Bupropion in Bipolar Disorder: Use with Extreme Caution
Bupropion can be prescribed for bipolar depression, but only with concurrent mood stabilizer therapy and close monitoring, as it carries a significant risk of precipitating manic or hypomanic episodes. 1, 2
Key Safety Concerns
Risk of Mood Destabilization
The FDA label explicitly warns that antidepressant treatment can precipitate a manic, mixed, or hypomanic episode, with increased risk in patients with bipolar disorder. 1 Prior to initiating bupropion, you must screen patients for bipolar disorder history and risk factors (family history of bipolar disorder, suicide, or depression). 1
Bupropion is NOT FDA-approved for treatment of bipolar depression. 1
Clinical Evidence on Manic Switch Risk
The evidence on bupropion's safety in bipolar disorder is mixed but concerning:
In one case series, 6 of 11 bipolar patients (55%) experienced manic or hypomanic episodes requiring bupropion discontinuation, even when stabilized on lithium plus carbamazepine or valproate. 2 The authors concluded that bupropion "may pose the same risks as other antidepressants in precipitating manic episodes." 2
A double-blind trial found lower switch rates with bupropion (1 of 9 patients, 11%) compared to desipramine (5 of 10 patients, 50%) when added to lithium or anticonvulsant therapy. 3 This suggests bupropion may be relatively safer than tricyclic antidepressants, but risk remains substantial.
Case reports document psychotic mania occurring after bupropion addition to mood stabilizers (lithium/valproate and lithium/quetiapine combinations). 4 Symptoms regressed rapidly after bupropion discontinuation. 4
Dose-Related Risk
The risk of manic switch may be dose-dependent. 5 One case report documented that a patient remained stable on bupropion ≤450 mg/day but switched to mania when the dose was increased to 600 mg/day. 5 Never exceed 450 mg/day in bipolar patients. 5
When Bupropion May Be Considered
Potential Candidates
Bupropion can be considered as an add-on strategy in bipolar depression when:
- The patient is already on therapeutic doses of mood stabilizers (lithium, valproate, carbamazepine, or atypical antipsychotics). 2, 6
- Other antidepressants have failed or caused problematic side effects. 6
- The patient has severe, treatment-resistant bipolar depression. 6
Supporting Evidence for Efficacy
In a small open study of difficult-to-treat bipolar depressive inpatients, 8 of 13 patients (62%) showed >50% reduction in depression ratings within 4 weeks when bupropion was added to mood stabilizers and other medications. 6 No manic switches occurred when doses were kept ≤450 mg/day. 6
Prescribing Algorithm
If you decide to prescribe bupropion for bipolar depression:
Ensure adequate mood stabilizer coverage first - therapeutic lithium levels (0.6-1.2 mEq/L), valproate levels (50-125 mcg/mL), or appropriate atypical antipsychotic dosing. 2, 6
Start low and titrate slowly - begin with 150 mg/day and increase gradually while monitoring for mood elevation. 6
Never exceed 450 mg/day - higher doses substantially increase manic switch risk. 5
Monitor closely for early signs of hypomania/mania - decreased need for sleep, increased energy, racing thoughts, impulsivity, irritability. 1, 4
Discontinue immediately if mood elevation occurs - symptoms typically regress rapidly after stopping bupropion. 4
Monitor blood pressure - bupropion can cause hypertension, particularly relevant given mood stabilizer side effects. 1
Critical Warnings
Discontinue bupropion if the patient develops: 1
- Manic, hypomanic, or mixed symptoms
- Psychotic symptoms (delusions, hallucinations, paranoia, confusion)
- Severe agitation or behavioral changes
Common pitfall: Assuming that concurrent mood stabilizer therapy eliminates manic switch risk - it does not. Even patients on dual mood stabilizers have experienced treatment-emergent mania with bupropion. 2