Warfarin-quetiapine interaction causing hemorrhage.

Sir,

Psychotropic drugs have been reported to have a drug-drug interaction with warfarin, raising the international normalizing ratio (INR), with a potential to develop hemorrhage.[1] We report a rare case of warfarin-quetiapine interaction causing gastrointestinal hemorrhage. Extensive review of literature has revealed only one such case, hitherto.

A 72-year-old female patient developed deep vein thrombosis, 6 months back. She had hypertension since the age of 40 years, for which she was on regular treatment. She was started on warfarin, and in about 3 weeks, her INR readings ranged from 2 to 3, which was the desired range. A month later, she developed sleep disturbance, restlessness, and occasional visual hallucinations at night, for which, quetiapine was started in a dose of 25 mg, given at bedtime. These symptoms subsided within a week. About 1 week later, she complained of passing blood stained stools. Detailed evaluations including upper gastrointestinal endoscopy and colonoscopy were normal. The stool analysis showed plenty of red blood corpuscles, with no other significant finding. Quetiapine-warfarin interaction causing gastrointestinal hemorrhage was made. The INR had risen to 3.2 at this point of time. Quetiapine was immediately stopped and warfarin was continued. There was no bleeding after 3 days, at which time the INR was 2.2 and was within the desired range. She received warfarin for the next 2 months, and when Doppler studies showed no clot and the blood flow was normal, warfarin was tapered and stopped; 10 days after this, the INR was 1.2 which is normal.

Warfarin is metabolized in the liver and is highly protein bound, therefore, increasing the risk of drug interactions, particularly hemorrhagic adverse events, which is further increased by the fact that it has a low therapeutic index. While the interaction of warfarin with many drugs is well studied, there is, in comparison, insufficient research of its interaction with psychotropic drugs.

The available literature on the interaction between psychotropic drugs and warfarin indicates that some drugs such as trazodone and carbamazepine have long been known to lower the levels of warfarin. More recently, bupropion too has been reported to seriously decrease the activity of warfarin.[2]

Of the interactions between psychotropic drugs and warfarin that have been reported, very few are “definite” interactions; the rest are reported as “could possibly be implicated,” as they were used along with drugs known to cause hemorrhage when used with warfarin.

This is the second case of quetiapine reported to cause bleeding, in a patient, on a stable regimen of warfarin. CYP2C9 and CYP1A2 are known to be the major pathways of metabolism of warfarin S and R enantiomer, respectively. CYP3A4 and CYP2C19 are minor pathways of the far less potent R-enantiomer of warfarin.[3] Quetiapine-warfarin reaction occurred, though quetiapine does not have any action on the major pathways mentioned; except in vitro, where CYP 2C9 has been shown to cause this, but not in vivo. CYP3A4 is the only enzyme responsible for the biotransformation of quetiapine,[4] and therefore, inhibition of CYP3A4, a minor pathway, was the cause of the quetiapine-warfarin reaction in both cases.

In the previous reported case, the INR was 3.4 when the bleeding occurred.[5] In this case, the INR was 3.2 when the bleeding occurred. The INR was considerably lower than the levels that generally cause bleeding, in both the cases. The possible reason could be that, in both cases, there were risk factors for hemorrhage; age above 70 years, female sex, and the presence of hypertension.

Though the interactions between psychotropic drugs and warfarin leading to hemorrhage are not many in literature, this case indicates that caution is warranted while combining them. A life-threatening drug interaction, as a result of increased INR with hemorrhage, is known to occur.

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Nil.

Conflicts of interest

There are no conflicts of interest.