long - term high dosage and impaired metabolism apparently accounted for accumulation of high , but presumably non - lethal levels , of citalopram and desmethylcitalopram in a 44-year - old woman who died while scuba diving.prolongation of the qt interval , a well - known effect of citalopram , increases the risk of fatal cardiac rhythms ; a risk that is further increased by bradyarrhythmias.it is suggested that citalopram - induced long qt coupled with the mammalian dive reflex resulted in a fatal cardiac rhythm in this case . in august 2011 , the us fda issued a drug alert concerning citalopram ( celexa ) . the alert indicated that citalopram should not be used at doses greater than 40  mg per day because it causes dose - dependent qt interval prolongation . the maximum recommended dose was 20  mg per day for patients with hepatic impairment , age greater than 60  years , cytochrome p450 ( cyp ) 2c19 poor metabolizers , or patients taking concomitant cyp2c19 inhibitors , such as cimetidine . it was further noted that citalopram should not be used in patients with congenital long qt syndrome ( lqts ) . electrocardiographic monitoring was recommended if citalopram is used in patients with congestive heart failure , bradyarrhythmias , predisposition to hypokalemia or hypomagnesemia , or in combination with other qt - prolonging drugs . the 44-year - old patient , who was a non - smoker and rarely consumed small amounts of alcohol , had taken citalopram 40  mg per day for mild depression since before july 2009 . at that time , she was also taking bupropion ( wellbutrin ) 200  mg per day . likewise , since before july 2009 she had taken nadolol 40  mg / day for mild hypertension that was well controlled . in july 2009 she was prescribed divalproex ( depakote extended release [ er ] ) 250  mg / day , the dosage of which was increased to 500  mg per day in 2010 and increased again to 1000  mg per day in january 2011 . at that time the latter two medications were given for frequent migraine headaches . in january 2011 , bupropion was discontinued when the dosage of citalopram was increased from 40 to 60  mg per day . on 5 may 2011 , aspartate aminotransferase ( ast ) was 146 ( range 635 u / l ) and alkaline phosphatase ( alk phos ) was 118 ( range 30125 u / l ) . repeat testing on 8 may 2011 found ast at 75 , alk phos at 210 , and alanine transaminase ( alt ) at 172 ( range 840 u / l ) . at that time , the meloxicam dosage was discontinued . however , divalproex was continued at 1000  mg per day and citalopram at 60  mg per day . no further liver function tests were performed , and no electrocardiogram testing or therapeutic drug monitoring was performed in 2011 . the patient was a certified scuba diver , although she had not been diving for over a year when , in december 2011 , she arranged to dive in a tropical location while on a family vacation . while diving with a small group of scuba divers led by a qualified guide , the patient  developed problems  during the initial descent to a depth of about 40 feet . the guide immediately took her to the surface and she was placed on the deck of the nearest dive boat  a boat equipped with an automatic defibrillator . although no permanent recording exists , the patient s rhythm changed from apparent torsade de pointes ( tdp ) to ventricular fibrillation , and defibrillation was not successful . autopsy performed the next day by the local medical examiner revealed an obese ( body mass index [ bmi ] ~36 ) caucasian body with pulmonary congestion and edema , hepatic congestion , splenic congestion , and cardiomegaly . microscopic examination revealed interstitial myocardial fibrosis and cardiomyocyte hypertrophy as well as an isolated liver granuloma . the post mortem blood concentration of citalopram was reported at 1300  ng / ml , well above the therapeutic level . in addition , analysis of post mortem blood resulted in the following findings : ethanol 35  mg / dl , ibuprofen 10 mcg / ml , and caffeine positive but not quantified . while a high level of caffeine might have contributed to the fatal outcome , it seems unlikely since caffeine is routinely positive in the blood of those who consume beverages containing caffeine . in view of the  slightly enlarged heart  and level of citalopram , and in the absence of other relevant findings , the medical examiner concluded that the cause of death was a fatal cardiac arrhythmia . for ease of comparison , the blood levels of citalopram reported by various authors are expressed