Disposition of citalopram in biological specimens from postmortem cases

Citalopram is a bicyclic phthalate compound approved in 1998 by the U.S. Food and Drug Administration for the treatment of depression. It is a highly selective serotonin reuptake inhibitor that appears to have little effect on noradrenaline or dopamine reuptake. Since this drug has only recently been released on the U.S. market, information regarding therapeutic, toxic, and lethal concentrations is sparse. This study reports the detection of citalopram in 22 postmortem cases. Citalopram was identified and quantitated by capillary column gas chromatography with nitrogen phosphorus detection after basic liquid-liquid extraction. Confirmation was achieved by full scan electron impact gas chromatography/mass spectrometry. In the 22 cases studied, heart blood citalopram concentrations ranged from 0.09 to 1.64 mg/L (n = 22, mean +/- SD = 0.51+/-0.43, median = 0.34); femoral blood concentrations ranged from 0.09 to 0.76 mg/L (n = 14, mean +/- SD = 0.34+/-0.23, median = 0.28); and urine concentrations ranged from 0.05 to 276.00 mg/L (n = 13). Liver was analyzed in three cases with citalopram concentrations ranging from 2.22 to 8.08 mg/kg. The average heart blood/femoral blood ratio was 1.26 (range 0.75 to 1.98, n = 14). In each case, the cause of death was not considered to be related to citalopram toxicity. These data may therefore provide a basis for establishing post mortem citalopram concentrations following therapeutic doses.     

Postmortem citalopram concentrations: alone or along with other compounds

Citalopram, an antidepressant whose use has become more widespread in Spain in recent years participates directly and indirectly in the lethal mechanism in voluntary and involuntary poisonings. There were 30 cases of autopsies in the Madrid region where citalopram and other psychoactive substances (psychotropic drugs, alcohol, opiates) were detected in the corpses. The postmortem citalopram levels in relation to the manner and mechanism of death were evaluated, and a significant difference between the toxic and nontoxic cases (p < 0.01) was found. We studied the citalopram blood levels alone and along with other psychoactive products, and these cases were then further divided into those where the compounds were at deadly levels and those which were not. We found a range of citalopram levels between 0.37 and 0.83 microg/mL in which some cases were associated with citalopram toxicity and others were not. Citalopram blood levels of less than 0.35 microg/mL did not lead to fatal poisoning when it was the sole substance detected.     

The relationship of methanol and formate concentrations in fatalities where methanol is detected

An automated headspace gas chromatography method was developed for the determination of formate (formic acid) in postmortem specimens, based on the in situ sulfuric acid-methanol methylation of formic acid to methyl formate. Diisopropyl ether was used as an internal standard. The method was applied to over 150 postmortem cases where methanol was detected. Of the 153 cases presented, 107 deaths were attributed to acute methanol toxicity. In the vast majority of the remaining 46 deaths, the methanol was determined to be present as a postmortem or perimortem artifact, or was otherwise incidental to the cause of death. Of the 76 victims who were found dead and blood was collected by the medical examiner, all but one had a postmortem blood formate concentration greater than 0.50 g/L (mean 0.85 g/L; n = 74). The sole exception involved suicidal ingestion of methanol where the blood methanol concentration was 7.9 g/L (790 mg/100 mL) and blood formate 0.12 g/L. In 97% (72/74) of the cases where blood was available, the blood formate was between 0.60 and 1.40 g/L. In 31 of the 153 cases, the victim was hospitalized and blood obtained on admission or soon after was analyzed for methanol and formate during the subsequent death investigation; the vast majority (27/30) had antemortem blood formate concentrations greater than 0.50 g/L. Cases with samples taken prior to death with blood formate concentrations less than 0.5 g/L can readily be explained by active treatment such as dialysis. The blood formate method has also been useful in confirming probable perimortem or postmortem contamination of one of more fluids or tissues with methanol (e.g., windshield washer fluid or embalming fluid), where methanol ingestion was unlikely.     

