Bupropion for ADHD

1. Bupropion: An Alternative Treatment for Pediatric and Adolescent ADHD? Amy Yeh PharmD Student Class of 2015 Doctoral Seminar March 24, 2014

2. Learning Objectives Describe the clinical presentation of ADHD and how the disorder is diagnosed. Compare and contrast the first-line treatments of ADHD. A nalyze the clinical trials on bupropion versus methylphenidate for ADHD. Determine bupropion’s place in therapy.

3. Abbreviations ADHD: Attention Deficit Hyperactivity Disorder NT: neurotransmitter QOL: quality of life CV: cardiovascular MOA: mechanism of action ADR: adverse drug reactions CI: contraindications

4. What is ADHD? 1-4 Attention Deficit Hyperactivity Disorder One of the most prevalent psychiatric illnesses among children and adolescents in the USA (8.7%) Etiology unknown; low levels of NTs Risk Factors: genetics maternal exposure to lead/PCBs, smoking, alcohol

5. Why Should We Care? 1-4 Greatly decreases QOL Linked to: low self-esteem, difficulties with social interactions, and poor academic performance Often persists into adulthood, with serious consequences < 33% of patients are treated

6. http://stavishclan.com/2012/09/attention-deficit-hyperactivity-disorder-what-does-it-mean-for-speech-and-language.html

7. Clinical Presentation: Inattention 1-4 Careless mistakes Easily distracted/bored Trouble staying focused on tasks Disorganized Loses things Forgetful Does not listen when spoken to

8. Clinical Presentation: Hyperactivity/Impulsivity 1-4 Inability to stay seated Fidgeting/squirming Restlessness Excessive talking Impatience with waiting Interrupts/intrudes on others Low stress tolerance/emotional instability

9. DSM-V Diagnostic Criteria 1-4 ≥ 6 symptoms (per domain) present for ≥ 6 months in multiple settings several before 12 years of age Not due to another mental disorder Interfere with functioning/daily life Interviews, diagnostic rating scales, academic records, physical exam

10. ADHD Subtypes 1-2 Combined Presentation I nattention + hyperactivity/impulsivity Predominately Inattentive Presentation Inattention Predominately Hyperactive-Impulsive Hyperactivity/Impulsivity *Symptoms/presentation can change over time

11. http://www.ourkidsfirstfoundation.org/wp-content/uploads/2012/10/ADHD-types.png

12. Treatment 1-4 No cure for ADHD Medication +/- behavioral therapy Medications reduce symptoms, improve functioning, and QOL Long-term benefits are unknown

13. Stimulants 1-4 Mainstay of treatment, used for decades Methylphenidate, amphetamine, dextroamphetamine, dexmethylphenidate For age 6 and older Equally effective; patients may respond to one drug better than another C-II; concerns with drug abuse/dependence

14. Methylphenidate 4-6 The gold standard of treatment Brand names: Concerta, Daytrana, Ritalin, Metadate, Methylin Generic available Oral, transdermal patch MOA: CNS stimulant; blocks pre-synaptic reuptake of NE and dopamine

15. Methylphenidate: Safety 4-6 ADR: decreased appetite, insomnia, stomach upset, weight loss Pregnancy Category C No renal/hepatic dosing Warning: Associated with CV events See provider: chest pain, shortness of breath Use the lowest effective dose CI: serious heart problems Evaluate for cardiac disease prior to start

16. Oral Methylphenidate Dosing 4-6 Immediate-Release 5 mg bid prior to breakfast and lunch Increase by 5-10 mg daily at weekly intervals Max: 60 mg daily in 2-3 divided doses Long-acting Starting dose based on clinical judgment Take once daily in the morning with a full glass of water May increase dose weekly

17. FDA-approved Nonstimulants 4-6 No known risk of abuse Indications refractory/intolerant to stimulants concerns about drug abuse For ages 6 and older Atomoxetine (Strattera) Clonidine (Kapvay) Guanfacine (Intuniv)

18. Bupropion Hydrochloride 5-6 Used off-label for ADHD Brand name: Wellbutrin Generic available MOA: inhibits reuptake of norepinephrine, serotonin, and dopamine Dosing: 1.4-6 mg/kg/day in 1-3 doses

19. Bupropion: Safety 5-6 ADR: tachycardia, headache, insomnia, weight loss, dry mouth CI: seizure history, eating disorders Black box: suicidal ideation Caution in bipolar disorder Pregnancy Category C Renal/hepatic dosing

20. Rationale for Analysis 4,7-8 Therapeutic alternatives to stimulants are needed Some serious ADRs Tolerance can develop Drug abuse/dependence C-II medications are highly regulated; costs of lab monitoring/office visits *Bupropion affects the same NTs, may provide another option for ADHD patients