as ng / ml or ng / mg . the ratio of plasma to whole blood concentration of citalopram is 0.74    0.04 . thus , the blood concentration of 1300  ng / ml is equivalent to a plasma level of approximately 962  ng / ml . citalopram therapeutic and comatose - fatal plasma concentrations are reported to be 5110 and 50006000  ng / ml , respectively . thus , although the level of citalopram in the patient s post mortem blood was substantially above the therapeutic range , it was not an obvious cause of death , per se . it was much higher than would be predicted if the patient had normal metabolism of citalopram , even at the dosage of 60  mg per day . furthermore , why did the patient die only after approximately 11  months of such high dosage ? one possible explanation for a high level of citalopram and death might be an acute overdose ; possibly suicidal . however , there is no evidence that the patient was suicidal , and family members were confident that she was happily enjoying a vacation . also inconsistent with acute overdose is the fact that additional toxicology analysis in a different laboratory resulted in a blood level of citalopram of 1426  ng / ml and a level of desmethylcitalopram of 846  ng / ml . in patients chronically taking citalopram , the levels are typically three to four times higher than the metabolite , desmethylcitalopram . in acute overdose , the ratio of the parent drug to metabolite would be higher . in this patient , the ratio of parent drug to metabolite was lower than expected and is inconsistent with acute overdose . compared with citalopram , the relatively high level of the metabolite that is normally eliminated mainly by cyp2d6 supported the speculation that the deceased might have been a poor metabolizer via 2d6 . subsequent testing of post mortem blood indicated that , genotypically , she was an intermediate metabolizer via 2d6 . in any event , acute overdose , suicidal or accidental , was not the cause of the high level of citalopram and its metabolite in this patient at the time of her death . metabolism of citalopram to desmethylcitalopram is carried out mainly by cyp2c19 . in turn , the metabolism of desmethylcitalopram to didesmethylcitalopram is carried out mainly by cyp2d6 . while about 7  % of caucasians are poor metabolizers via 2d6 , only about 3  % are poor metabolizers via 2c19 . the probability that a person would be a poor metabolizer via both pathways is very low , although such cases have been reported [ 46 ] . the patient in this case was found to be a genotypically normal metabolizer via cyp2c19 and an intermediate metabolizer via cyp2d6 . the question thus arose regarding the post mortem blood level of citalopram of approximately 13001400  ng / ml . how did the level get so high , and was citalopram the cause of the patient s death ? post mortem redistribution did not account for the high level of citalopram in the patient s blood . because the autopsy was performed the morning after death , there was little time for redistribution . while some antidepressants show substantial post mortem increases in blood concentration , citalopram increased by only 25  % , even after 6.4  days post mortem . many drugs are inhibitors of one or more cyp isoforms , but such classical drug interactions were not apparent in this case . on the other hand , low activity of cyp2c19 and/or cyp2d6 ( especially and ) as caused by a poorly functioning liver , would promote the accumulation of citalopram and desmethylcitalopram to higher than expected levels [ 8 , 9 ] . irrespective of her genetic background , it is apparent that the patient in this case became a poor metabolizer phenotypically via both 2c19 and 2d6 . both drugs have warnings regarding liver dysfunction ; the latter with a prominent black box warning . meloxicam was discontinued when the patient s liver enzymes were found to be elevated in may of 2011 . divalproex , the dose of which had been increased from 500  mg per day to 1000  mg per day in january of 2011 , was continued to the time of her death . at autopsy , her liver did not show gross anatomical defects , but impaired function of cyp enzymes would not be apparent . mild to moderate liver disease is associated with a 77  % decrease in the clearance of mephenytoin ( cyp2c19 ) [ 8 , 10 ] . essentially , all cyp enzymes are inhibited in later stages of liver disease , with a 28  % decrease in the clearance of dapsone ( cyp3a4 ) and a 4  % decrease in clearance of debrisoquine ( cyp2d6 ) . the fact that mild to