Contributory and Incidental Blood Concentrations in Deaths Involving Citalopram

All cases presenting to the New South Wales Department of Forensic Medicine between January 1, 2001 and December 31, 2010 in which citalopram was detected were retrieved. A total of 348 cases were identified. Citalopram contributed to death in 21.0%, and was incidental in 79.0%. Cases in which citalopram was contributory to death had significantly higher blood citalopram concentrations than incidental cases (0.50 mg/L vs. 0.30 mg/L). Citalopram concentrations varied significantly by contributory status: sole citalopram toxicity (median = 1.30 mg/L), citalopram/other drug toxicity (0.50 mg/L), and incidental cases (0.30 mg/L). Citalopram concentrations also varied by suicide status, with the highest concentration found in suicides where citalopram contributed to death (0.70 mg/L) compared with 0.50 mg/L for nonsuicide cases where citalopram contributed to death. In almost all contributory cases (69/73), other psychoactive substances were also detected, most commonly benzodiazepines (47.9%), alcohol (45.2%), and opioids (40.1%).     

Fatality caused by a combined trimipramine-citalopram intoxication

A 53-year-old woman who was diagnosed as suffering from depression was found dead in her bed. The autopsy revealed no morphological changes sufficient to explain death. Toxicological analysis was performed and the drugs trimipramine (2.33 mg/l), citalopram (4.81 mg/l) and zolpidem (0.07 mg/l) were identified in the femoral blood. A combined drug intoxication resulting in synergistic effects to cardiovascular disorders was proposed as the cause of death. An acute overdose and suicide was suggested by calculation of the parent drug to main metabolite ratios in femoral blood and liver tissue. The trimipramine to desmethyltrimipramine ratios were calculated to be 2.06 and 3.18, the citalopram to desmethylcitalopram ratios were 1.96 and 2.02.     

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.     

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.     

Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine.

Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin, diphenhydramine, and chlorpheniramine detected in the heart blood were 27.4, 8.8, and 0.2 mg/L, respectively. The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication.     

Segmental Hair Analysis—Interpretation of the Time of Drug Intake in Two Patients Undergoing Drug Treatment

The present study involved segmental testing of hair in two clinical cases with known dosage histories. Hair analysis confirmed the first patient's exposure to the prescribed sertraline and citalopram for several months. Citalopram was generally distributed along the hair shaft in accordance with the drug ingestion period. By contrast, “false” positive results were observed for sertraline in distal hair segments, corresponding to a period of no sertraline exposure, which may indicate incorporation from sweat or sebum, which transport the drugs along the hair surface. The second patient received various drugs during her treatment for brain cancer. Metoclopramide, morphine, oxazepam, paracetamol, sumatriptan, tramadol, and zopiclone, which had been part of the therapy, were all detected in the proximal hair segment. The results of these two cases indicated that results—especially concerning the time of drug intake—must be interpreted with caution and allow for the possibility of incorporation from sweat or sebum.     

A fatality involving metaxalone

A case is presented of a 54-year-old white female found dead in a secured apartment. Postmortem toxicologic analysis of the heart blood identified acetaminophen (97 mg/L), citalopram (0.4 mg/L), gabapentin (24 mg/L) and metaxalone (21 mg/L). The metaxalone concentration is within the range of previously reported fatalities involving metaxalone. The medical examiner ruled that the cause of death was metaxalone and gabapentin intoxication and the manner of death was suicide.     

Death during patient-controlled analgesia: piritramide overdose and tissue distribution of the drug

We report about a fatality during patient-controlled analgesia (PCA). Piritramide peripheral blood concentration was measured with 0.1 mg/l and exceeded the normal therapeutic range. Therefore, a fatal overdose was considered as the cause of death with respiratory depression as the underlying pathophysiological mechanism. The tissue distribution was studied; highest concentrations of piritramide were measured in kidney, bile and urine. Due to a large volume of distribution a difference in the drug concentration found in heart and peripheral bloods the phenomenon of drug redistribution was observed. Confronted with toxicological results, investigations revealed, that the PCA pump had been changed during a previous servicing from displaying mg/h to ml/h, therefore, the anesthetist had entered "1.5" assuming mg/h, but actually applying 1.5 ml/h (which was therefore equivalent to 2.25 mg/h, given a concentration in the cartridge of 1.5 mg piritramide/ml). In total, 61.5 ml (instead of 61.5 mg) had been infused, equivalent to 92.25 mg piritramide. This case report is a further example that human errors can play a crucial role in the safety of medical equipment. Experts in anesthesia recommended human factors engineering design principles to improve the safety of medical devices.     