Case report of a fatal intoxication by citalopram

Citalopram is an antidepressant drug within the group of the selective serotonin reuptake inhibitors (SSRI). It is widely prescribed both in Europe and in United States, and it has always been considered a "safe" drug as pure intoxication with lethal outcome is rare, and most cases of overdose, even with high doses of citalopram ingested, are reported to have an uneventful course.We report the case of a young woman found dead at home. She had been prescribed citalopram by her family doctor 3 weeks before her death for a depressive syndrome. Police found in her house 3 empty blister packages of 28 citalopram tablets (20 mg) and 2 bottles of citalopram oral solution (4%, 15 mL each). The autopsy findings were unremarkable. Nasal swabs, blood from femoral vein, urine, bile and tissue samples were collected for toxicologic investigation. Citalopram separation was performed by solid/liquid method, using Bond-Elute columns. The extracts were analyzed by GLC and GC/MS methods. The toxicologic analysis showed high levels of citalopram in all the examined fluids and tissue samples (blood concentration: 11.60 mg/L). No other drugs and alcohol were detected. Our data confirm that if no other drug is involved, fatal complications occur only after ingestion of very high doses. However, there is no predefined "toxic dose," and the conditions under which the overdose occurs can be very important. We report the exact concentrations of the citalopram in the organs, and wethink that this can be useful in the cases where the blood samples were not available (ie, carbonized or decomposed body).     

Post-mortem cases involving amphetamine-based drugs in the Netherlands: Comparison with driving under the influence cases

In this study we reviewed the post-mortem cases in the years 1999–2004 that were presented at the Netherlands Forensic Institute. The concentrations of amphetamine-based drugs in femoral blood from cases of suspected unnatural death were compared with concentrations in whole blood from non-fatal cases of driving under the influence (DUI cases) and with literature. Furthermore, the combinations with other drugs and/or alcohol were investigated. Amphetamine-based drugs were present in 70 post-mortem cases and 467 DUI cases. The most detected amphetamine-based drug was MDMA, followed by amphetamine. The presence of MDA could usually be explained by metabolism of MDMA. Methamphetamine and MDEA were rarely present. Frequently, the amphetamine-based drugs were taken in combination with alcohol and/or other non-amphetamine-based drugs such as cocaine or cannabinoids. The 70 post-mortem cases were divided into 38 amphetamine-based drug caused (i.e. the amphetamine-based drug directly caused or contributed to the death) and 32 amphetamine-based drug related deaths (i.e. death was not directly caused by the amphetamine-based drug). In the latter category, other (poly)drug intoxications and death by violence or drowning were the most frequent causes of death.In 30 cases, MDMA caused death directly. The range in blood concentrations of MDMA in these cases was substantial, i.e. 0.41–84 mg/L with a median concentration of 3.7 mg/L (n = 30). MDMA blood concentrations in the MDMA related deaths (n = 20) and in the DUI cases (n = 360) varied up to 3.7 and 4.0 mg/L, respectively. Seven victims died from the direct effects of amphetamine; the blood concentration of amphetamine ranged from 0.24 to 11.3 mg/L, with a median concentration of 1.7 mg/L (n = 7). The median concentrations of amphetamine in the amphetamine related deaths (n = 13) and the DUI cases (n = 208) were much lower, i.e. 0.28 and 0.22 mg/L, respectively. Amphetamine blood concentrations up to 6.0 and 2.3 mg/L were seen in the drug related deaths and DUI cases, respectively. The most frequently encountered amphetamine-based drugs in the investigated deaths were MDMA and amphetamine. The majority of MDMA- and amphetamine-caused deaths, i.e. 90% of these deaths, occurred with blood concentrations above 1.5 and 0.80 mg/L, respectively. MDMA and amphetamine blood concentrations in drug related deaths and DUI cases, however, overlap the range of fatal concentrations. Therefore, MDMA or amphetamine concentrations should never be used alone to establish the cause of death.     

Toxicology and characteristics of deaths involving zolpidem in new South wales, australia 2001-2010*

Abstract: All cases presenting to the New South Wales Department of Forensic Medicine between January 1, 2001 and September 31, 2010 in which zolpidem was detected, were retrieved. A total of 91 cases were identified. The mean age was 49.4 years, 65.9% were male, and 61.5% were suicides. Zolpidem was a factor contributing to death in 35 (37.3%) cases, of which 31 (34.1%) involved zolpidem toxicity. The median blood zolpidem concentration was 0.20 mg/L (range 0.05–3.50 mg/L), with no significant gender difference. Drug toxicity cases involving zolpidem had significantly higher median blood zolpidem concentrations than other cases (0.50 vs. 0.10 mg/L). In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide.     

