What is the evidence for off-label use of Wellbutrin (bupropion) in adolescents?

Off-Label Use of Wellbutrin (Bupropion) in Adolescents

Safety and effectiveness of bupropion in the pediatric population have not been established by the FDA, and the potential risks must be carefully balanced against clinical need when considering off-label use in adolescents. 1

FDA Status and Regulatory Position

• Bupropion lacks FDA approval for any indication in children and adolescents, making all pediatric use technically off-label 1
• The FDA label explicitly states: "Safety and effectiveness in the pediatric population have not been established" and advises clinicians to "balance the potential risks with the clinical need" when considering use in this age group 1
• Bupropion carries a black box warning for increased risk of suicidal thoughts and behavior in patients younger than 24 years with depression, requiring close monitoring especially during the first few months of treatment 2, 3

Evidence for Off-Label Uses

ADHD in Adolescents

• Off-label prescribing of psychotropic medications, including bupropion for ADHD, is recognized as sometimes necessary to be consistent with the standard of care when evidence supports its use 4
• A systematic review found that all available open, controlled, and randomized trials demonstrated bupropion's efficacy in improving ADHD symptoms in children and adolescents 5
• Three head-to-head trials found bupropion had efficacy comparable to methylphenidate (p > 0.05), though one large multicenter study found smaller effect sizes for bupropion compared to methylphenidate based on teacher and parent ratings 5
• Bupropion should be considered for pharmacological management of childhood and adolescent ADHD, particularly when stimulants are contraindicated or not tolerated, though more randomized controlled trials with larger sample sizes are needed 5

Depression in Adolescents

• A retrospective chart review of 127 youth (mean age 15.3 years) with depressive disorders found that 45.7% were responders at 12 weeks (defined by CGI-Depression-I score ≤ 2), with bupropion generally well tolerated 6
• The mean dose used was 180.0 ± 52.6 mg/day (range 75-300 mg/day) over a mean duration of 33.9 weeks 6
• These findings provide preliminary evidence of effectiveness and safety, but large, prospective, placebo-controlled studies are needed to confirm these results 6
• Current evidence for bupropion in adolescent depression is mixed with poorly conducted randomized clinical trials, small sample sizes, and lack of long-term assessments 7

Comorbid ADHD and Depression

• An open-label study of 24 adolescents (aged 11-16 years) with comorbid ADHD and depression found that 58% were rated as responders in both conditions, with significant improvements in depressive and ADHD symptomatology 8
• Bupropion SR may be effective and well-tolerated in adolescents with comorbid ADHD and depressive disorders, though randomized, placebo-controlled studies are needed 8
• There is some evidence of benefits in children with comorbid ADHD and conduct, substance use, or depressive disorders 5

Critical Safety Concerns

Overdose Risk and Toxicity

• Adolescents who attempt self-harm are at significantly higher risk for serious morbidity and poor outcomes with bupropion compared to SSRIs 9
• Bupropion exposure in overdose was significantly associated with death (0.23% vs 0% for SSRIs; p < 0.001) and serious outcomes (58.1% vs 19% for SSRIs; p < 0.001) 9
• Bupropion overdose was associated with seizures (27.0% vs 8.5% for SSRIs; p < 0.001), hallucinations (28.6% vs 4.3%; p < 0.001), and need for intubation (4.9% vs 0.3%; p < 0.001) 9
• These overdose risks and the patient's propensity for self-harm must be carefully evaluated when considering bupropion therapy in adolescents 9

Seizure Risk

• Bupropion significantly lowers the seizure threshold, with a documented 0.1% seizure risk in clinical trials 10
• The medication is absolutely contraindicated in patients with current or prior seizure disorder, eating disorders (bulimia or anorexia nervosa), or abrupt discontinuation of alcohol or sedatives 10, 3
• Maximum recommended daily dose is 450 mg to minimize seizure risk 3

Common Adverse Effects

• In the retrospective study, 36.2% of adolescents discontinued bupropion before 12 weeks (19 due to adverse events, 15 due to poor effectiveness) 6
• The most common adverse event was irritability (9.4%), which resolved spontaneously in most cases or after drug discontinuation 6
• Headache was observed less frequently with bupropion than methylphenidate in head-to-head trials 5

Clinical Decision-Making Algorithm

When considering off-label bupropion use in adolescents:

1. Assess suicide risk thoroughly - Given the black box warning and significantly worse overdose outcomes compared to SSRIs, bupropion should generally be avoided in adolescents with active suicidal ideation or recent suicide attempts 2, 3, 9

2. Screen for absolute contraindications - Seizure history, eating disorders, uncontrolled hypertension, concurrent MAOI use, or conditions predisposing to seizures 10, 3

3. Consider first-line alternatives - For depression, fluoxetine has FDA approval and the most evidence in adolescents 4; for ADHD, stimulants remain first-line 4

4. Identify appropriate candidates - Adolescents who may benefit include those with:

   • ADHD who cannot tolerate or have contraindications to stimulants 4, 5
   • Comorbid ADHD and depression 8, 5
   • Depression with prominent apathy, low energy, or hypersomnia 2
   • Concerns about sexual dysfunction or weight gain with SSRIs 2

5. Implement careful monitoring - Close follow-up within 1-2 weeks of initiation, monitoring for suicidal ideation, behavioral changes, seizures, and vital signs (blood pressure and heart rate) 2, 10

Dosing Considerations for Adolescents

• Start with lower doses (37.5-75 mg daily) and titrate gradually by 37.5 mg every 3 days as tolerated 2
• Target therapeutic doses typically range from 150-300 mg/day in divided doses for SR formulation 2, 6
• Administer second dose before 3 PM to minimize insomnia risk 2
• Maximum dose should not exceed 450 mg/day 3

Context Within Broader Guidelines

• Off-label prescribing is broadly recognized in pediatric medicine and is not unique to adolescent substance use or psychiatric treatment 4
• The majority of medications for various pediatric conditions are prescribed off-label, and this practice may be necessary when rigorous clinical trials have not been conducted but clinical need exists 4
• However, the robust evidence base for psychosocial interventions in adolescent depression and ADHD should be considered first-line when appropriate 4