In an adult who recently had a cerebrovascular accident and is already on fluoxetine (Prozac) for depression, what non‑serotonergic antidepressant can be safely added?

Adding a Non-Serotonergic Antidepressant to Fluoxetine After Stroke

Bupropion is the preferred non-serotonergic antidepressant to add to fluoxetine in post-stroke depression, as it provides complementary mechanisms of action through dopamine and norepinephrine reuptake inhibition without increasing serotonergic burden or bleeding risk. 1, 2

Rationale for Bupropion Selection

• Bupropion acts via dopamine and norepinephrine pathways rather than serotonin, making it mechanistically complementary to fluoxetine's SSRI action 2
• The American Heart Association guidelines support SSRIs as first-line agents for post-stroke depression, with continuation or initiation appropriate for mood disorders after cerebrovascular events 3
• Bupropion avoids the increased bleeding risk associated with dual serotonergic agents, which is particularly important given the 2025 VA/DOD guidelines' caution about fracture risk with SSRIs and the American Stroke Association's warning about rebleeding risk in intracerebral hemorrhage patients 3, 1

Critical Safety Considerations

Seizure Risk Assessment

• Bupropion lowers seizure threshold and must be dosed cautiously in stroke patients 2
• Avoid bupropion if the patient has:
  • History of seizures post-stroke
  • Structural brain lesions in seizure-prone areas
  • Concurrent medications that lower seizure threshold 2

Drug Interaction Monitoring

• Bupropion inhibits CYP2D6, which can increase fluoxetine concentrations since fluoxetine is partially metabolized by this pathway 2
• Monitor for serotonin syndrome symptoms despite bupropion's non-serotonergic mechanism, as elevated fluoxetine levels could theoretically increase risk 2
• Baseline and periodic ECGs are recommended to detect QTc prolongation, as both agents can affect cardiac conduction 1

Dosing Algorithm

1. Start bupropion extended-release at 150 mg once daily in the morning to minimize insomnia risk 2
2. Assess response after 4 weeks before increasing dose 1
3. If inadequate response, increase to 300 mg daily (maximum recommended dose) 2
4. Do not exceed 300 mg daily when combined with fluoxetine due to CYP2D6 inhibition concerns 2

Alternative Non-Serotonergic Options

Mirtazapine

• Mirtazapine provides noradrenergic and specific serotonergic activity through alpha-2 antagonism rather than reuptake inhibition 1
• Useful when insomnia or poor appetite complicates post-stroke depression 1
• Sedation and weight gain are common, which may be beneficial or problematic depending on the patient's status 1

Tricyclic Antidepressants (Not Recommended)

• TCAs should be avoided in stroke patients due to orthostatic hypotension, cardiac arrhythmias, and anticholinergic effects that worsen cognitive recovery 1
• The current doxepin 10 mg dose mentioned in guidelines is sub-therapeutic for depression and likely prescribed for sleep rather than mood 1

Monitoring Requirements

• Use validated depression scales (PHQ-9, Hamilton Depression Rating Scale, or Beck Depression Inventory) every 2-4 weeks during initial treatment phase 1, 4
• Screen for anxiety concurrently, as 75% of anxious stroke patients also have depression 5
• Monitor blood pressure, as bupropion can cause hypertension in some patients 2
• Assess for neurological changes, including any new focal deficits or worsening of existing stroke symptoms 1

Common Pitfalls to Avoid

• Do not add another SSRI or SNRI to fluoxetine, as this increases serotonin syndrome risk and bleeding complications without clear benefit 3, 1
• Do not use MAOIs in combination with fluoxetine due to severe hypertensive reaction risk 2
• Avoid prophylactic antidepressants in non-depressed stroke patients, as the 2025 VA/DOD guidelines recommend against this practice due to fracture risk (doubling in the FOCUS trial) 3, 1
• Do not rely solely on pharmacotherapy—cognitive behavioral therapy should be offered concurrently, as combination approaches may enhance outcomes 1, 4

Expected Timeline and Outcomes

• Continue combination therapy for 6-12 months after achieving remission to minimize relapse, given high recurrence rates of post-stroke depression 1
• Effective depression treatment is associated with better functional recovery and potentially longer survival in stroke survivors 1, 4
• Reassess psychiatric symptoms periodically throughout stroke recovery, as depression and anxiety may fluctuate over time 1, 4

When to Refer

• Consult psychiatry if depression causes persistent distress or worsening disability despite adequate pharmacotherapy trials 3, 4
• Specialist input is warranted when considering complex polypharmacy in patients on multiple cardiovascular and neurological medications 1