Polydrug fatality involving metaxalone

A 29-year old female with a history of depression was found dead in a hotel room. The death scene investigation found empty pill bottles and an empty liter bottle of wine. Metaxalone, a centrally acting muscle relaxant, along with citalopram, ethanol, and chlorpheniramine were identified in the postmortem samples and quantitated by gas chromatography-mass spectrometry. The concentration of metaxalone in femoral vein blood was 39 mg/L. The heart blood concentration was 54 mg/L. Femoral vein blood concentrations of citalopram and chlorpheniramine were 0.77 mg/L and 0.04 mg/L, respectively. Ethanol levels were 0.13 g/dL in vitreous and 0.08 g/dL in heart blood. Other tissue samples were also analyzed. The authors consider the metaxalone concentrations toxic and potentially fatal. The citalopram concentrations were lower than those reported in fatal cases for this drug alone. Death was ascribed to polydrug abuse/overdose with metaxalone a major contributor. This represents the first reported case to our knowledge in which a metaxalone overdose significantly contributed to death.     

Postmortem tissue distribution of olanzapine and citalopram in a drug intoxication

A 40-year-old white male was found dead in bed in a group home for mentally ill adults. The decedent had been diagnosed a paranoid schizophrenic. An autopsy was performed at the Office of the Cuyahoga County Coroner in Cleveland, Ohio. Toxicological testing detected olanzapine and citalopram in post mortem specimens. Multiple fluids and tissues were assayed by liquid-liquid extraction followed by gas chromatography with nitrogen phosphorus detection, and qualitative confirmation by electron impact gas chromatography/mass spectrometry. Drug concentrations [olanzapine: citalopram; mg/L or mg/Kg] determined in this case are the highest reported to date involving these drugs- 1.38:3.35 heart blood, 1.11:1.65 femoral blood, 60.24:32.43 urine, 6.47:10:71 liver, and 38.36:49.16 lung, respectively. Drug concentrations in tissues were found to be the highest in lung for both drugs and lowest in the heart. Citalopram but not olanzapine was detected in bone. The cause of death was ruled acute intoxication by the combined effects of olanzapine and citalopram and the manner, accident.     

“Bath Salts” the New York City Medical Examiner Experience: A 3‐Year Retrospective Review

“Bath salts” are synthetic derivatives of cathinones, compounds found in the leaves of Catha edulis, which possesses amphetamine‐like properties. At the New York City Office of Chief Medical Examiner, we conducted a 3‐year retrospective analysis of deaths in which cathinones were detected. Two categories emerged; those in which cathinones were a contributory cause of death (15 cases) and those in which they were an incidental finding (15 cases). Of the former group, 13 were associated with additional intoxicants; two deaths were attributed solely to cathinone intoxication, both survived 10 h: a man whose postmortem blood methylone concentration was 0.71 mg/L and a woman whose postmortem blood ethylone concentration was 1.7 mg/L. In the latter category, there were several individuals who had higher concentrations of cathinones than the above two, the highest being a blood methylone of 4.8 mg/L. Based upon our data and the literature presented, lethal concentrations of cathinones cannot be established.     

Utility of Postmortem Vitreous Beta-Hydroxybutyrate Testing for Distinguishing Sudden from Prolonged Deaths and for Diagnosing Ketoacidosis

A retrospective, cross-sectional analysis of vitreous beta-hydroxybutyrate (BHB) on 967 forensic cases over a two-year period was conducted. Cases were sorted into six categories of death: (i) sudden traumatic/non-natural (ST), (ii) sudden natural (SN), (iii) prolonged traumatic/non-natural (PT), (iv) prolonged natural (PN), (v) diabetic ketoacidosis (DKA), and (vi) alcoholic ketoacidosis (AKA). The mean BHB for all cases was 1.67 mmol/L (17.4 mg/dL; range: 0.11–18.02 mmol/L). The numbers of DKA, AKA, PN, PT, SN, and ST deaths were 21, 5, 155, 258, 275, and 253, respectively. Their mean vitreous BHBs were as follows: 11.04 mmol/L (DKA), 8.88 mmol/L (AKA), 1.56 mmol/L (PN), 1.55 mmol/L (PT), 1.26 mmol/L (SN), and 1.38 mmol/L (ST). There was a statistically significant difference between the mean BHBs of the PN and SN death groups (p < 0.001), as well as between those of the PT and ST death groups (p = 0.004). Given the overlapping ranges seen between the prolonged and sudden death groups, the identified differences did not hold clinical significance. In addition, we sought to determine a threshold value for vitreous BHB to definitely diagnose cases of ketoacidosis. BHB threshold concentrations between 2.5 and 5 mmol/L produced sensitivities >92% and specificities >96%. A receiver operator characteristic curve found 3.43 mmol/L to be the optimal cutoff value, demonstrating a specificity of 98.3% and a sensitivity of 96.2%.     

