Treatment Options for PMDD When SSRIs Fail
If SSRIs are not effective for PMDD, switch to a combined oral contraceptive containing drospirenone 3 mg with ethinyl estradiol 20 mcg (24 days active/4 days inactive), which is FDA-approved specifically for PMDD treatment. 1
First-Line Alternatives to SSRIs
Hormonal Treatment: Drospirenone-Containing Oral Contraceptives
Drospirenone/ethinyl estradiol is the only FDA-approved oral contraceptive specifically indicated for PMDD treatment and should be considered as first-line therapy when SSRIs fail or are contraindicated 1
The FDA-approved regimen is drospirenone 3 mg/ethinyl estradiol 20 mcg taken for 24 consecutive days followed by 4 inactive days 1
In two multicenter, double-blind, placebo-controlled trials, drospirenone/ethinyl estradiol demonstrated statistically significant improvement in PMDD symptoms measured by the Daily Record of Severity of Problems scale, with average decreases of 37.5 points versus 30.0 points for placebo 1
This option is only appropriate if the patient also desires contraception, as the FDA label explicitly states patients should not start this medication solely for PMDD treatment without also wanting birth control 1
Important Safety Considerations for Drospirenone
Drospirenone has antimineralocorticoid activity that may increase serum potassium, requiring baseline potassium monitoring in patients with kidney, liver, or adrenal disease 1
Avoid in patients taking daily long-term medications that increase potassium: NSAIDs, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptor antagonists, aldosterone antagonists, or heparin 1
Check potassium levels during the first month of treatment if the patient is on any of these medications 1
Contraindicated in women over 35 who smoke due to increased cardiovascular risk 1
Second-Line Pharmacologic Options
Alternative Antidepressants
Switch to venlafaxine (SNRI) or duloxetine (SSNRI) if multiple SSRI trials have failed, as these serotonergic agents with norepinephrine activity may provide benefit 2, 3
Consider alprazolam or buspirone as anxiolytic alternatives, though evidence is more limited than for SSRIs 3
Avoid tricyclic antidepressants like clomipramine as first alternatives due to inferior side effect profiles compared to SSRIs 4
Dosing Strategies to Optimize SSRI Response
Before abandoning SSRIs entirely, consider these modifications:
Switch from continuous dosing to luteal-phase-only dosing (from ovulation to menses), which has demonstrated efficacy in multiple trials and may improve tolerability 5, 6
Try symptom-onset dosing (taking medication only when symptoms begin), though this requires further research validation 5, 6
Ensure adequate trial duration: SSRIs show rapid onset in PMDD (unlike depression), but full response may require 2-3 menstrual cycles 5, 6
Verify adequate dosing: fluoxetine 10-20 mg/day, sertraline 50-150 mg/day, escitalopram 10-20 mg/day, or paroxetine 12.5-25 mg/day 2
Psychotherapeutic Interventions
Cognitive Behavioral Therapy (CBT)
CBT demonstrates effectiveness in reducing functional impairment, depressed mood, anxiety, mood swings, irritability, and conflict in PMDD 2
CBT can reduce the intensity and handicap of premenstrual symptoms and their impact on daily life 2
Consider CBT as monotherapy for patients who refuse or cannot tolerate medications, or as augmentation to pharmacotherapy 2
CBT may become first-line treatment as more evidence accumulates, particularly for patients preferring non-pharmacologic approaches 2
Clinical Algorithm for SSRI-Refractory PMDD
Step 1: Verify PMDD diagnosis with prospective daily symptom charting for 2 consecutive cycles (not just retrospective recall) 1
Step 2: Ensure adequate SSRI trial:
- Correct dose for at least 2-3 menstrual cycles 5, 6
- Trial of at least 2 different SSRIs (sertraline, fluoxetine, escitalopram, or paroxetine) 2, 5
- Consider switching from continuous to luteal-phase dosing 5, 6
Step 3: If patient desires contraception:
- Switch to drospirenone 3 mg/ethinyl estradiol 20 mcg (24/4 regimen) 1
- Check baseline potassium and screen for contraindications 1
- Monitor potassium during first month if on interacting medications 1
Step 4: If patient does not desire contraception or hormonal therapy fails:
- Switch to venlafaxine or duloxetine 2, 3
- Consider adding or switching to CBT 2
- Trial of calcium supplementation 1200 mg/day (only supplement with consistent evidence) 3
Step 5: For refractory cases:
- Refer to psychiatry for consideration of anxiolytics (alprazolam, buspirone) 3
- Consider combination therapy (SSRI/SNRI + CBT + hormonal treatment) 2
Critical Pitfalls to Avoid
Do not diagnose PMDD based on retrospective recall alone—require prospective daily symptom charting to confirm luteal-phase-only symptoms 1
Do not prescribe drospirenone/ethinyl estradiol solely for PMDD unless the patient also wants contraception, as other PMDD treatments exist without the cardiovascular and thromboembolic risks of combined oral contraceptives 1
Do not overlook potassium monitoring when prescribing drospirenone, especially in patients on ACE inhibitors, ARBs, NSAIDs, or potassium-sparing diuretics 1
Do not assume treatment failure after only one menstrual cycle—SSRIs show rapid onset in PMDD but optimal response may require 2-3 cycles 5, 6
Do not confuse PMDD with premenstrual syndrome (PMS)—PMS involves milder symptoms and does not warrant the same aggressive treatment approach 1, 6
Evidence Quality Considerations
The evidence base shows that approximately 40-60% of women with PMDD do not respond adequately to SSRIs even after accounting for placebo effects 7. This substantial non-response rate underscores the importance of having effective alternatives. The FDA approval of drospirenone/ethinyl estradiol for PMDD provides the strongest regulatory endorsement for a non-SSRI treatment option 1. However, research on optimal treatment algorithms for SSRI-refractory PMDD remains limited, with most studies focusing on first-line SSRI efficacy rather than sequential treatment strategies 2, 3.