The redistribution of selected psychiatric drugs in post-mortem cases

The post-mortem redistribution of a number of psychiatric drugs was investigated. A portion of liver, the gastric contents and blood collected from heart and femoral sites was obtained from 13 cases and analyzed by liquid chromatography-mass spectrometry. Drugs detected included five selective serotonin reuptake inhibitors; venlafaxine, a serotonin/noradrenaline reuptake inhibitor; and risperidone, an atypical antipsychotic. Heart blood concentrations were significantly higher (3.4-fold on average) than those measured in femoral blood when results from all drugs were included together. The range for parent drug concentrations in these two blood specimens was 0.5-6.2. There was no significant correlation of the post-mortem interval, the liver concentration and content of drugs in the gastric contents to the heart:femoral blood concentration ratio. These data serve to demonstrate that variable increases in blood concentration occur post-mortem and limit the interpretative value of such toxicological data.     

The incidence of drugs in drivers killed in Australian road traffic crashes

The incidence of alcohol and drugs in fatally injured drivers were determined in three Australian states; Victoria (VIC), New South Wales (NSW) and Western Australia (WA) for the period of 1990-1999. A total of 3398 driver fatalities were investigated which included 2609 car drivers, 650 motorcyclists and 139 truck drivers. Alcohol at or over 0.05 g/100ml (%) was present in 29.1% of all drivers. The highest prevalence was in car drivers (30.3%) and the lowest in truckers (8.6%). WA had the highest rate of alcohol presence of the three states (35.8%). Almost 10% of the cases involved both alcohol and drugs. Drugs (other than alcohol) were present in 26.7% of cases and psychotropic drugs in 23.5%. These drugs comprised cannabis (13.5%), opioids (4.9%), stimulants (4.1%), benzodiazepines (4.1%) and other psychotropic drugs (2.7%). 8.5% of all drivers tested positive for Delta(9)-tetrahydrocannabinol (THC) and the balance of cannabis positive drivers were positive to only the 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid (carboxy-THC) metabolite. The range of THC blood concentrations in drivers was 0.1-228 ng/ml, with a median of 9 ng/ml. Opioids consisted mainly of morphine (n=84), codeine (n=89) and methadone (n=33), while stimulants consisted mainly of methamphetamine (n=51), MDMA (n=6), cocaine (n=5), and the ephedrines (n=61). The prevalence of drugs increased over the decade, particularly cannabis and opioids, while alcohol decreased. Cannabis had a larger prevalence in motorcyclists (22.2%), whereas stimulants had a much larger presence in truckers (23%).     

Involvement of Amphetamines in Sudden and Unexpected Death

Abstract:  In the present study, the effects of amphetamine-class drugs were examined in cases reported to the Victorian coroner from 2001 to 2005 to determine if death can occur from the use of amphetamine-class drugs alone. A total of 169 cases were reviewed where a forensic autopsy detected amphetamine(s) in the blood. Pathology, toxicology, and police reports were analyzed in all cases to ascertain the involvement of amphetamine-class drugs in these deaths. In Victoria, methamphetamine (MA) is the principal abused amphetamine-class followed by methylenedioxymethamphetamine (MDMA). There were six cases in which a cerebral hemorrhage caused death and three cases in which serotonin syndrome was established as being caused by the interaction of MDMA and moclobemide. There were 19 cases in which long-term use of amphetamines was associated with heart disease. There were three cases where amphetamine-class drugs alone were regarded as the cause of death, of which two cases exhibited high levels of MDMA and lesser amounts of MA and/or amphetamine. There were no cases in which significant natural disease was absent and death was regarded as caused by the use of MA. There was no correlation between blood concentration of drug and outcome.     

Methadone toxicity causing death in ten subjects starting on a methadone maintenance program.

