What medication can be used to augment bupropion (Bupropion) in an adult patient with treatment-resistant depression?

Augmentation Strategy for Bupropion in Treatment-Resistant Depression

Direct Recommendation

For adults under 85 years with treatment-resistant depression on bupropion, augment with an SSRI (such as sertraline or citalopram) rather than switching medications or adding other agents. 1

Evidence-Based Rationale

Primary Augmentation Options

The 2023 American College of Physicians systematic review found moderate certainty evidence that augmenting with buspirone or adding an SSRI to bupropion showed similar efficacy for treatment-resistant depression. 1 However, the clinical context matters significantly:

Buspirone augmentation advantages:

• Significantly lower discontinuation rates due to adverse events (12.5%) compared to other medication augmentation strategies (20.6%; P < 0.001) 1
• No addiction potential, tolerance, or cognitive impairment unlike benzodiazepines 2
• Particularly useful when residual anxiety symptoms predominate 2

Buspirone augmentation limitations:

• Requires 2-4 weeks to reach full therapeutic effect—not immediately effective 2, 3
• Low-quality evidence shows no superiority over other augmentation options in efficacy 1
• Start at 5 mg twice daily, titrate to maximum 20 mg three times daily 2, 3

Alternative Augmentation: Aripiprazole

Aripiprazole should generally be avoided as first-line augmentation despite one small trial showing higher remission rates (55.4% vs 34.0%; P = 0.031) compared to bupropion augmentation. 1

Critical reasons to avoid aripiprazole:

• A 2025 risk-benefit analysis found aripiprazole offered only 8.0 depression-free day-equivalents after accounting for tardive dyskinesia risk 4
• In overweight adults (BMI ≥25), aripiprazole resulted in a net harm of -22.8 depression-free day-equivalents when metabolic complications were included 4
• Risks include weight gain, metabolic syndrome, and irreversible tardive dyskinesia 4

Cognitive Therapy as Augmentation

Cognitive therapy augmentation showed similar efficacy to medication augmentation with potentially fewer adverse events (9.2% vs 18.8% discontinuation; P = 0.086) and should be discussed as an alternative or adjunctive option. 1

Age-Specific Considerations

For adults aged 18-64 years:

• Combination therapy with an SSRI provides approximately 20.7 depression-free day-equivalents benefit (equivalent to 3 weeks faster remission) 4
• This represents the optimal risk-benefit profile in this age group 4

For adults aged 65-84 years:

• SSRI augmentation remains preferred, though fall risk partially offsets benefits 4
• Monitor closely for orthostatic hypotension and fall risk 4

For adults aged 85+ years:

• Fall risk with combination therapy becomes more significant 4
• Consider cognitive therapy augmentation as safer alternative 1

Monitoring Requirements

When augmenting bupropion with an SSRI:

• Monitor intensively for serotonin syndrome in the first 24-48 hours after initiation or dose increases 2, 3
• Watch for the triad: mental status changes, neuromuscular hyperactivity, autonomic hyperactivity 2, 3
• Advanced symptoms requiring immediate hospitalization include fever, seizures, arrhythmias, unconsciousness 2

When augmenting with buspirone:

• Start at 5 mg twice daily, increase slowly 2, 3
• Allow 2-4 weeks for full therapeutic assessment 2, 3
• Monitor for theoretical serotonin syndrome risk, though lower than with SSRI combinations 2

Common Pitfalls to Avoid

Expecting immediate results from buspirone is the most critical error—unlike benzodiazepines, buspirone requires 2-4 weeks to reach full therapeutic effect. 2, 3

Choosing aripiprazole in overweight patients leads to net harm when metabolic complications are considered. 4

Failing to consider cognitive therapy as an equally effective option with better tolerability profile. 1

Abrupt discontinuation of SSRIs can cause discontinuation syndrome—taper gradually if switching strategies. 2

Missing early signs of serotonin syndrome by attributing symptoms to worsening depression or anxiety. 2, 3

Supporting Research Evidence

Open-label studies support SSRI-bupropion combinations: one trial showed 54% response rate when augmenting SSRIs/venlafaxine with bupropion 5, and a randomized controlled trial demonstrated 60% remission with bupropion augmentation versus 24% with placebo augmentation (p < 0.05). 6