Clinical Relevance of Pharmacogenetics in Serotonin Syndrome

Abstract

Serotonin syndrome is a predictable life-threatening condition that is caused by serotonergic stimulation of the central and peripheral nervous systems. A patient’s genetic profile can amplify exposure risk as many serotonergic drugs are metabolized by CYP450 enzymes, and these enzymes may be altered in functionality. We report a case of an elderly man who presented with serotonin syndrome after a dose change in valproic acid 5 weeks prior. His medication list consisted of low-dose serotonergic agents, which is unusual as most cases of serotonin syndrome involve higher doses. A review of his pharmacogenetic profile is presented to retrospectively evaluate the additive risk for serotonin syndrome and implications on resuming serotonergic agents.

A Rare Case of Serotonin Syndrome With Buprenorphine and Other Serotonergic Medications

“…Although our patient was not taking an SSRI, venlafaxine has 30-fold higher affinity for blocking the serotonin transporter than the norepinephrine transporter; even at a low dose of 75 mg daily, it has been documented to confer relatively high frequencies of serotonin-related acute adverse effects (eg, nausea, vomiting, and diarrhea) 9 . Similarly low doses of venlafaxine could cause serotonin syndrome in individuals with genetic polymorphisms impacting CYP450 2D6 functioning 10 . Venlafaxine is also metabolized by P450 3A4, which is inhibited by buprenorphine, yet in vitro studies suggest that this interaction is unlikely of clinical significance at therapeutic doses 11,12 …”

“…9 Similarly low doses of venlafaxine could cause serotonin syndrome in individuals with genetic polymorphisms impacting CYP450 2D6 functioning. 10 Venlafaxine is also metabolized by P450 3A4, which is inhibited by buprenorphine, yet in vitro studies suggest that this interaction is unlikely of clinical significance at therapeutic doses. 11,12 It has been postulated that catatonia can predispose patients to serotonin syndrome.…”

Serotonin Syndrome: The Role of Pharmacology in Understanding Its Occurrence

“…Interestingly, changes in the pharmacokinetic parameters of SSRIs leading to adverse reactions have been associated with polymorphisms in CYP2D6 and CYP2C19 [9,68,69], mainly in slow metabolizers and intermediate metabolizers, as shown by several case reports [70][71][72][73]. A study with 100 patients treated with only venlafaxine (orally), within the recommended doses for major depressive disorder, identified 25 with polymorphisms in CYP2D6 (at least one defective allele) responsible for most of the metabolism of venlafaxine.…”