Can an adult patient with a history of social anxiety, attachment anxiety, and depression or Attention Deficit Hyperactivity Disorder (ADHD), who has failed or not tolerated Selective Serotonin Reuptake Inhibitors (SSRIs), take Wellbutrin (bupropion) and Vyvanse (lisdexamfetamine) together?

Can Wellbutrin and Vyvanse Be Taken Together?

Yes, bupropion (Wellbutrin) and lisdexamfetamine (Vyvanse) can be taken together for an adult patient with ADHD, depression, and social anxiety who has failed SSRIs, though this combination requires careful monitoring for cardiovascular effects and anxiety exacerbation.

Rationale for Combination Therapy

Bupropion for Depression and ADHD

• Bupropion has demonstrated efficacy for ADHD in adults, with low-quality evidence showing it decreases ADHD symptom severity (standardized mean difference -0.50,95% CI -0.86 to -0.15) and increases the proportion achieving clinical improvement (RR 1.50,95% CI 1.13 to 1.99) 1
• Bupropion is an appropriate choice for depression when SSRIs have failed, as moderate-quality evidence shows no difference in response when switching from one second-generation antidepressant to another (bupropion vs. sertraline or venlafaxine), making it a reasonable alternative 2
• The tolerability of bupropion is similar to placebo in ADHD trials, with similar withdrawal rates due to adverse effects (RR 1.20,95% CI 0.35 to 4.10) 1

Vyvanse for ADHD

• Lisdexamfetamine (Vyvanse) is a first-line stimulant medication for ADHD with established efficacy and should remain the primary treatment for ADHD symptoms in this patient

Critical Limitation: Bupropion and Social Anxiety

• Bupropion is contraindicated for anxiety disorders because it is activating and can exacerbate anxiety symptoms, agitation, and nervousness 3
• For social anxiety disorder, SSRIs (paroxetine, sertraline, fluoxetine, fluvoxamine, escitalopram) or venlafaxine (SNRI) are the recommended first-line pharmacological treatments with weak recommendation strength but consistent evidence (GRADE 2C) 2
• Individual cognitive-behavioral therapy specifically designed for social anxiety disorder has the strongest evidence (SMD -1.19,95% CrI -1.56 to -0.81) and should be prioritized over pharmacotherapy alone 4

Recommended Treatment Algorithm

Step 1: Address Social Anxiety First

• Restart an SSRI different from the one previously failed (e.g., if sertraline failed, try paroxetine 10-20 mg daily or escitalopram 10-20 mg daily), as SSRIs and SNRIs show high-certainty evidence for efficacy in both anxiety and depression (RR 1.41,95% CI 1.29 to 1.55 for treatment response) 5
• Refer for individual CBT specifically designed for social anxiety disorder (Clark and Wells model or Heimberg model), as this has superior efficacy compared to pharmacotherapy alone (SMD -0.56 vs psychological placebo) 2, 4

Step 2: Continue Vyvanse for ADHD

• Maintain lisdexamfetamine as the primary ADHD treatment, as stimulants remain first-line therapy for ADHD

Step 3: Add Bupropion for Depression and ADHD Augmentation

• Add bupropion extended-release 150-300 mg daily to target residual depressive symptoms and provide additional ADHD benefit 1
• Augmenting with bupropion decreases depression severity more than augmentation with buspirone (low-quality evidence), supporting its use as an augmentation strategy 2

Monitoring Requirements and Safety Considerations

Cardiovascular Monitoring

• Monitor blood pressure and heart rate regularly, as both bupropion and lisdexamfetamine can increase cardiovascular parameters
• Assess for tachycardia, palpitations, and hypertension at each visit

Anxiety Monitoring

• Watch closely for worsening anxiety symptoms when initiating bupropion, as it may exacerbate social anxiety 3
• If anxiety worsens significantly, discontinue bupropion and optimize SSRI/SNRI dosing instead
• Consider that fewer participants drop out due to lack of efficacy with antidepressants (RR 0.41,95% CI 0.33 to 0.50; NNTB 27) but more drop out due to adverse effects (RR 2.18,95% CI 1.81 to 2.61; NNTH 17) 5

Seizure Risk

• Bupropion lowers seizure threshold, particularly at doses above 450 mg daily
• Avoid in patients with eating disorders, seizure history, or abrupt alcohol/benzodiazepine withdrawal

Common Pitfalls to Avoid

• Do not use bupropion as monotherapy for social anxiety, as it lacks efficacy and may worsen symptoms 3
• Do not abandon SSRI/SNRI therapy prematurely—allow 8-12 weeks at therapeutic doses before declaring treatment failure, as maximal benefit may take 12+ weeks 3
• Do not combine bupropion with MAO inhibitors due to risk of hypertensive crisis
• Do not neglect psychotherapy—combining medication with CBT provides superior outcomes compared to either treatment alone for anxiety disorders 3, 4

Alternative Consideration

If social anxiety remains the predominant concern and worsens with bupropion, consider switching to venlafaxine extended-release 75-225 mg daily, which has evidence for both depression and social anxiety disorder (GRADE 2C), while maintaining Vyvanse for ADHD 2, 3. This avoids the anxiety-exacerbating effects of bupropion while still addressing depression and providing some ADHD benefit.