Wellbutrin (Bupropion) in Treatment-Resistant Depression
Bupropion is an effective alternative augmentation strategy for treatment-resistant depression, with strong evidence supporting its use in combination therapy, particularly when added to SSRIs or SNRIs in patients who have failed initial antidepressant monotherapy. 1, 2
Role as Augmentation Strategy
Bupropion serves as a well-established augmentation option after failure of initial antidepressant therapy, though atypical antipsychotics (aripiprazole, quetiapine, olanzapine) remain the primary first-line FDA-approved augmentation strategy. 3, 2, 4
The STAR*D trial demonstrated that switching to bupropion sustained-release achieved remission in 1 in 4 patients whose initial therapy failed, with no significant difference compared to sertraline or venlafaxine extended-release. 1
Combination therapy of bupropion with other second-generation antidepressants has been shown to improve outcomes in patients failing antidepressant monotherapy, converting partial response to full response. 5, 6
Bupropion has a unique mechanism as a dopamine and norepinephrine reuptake inhibitor, offering a different pharmacologic approach compared to SSRIs and SNRIs. 5, 7
Specific Clinical Advantages in TRD
Bupropion offers distinct advantages in treatment-resistant depression, particularly for patients with specific symptom profiles or tolerability concerns:
Sexual dysfunction: Bupropion is associated with significantly lower rates of sexual adverse events compared to SSRIs like fluoxetine, paroxetine, or sertraline, making it particularly valuable when sexual side effects limit adherence. 1, 5
Weight and sedation: Bupropion demonstrates lower rates of weight gain and sedation compared to other commonly used antidepressants, with minimal effect on these parameters. 5, 7
Atypical depression features: Bupropion has demonstrated efficacy in patients with atypical depression who may be resistant to other agents. 8
Dosing and Safety Considerations
The maximum daily dose should not exceed 450 mg/day in divided doses to minimize seizure risk, which is the most prominent safety concern with bupropion. 8, 9
When maintained at 450 mg/day or less in a divided schedule, the seizure rate is comparable to other antidepressant drugs in patients without increased seizure risk factors. 8
Bupropion should not be used in patients predisposed to seizures, including those with epilepsy, eating disorders, or abrupt discontinuation of alcohol or benzodiazepines. 8
Bupropion is 10 to 100 times less likely to induce cardiac conduction problems than tricyclic antidepressants, with rare orthostatic hypotension and minimal anticholinergic effects. 8
Position in Treatment Algorithm
After confirming TRD diagnosis (failure of at least 2 adequate antidepressant trials at minimum effective dosage for ≥4 weeks with different mechanisms), the evidence-based hierarchy is:
First-line augmentation: Atypical antipsychotics (aripiprazole, quetiapine, olanzapine-fluoxetine combination) have the most extensive and rigorous evidence base. 3, 2, 4
Alternative augmentation strategies with strong evidence: Bupropion combination therapy, lithium, liothyronine (T3), lamotrigine, tricyclics, or mirtazapine. 2, 4
Highly refractory cases: Esketamine/ketamine or transcranial magnetic stimulation (TMS) for patients who have failed multiple augmentation strategies. 3, 2, 4
Common Pitfalls to Avoid
Do not count discontinuation before 4 weeks due to side effects as treatment failure unless there is clear evidence of non-response, as this does not meet criteria for establishing TRD. 3, 4
Avoid exceeding 450 mg/day of bupropion to prevent increased seizure risk, particularly in bipolar depression where this threshold should be strictly observed. 9
Monitor for drug interactions when combining bupropion with other antidepressants, particularly fluoxetine which has a long half-life and inhibits cytochrome P450 enzymes. 2
Ensure adequate trial duration of at least 4 weeks at therapeutic doses before declaring treatment failure and switching or augmenting. 3, 4