Methyl tert‐Butyl Ether (MTBE) Detected in Abnormally High Concentrations in Postmortem Blood and Urine from Two Persons Found Dead Inside a Car Containing a Gasoline Spill

Two deep frozen persons, a female and a male, were found dead in a car. There had been an explosive fire inside the car which had extinguished itself. On the floor inside the car were large pools of liquid which smelled of gasoline. The autopsy findings and routine toxicological analyses could not explain the cause of death. Carboxyhemoglobin levels in the blood samples were <10%. Analysis with a headspace gas chromatography revealed methyl tert‐butyl ether (MTBE) concentrations of 185 mg/L (female victim) and 115 mg/L (male victim) in peripheral blood. The urine MTBE concentrations were 150 mg/L and 256 mg/L, respectively. MTBE is a synthetic chemical which is added to gasoline as a fuel oxygenate. Gasoline poisoning is likely to be the cause of the death in these two cases, and MTBE can be a suitable marker of gasoline exposure, when other volatile components have vaporized.     

Fatalities by ingestion of propylene glycol

Propylene glycol (PG), a widely used solvent and lubricant, is thought to have low toxicity when ingested. Three cases were identified where PG, either alone or in combination with other chemical agents, contributed to death. The decedent in whom PG was the sole agent was a 32-year-old schizophrenic man with cardiomegaly and renal impairment. The blood PG concentration was 4410 mg/L at least 9.5 h following ingestion.     

Methamphetamine-related deaths in San Francisco: demographic, pathologic, and toxicologic profiles

A study was undertaken to develop demographic, toxicologic, and pathological profiles of methamphetamine-related deaths. Anatomic and toxicologic findings in 413 deaths where methamphetamine was detected were compared with findings in a control group of 114 drug-free trauma victims. The number of cases per year did not change significantly over the course of the study. Mean age was 36.8 years, but 11% were over the age of 50. Decedents were overwhelmingly male (85.2%) and Caucasian (75%). Blood concentrations of methamphetamine and amphetamine were indistinguishable in cases where methamphetamine was related to the cause of death (MR) and cases where it was not (non-MR) (2.08 vs. 1.78 mg/L, p = 0.65, and 0.217 vs. 0.19 mg/L, p = 0.82). Coronary artery disease, ranging from minimal to severe multivessel, was identified in 79 of the 413 drug users, but in only six of the 114 drug-free controls (p = 0.0004), and MR decedents had enlarged hearts compared with controls. There were also ten cases of subarachnoid and intracranial hemorrhage in the MR group. Abnormalities of the liver (34%) and lungs (24.7%) were frequent. In 65% of these cases, death was due to accidental methamphetamine toxicity. In the remaining cases, methamphetamine was an incidental finding. We conclude that, in our jurisdiction, neither the rate of detection nor the number of methamphetamine deaths has increased significantly in the past 13 years. Decedents are almost all Caucasian males, and many were approaching middle-age. Methamphetamine use is strongly associated with coronary artery disease and with subarachnoid hemorrhage.     

Acute Benztropine Intoxication and Fatality

A woman was found unresponsive with an empty bottle of Cogentin^® prescribed to another. Admitted to an area hospital, her condition steadily declined until death 29 h after admission. Following toxicological screening on hospital (admission) whole blood, the only significant compound detected was benztropine. Benztropine was confirmed at 0.28 mg/L – the highest antemortem blood concentration recorded in a case of toxicity or fatality uniquely associated with benztropine. A second serum antemortem specimen showed a benztropine concentration of 0.19 mg/L. Despite over 24 h in the hospital, benztropine was also found in the postmortem specimens collected at autopsy. Peripheral blood, central blood, liver, and gastric concentrations were 0.47 mg/L, 0.36 mg/L, 9.6 mg/kg, and 44 mg, respectively. These results indicate that benztropine exhibited a potential difference between whole‐blood and serum (plasma) concentrations. Additionally, in consideration of literature data, benztropine was found indicative of a compound prone to at least some postmortem redistribution.     

Post-mortem cases involving amphetamine-based drugs in The Netherlands. Comparison with driving under the influence cases

