How can SSRI‑induced sexual dysfunction be reversed—by lowering serotonergic activity, increasing dopaminergic activity, or both?

Reversing SSRI-Induced Sexual Dysfunction

Switch to bupropion or add bupropion to your current SSRI—this increases dopaminergic activity and is the most effective evidence-based strategy, with sexual dysfunction rates of only 8-10% compared to 14-70% with SSRIs. 1, 2

Primary Strategy: Increase Dopamine

Switching to bupropion is the first-line recommendation when SSRI-induced sexual dysfunction occurs, as endorsed by the American College of Physicians. 1, 2 This works by:

• Enhancing dopaminergic and noradrenergic transmission rather than reducing serotonin, which reverses the neurochemical imbalance causing sexual dysfunction 1
• Achieving dramatically lower sexual dysfunction rates (8-10%) versus SSRIs like sertraline (14%) or paroxetine (70.7%) 1, 2

If you cannot discontinue the SSRI (because it's the only antidepressant that controls your depression), add bupropion as augmentation therapy to counteract the sexual side effects while maintaining serotonergic antidepressant effects. 3

Critical Contraindications to Bupropion

• Do not use bupropion if you have seizure disorders or are highly agitated, as it lowers seizure threshold 1
• Avoid bupropion in breast cancer patients on tamoxifen, as it inhibits CYP2D6 and reduces tamoxifen efficacy (though less than paroxetine or fluoxetine) 1

Alternative Dopaminergic Strategy: Psychostimulants

Low-dose dextroamphetamine or methylphenidate taken on an as-needed basis (1-2 hours before sexual activity) can reverse SSRI-induced sexual dysfunction by acutely increasing dopamine. 4 This approach:

• Works through direct dopamine receptor agonism 4
• Has been shown to restore sexual function in patients on fluoxetine, sertraline, and paroxetine 4
• Enhances arousal, orgasmic sensation, and erectile firmness 4

This is an off-label strategy with limited evidence but may be considered when switching antidepressants is not feasible. 4

Why Not Just Reduce Serotonin?

Dose reduction of your SSRI is a secondary strategy that may help, as sexual side effects are strongly dose-related. 5, 6 However:

• Lowering the dose risks losing antidepressant efficacy 5
• Many patients still experience sexual dysfunction even at minimal effective doses 6
• This approach reduces serotonergic activity but does not actively restore dopaminergic function, making it less effective than switching to bupropion 5

Drug holidays (skipping SSRI doses before sexual activity) have been studied but are problematic because they risk antidepressant withdrawal symptoms and loss of therapeutic effect. 7, 5

Second-Line Alternative: Mirtazapine

Switch to mirtazapine 15-30 mg at bedtime if bupropion is contraindicated or ineffective. 1, 2 Mirtazapine:

• Has minimal to no sexual side effects and may actually improve sexual function 2
• Works through alpha-2 antagonism and 5-HT2/5-HT3 receptor blockade rather than serotonin reuptake inhibition 1
• Major caveat: causes significant sedation and weight gain, which may limit tolerability 1, 2

Adjunctive Strategies (If You Must Stay on an SSRI)

If switching is absolutely not an option:

• PDE5 inhibitors (sildenafil, tadalafil) can address erectile dysfunction but do not improve libido or orgasmic dysfunction 8
• Alpha-1 adrenoreceptor antagonists may help in refractory cases 8
• Topical anesthetics (lidocaine/prilocaine) are paradoxically useful for genital numbness and pain 1, 8

Do not use buspirone—the American College of Physicians explicitly recommends against it, as there is no evidence supporting its effectiveness for SSRI-induced sexual dysfunction. 1

Monitoring Timeline

• Begin monitoring for sexual side effects within 1-2 weeks of starting any SSRI, as most sexual dysfunction emerges early 1, 2
• Modify treatment if no improvement within 6-8 weeks of implementing a management strategy 1, 2
• Check testosterone levels (morning total testosterone >300 ng/dL) to rule out hypogonadism as a contributing factor 1

The Bottom Line

The answer is increasing dopamine, not reducing serotonin. Bupropion (or psychostimulants as a distant second option) actively restores dopaminergic tone that SSRIs suppress, which is the primary mechanism of SSRI-induced sexual dysfunction. 1, 2, 4 Simply reducing serotonin through dose reduction or drug holidays is less effective and risks losing antidepressant benefit. 5, 6