Add-On Medication for Anxiety and Depression with SSRIs
Bupropion is the most evidence-based add-on medication to SSRIs for anxiety and depression, particularly when patients exhibit prominent apathy, fatigue, or low energy alongside their anxiety symptoms. 1
Primary Recommendation: Bupropion
Bupropion augmentation of SSRIs provides dual benefits through its dopaminergic and noradrenergic effects, complementing the serotonergic action of SSRIs. 1 This combination is particularly effective because:
- Bupropion specifically targets apathy and lack of energy through dopamine enhancement, symptoms often resistant to SSRIs alone 1
- The American Academy of Family Physicians recommends bupropion as an activating antidepressant that improves energy levels and reduces apathy, making it beneficial for patients with depression and comorbid anxiety who also have prominent apathy, fatigue, or low energy 1
- Efficacy is comparable to other antidepressants for major depressive disorder, with response evaluation recommended after 12 weeks 1
Dosing and Administration
- Take the second daily dose before 3 PM to minimize insomnia risk 1
- In patients with moderate to severe renal impairment, reduce total daily dose to 150 mg/day 1
- In patients with moderate to severe hepatic impairment, do not exceed 150 mg/day 1
Key Contraindications and Precautions
- Avoid in patients with seizure disorders, anorexia, bulimia nervosa, or conditions predisposing to seizures 1
- Do not use with MAOIs or within 14 days of discontinuing MAOIs 1
- Monitor blood pressure, especially at treatment initiation 1
- Particularly appropriate for patients also trying to quit smoking or reduce alcohol intake 1
Alternative Option: Buspirone
Buspirone represents a second-line augmentation strategy, though evidence is more mixed:
Evidence for Buspirone Augmentation
- FDA-approved for generalized anxiety disorder and has demonstrated efficacy in patients with coexisting depressive symptoms 2
- One open-label study showed 59% (13/22) of patients adding buspirone (20-30 mg/day) to SSRIs (fluoxetine, paroxetine, or citalopram) achieved complete or partial remission after 4-5 weeks 3
- Mean Clinical Global Impressions Scale scores fell by 64% in treatment responders, with 79% of initial responders remaining symptom-free at 4-month follow-up 3
Contradictory Evidence
However, the only placebo-controlled trial failed to demonstrate superiority over placebo. 4 In this study of 119 patients, 50.9% responded with buspirone augmentation versus 46.7% with placebo augmentation—a non-significant difference 4. The authors noted an unusually high placebo response rate, rendering the study potentially inconclusive 4.
Buspirone Dosing and Safety
- Typical augmentation dose: 20-30 mg/day 3
- Well-tolerated with no serious side effects observed in combination therapy 3, 4
- Contraindicated with MAOIs due to risk of elevated blood pressure 2
- Risk of serotonin syndrome when combined with other serotonergic drugs, requiring careful monitoring 2
Clinical Decision Algorithm
Choose bupropion when:
- Patient exhibits prominent apathy, fatigue, or low energy 1
- Patient is attempting smoking cessation or alcohol reduction 1
- No history of seizures, eating disorders, or uncontrolled hypertension 1
Consider buspirone when:
- Bupropion is contraindicated 2
- Patient has pure generalized anxiety disorder with depression 2, 5
- Avoiding dopaminergic/noradrenergic activation is preferred 5
Common Pitfalls to Avoid
- Do not combine either medication with MAOIs—both bupropion and buspirone are contraindicated with MAOIs 1, 2
- Monitor for serotonin syndrome when adding buspirone to SSRIs, particularly with concomitant use of triptans or other serotonergic agents 2
- Do not use bupropion in patients with eating disorders or conditions lowering seizure threshold 1
- Evaluate response after 12 weeks before considering medication changes 1
- With buspirone, be aware that efficacy beyond 3-4 weeks lacks controlled trial support, though long-term use up to 1 year has been reported safe 2