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 .
 depressive illness and thromboembolic disorders are both highly prevalent . 
 warfarin is frequently combined with an antidepressant drug , the choice of which depends mainly on the risk of a hemorrhagic complication . 
 patients requiring the warfarin are often in the older age group , where the newer antidepressants with a better safety profile are preferred over tricyclic antidepressants . 
 we report herein , a patient who was on bupropion for depression , when he developed deep vein thrombosis high - risk . 
 warfarin was started . 
 while on this combination bupropion was abruptly stopped . 
 this caused a more than two - fold elevation of international normalized ratio ( inr ) above the level , which is considered a high - risk for a hemorrhagic complication . 
 inr reverted back to the desired level on reintroduction of bupropion . 
 this indicates that a bupropion - warfarin combination should be used with the caution , though there has been no reported interaction so far . 
INTRODUCTION
CASE REPORT
DISCUSSION