A mixed-drug intoxication involving venlafaxine and verapamil

This case report describes the suicide of a 52-year-old woman whose cause of death was attributed to a mixed-drug intoxication involving venlafaxine and verapamil. Venlafaxine is prescribed for the treatment of depression and should be used with caution in patients with cardiovascular disease. Verapamil is a calcium channel blocker primarily used for treatment of cardiovascular disorders. The following drug concentrations were determined in postmortem fluids: verapamil--3.5 mg/L (femoral blood), 9.4 mg/L (subclavian blood), and 1.0 mg/L (vitreous fluid); norverapamil--1.0 mg/L (femoral blood), 2.1 mg/L (subclavian blood), and 0.20 mg/L (vitreous fluid); verapamil and norverapamil could not be detected in bile or urine due to the high levels of erythromycin present; venlafaxine--6.2 mg/L (femoral blood), 8.6 mg/L (subclavian blood), 5.3 mg/L (vitreous fluid), 54.0 mg/L (bile), and 72.3 mg/L (urine); and O-desmethylvenlafaxine--5.4 mg/L (femoral blood), 8.3 mg/L (subclavian blood), positive (vitreous fluid), 29.2 mg/L (bile), and 9.5 mg/L (urine). The cause of death was determined to be a mixed-drug intoxication resulting from an overdose of verapamil and venlafaxine. The manner of death was determined to be suicide.     

Acute flurazepam intoxication: a case report

A fatality due to ingestion of flurazepam is reported. Flurazepam is a benzodiazepine, a widely prescribed hypnotic drug for use in sleep disorders. There are only few documented reports of the disposition of flurazepam in deaths due to overdose. A 68-year-old woman was found deceased at home with no evidence of trauma or asphyxia. Toxicologic analyses were performed and drug levels measured by means of gas chromatography coupled to mass spectrometry. The flurazepam concentration in each specimen was as follows: heart blood 2.8 microg/mL, bile 323 microg/mL, and urine 172 microg/mL. Presence of flurazepam into gastric content was observed too. Based on the autopsy findings, patient history, and toxicologic results, the cause of death was determined to be acute intoxication of flurazepam and the manner, suicide.     

Tissue distribution of cocaine in a pregnant woman

Reports of cocaine-related obstetrical problems, including abruptio placentae and spontaneous abortion, have become increasingly evident in the medical literature; however, little is known about tissue distribution of cocaine in the pregnant woman. We report the toxicologic results of distribution studies performed on a pregnant woman and her fetus. Maternal/fetal cocaine concentration ratios were high when comparing blood (9:1), brain (6:5), and kidney (10:6). Possible explanations of the mechanism for lower fetal cocaine concentrations may include uterine vasoconstriction, incomplete maternal/fetal equalibration, or rapid placental/fetal clearance.     

Toxicologic findings in suicide with doxepin and paroxetine]

A young nurse was found dead in her flat. In chemical-toxicological analysis the following femoral blood drug concentrations were determined: paroxetine 0.176 mg/l, doxepine 82.12 mg/l, desmethyldoxepine 0.34 mg/l. Additionally the drug concentrations were determined in various body fluids and organs. The results of the described fatality are discussed. For interpretation of toxicologic results in antidepressant fatalities ratios of parent drug to metabolite and postmortem drug redistribution should be taken into account.     

