Atypicals Antidepressants

Mirtazapine, trazodone, vortioxetine

Mirtazapine, trazodone, and vortioxetine are often labeled “atypical” antidepressants, but they still strongly affect serotonin and other brain signaling systems. Mirtazapine increases serotonin/norepinephrine release by blocking α2 receptors and also blocks 5-HT2/5-HT3 and H1 (often very sedating). Trazodone is a serotonin antagonist/reuptake inhibitor (SARI): it blocks 5-HT2A and inhibits serotonin reuptake, and it also blocks α1 and H1, which is why it’s commonly used for sleep. It is not typically described as acting on the androgen receptor; its notable sexual adverse event is rare priapism, usually linked to adrenergic effects. Vortioxetine still inhibits the serotonin transporter (SERT)and also modulates multiple serotonin receptors (it’s serotonergic even if it’s branded as “multimodal”).

For people with PFS/PSSD/PAS, these three are best treated as high-risk. Even though vortioxetine is often promoted as having fewer sexual side effects than classic SSRIs in general populations, it still meaningfully targets serotonin systems and, in community anecdotes, does not reliably avoid PSSD/PFS-style sensitivities. Likewise, mirtazapine and trazodone can be destabilizing because they shift serotonin/norepinephrine/histamine/adrenergic tone and can affect sleep, arousal, and emotional regulation. Bottom line for your site: mirtazapine, trazodone, and vortioxetine all carry a high risk of triggering a crash/flare in sensitized individuals, and many choose to avoid them during stabilization.

Crash Anecdotes:

https://www.reddit.com/r/PSSD/comments/ztt123/vortioxetine_trintellix_victims_here/

https://www.reddit.com/r/PSSD/comments/1ffqnzc/update_mirtazapine_destroyed_me/

https://www.reddit.com/r/PSSD/comments/o0v46z/trazadone/

My Personal Risk Ranking:

High Risk of Permanent Worsening (for PFS/PSSD/PAS):

If you currently have PFS/PSSD/PAS, St. John’s Wort may carry a moderate-to-high risk of worsening symptoms—potentially in a lasting way—because it can act in SSRI-like ways and strongly shift serotonin-related signaling. Given the number of community “crash” reports (despite a few improvement stories) and its high interaction potential, it’s generally best avoided, especially during stabilization.