moderate liver disease selectively and profoundly inhibits cyp2c19 , but barely inhibits cyp2d6 , is nevertheless consistent with the relatively high level of desmethylcitalopram found in post mortem blood because the patient inherited intermediate metabolism via cyp2d6 . as noted above , no liver function or tests were carried out after may 2011 , and no determination of citalopram levels was ever performed . although we can not rule out other explanations , based on the scant but abnormal liver function tests in may 2011 , as well the continued application of divalproex , we suggest that impaired metabolism caused accumulation of citalopram in this patient . no electrocardiogram was performed during 2011 ; thus , we are also uncertain of the extent of qt prolongation caused by the high level of citalopram . even in the absence of measured levels of the drug , it is evident that impaired metabolism of citalopram and its metabolite were present in this patient . most likely , accumulation of citalopram to such a high level occurred slowly during 2011 . the post mortem blood level of 1300  ng / ml ( equivalent to a plasma level of 962  ng / ml   was thus about nine times the upper limit of the therapeutic plasma level range ( 5110  ng / ml ) but less than that usually associated with death ( 50006000  ng / ml ) . in cases in which citalopram was judged to be the cause of death , concentrations ranged from 2000 to 6200  ng / mg whole blood . the specific density of blood is approximately 1.04 at 25  c ; thus , concentrations expressed as ng / mg toxic concentrations of citalopram in autopsy cases ( most were accidental death ) ranged from 400 to 900  ng / mg whole blood . in living individuals ( mostly traffic violations ) citalopram concentrations ranged from 0.0 to 300  ng / mg . the blood alcohol in these samples ranged from 0.0 to 3.1  mg / g ( ~310  mg / dl ) . some individuals were alive with supratherapeutic concentrations of citalopram and , in many cases , very high levels of alcohol . therefore , alcohol does not necessarily increase citalopram mortality and moderately supratherapeutic concentrations of citalopram do not increase alcohol mortality . however , the authors speculated that  lower concentrations [ of citalopram ] may cause death if combined with the intake of high concentrations of alcohol . the low level of alcohol ( 35  mg / dl ) in the post mortem blood of the patient in this case may or may not have contributed to the outcome . in 13 cases examined forensically , citalopram was not judged to be the underlying cause of death , but only an the authors concluded ,  there is a large apparent therapeutic index with postmortem concentrations in blood possibly ranging as least as high as 1300  ng / ml compared to its therapeutic concentration of approximately 200  ng / ml  . some other individuals survived levels of citalopram ranging from 90 to 1640  ng / ml in post mortem blood only to die of what were judged to be other causes . these observations may help explain how , in the case reported here , the patient survived for nearly a year as citalopram accumulated in her body to a concentration that was between therapeutic and a more patently fatal concentration . they also raise the questions of the effect of citalopram on the qt interval and why she died while scuba diving . citalopram , like a number of drugs listed on crediblemeds ( http://www.crediblemeds.org ) , is known to cause prolonged qt . the official labeling for celexa ( citalopram ) includes the following :  citalopram causes dose - dependent qtc prolongation , an ecg abnormality that has been associated with torsade de pointes ( tdp ) , ventricular tachycardia , and sudden death , all of which have been observed in postmarketing reports for citalopram .   citalopram causes dose - dependent qtc prolongation , an ecg abnormality that has been associated with torsade de pointes ( tdp ) , ventricular tachycardia , and sudden death , all of which have been observed in postmarketing reports for citalopram . the risk of a fatal outcome as a consequence of drug - induced long qt syndrome ( dilqts ) and tdp is substantial [ 15 , 16 ] . qtc is linearly dependent on the predicted citalopram plasma concentration , with a slope of 40  ms per mg per liter of citalopram  with a between - subject coefficient of variation of 70  % . if that average value were applied in this case , then the predicted increase in qtc would be 38  ms . wide inter - individual variability precludes precise