One hundred seventy two deaths involving the use of oxycodone in Palm Beach County

Oxycodone is a potent semi-synthetic narcotic prescribed for the management of pain. Previous investigators have reported that the abuse of oxycodone is most frequently seen in conjunction with the abuse of other drugs, although fatalities have been reported with oxycodone alone. We undertook a retrospective review of cases investigated by the Palm Beach County Medical Examiner's Office in which postmortem toxicologic studies indicated the presence of oxycodone. A total of 172 consecutive cases were studied, including 18 in which death was attributed to oxycodone toxicity, 117 to combined drug toxicity, 23 to trauma, 9 to natural causes and 5 to another drug or drugs. The postmortem blood concentrations of oxycodone overlapped among the groups. The mean blood oxycodone concentration among the cases of oxycodone toxicity was 0.69 mg/L, combined drug toxicity 0.72 mg/L and trauma 0.62 mg/L. Concentrations were lower in cases of deaths attributed to natural causes and to another drug or drugs (mean each 0.087 mg/L). Benzodiazepines, detected in 96 cases, were the most common co-intoxicants in the cases of combined drug toxicity, followed by cocaine, which was found in 41. The most frequently encountered benzodiazepine was alprazolam. This study confirms that deaths in which oxycodone is a factor are most commonly cases of combined drug toxicity. The high incidence of alprazolam as a co-intoxicant has not been previously recognized.     

Evaluating suspected co-proxamol overdose.

In three instances of suicidal poisoning by co-proxamol (paracetamol and dextropropoxyphene) blood samples were obtained from 11 sites together with eight tissue samples, bile, urine, gastric contents and duodenal contents. Site-dependent differences in blood propoxyphene concentration varied between the three cases but concentrations were consistently lowest in peripheral blood and highest in central sites: 3.9-5.5 (pulmonary vein) mg/l; 4.6-25 (pulmonary vein) mg/l; 3.2-40 (aorta) mg/l. There was a less than twofold variation in corresponding blood paracetamol concentrations. Reference data on fatal propoxyphene blood concentrations do not specify the blood sampling site and can be misleading. The intra-individual variability of propoxyphene concentrations in blood in these three cases underscores this problem. Tissue concentrations of propoxyphene showed considerable inter-individual variability in degree and pattern. Tissue concentrations of paracetamol showed a less than twofold intra-individual variation. Body drug loads were calculated by two methods: from organ weights and tissue concentrations; from published volume of distribution data (Vd). For paracetamol the body drug load is underestimated by the organ weight calculation but the Vd calculation approximates the suspected dose based on anamnestic information. For propoxyphene the body drug load is seriously underestimated by the organ weight calculation and overestimated up to 2.5 times by the Vd calculation. Since the two drugs have a fixed ratio in co-proxamol then the dose of propoxyphene (the effective lethal agent) can be inferred from the paracetamol dose calculated by Vd. This approach may be applicable to cases of overdose with other compounded drug preparations.     

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.     

Evaluation of the addiction history of a dead woman after exhumation and sectional hair testing.

In Greece, sectional hair analysis, in addition to clinical examination, has been used as a valuable tool for the confirmation of a person's history of drug use. The present report concerns the toxicologic analysis of the exhumed remains and hair samples of an 18-year-old woman. Postmortem toxicologic analysis of blood and urine confirmed recent opiate and cannabis use and indicated that death was associated with heroin abuse. Several months later, the woman's family asked for exhumation and reexamination of the body, insisting that the cause of death was homicide. The investigating judge ordered exhumation and new medicolegal examination of the body. The investigation of the drug profile along the hair shaft was undertaken by analyzing hair sections 1 cm from the hair root for morphine, 6-monoacetylmorphine, heroin, and cannabinoids. The total lengths of the hair samples ranged from 8 to 11 cm. The total morphine levels in the hair sections corresponding to the 3-month period before death were significantly lower (1.5-2.85 ng/mg) than those of the 4- to 10-month period before death (7.4-14.8 ng/mg). An interpretation of these results may be occasional drug use (with considerable attenuation of use during the last 3 months before death). Decrease of tolerance to heroin caused by abstinence and relapse in use could have been the cause of 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.