Methadone maintenance therapy is designed to reduce the need for addicts to use heroin or other illegal opiates. Death in patients starting on such a program has not previously been documented. We report the death of 10 persons who died within days of starting a methadone maintenance program administered by general practitioners. Their bodies were subject to a full autopsy by forensic pathologists, with a full toxicological examination. The mean starting dose had been 53 mg, which had been increased to a mean of 57 mg by the final dose. Death occurred after a mean of 3 days. The mean blood methadone concentration at death was 2.1 mumol/L. Complete toxicological analysis showed that six subjects had additional drugs present including two with alcohol, two with benzodiazepines and morphine, and one with benzodiazepines alone. Pathological examination revealed the presence of chronic persistent hepatitis in all subjects and bronchopneumonia in five. The causes of death were given as methadone toxicity or methadone toxicity in combination with bronchopneumonia. Our observations highlight the dangers of methadone in the first days of starting on a maintenance program, particularly when the starting doses are relatively high and subjects have no demonstrated tolerance to opiates.     

Post-mortem toxicology

Studies examining post-mortem processes are difficult to conduct since changes will have already occurred when the body arrives at the mortuary. While control of collection site for blood can minimize changes in concentration it is very difficult to conduct experiments in humans aimed at understanding the mechanisms and determining the extent of such changes. The use of appropriate animal models can be useful in this regard providing the species and conditions are carefully chosen. Pharmacokinetic studies in humans are also very useful for understanding the changes in drug concentration with time in blood (and other fluids) and also for improving our understanding of drug effects. Unfortunately, doses of illicit drugs that can be given are relatively low to guarantee safety hence extrapolations are made to real life situations. Individual case studies can be useful to describe an unusual or particularly interesting circumstances but little useful information can be obtained when trying to ascertain the role of competing factors, e.g. role of individual drugs when multiple drugs are present, varying toxicity between route of administration, and the role of age or natural disease when drugs are also present. Epidemiological approaches by reviewing large numbers of related cases are the most powerful tool to obtain this information. All of these studies need to operate under the ethical and legal framework appropriate for a jurisdiction. This paper discusses the relative merits of scientific approaches to research in post-mortem toxicology and provides guidance on the most appropriate techniques for future studies.     

The contribution of DNA to the disaster victim identification (DVI) effort

As part of the disaster victim identification (DVI) response to the 2009 Victorian bushfires disaster, a number of scientific disciplines contributed to the human identification process--forensic pathology, anthropology and odontology, as well as fingerprinting and DNA profiling. The DNA laboratory received 182 post-mortem (PM) samples from 120 DVI cases and 236 reference samples corresponding to 163 missing persons (and two non-DVI cases). DNA analysis yielded full DNA profiles for 102 DVI cases and 190 ante-mortem (AM) samples (relating to all 163 missing persons), respectively. Subsequent comparison of DNA profiles, through direct and kinship matching, resulted in the submission of 76 DNA reports to the DVI Reconciliation Centre which assisted in the identification of 67 deceased. This paper describes the contribution of DNA analysis towards the DVI response to the 2009 Victorian bushfires disaster.     

The time-dependant post-mortem redistribution of antipsychotic drugs

The post mortem redistribution of ten commonly prescribed antipsychotic drugs (APs) was investigated. Femoral blood was collected from 273 cases at admission to mortuary (AD) and at post-mortem (PM). The PM samples were collected at various times up to nine days after admission and the sample pairs analysed using LC-MS/MS. The drugs included in this study were 9OH-risperidone (paliperidone), amisulpride, chlorpromazine, clozapine, haloperidol, olanzapine, promethazine, quetiapine, risperidone, and zuclopenthixol. Haloperidol, quetiapine and risperidone showed minimal changes between AD and PM specimens, whereas the majority of drugs showed significant changes between the sample pairs collected at different time points post mortem (p<0.01) in addition to an average concentration change greater than the uncertainty of measurement of the applied method. Average increases in blood concentrations after admission to the mortuary ranged up to 112% (chlorpromazine and olanzapine) but also decreases up to -43% (9OH-risperidone) were seen. There were large standard deviations between sample pairs and substantial day-to-day unpredictable changes that highlight the difficulty in the interpretation of drug concentrations post-mortem. Based on the presented data, we recommend that specimens for toxicological analysis should to be taken as soon as possible after admission of a deceased person to the mortuary in order to minimise the effects of the PM interval on the drug concentration in blood.     

