Recurrent serotonin syndrome during low-dose venlafaxine treatment in a patient with reduced CYP2D6 activity

Abstract

Summary Serotonin syndrome is a potentially life-threatening toxicity diagnosed clinically and characterised by a variable clinical presentation. Spontaneous clonus in a patient receiving a serotonergic antidepressant should prompt immediate consideration of serotonin syndrome, even when the prescribed dose and measured drug concentrations are not high. Unexpected toxicity at low doses should also prompt a systematic review of pharmacokinetic interactions, organ function and pharmacogenetic susceptibility. A man in his late 70s with transthyretin amyloidosis experienced at least five episodes of serotonin syndrome (four on venlafaxine immediate release (IR) ≤75 mg/day), all meeting Hunter criteria. Trough plasma concentrations revealed markedly elevated exposure relative to the administered venlafaxine dose. At the highest measured dose, venlafaxine and O-desmethylvenlafaxine (ODV) concentrations were 377 nmol/L and 1330 nmol/L, respectively, yielding an active moiety concentration of 1707 nmol/L. All trough concentrations exceeded the expected values for a 75 mg dose (venlafaxine ~38 nmol/L, ODV ~330 nmol/L, active moiety ~365 nmol/L), while remaining within the therapeutic reference range of approximately 518–2220 nmol/L. The metabolite to parent ratio was low, suggestive of reduced CYP2D6 activity.