Drug interactions of several kinds can result in serotonin syndrome, which is diagnosed from its clinical features.
CASE HISTORY
A man of 56 weighing 68 kg had been taking venlafaxine 37.5 mg twice daily for 10 months as maintenance treatment for depression. He was otherwise healthy, on no other treatment, and had no history of allergies or drug reactions. Co-amoxiclav 375 mg three times daily was prescribed for gingivitis and incipient dental abscess. The patient had previously taken this drug uneventfully for the same indication at a time when he was not using venlafaxine, but on this occasion he developed tingling in the tip of his tongue, intense paraesthesiae in the fingers, severe abdominal cramps, profuse diarrhoea, cold sweats (temperature not recorded) and uncontrollable shivering and tremor. He was agitated and frightened but not confused. The symptoms started about 3 hours after the coamoxiclav was taken and lasted for 6 hours, after which he slept for a further 8 hours. The symptoms were assumed to be due to intercurrent infective gastroenteritis. Because the abscess deteriorated the tooth was extracted the next day and no further doses of co-amoxiclav were taken. However, two months later, and while still venlafaxine 37.5 mg twice daily, he developed identical symptoms after taking a single dose of co-amoxiclav 375 mg, again for an incipient dental abscess. This coincidence led to the recognition that the symptoms were due to the serotonin syndrome. The patient has continued venlafaxine without any further episodes of the syndrome.
COMMENT
Venlafaxine is a dual serotonin and noradrenaline reuptake inhibitor that can cause the serotonin syndrome when taken either alone in overdose1 or in therapeutic dosage with other medications2. Compounds that increase serotonergic activity in the central nervous system and which have the potential to cause the serotonin syndrome include those which inhibit serotonin uptake (selective serotonin reuptake inhibitors [SSRIs], and tramadol, tricyclics and trazodone), those which decrease serotonin metabolism (all types of monoamine oxidase inhibitors including selegiline), those which increase serotonin synthesis (L-tryptophan) or serotonin release (amphetamines, cocaine, fenfluramine, sibutramine, reserpine), dopamine serotonin receptor agonists (buspirone, LSD, sumatriptan, lithium) and dopamine agonists (bromocriptine, cabergoline, levodopa, buproprion, amantadine)2. Other drugs that have been associated with the serotonin syndrome in patients taking an SSRI include ciclosporin3, linezolid4 and metoclopramide5.
Venlafaxine and co-amoxiclav are both frequently prescribed and numerous patients must have taken this combination, but I have been unable to find any previous reports of an interaction, the manufacturer of venlafaxine is not aware of any such cases (Wyeth Pharmaceuticals, personal communication) and none of the cases of serotonin syndrome in patients treated with venlafaxine which have been reported to the Committee on Safety of Medicines have involved simultaneous treatment with co-amoxiclav6. However, the temporal association on two occasions in this case is strongly suggestive that the serotonin syndrome was due to an interaction between venlafaxine and single doses of co-amoxiclav. The mechanism for such an interaction is not apparent. Venlafaxine is metabolized mainly by the CYP2D6 isoenzyme of cytochrome P4507 and typical substrates and inhibitors of this enzyme are, like venlafaxine, basic compounds, whereas amoxicillin and clavulanic acid are both acids. Whether co-amoxiclav, although not a substrate for CYP2D6, could nevertheless inhibit it does not seem to have been investigated.
The serotonin syndrome is characterized by a sudden onset of cognitive changes (agitation, confusion, coma), autonomic features (tachycardia, sweating, nausea, vomiting, diarrhoea, mydriasis) and neuromuscular features (myoclonus, rigidity, trismus, hyper-reflexia)8. Clinicians need to be aware of the features of the syndrome and of the drug interactions, including those involving non-prescribed drugs, which may cause it. The British National Formulary makes no mention of the peripheral features of the serotonin syndrome, referring only to the potential for increased risk of central nervous system toxicity for some, but not all, of the known interactions9.
Acknowledgments
I am grateful to Professor G T Tucker for helpful discussion.
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