Identification of 2-hydroxymethyl-olanzapine as a novel degradation product of olanzapine

Olanzapine (OLZ) is amongst the most commonly prescribed antipsychotic drugs and is associated with substantial instability. The aim of this study was to investigate the instability of OLZ and to identify the degradants formed from its breakdown. Three experiments were conducted to monitor the degradation of OLZ and the formation of degradants in blood (1), water (2), and post-extraction at 4 °C (3). All three sample sets were analysed in duplicate and repeated in the absence (A) and presence (B) of 0.25% ascorbic acid. One degradant was identified in sample sets 2A and 3A with m/z 329 and confirmed as 2-hydroxymethyl-OLZ (2-OH-OLZ) using LC-MS techniques. The addition of 0.25% ascorbic acid slowed the degradation of OLZ down in all three experiments and inhibited the formation of 2-OH-OLZ in sample sets 2A and 3A. To investigate the influence of oxygen on the degradation of OLZ and the formation of 2-OH-OLZ in water, an additional experiment (4) was conducted. Sample sets were prepared containing different vortexing or sonication steps in order to alter the oxygen content in the samples. Statistical analysis confirmed that degradation increased significantly following vortexing for 1 min while sonication did not affect the rate of degradation of OLZ further suggesting the involvement of oxygen in the degradative processes. 2-OH-OLZ was only identified as a degradant of OLZ in aqueous solutions. It also degrades over time but its product is currently unknown and is under investigation.     

Postmortem concentrations of citalopram

The postmortem concentrations of citalopram in blood, bile, liver, and vitreous humour were investigated in 14 cases using a specially developed high performance liquid chromatography assay. Concentrations from drug and non-drug related deaths were categorized to determine a postmortem therapeutic and toxic range. Therapeutic citalopram concentrations for blood, bile, liver, and vitreous humour ranged to 0.4 mg/L, 2.1 mg/l, 6.6 mg/kg, and 0.2 mg/L, respectively. In one potentially fatal response to citalopram, concentrations were 0.8 mg/L, 6.0 mg/L, 0.3 mg/L for blood, bile and vitreous humour, respectively.     

Postmortem investigation of lamotrigine concentrations

Lamotrigine is a relatively new anticonvulsant. Therapeutic plasma concentrations generally range from 1 to 4 mg/L, although several studies have shown that good control of epilepsy has been achieved with concentrations reaching 10 mg/L generally, with little toxicity. In overdose, however, the drug has been linked to ECG changes that may suggest a possible arrythmogenic effect and hence cardiac toxicity. Lamotrigine has also been shown to cause encephalopathy and thus neurotoxicity. There is no information concerning postmortem lamotrigine concentrations and their interpretation. We describe lamotrigine concentrations in postmortem specimens including blood, liver, bile, vitreous humour, and urine from eight cases. A high performance liquid chromatography (HPLC) method is described with extraction procedures for the various tissues. Two possible groups were identified. The first being the "broader therapeutic" group with blood concentrations ranging from 0.9 to 7.2 mg/L and corresponding liver concentrations ranging from 16 to 36 mg/kg. The second being a "supratherapeutic" group with blood concentrations ranging from 20 to 39 mg/L and corresponding liver concentrations ranging from 53 to 350 mg/kg. Although none of the eight cases described were attributed to overdose by lamotrigine alone, the cause of death for one of the three cases in the "supratherapeutic" group was given as mixed drug toxicity. Cause of death for the remaining two cases in this group was reported as epilepsy. However, both these cases showed elevated concentrations of lamotrigine and both were co-medicated with valproic acid. Such co-administration has been shown in the literature to lead to elevated lamotrigine concentrations and a reduction in lamotrigine dose has been recommended. With such data, we highlight the importance of monitoring lamotrigine concentrations in cases co-medicated, particularly with valproic acid.