What are the considerations for using Wellbutrin (bupropion) to treat attention deficit hyperactivity disorder (ADHD) in patients with bipolar disorder?

Using Bupropion for ADHD in Patients with Bipolar Disorder

Bupropion should not be used as first-line treatment for ADHD in patients with bipolar disorder; mood stabilization must be achieved first with lithium or divalproex for 12-24 months, followed by stimulants or atomoxetine as preferred ADHD treatments, with bupropion reserved only as an alternative option after careful risk-benefit assessment. 1

Critical Treatment Sequencing

The fundamental principle is that bipolar disorder must be stabilized before addressing ADHD symptoms, as treating unstabilized bipolar disorder with any ADHD medication significantly increases the risk of mood destabilization and can trigger manic or mixed episodes. 1

Step 1: Achieve Mood Stabilization First

• Initiate treatment with lithium or divalproex as first-line mood stabilizers before considering any ADHD treatment. 1
• Maintain the mood stabilizer regimen for a minimum of 12-24 months, as most patients with bipolar disorder require ongoing medication therapy to prevent relapse. 1
• Over 90% of patients who are noncompliant with lithium treatment relapse, compared to 37.5% relapse rate for those compliant with treatment. 1

Step 2: Add ADHD Treatment Only After Mood Control

Once mood symptoms are adequately controlled on a mood stabilizer regimen:

• Stimulant medications are the preferred first choice for ADHD symptoms, with low-dose mixed amphetamine salts being safe and effective for comorbid ADHD once mood is stabilized with divalproex. 1
• Atomoxetine is the preferred first-line ADHD medication for patients with concerns about mood destabilization or substance abuse history, providing effective symptom control without exacerbating mood instability. 1

Bupropion's Role: A Cautious Alternative

Evidence for Efficacy in Comorbid ADHD-Bipolar

• One open trial (n=36,83% completion rate) showed bupropion SR (up to 200 mg twice daily) resulted in significant reductions in ADHD symptom checklist scores (-55%) and CGI severity of ADHD (-40%) in adults with ADHD plus bipolar disorder, with most patients (90% bipolar II, 10% bipolar I) receiving adjunct mood stabilizers. 2
• Low-quality evidence from Cochrane review demonstrates bupropion decreased ADHD symptom severity (standardized mean difference -0.50) and increased clinical improvement rates (RR 1.50) in adults with ADHD, though these studies excluded psychiatric comorbidity. 3

Critical Safety Concerns with Bupropion in Bipolar Disorder

The FDA label explicitly warns that antidepressant treatment can precipitate manic, mixed, or hypomanic episodes, with the risk appearing increased in patients with bipolar disorder. 4 Specific concerns include:

• In one case series, 6 of 11 bipolar patients (55%) experienced manic or hypomanic episodes requiring bupropion discontinuation, with 5 of these 6 patients having been stabilized on lithium plus carbamazepine or valproate prior to bupropion addition. 5
• These findings suggest bupropion may pose the same risks as other antidepressants in precipitating manic episodes in depressed bipolar patients. 5
• However, a smaller study (n=13) of severely ill bipolar depressive inpatients showed no switches to hypomania or mania when bupropion was kept at ≤450 mg daily as add-on to mood stabilizers. 6

Additional FDA Warnings Specific to Bipolar Patients

• Screen patients for a history of bipolar disorder and risk factors (family history of bipolar disorder, suicide, or depression) before initiating bupropion. 4
• Bupropion is not FDA-approved for the treatment of bipolar depression or ADHD in bipolar disorder. 4
• Depressed patients treated with bupropion have experienced neuropsychiatric signs including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion, with some having a diagnosis of bipolar disorder. 4
• Bupropion may lower the seizure threshold and should be avoided in patients with epilepsy or used with caution in those with history of seizures. 7, 4

Clinical Algorithm for Decision-Making

When to Consider Bupropion (After Mood Stabilization)

Consider bupropion only if:

1. Mood has been stable on lithium or divalproex for ≥12 months 1
2. Stimulants have failed or are contraindicated 3
3. Atomoxetine has failed or is not tolerated 1
4. Patient has no history of seizures 4
5. Patient has no active substance use disorder requiring opioids 7

Dosing Strategy if Bupropion is Used

• Start with sustained-release or extended-release formulation only 2, 6
• Begin at low dose (150 mg daily) and titrate slowly 6
• Do not exceed 450 mg daily to minimize switch risk 6
• Continue mood stabilizer indefinitely while using bupropion 1

Monitoring Requirements

• Assess ADHD effectiveness after 6-8 weeks at therapeutic dose using standardized ADHD rating scales 1
• Monitor closely for signs of mood destabilization, particularly manic or hypomanic symptoms 4, 5
• Regular monitoring of lithium levels, renal and thyroid function if on lithium 1
• Monitor blood pressure, as bupropion can cause hypertension 4

Common Pitfalls to Avoid

• Never initiate bupropion or any ADHD treatment before achieving mood stability, as this significantly increases risk of mood destabilization. 1
• Do not assume bupropion will treat both conditions effectively; comorbid ADHD predicts poorer response to bipolar treatment, necessitating adequate mood control first before addressing ADHD symptoms. 1
• Do not use bupropion as first-line ADHD treatment when stimulants or atomoxetine are appropriate alternatives with better evidence in this population. 1
• Avoid exceeding 450 mg daily dose, as higher doses may increase switch risk. 6
• Do not discontinue mood stabilizers when adding bupropion, as the use of ADHD medications does not affect relapse rates when mood stabilizers are maintained. 1

Quality of Evidence Considerations

The evidence for bupropion in comorbid ADHD-bipolar disorder is limited and mixed. The single open trial showing benefit had no control group and small sample size. 2 The Cochrane review rated overall evidence quality as low due to serious risk of bias and small sample sizes, with most studies excluding psychiatric comorbidity. 3 The conflicting data on switch rates (55% in one series 5 versus 0% in another 6) highlights the uncertainty and need for caution in real-world practice.