## Mechanism of Sexual Dysfunction with SSRIs **Key Point:** SSRIs cause sexual dysfunction (erectile dysfunction, delayed orgasm, decreased libido) via serotonergic inhibition of dopamine and norepinephrine in the mesolimbic reward pathway and spinal cord. Serotonin suppresses nitric oxide release and inhibits sexual arousal centres. ## Bupropion: The Exception **High-Yield:** Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) that: - Does NOT inhibit serotonin reuptake - Increases dopamine and norepinephrine activity in reward and sexual centres - Has a **pro-sexual** or neutral sexual side effect profile - Often used as an augmentation agent or switch for SSRI-induced sexual dysfunction - Also associated with weight loss rather than weight gain ## Comparison of Antidepressants and Sexual Side Effects | Agent | Class | Sexual Dysfunction Risk | Mechanism | | --- | --- | --- | --- | | **Bupropion** | NDRI | **Minimal/None** | ↑ DA, NE; no 5-HT inhibition | | Sertraline | SSRI | **High** | ↑ 5-HT → ↓ DA/NE in sexual centres | | Fluoxetine | SSRI | **High** | ↑ 5-HT → ↓ DA/NE in sexual centres | | Paroxetine | SSRI | **Highest** | Most potent 5-HT reuptake inhibition | | Amitriptyline | TCA | **Moderate–High** | Anticholinergic effects + 5-HT ↑ | **Clinical Pearl:** Paroxetine is notorious for sexual dysfunction and weight gain — it would worsen both problems. Amitriptyline's anticholinergic properties impair erectile function and ejaculation. Fluoxetine is another SSRI with the same mechanism as sertraline. ## Why Bupropion is Ideal Here 1. Maintains antidepressant efficacy (dopamine ↑ improves mood) 2. Reverses sexual dysfunction (dopamine ↑ in sexual centres) 3. Promotes weight loss (sympathomimetic effect) 4. Addresses all three complaints: mood, sexual function, and weight [cite:KD Tripathi 8e Ch 12] [cite:Harrison 21e Ch 470]
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