antidepressants are widely used in the treatment of depression , which is the most common psychiatric disorder with an enormous burden globally . for a long time , tricyclic antidepressants ( tcas ) were the mainstay of drug treatment of depression . thromboembolic phenomena are also very common and need treatment with anticoagulants . of the oral anticoagulants , studies of drug interaction between warfarin and antidepressant drugs show that bleeding is the most common and also the most feared manifestation of the interaction . we report a patient who was started on warfarin for treatment of deep vein thrombosis ( dvt ) , who was receiving bupropion for depression . while the international normalized ratio ( inr ) had been stable at the desired level , bupropion was stopped and this resulted in an alarmingly high inr . higher values of inr than the desired levels for adequate anticoagulation indicate a high risk of bleeding . to our knowledge , there is no reported case so far , of drug interaction between bupropion and warfarin . a 55-year - old male was on treatment for dysthymic disorder ( dsm iv tr ) since 12 years . he was mostly on bupropion , in doses ranging from 150 mg/ day to 300 mg / day . he responded well to treatment , had few depressive symptoms intermittently , and his smoking had decreased to about 6 - 8 cigarettes a day . a year back , he developed dvt , at which time , the dose of bupropion was 300 mg / day . he was put on warfarin and the desired level of inr , that is , 2 - 3 , was achieved . at this time , the surgeon did not know that the patient was taking bupropion 300 mg / day . after a couple of weeks , when the patient informed him of this , bupropion was abruptly stopped . the patient was under observation , and the surgeon put him back on bupropion , 300 mg / day . it is among the 15 most prescribed drugs in the united states , with more than 1 million prescriptions / year and 75.7% of those on warfarin are elderly . considering that antidepressant drugs are so widely prescribed across all age groups need to study the drug interactions between warfarin and antidepressants is obvious . warfarin has a narrow therapeutic range , and for most patients on this drug the target inr usually is 2.0 - 3.0 . a higher target inr of 3.0 - 4.0 is recommended for patients with the mechanical prosthetic heart valves . above a level of 4.0 , the risk of bleeding is very high , especially intracranial hemorrhage . in our patient , the average dose of warfarin to achieve the desired level of inr ranges from 2 mg / day to 10 mg / day . the dose of warfarin can vary according to the individual sensitivity to it . in a sensitive individual if there is warfarin resistance , a dose in excess of 20 mg may be required . the list of drugs and other factors like diet and food supplements containing vitamin k , that affect the action of warfarin , is prodigious and expanding ; for example , acetaminophen , barbiturates , phenytoin , rifampin , phenylbutazone , sulfinpyrazone , metronidazole , disulfiram , allopurinol , cimetidine , and ingestion of large amounts of alcohol . there are four hypothetical mechanisms by which antidepressants or any other drugs can alter warfarin levels : by decreasing absorption ; by inhibiting cytochrome p2c9 ( cyp2c9 ) isoenzyme - causing an increase of inr ; by enzyme induction of cyp2c9 causing decrease in inr ; by increased protein binding of the drug , resulting in dislodging warfarin , which is highly bound to plasma albumin . while more than 40 hepatic enzymes have been identified , only six isoenzymes ( 1a2 , 3a4 , 2c9 , 2c19 , 2d6 , and 2e1 ) significantly affect the metabolic clearance of more than 90% of all drugs . for warfarin , the isoenzyme 2c9 is the most important , followed by 1a2 . in recent studies , specific serotonin reuptake inhibitors ( ssris ) have been studied the most and tcas the least in terms of interaction with warfarin . as mentioned earlier , about three - fourth of all patients on warfarin are older people . in this population , reported drug interactions between antidepressants and warfarin , of which bleeding is the commonest , are seen most with fluoxetine and fluoxamine . tcas , serotonin norepinephrine reuptake inhibitors  venlafexine , duloxetine and desvenlafexine , and mirtazapine , are relatively , safe and have no clinically significant interaction with warfarin . this perhaps is due to their minimal or no inhibitory action on relevant cyp450 isoenzymes , 2c9 and 1a2 . there are no reports or empirical data suggesting that there is any risk in using the combination of bupropion and warfarin . it needs to be mentioned though that bupropion has been much less studied compared to ssris . this makes the bupropion - warfarin interaction , in this case , difficult to explain in the light of available evidence . it is possible that there is a hitherto unknown mechanism of action that causes an adverse interaction with warfarin .