prediction and the rr interval has a large effect on qt that would be additive to the effects of citalopram in this case . it is unlikely that the low concentration of alcohol in this patient contributed to qt prolongation that is observed with moderate and high levels of alcohol [ 18 , 19 ] . found a close relationship between the qtc and serum level as citalopram was eliminated from the body following an acute overdosage . at the initial serum level of 1200  ng / ml , equivalent to 1620  ng / l blood level , the qtc was approximately 540  ms . when the drug was finally eliminated , the qtc was 430  ms . at a blood level of 1300  ng / ml , as in the case described here , the best fit curve predicts a qtc ( bazett ) of about 497  ms . individuals with genetically determined lqts are particularly at risk for further increases in the qt interval when the dive reflex is initiated . facial immersion in water causes greater increases in qt interval in children with non - familial lqts , and nearly 30  % of swimming - related drowning cases that were referred to tester et al many such drownings occur in lqts children because their risk of a fatal cardiac arrhythmia is significantly increased when the dive reflex is elicited . catecholaminergic polymorphic ventricular tachycardia ( cpvt ) , a condition that mimics lqts in some ways , is also associated with drowning or near drowning . the mammalian dive reflex involves concurrent sympathetic and parasympathetic activation   and parasympathetically mediated bradycardia . in addition , the  cold shock response involves sympathetically mediated tachycardia . various conduction abnormalities , with individual differences , are observed when a subject s face is immersed in water . autonomic conflict and abnormal cardiac rhythms may arise when parasympathetic and sympathetic divisions of the nervous system innervating the heart are simultaneously activated . the fda warning concerning citalopram and prolonged qt specifically mentions bradyarrhythmias . the bradycardia and autonomic conflict associated with scuba diving is a potential trigger for sudden death in a person with a prolonged qt interval . other contributing factors may have included hypoxia caused by breath holding while equilibrating to depth . in the case described here , dilqts caused by a high level of citalopram , which in turn was related to excessive dosage and poor metabolism , may have set the patient up for a fatal cardiac arrhythmia while diving . in light of the occurrence of sudden death ( i.e. , fatal cardiac rhythm ) in water of individuals with inherited lqts , it seems reasonable to suggest that , in general , dilqts is an independent risk factor for apparent drowning . it is well known that alcohol is the drug most commonly associated with drowning [ 27 , 28 ] . what is not commonly appreciated is that moderate levels of alcohol induce prolonged qt and increased qt dispersion [ 18 , 19 ] . the question arises whether alcohol - associated drowning in any particular case is due to psychomotor impairment and/or to a fatal cardiac arrhythmia . preliminary data , to be published separately , suggest an association of citalopram with drowning . the case reported here is an example of a fatal outcome when prolonged qt interval was combined with the autonomic conflict of the mammalian dive reflex .
while scuba diving , a 44-year - old caucasian patient had an abnormal cardiac rhythm , presumably torsade de pointes ( tdp ) , during the initial descent to depth . 
 upon surfacing , she developed ventricular fibrillation and died . 
 the patient had been treated for mild depression for nearly a year with citalopram 60  mg per day , a drug known to cause prolonged qt interval . 
 she had also been treated with two potentially hepatotoxic drugs . 
 liver impairment causes selective loss of cytochrome p450 ( cyp ) 2c19 activity , the major pathway for metabolism of citalopram . 
 the post mortem blood level of citalopram was 1300  ng / ml . the patient was found to be an intermediate metabolizer via cyp2d6 , the major pathway for metabolism of desmethylcitalopram ; the level of which was also abnormally high . 
 it is suggested that drug - induced long qt syndrome ( dilqts ) , caused by citalopram , combined with the mammalian dive reflex triggered malignant ventricular rhythms resulting in the patient s death . 
 it is further suggested that , in general , the dive reflex increases the risk of fatal cardiac rhythms when the qt interval is prolonged by drugs .