Buspirone for PMDD When SSRIs Are Not Tolerated
Buspirone can be used as an alternative treatment for PMDD when SSRIs are not tolerated, though the evidence supporting its efficacy is limited and it should be considered a second-line option after SSRIs have failed or caused intolerable side effects.
Evidence for Buspirone in PMDD
The FDA label for buspirone does not include PMDD as an approved indication 1. However, research evidence suggests potential benefit:
A single-blind comparative trial found buspirone 10 mg/day showed similar efficacy to fluoxetine 20 mg/day for PMS treatment over 2 months, with both drugs demonstrating significant symptom reduction 2. Importantly, buspirone had fewer side effects than fluoxetine in this study.
A randomized trial comparing buspirone to nefazodone and placebo found that buspirone was significantly superior to placebo (P<0.001) for global improvement, particularly for premenstrual irritability 3. The mean daily dose was 21 mg during luteal-phase dosing and 27 mg during continuous dosing. Notably, sexual dysfunction was not significantly more common with buspirone than placebo—a key advantage over SSRIs.
Buspirone is mentioned as a "useful treatment" for PMDD in a comprehensive 2015 review, though it is positioned after SSRIs as first-line therapy 4.
Clinical Approach
When to Consider Buspirone
Use buspirone when:
- SSRIs have caused intolerable side effects (particularly sexual dysfunction, nausea, or insomnia)
- Patient has failed multiple SSRI trials
- Patient specifically cannot tolerate serotonergic side effects
Dosing Strategy
Based on the available evidence 3:
- Start with luteal-phase dosing: 10 mg daily during the luteal phase (approximately 14 days before expected menses)
- If inadequate response: Increase to 20-30 mg daily during luteal phase
- Alternative: Continuous daily dosing at 25-30 mg if luteal-phase dosing is insufficient
Important Caveats
Critical drug interactions 1:
- Absolutely contraindicated with MAOIs due to risk of elevated blood pressure
- Risk of serotonin syndrome when combined with other serotonergic drugs (triptans, SSRIs, SNRIs)
- Can interfere with urinary metanephrine/catecholamine assays—discontinue 48 hours before testing for pheochromocytoma 1
Limitations of evidence:
- Studies are small and older (2001-2013)
- Only one study was placebo-controlled 3
- The single-blind design of the comparative trial 2 introduces bias
- No recent high-quality RCTs specifically for PMDD
Why SSRIs Remain First-Line
Despite buspirone's potential utility, SSRIs are definitively the first-line treatment for PMDD 4, 5, 6:
- SSRIs reduce premenstrual symptoms with moderate-certainty evidence (SMD -0.57) 5
- Continuous SSRI dosing is more effective than luteal-phase dosing (SMD -0.69 vs -0.39) 5
- Multiple high-quality studies support SSRI efficacy
- Intermittent (luteal-phase) SSRI dosing can minimize withdrawal risks while maintaining efficacy 7
Practical Algorithm
First attempt: Trial different SSRIs (sertraline 50-150 mg, fluoxetine 10-20 mg, escitalopram 10-20 mg) with intermittent dosing to minimize side effects 6, 7
If SSRI side effects are intolerable across multiple agents: Consider buspirone 10-30 mg daily (luteal phase or continuous) 2, 3
Monitor for: Improvement in irritability specifically (buspirone's strongest effect), and absence of drug interactions 3
If buspirone fails: Consider hormonal options (drospirenone-containing oral contraceptives) or cognitive behavioral therapy 6
The evidence for buspirone is substantially weaker than for SSRIs, but it represents a reasonable alternative when serotonergic side effects preclude SSRI use, particularly given its favorable side effect profile regarding sexual function 3.