Phenotypic considerations in medication choice: Paroxetine (Paxil)

Ideal Use Case: The Anxious, Ruminative, Somatic Depressive

Paroxetine has a somewhat negative reputation in psychiatry. Many clinicians rarely use it as a first-line SSRI due to its textbook reputation of having a severe discontinuation syndrome, potential to cause significant sexual side effects, and anticholinergic effects causing concern for use in the elderly. While this reputation contains truth, it also obscures the value of the medication. In this post, I argue that when used in the right patient population, with awareness and caution of its pharmacodynamics, paroxetine is a valuable tool in psychiatry.

A lecturing clinician during my fourth year of medical school told us "I have never seen paroxetine discontinued due to a lack of efficacy"

I think this quote characterizes the usefulness of Paroxetine quite well. Based on my conversations with clinicians more experienced than me, and with patients who have had success with this medication, it seems that paroxetine seems most beneficial for patients with prominent anxiety, and/or tearfulness, ruminative paralysis, trauma, and agoraphobia. This may be due to paroxetine's non SSRI effects Anticholinergic and antihistaminic effects, which contribute to its sedating and anxiolytic properties. Paxil also mildly inhibits nitric oxide synthase, blocks sodium channels, and has some influence on dopamine transporter (DAT) function—all of which may contribute to its distinct feel compared to other SSRIs.

Paroxetine is the most potent SERT inhibitor of all SSRIs. Based on evidence from four weeks of administration in rats, the equivalent of 20 mg paroxetine taken once daily occupies approximately 88% of serotonin transporters in the prefrontal cortex. Hence, due to its high affinity for SERT; pushing the dose beyond 20–30 mg often adds side effects without additional benefit.