In this study we reviewed the post-mortem cases in the years 1999-2004 that were presented at the Netherlands Forensic Institute. The concentrations of amphetamine-based drugs in femoral blood from cases of suspected unnatural death were compared with concentrations in whole blood from non-fatal cases of driving under the influence (DUI cases) and with literature. Furthermore, the combinations with other drugs and/or alcohol were investigated. Amphetamine-based drugs were present in 70 post-mortem cases and 467 DUI cases. The most detected amphetamine-based drug was MDMA, followed by amphetamine. The presence of MDA could usually be explained by metabolism of MDMA. Methamphetamine and MDEA were rarely present. Frequently, the amphetamine-based drugs were taken in combination with alcohol and/or other non-amphetamine-based drugs such as cocaine or cannabinoids. The 70 post-mortem cases were divided into 38 amphetamine-based drug caused (i.e. the amphetamine-based drug directly caused or contributed to the death) and 32 amphetamine-based drug related deaths (i.e. death was not directly caused by the amphetamine-based drug). In the latter category, other (poly)drug intoxications and death by violence or drowning were the most frequent causes of death. In 30 cases, MDMA caused death directly. The range in blood concentrations of MDMA in these cases was substantial, i.e. 0.41-84 mg/L with a median concentration of 3.7 mg/L (n=30). MDMA blood concentrations in the MDMA related deaths (n=20) and in the DUI cases (n=360) varied up to 3.7 and 4.0 mg/L, respectively. Seven victims died from the direct effects of amphetamine; the blood concentration of amphetamine ranged from 0.24 to 11.3 mg/L, with a median concentration of 1.7 mg/L (n=7). The median concentrations of amphetamine in the amphetamine related deaths (n=13) and the DUI cases (n=208) were much lower, i.e. 0.28 and 0.22 mg/L, respectively. Amphetamine blood concentrations up to 6.0 and 2.3 mg/L were seen in the drug related deaths and DUI cases, respectively. The most frequently encountered amphetamine-based drugs in the investigated deaths were MDMA and amphetamine. The majority of MDMA- and amphetamine-caused deaths, i.e. 90% of these deaths, occurred with blood concentrations above 1.5 and 0.80 mg/L, respectively. MDMA and amphetamine blood concentrations in drug related deaths and DUI cases, however, overlap the range of fatal concentrations. Therefore, MDMA or amphetamine concentrations should never be used alone to establish the cause of death.     

Death of an infant involving benzocaine

This report describes the death of a four-month-old Hispanic male which may be related to benzocaine toxicity. A toxicological evaluation revealed benzocaine at a concentration of 3.48 mg/L, and postmortem methemoglobin of 36% (normal 0.4-1.5). Methemoglobinemia is a complication of benzocaine toxicity. In light of the toxicology findings, the coroner investigated the source of the benzocaine and discovered that the child was treated with Zenith Goldline Allergen Ear Drops containing 0.25% w/v benzocaine and 5.4% w/v antipyrine. There was an admission by a caregiver that on the day prior to the child's death, he had been treated with three times the prescribed dose. Blood benzocaine concentrations in nine other unrelated cases were determined and concentrations ranged from <0.05-5.3 mg/L (mean 1.48 mg/L). Seven of the nine cases were positive for drugs of abuse, and one additional case was described as a known drug user. Methemoglobin in these benzocaine positive cases ranged from 6-69%; however, methemoglobin concentrations in postmortem cases are frequently elevated and should be interpreted with caution. The unknown significance of the benzocaine, and the circumstances of the case raise questions about the ultimate attribution of this death to SIDS.     

Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies

The concentrations of zolpidem and zopiclone were determined in peripheral blood samples in two forensic materials collected over a 10-year period (2001-2010). The z-hypnotics were determined in venous blood from living subjects (impaired drivers) and in femoral blood from deceased persons (forensic autopsies), with the latter classified as intoxication or other causes of death. The z-hypnotics were determined in blood by capillary column gas chromatography (GC) with a nitrogen-phosphorous (N-P) detector after solvent extraction with n-butyl acetate. The analytical limit of quantitation (LOQ) was 0.02mg/L for zopiclone and 0.05mg/L for zolpidem and these have remained unchanged throughout the study. When death was attributed to drug intoxication (N=918), the median concentration of zopiclone in blood was 0.20mg/L compared with 0.06mg/L for other causes of death (N=1215) and 0.07mg/L in traffic offenders (N=691) (p<0.001). Likewise, a higher median concentration (0.30mg/L) was found in intoxication deaths involving zolpidem (N=357) compared with 0.13mg/L for other causes of death (N=397) or 0.19mg/L in impaired drivers (N=837) (p<0.001). Median concentration in blood of both z-hypnotics were appreciably higher in intoxication deaths when no other substances were identified; 0 70mg/L (N=12) for zopiclone and 1.35mg/L (N=12) for zolpidem. The median concentrations of z-hypnotics in blood decreased as the number of co-ingested substances increased for intoxication deaths but not other causes of death. The most prevalent co-ingested substances were ethanol in autopsy cases and diazepam in the motorists. This large compilation of forensic cases should prove useful when toxicologists are required to interpret concentrations of z-hypnotics in blood samples in relation to cause of death.