Bupropion: An Alternative Treatment for Pediatric and

Adolescent ADHD?

Amy YehPharmD Student

Class of 2015Doctoral Seminar

March 24, 2014

Learning Objectives Describe the clinical presentation of

ADHD and how the disorder is diagnosed.

Compare and contrast the first-line treatments of ADHD.

Analyze the clinical trials on bupropion versus methylphenidate for ADHD.

Determine bupropion’s place in therapy.

Abbreviations ADHD: Attention Deficit Hyperactivity

Disorder NT: neurotransmitter QOL: quality of life CV: cardiovascular MOA: mechanism of action ADR: adverse drug reactions CI: contraindications

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

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

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

Clinical Presentation: Inattention1-4

Careless mistakes Easily distracted/bored Trouble staying focused on tasks Disorganized Loses things Forgetful Does not listen when spoken to

Clinical Presentation:Hyperactivity/Impulsivity1-4

Inability to stay seated Fidgeting/squirming Restlessness Excessive talking Impatience with waiting Interrupts/intrudes on others Low stress tolerance/emotional

instability

DSM-V Diagnostic Criteria1-4

≥ 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

ADHD Subtypes1-2

Combined Presentation› Inattention + hyperactivity/impulsivity

Predominately Inattentive Presentation› Inattention

Predominately Hyperactive-Impulsive› Hyperactivity/Impulsivity

*Symptoms/presentation can change over time

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

Treatment1-4

No cure for ADHD Medication +/- behavioral therapy Medications reduce symptoms,

improve functioning, and QOL› Long-term benefits are unknown

Stimulants1-4

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

Methylphenidate4-6

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

Methylphenidate: Safety4-6

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

Oral Methylphenidate Dosing4-6

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

FDA-approved Nonstimulants4-6

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)

Bupropion Hydrochloride5-6

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

Bupropion: Safety5-6

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

Rationale for Analysis4,7-8

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

Trial 1:Bupropion versus methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder: randomized double-blind study7

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

Participants Inclusion: ADHD-diagnosed, ages 6-17 Exclusion

› Psychiatric comorbidities› Suicidal ideation› Mental retardation› Epilepsy› Drug abuse/dependence› Hypertension/hypotension› Cardiac issues

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

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

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

Trial 2:Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder8

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

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

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

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

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

Recommendation2-6

Methylphenidate remains the gold standard for ADHD therapy

Stimulants are first-line› Use with caution if CV/BP issues› Drug 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

Recommendation2-6

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

http://sangrea.net/free-cartoons/social-cartoons.html

References1. Centers for Disease Control and Prevention Web site. ADHD

diagnosis and treatment. Accessed at http://www.cdc.gov/ncbddd/ADHD/ on March 3, 2014.

2. 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.

3. 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.

References4. 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.

5. Clinical Pharmacology Web site. Available at: http://clinicalpharmacology-ip.com.proxy.pba.edu/default.aspx. Accessed March 1, 2014.

6. Lexicomp Online Web site. Available at: http://online.lexi.com.proxy.pba.edu/lco/action/home/switch. Accessed March 1, 2014.

7. 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.

8. 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.