What are the guidelines for combining duloxetine (Cymbalta) and buspirone (Buspar)?

Combining Duloxetine and Buspirone

Duloxetine and buspirone can be safely combined for treatment-resistant depression or anxiety disorders, though clinicians should monitor for serotonin syndrome and expect higher discontinuation rates with buspirone augmentation compared to other strategies.

Evidence for Combination Therapy

Depression Treatment

• Buspirone augmentation of duloxetine (or other antidepressants) shows moderate efficacy for treatment-resistant depression, with 59-63% of patients achieving complete or partial remission when buspirone 20-30 mg/day is added to existing antidepressant therapy after 4-5 weeks 1
• Low-quality evidence from the STAR*D trial showed no significant difference in response or remission rates when augmenting citalopram with buspirone versus bupropion, though buspirone had higher discontinuation rates due to adverse events 2
• Among patients who initially respond to buspirone augmentation, 79% remained symptom-free at 4-month follow-up, suggesting durability of response 1

Anxiety Disorders

• Duloxetine 60-120 mg once daily is effective as monotherapy for generalized anxiety disorder, demonstrating superiority to placebo in reducing Hamilton Anxiety Rating Scale scores over 9-10 weeks 3
• Buspirone 5-20 mg three times daily is recommended for mild to moderate agitation in elderly patients, though it may take 2-4 weeks to become effective 2
• For patients with partial response to duloxetine monotherapy for anxiety, adding buspirone represents a reasonable augmentation strategy, though direct evidence for this specific combination in anxiety disorders is limited 2, 3

Safety Considerations and Monitoring

Serotonin Syndrome Risk

• While rare, serotonin syndrome has been reported with buspirone-SSRI combinations and theoretically could occur with duloxetine given its serotonergic activity 4
• Monitor for confusion, diaphoresis, incoordination, diarrhea, myoclonus, and agitation when initiating combination therapy 4
• The risk appears low because buspirone has variable effects on 5-HT1A receptors that may reduce serotonin syndrome risk as monotherapy, but caution is warranted in combination 4

Common Adverse Effects

• Duloxetine commonly causes nausea (most common reason for discontinuation), dry mouth, headache, constipation, dizziness, and fatigue 3, 5
• Buspirone augmentation was generally well-tolerated in clinical trials with no serious side effects reported 1
• Discontinuation due to adverse events was significantly higher with buspirone augmentation compared to bupropion augmentation in the STAR*D trial 2

Contraindications and Drug Interactions

• Avoid combining duloxetine with potent CYP1A2 inhibitors (such as fluvoxamine), as this increases duloxetine exposure by 460% and bioavailability from 43% to 82% 6
• Duloxetine is a moderate CYP2D6 inhibitor; use caution with drugs extensively metabolized by this pathway, particularly those with narrow therapeutic indices 6, 5
• Do not combine duloxetine with MAOIs due to serotonin syndrome risk 2
• Buspirone does not significantly inhibit or induce CYP enzymes, minimizing pharmacokinetic interactions 1

Practical Dosing Algorithm

Initiating Duloxetine

1. Start duloxetine 30 mg once daily for one week 7
2. Increase to 60 mg once daily (target dose for most indications) 2, 7, 3
3. Maximum approved dose is 120 mg daily (60 mg twice daily) for depression and anxiety 3, 5
4. Allow 6-8 weeks for adequate therapeutic trial before considering augmentation 2

Adding Buspirone for Partial Response

1. If partial response to duloxetine after 6-8 weeks, initiate buspirone 5 mg twice daily 2
2. Titrate buspirone to 20-30 mg/day in divided doses over 1-2 weeks 2, 1
3. Maximum dose is 60 mg/day (20 mg three times daily) 2
4. Allow 4-5 weeks to assess response to combination therapy 1
5. Educate patients that buspirone requires 2-4 weeks to become effective and is not an as-needed anxiolytic 2

Discontinuation Considerations

Duloxetine Tapering

• Taper duloxetine over at least 2-4 weeks when discontinuing after more than 3 weeks of treatment to minimize discontinuation syndrome 2
• Discontinuation symptoms (nausea, dizziness) occur in up to one-third of patients 3
• Monitor for withdrawal symptoms including sensory disturbances, anxiety, and mood changes 5

Buspirone Discontinuation

• Buspirone can typically be discontinued without tapering as it does not cause significant withdrawal symptoms 2
• However, gradual discontinuation over 1-2 weeks is prudent to avoid symptom rebound 1

Clinical Pitfalls to Avoid

• Do not use this combination as first-line therapy; reserve buspirone augmentation for patients with inadequate response to duloxetine monotherapy after an adequate trial 2, 1
• Do not expect immediate anxiolytic effects from buspirone; unlike benzodiazepines, it requires several weeks for therapeutic benefit 2
• Monitor blood pressure and pulse with duloxetine, as SNRIs can cause sustained hypertension 2
• Screen for hepatic dysfunction before initiating duloxetine and discontinue if jaundice or significant transaminase elevation develops 2
• Be aware that duloxetine may increase bleeding risk when combined with NSAIDs or antiplatelet agents 7