Drug-Drug Interactions Between Warfarin and Psychotropics: Updated Review of the Literature

Abstract

As the number of psychotropics on the market expands, the likelihood increases that a patient requiring anticoagulation with warfarin will receive concurrent treatment with a psychotropic drug. Because warfarin undergoes hepatic metabolism and is highly protein bound, it is particularly prone to drug interactions; in addition, its relatively narrow therapeutic window places patients at risk of either hemorrhagic or thrombotic complications. Although warfarin's interactions with other drugs have long been studied, the most recent review of the literature of warfarin's interactions with psychotropics was over a decade ago. Thus, we conducted a systematic review of the literature documenting the interaction between warfarin and psychotropics, with a focus on interactions mediated through the cytochrome P450 system and protein binding. A search of the MEDLINE database was performed, and reports of warfarin interactions with psychotropics were identified. The results suggest that interactions between warfarin and psychotropic drugs are important and likely underrecognized. They also have notable implications for both safety and drug compliance. When certain psychotropics are started or discontinued in patients receiving warfarin therapy, or when warfarin is introduced to a patient receiving a stable dose of a psychotropic, clinicians should monitor a patient's international normalized ratio (INR) closely to ensure it remains within therapeutic range. Psychotropics that pose a particular risk of increasing the INR when used with warfarin include fluoxetine, fluvoxamine, quetiapine, and valproic acid. Psychotropics that may significantly decrease the INR when used with warfarin include trazodone, St. John's wort, carbamazepine, and the polycyclic aromatic carbons in tobacco cigarettes; however, nicotine itself, as in nicotine replacement strategies, is not known to alter warfarin's anticoagulant effect. In certain cases, the need for anticoagulation may also necessitate switching to a different psychotropic.

Effects of Depressive and Other Psychiatric Disorders on Anticoagulation Control in a Pharmacist-Managed Anticoagulation Clinic

“…It is also likely that patients with psychiatric disorders may experience issues with polypharmacy and, thus, would be more likely to experience drug interactions with warfarin, especially because numerous psychiatric medications have been associated with increases and decreases in the INR. 26,27…”

Probable Interaction Between Warfarin and Divalproex Sodium

“…Warfarin and valproic acid are independently known for their drug interaction potential, but relatively little documented regarding their interaction(s) with each other. [2][3][4][6][7][8][9] The 2 most likely mechanisms by which a warfarin-valproic acid interaction may occur includes cytochrome P450 (CYP) isoenzymes and protein-binding displacement. Valproic acid is known to inhibit several isoenzymes with a preferential inhibition of CYP2C9, which is the isoenzyme responsible for metabolism of the more pharmacologically active S-enantiomer of warfarin.…”

“…The divalproex dose was then held and reintroduced at 250 mg twice daily, and the patient was discharged with an INR of 1.73. 4 In each case an intervention was made to decrease the INR and no clinically relevant bleeding ensued.…”

“…One such drug-drug interaction exists with valproic acid, another commonly prescribed medication for a variety of indications, but few case reports have described this interaction. [2][3][4] We report the case of a patient chronically anticoagulated with warfarin who had a supratherapeutic international normalized ratio (INR) following the recent addition of divalproex sodium, a valproic acid derivative, to her medication regimen.…”

Case report: dose adjustment of warfarin using genetic information and plasma concentration monitoring

“…Information on the patient's genotype can inform such dose adjustments.Two genes are known to have a large impact on warfarin dose requirement: (i) cytochrome P450 2C9 (CYP2C9), which is the primary metabolic enzyme of warfarin, and vitamin K epoxide reductase complex, subunit 1 (VKORC1), which is a target protein of this drug. [2][3][4][5] Moreover, the effect of this drug is highly influenced by its interactions with a large number of medications and foods, such as carbamazepine, and vitamin K. [6][7][8] We saw a patient in whom a sufficient anticoagulant effect was not obtained during concomitant administration of warfarin and carbamazepine. To determine the cause of the warfarin resistance in this patient, we genotyped for CYP2C9 and VKORC1 variants and measured the plasma concentration of the drug.…”