21. Trial 1: Bupropion versus methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder: randomized double-blind study 7

22. Introduction Objective: Compare the efficacy of methylphenidate and bupropion in the treatment of children/adolescents with ADHD Design: single-center, 6 week, randomized, double-blind, parallel study

23. Participants Inclusion: ADHD-diagnosed, ages 6-17 Exclusion Psychiatric comorbidities Suicidal ideation Mental retardation Epilepsy Drug abuse/dependence Hypertension/hypotension Cardiac issues

24. Methods Treatment arms Bupropion 100-150 mg/day (N=20) Methylphenidate 20-30 mg/day (N=20) Weight-based dosing; 3 doses/day Titrated over 3 weeks Primary outcome: Change in the score of the parent-rated ADHD-RS-IV from baseline to week 6

25. Results Mean change in score from baseline Efficacy: p < 0.001 for both groups Treatment difference: -1.4 p=0.554 (95 % Confidence interval: -6.4 to 3.5) Statistics : RM ANOVA/independent t-test Inappropriate for ordinal data ADR: Methylphenidate & Headache; adjusted p-value (Chi Square) was not significant

26. Limitations Wrong statistics used; no conclusions can be made No placebo group Small sample size Medication adherence not assessed Ancillary medications not considered Short study duration

27. Trial 2: Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder 8

28. Introduction Objective: Contrast the efficacy of methylphenidate and bupropion in the treatment of children/adolescents with ADHD Design: single-center, randomized, double-blind, 12 week crossover study

29. Participants Inclusion ADHD-diagnosed, 7-17 years of age No ADHD medication for past 14 days Select psychiatric comorbidities allowed Exclusion Mental retardation (IQ < 70) Other psychiatric disorders Seizure history Eating disorders MAOI use

30. Methods Treatment arms Bupropion 50-200 mg/day (N=30) Methylphenidate 20-60 mg/day (N=30) Weight-based dosing; 2-3 doses/day Titrated over 3 weeks Primary outcome: Change in the parent and teacher-rated Iowa- Conners Teacher’s Rating Scale from baseline to week 6

31. Results Mean change in score from baseline Efficacy: p < 0.001 for both groups Treatment difference: 3.1 p > 0.05; confidence interval not provided Statistics : RM ANOVA/paired t-test Inappropriate for ordinal data ADR: no statistics reported

32. Limitations Wrong statistics used No placebo group Small sample size Medication adherence not assessed Ancillary medications not considered Short study duration

33. Recommendation 2-6 Methylphenidate remains the gold standard for ADHD therapy Stimulants are first-line Use with caution if CV/BP issues D rug abuse/dependence  Daytrana patch, Vyvanse Avoid other CNS stimulants (caffeine, ephedra ) Extra costs: office visits/drug monitoring Monitoring: HR, BP, ECG/EKG prior to start, psychiatric health

34. Recommendation 2-6 When to consider bupropion? ADHD + depression No seizure history Drug abuse/dependence Refractory to FDA-approved drugs Avoid MAOI, tamoxifen, CNS depressants Monitor: HR, BP, ECG/EKG prior to start, psychiatric health , renal/hepatic function

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36. References Centers for Disease Control and Prevention Web site. ADHD diagnosis and treatment. Accessed at http ://www.cdc.gov/ncbddd/ADHD / on March 3, 2014. American Academy of Pediatrics. ADHD: Clinical Practice Guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Accessed at http :// pediatrics.aappublications.org/content/early/2011/10/14/peds.2011-2654.full.pdf+html on March 1, 2014. American Academy of Pediatrics. Implementing the key action statements: an algorithm and explanation for process of care for the evaluation, diagnosis, treatment, and monitoring of ADHD in children and adolescents. Accessed at http :// pediatrics.aappublications.org/content/suppl/2011/10/11/peds.2011-2654.DC1/zpe611117822p.pdf on March 3, 2014.  

37. References Consumer Reports Health. Evaluating Prescription Drugs Used to Treat ADHD. Available at: http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/ADHDFinal.pdf. Accessed March 1, 2014. Clinical Pharmacology Web site. Available at: http://clinicalpharmacology-ip.com.proxy.pba.edu/default.aspx. Accessed March 1, 2014. Lexicomp Online Web site. Available at: http://online.lexi.com.proxy.pba.edu/lco/action/home/switch. Accessed March 1, 2014. Jafarinia M, Mohammadi MR, Modabbernia A, et al. Bupropion versus methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder: randomized double-blind study. Hum Psychopharmacol Clin Exp . 2012;27:411-418. Barrickman LL, Perry PJ, Allen AJ , et al. Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry.1995; 34(5):649-57 .