet Only one medication (risperidone) has been approved by the FDA as a treatment for autism spectrum disorders (ASD). However many medications can be helpful in alleviating some of the features of ASD. Medications can also treat the co-morbid disorders that often accompany ASD.

18. Know What You’re Treating Have realistic and clear expectations for the trial. Helpful to have data to support (or refute) a medication’s efficacy. Good communication is essential to ensure the child’s optimal health and to increase the chance for success with potential trials.

19. If considering a trial… Agree on a behavioral target, which is easily operationalized in multiple environments, and method of collecting data Establish a baseline of the behavior and perform other assessment measures if indicated Helpful to have positive and negative targets, if possible

20. While undergoing the trial… Continue collecting data at agreed upon intervals and frequency Coordinate potential dose adjustments with other treatment interventions Give medication doses adequate time to demonstrate change (trends in behavior may take time to manifest) Helpful to graph data

21. This assumes good communication with the treatment team, which can be a challenge in the “real world”. However, some objective measure is necessary to determine medication efficacy and treatment outcome.

22. Guiding Principles for ALL Trials. Start Low (REALLY LOW). Go Slow (REALLY SLOW).

23. Neurochemical Basis of Autism Literature primarily focused on two neurotransmitter systems: –Dopamine –Serotonin

24. dopamine Atypical neuroleptics are the medications of choice to address dopamine dysregulation –Risperidone (Risperdal)* –Olanzapine (Zyprexa) –Quetiapine (Seroquel) –Aripiprazole (Abilify)

25. Atypical Neuroleptic Targets Self-injury Severe agitation Stereotyped movements Severe behavior problems

26. RUPP Study Research Units in Pediatric Psychopharmacology Autism Network Large multi-site trial of the short-term and long-term safety and efficacy of risperidone in a group of over 100 children and adolescents with autism

27. RUPP Study Phase I –8 week double blind trial of placebo vs. risperidone –70% of those receiving medication rated as much or very much improved (12% on placebo) Phase II –4 month open label extension of the study –Benefits sustained at stable dose

28. RUPP Study Phase III –Subjects randomly assigned to continue active substance or to gradual withdrawal with placebo –Relapse rate significantly higher in placebo group (although not 100%) Most common side effects –Weight gain –Sedation –Drooling

29. serotonin Increase in blood serotonin Brain serotonin synthesis seems to be disrupted Post-pubertal children with autism have lower serotonin concentrations than pre-pubertal children with autism (opposite the typical pattern)

30. serotonin Selective Serotonin Reuptake Inhibitors (SSRI’s) are the medications of choice to address serotonin dysregulation –Fluoxetine (Prozac) –Fluvoxamine (Luvox) –Sertraline (Zoloft) –Citalopram (Celexa) –Escitalopram (Lexapro)

31. SSRI Targets Repetitive behaviors Stereotyped mannerisms Difficulty with change or transition Anticipatory anxiety Obsessive compulsive behaviors Depression

32. The research Only small open label studies to date A RUPP type study is underway for fluoxetine Widely used clinically Most common side effects –Disinhibition –Irritability –Sleep disturbance

33. Other Clinical Concerns ADHD-like behaviors –Stimulants can be helpful –Growing clinical use of atomoxetine (Strattera) Mood Instability –Anticonvulsants can be helpful –Be cautious with lithium

34. Sleep Issues Children with autism have greater difficulty falling asleep and more frequent awakenings to full arousal during the night Can have significant impact on the child’s ability to participate in programming Quality of life issue for the family

35. Sleep Issues If using medication for another indication, may try to exploit the sedating side effect of a particular agent Importance of good sleep hygiene is particularly important for this population

36. Trends in Medication Usage In 1995, a survey found that 30.5% of the population sample were prescribed a psychotropic medication In 1999, a survey of high functioning individuals with autism found 55% taking at least one psychotropic medication

37. Trends in Medication Usage A survey completed in 2006 found a prevalence of 70.2% among individuals with moderate autism

38. Factors Associated with Higher Usage Rates Greater age More severe autism More severe intellectual limitations Housing outside of the family home

39. Most Commonly Prescribed Antidepressants Antipsychotics Stimulants Antihypertensives Antiseizure medications

42. Thanks for listening. Questions? Michael Murray, M.D. mmurray2@psu.edu (717) 531-1115

43. References Volkmar, F et al. Autism and pervasive developmental disorders, Journal of Child Psychology and Psychiatry, 45:1 (2004), pp135-70. American Academy of Child and Adolescent Psychiatry, Practice Parameters for the Assessment and Treatment of Children, Adolescents, and Adults with Autism and Other Pervasive Developmental Disorders, available at www.aacap.org.