What is the most appropriate medication to add to a selective serotonin reuptake inhibitor (SSRI) in an adult woman who is experiencing sexual dysfunction (reduced libido, arousal difficulty, or difficulty achieving orgasm) as a side effect?

Best Medication to Add to SSRI for Female Sexual Dysfunction

Add bupropion sustained-release 150 mg twice daily to the existing SSRI regimen. This is the most evidence-based pharmacological augmentation strategy for women experiencing SSRI-induced sexual dysfunction who need to remain on their antidepressant therapy.

Primary Recommendation: Bupropion Augmentation

The strongest evidence supports bupropion as the add-on medication of choice. A high-quality randomized, double-blind, placebo-controlled trial demonstrated that bupropion SR 150 mg twice daily significantly improved all domains of female sexual function compared to placebo over 12 weeks 1. The improvements were substantial:

• Sexual desire increased by 86.4% (the most dramatic improvement)
• Lubrication improved by 69.2%
• Significant improvements in arousal, orgasm, and satisfaction (all p = 0.001)
• Mean Female Sexual Function Index total score: 25.9 vs 17.2 for placebo

This aligns with guideline evidence showing that bupropion has significantly lower rates of sexual adverse events than fluoxetine or sertraline 2, making it the logical choice for counteracting SSRI-induced sexual dysfunction.

Alternative Option: Mirtazapine Augmentation

If bupropion is contraindicated or not tolerated, mirtazapine 30 mg daily is a reasonable second-line option. Two studies showed that mirtazapine augmentation improved SSRI-induced sexual dysfunction 3, 4:

• Start at 15 mg/day for one week, then increase to 30 mg/day
• Improvement typically occurs after 4-8 weeks (not immediate)
• 48.5% of patients reported complete resolution of sexual dysfunction by week 8 4
• Well-tolerated with minimal side effects

Important caveat: Mirtazapine works more slowly than bupropion and requires patience—benefits emerge after 4 weeks, not immediately.

Emerging Option: Transdermal Testosterone

For women with predominant loss of libido (rather than arousal or orgasm difficulties), transdermal testosterone 300 mcg/day may be considered 5. A randomized controlled trial showed:

• Significant increase in satisfactory sexual events (2.3 vs 0.1 for placebo, p = 0.02)
• Target serum testosterone level: approximately 2.1 nmol/L
• No androgenic adverse events leading to withdrawal

However, this option requires specialized prescribing, monitoring of testosterone levels, and is best reserved for refractory cases or when libido is the primary complaint.

Options NOT Recommended

Do not add phosphodiesterase-5 inhibitors (PDE5i) like sildenafil or tadalafil. Despite one small case series suggesting benefit with tadalafil 6, guideline evidence explicitly states that PDE5i are not recommended for female sexual dysfunction due to lack of effectiveness data 7. The evidence is contradictory and insufficient.

Clinical Algorithm

1. First-line: Add bupropion SR 150 mg twice daily

   • Expect improvement within 4-12 weeks
   • Monitor for seizure risk (contraindicated if seizure history)
   • Continue existing SSRI at same dose

2. Second-line (if bupropion contraindicated/not tolerated): Add mirtazapine

   • Start 15 mg daily × 1 week, then 30 mg daily
   • Counsel patient that improvement takes 4-8 weeks
   • Monitor for sedation and weight gain

3. Refractory cases with predominant libido loss: Consider transdermal testosterone

   • Requires specialized prescribing and monitoring
   • Check baseline and follow-up testosterone levels

Critical Pitfalls to Avoid

• Don't switch the SSRI to another SSRI—paroxetine has the highest rates of sexual dysfunction among SSRIs 2, so switching from one SSRI to another rarely helps
• Don't wait indefinitely—sexual dysfunction does not spontaneously resolve in most patients and leads to medication nonadherence
• Don't assume it's depression—SSRI-induced sexual dysfunction includes specific somatic symptoms like genital numbness and anorgasmia that differ from depressive symptoms 8
• Don't forget non-pharmacological approaches—vaginal lubricants for dryness, pelvic floor physical therapy, and sex therapy should be offered concurrently 8, 9

Supporting Context

The mechanism behind bupropion's effectiveness is its dopaminergic and noradrenergic activity, which counteracts the excessive serotonergic effects causing sexual dysfunction. SSRIs cause sexual problems through 5-HT2 receptor stimulation, decreased dopamine, and potentially through neurosteroid depletion 10. Bupropion's different mechanism of action makes it uniquely suited as an augmentation strategy rather than requiring a complete medication switch that might destabilize mood.