Abstract
The serotonin and norepinephrine re-uptake inhibitor (SNRI) venlafaxine is one of the most commonly used antidepressant medications in Australia, with 2.8 million PBS/RPBS scripts for this medication in 2008 [1]. It is a potent inhibitor of serotonin reuptake, a weak inhibitor of dopamine reuptake, and at higher doses (>150 mg/day) it is also a potent inhibitor of norepinephrine reuptake [2] by pre-synaptic neurons.
Venlafaxine has been linked to delirium in the context of serotonin syndrome. In addition, venlafaxine may induce hyponatraemia, which can also cause delirium. Venlafaxine-induced hyponatraemia develops secondary to inappropriately high release or non-suppression of anti-diuretic hormone (ADH) [3]. Venlafaxine-induced delirium in the absence of either serotonin syndrome or hyponatraemia appears to be rare. A literature review by the authors produced only two previously documented cases of delirium under these circumstances [4,5] (the latter in the context of a drug interaction). We report a third case of venlafaxine-induced delirium in the absence of serotonergic syndrome or hyponatraemia.
A 53-year-old male patient, suffering from a depressive illness reported a 24 h period of confusion, disorientation, agitation and partial recollection of events soon after his dose of venlafaxine was increased from 150 mg/day to 225 mg/day. The onset of symptoms was acute and satisfied criteria for a DSM-IV diagnosis of delirium [6]. The delirium resolved with the reduction of medication dose to 150 mg of venlafaxine a day. He was subsequently put on escitalopram 20 mg a day without event. The patient was concomitantly on esomeprazole for the management of gastritis. He had used this for many years without event. A thorough physical examination and laboratory investigations were unremarkable. Laboratory tests included complete blood examination, electrolytes, urea/creatinine, troponin T, C-reactive protein, and a CT head scan. Serum venlafaxine levels were not undertaken.
Esomeprazole and other proton pump inhibitors have been implicated in the causation of delirium [7]. However, the patient had been on this drug for years without event and he continued to be on this medication post-discharge without a recurrence of delirium, suggesting that esomeprazole was unlikely to have been the cause of delirium. Venlafaxine is known to undergo extensive first-pass hepatic metabolism, being converted by the CYP2D6 enzyme to its active metabolite, desvenlafaxine (O-desmethylvenlafaxine), via demethylation. This patient may have had an impaired ability to metabolize venlafaxine due to a past diagnosis of non-alcoholic steatohepatitis (NASH). However, his current liver function tests were normal, with no suggestion of impaired hepatic function. An increase in the dose of venlafaxine with enhanced effects of serotonin and norepinephrine reuptake appear to be the most likely culprits in the induction of delirium. The exact mechanism by which delirium is induced has not been clarified, although an excess activation of the serotonin system and increased noradrenergic activity have both been implicated in the pathogenesis of delirium [8].
Given the popularity of venlafaxine use in outpatient situations, this uncommon but potentially life threatening adverse effect should receive more attention. In addition, clinicians need to be aware of potential drug interactions and physical conditions that may increase patient vulnerability to this side effect.