Mirtazapine's Unique Mechanism Reduces Sexual Side Effects
Mirtazapine causes fewer sexual side effects than other antidepressants because it lacks direct serotonergic activity at 5-HT2 and 5-HT3 receptors—the primary mediators of SSRI-related sexual dysfunction—while selectively enhancing only 5-HT1A receptor transmission. 1, 2
Pharmacologic Mechanism Explaining Reduced Sexual Dysfunction
Selective Serotonin Receptor Activity
Mirtazapine potently blocks postsynaptic 5-HT2 and 5-HT3 receptors rather than activating them, which prevents the serotonergic adverse effects commonly seen with SSRIs, including sexual dysfunction. 1, 3
The drug enhances only 5-HT1A-mediated serotonergic transmission through an indirect mechanism—by blocking presynaptic alpha-2 heteroreceptors on serotonin neurons, thereby increasing serotonin release that selectively activates 5-HT1A receptors. 3, 4
This contrasts sharply with SSRIs, which non-selectively increase serotonin at all receptor subtypes, including 5-HT2 and 5-HT3 receptors that mediate sexual side effects. 1
Dual Noradrenergic and Specific Serotonergic Action (NaSSA)
Mirtazapine antagonizes presynaptic alpha-2 adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin neurons, increasing noradrenergic activity alongside the specific serotonergic enhancement. 1, 3
This noradrenergic and specific serotonergic antidepressant (NaSSA) mechanism maintains equivalent antidepressant efficacy while minimizing adverse effects common to both tricyclic antidepressants and SSRIs. 1
Clinical Evidence of Reduced Sexual Side Effects
Mirtazapine demonstrates a relative absence of serotonergic adverse effects, specifically including sexual dysfunction, when compared to SSRIs and tricyclic antidepressants. 2
In contrast to SSRIs, mirtazapine has no sexual side effects based on clinical trial data and comparative studies. 4
The American College of Physicians guidelines note that SSRIs commonly cause sexual adverse events as part of their typical side effect profile, while this is not listed among mirtazapine's common adverse effects. 5
Common Pitfalls and Practical Considerations
Do not confuse mirtazapine's sedation with overall poor tolerability—sedation is dose-related and typically occurs at subtherapeutic dosages below 15 mg; it is reported in substantially fewer patients when appropriate dosages (≥15 mg as a single evening dose) are used from treatment initiation. 2
The most common adverse effects with mirtazapine are increased appetite, weight gain, and sedation—not sexual dysfunction, gastrointestinal symptoms, or insomnia that characterize SSRIs. 1, 2, 4
When selecting between antidepressants, the American College of Physicians recommends choosing based on adverse effect profiles, cost, and patient preferences, since efficacy does not differ significantly among second-generation antidepressants. 5, 6