Fatal Toxicity Index Research Articles

Three safety indices for the fourteen most prescribed antidepressants in the US, 2013–2020

ObjectiveThis study provides three prevalence-based metrics of potential harm, the fatal toxicity index (FTI), serious morbidity index (SMI) and healthcare utilization index (HUI) for fourteen of the most prescribed antidepressants in the US. MethodFor the years 2013–2020, adverse events for single drug exposures were obtained from the National Poison Data System. Prescription estimates were taken from the Agency for Healthcare Research and Quality's Medical Expenditure Survey. 95% confidence intervals were calculated using a Poisson distribution. Chi-square testing was used where significance was not clear. ResultsSSRIs and SNRIs had the lowest overall indices (FTI 0.02–0.26). Bupropion's FTI (0.27–0.43) was not statistically significantly different from that of imipramine (FTI 0–1.3, p = .62) or nortriptyline (FTI 0.25–0.78, p = .22), though its SMI and HUI were significantly greater. There was a statistically significant difference in all indices between TCAs (p < .0047). The difference between the FTI of all SSRIs did not remain significant after correction (p = .045). ConclusionSSRIs and SNRIs are safer than alternative agents on all measures. Bupropion exposure was as likely to cause mortality, and more likely to cause morbidity or require treatment in a healthcare facility, than TCAs nortriptyline and imipramine.

The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use.

Tricyclic antidepressants (TCAs) remain widely prescribed for depression and many other conditions. There may be important differences between individual TCA in regard to their overdose toxicity and their cardiac toxicity in clinical use. We conducted a systematic review to compare the toxicity of individual TCA in overdose and the risk of serious adverse cardiac events occurring with therapeutic doses. We used the fatal toxicity index (FTI) and case fatality ratio as markers of fatality in overdose, and hazard ratios or odds ratios for the risk of cardiovascular adverse events during normal clinical use. In all, 30 reports of mortality in overdose and 14 observational studies assessing the risk of cardiovascular adverse events in clinical use were included. FTI values were of the same order of magnitude (101-102) for all TCAs except lofepramine. Desipramine appears to be somewhat more likely than other TCAs to lead to death in overdose. Amitriptyline, clomipramine, dothiepin/dosulepin, doxepin, trimipramine and imipramine showed broadly similar toxicity and were usually reported to be less toxic than desipramine. Data on nortriptyline were contradictory. Lofepramine had the lowest risk of death in overdose. The rank order of overdose toxicity was broadly consistent between different FTI definitions and between markers used. With respect to the risk of cardiovascular events at clinically relevant exposure, amitriptyline, nortriptyline and lofepramine were associated with a greater risk of in-use cardiotoxicity. All measures of overdose toxicity were subject to external influences and confounding. The continued use of TCAs in depression and other conditions should be minimized when considering their undoubted toxicity in overdose and possible toxicity in normal clinical use.

Fatal Toxicity Index, Total Prescriptions per Death, a Unique View of Medical Examiner Deaths and Prescription Monitoring Data

Introduction: This study is the first of its kind in the United States to report a fatal toxicity index (FTI) of prescription drugs commonly implicated in deaths to quantify the dangers of prescription drugs. Death rates for the top fourteen schedule II-IV drugs implicated in overdoses were examined as deaths per million pills dispensed to a large county population over a one-year period to derive a fatal toxicity index (FTI), which is an indicator of the level of toxicity in accidental prescription-related overdose deaths. Medical Examiner data used to understand the prescription drugs, co-prescribing of multiple prescriptions, illicit drugs and alcohol in deaths. Methods: This retrospective, descriptive analysis examined all accidental prescription-related deaths (n=247) as determined by the San Diego Medical Examiner (ME) investigation during 2015. Data were analysed by age, sex, individual prescription drugs and combinations of prescription drugs. Prescribing data were obtained from the CURES reporting system, California’s prescription drug monitoring system. The CURES data in combination with ME data were used to derive an FTI for each of the selected drugs. Results: Approximately 57% (n=140) of the 247 prescription-related deaths in 2015 were among men with an average age of 48(SD=14.4). Of all single prescription deaths, the majority involved opioids (n=31; 67.4%). Over two-thirds of all deaths involved two or more substances with the most common contributory drugs being oxycodone (n=57, 23%), alprazolam (n=39, 15.8%), and morphine (n=36, 14.6%). Hydrocodone provided the largest quantity of prescribed pills (55,378,292) but accounted for only 12 percent of all accidental prescription deaths (n=30). Of all drugs examined hydrocodone had the lowest FTI (0.54 deaths per million pills dispensed). Drugs with the highest FTI included chlordiazepoxide (40.03), fentanyl (35.75) and methadone (9.1). Conclusions: Focus on the prescription drug epidemic has been on opioids however, data suggest that drugs from various classes are represented in deaths. A multi-drug approach and study of top prescription related deaths should be considered when working to promoting safe prescribing and to reduce accidental overdoses.

Fatal Toxicity Indices for Medicine-Related Deaths in New Zealand, 2008-2013.

The fatal toxicity index (FTI) is a measure for assessing the relative risks of death due to the medicines prescribed in a population. This knowledge is useful for prescribers and informs medicine safety initiatives. This study aimed to calculate FTIs for the New Zealand population using three methodologies. New Zealand coronial data describing medicine-related deaths from 1 January 2008 to 31 December 2013 were retrospectively extracted from the National Coronial Information System. Three fatal toxicity indices were derived using the number of deaths attributed to each pharmaceutical as the numerator and the total defined daily doses, number of patients and number of prescriptions as denominators. There were 703 medicine-related deaths, of which 627 were assessed as due to one primary contributor. Median decedent age was 48years (interquartile range 37-58), and 319 (51%) were male. Deaths were intentional in 252 cases (40%), unintentional in 284 (45%) and unknown in 91 (15%). The majority of deaths (n = 486, 78%) occurred in the community. Opioids, antidepressants, antipsychotics and hypnotic-anxiolytics caused most fatalities. While the FTIs for individual medicines varied by denominator applied, methadone and clozapine fatalities were prominent in all three indices. The antidepressants clomipramine, dosulepin and doxepin consistently returned the highest FTIs in their group. New Zealand prescribers should be aware of the high relative risk of death associated with methadone and clozapine; that clomipramine, dosulepin and doxepin were identified as the most dangerous antidepressants; and that zopiclone carries a similar fatal risk to benzodiazepines. Varying results were found between the FTIs calculated, making comparisons, particularly between populations, difficult.

The relative lethal toxicity of pharmaceutical and illicit substances: A 16-year study of the Greater Newcastle Hunter Area, Australia.

We aim to calculate 2 metrics of relative lethal toxicity; the fatal toxicity index (FTI; number of deaths per year of a daily dose) and the case fatality (CF; number of deaths per overdose) with a focus on opioids, antidepressants, antipsychotics, benzodiazepines and illicit drugs. This descriptive cohort study used the Australian National Coronial Information System (NCIS) to identify a population of individuals with drug-associated deaths in the Greater Newcastle Hunter Area between January 2002 and December 2016. This was combined with Australian medicine dispensing data and corresponding data from the Hunter Area Toxicology Service to calculate FTI and CF. There were 444 drug-related deaths and 21,296 overdoses during the study period. FTI and CF were well correlated (Spearman's rho 0.64, P<.001). Of the classes of interest, opioids had the highest FTI (40.3 95% confidence interval [CI] 35.2-45.4 deaths per 100years of use at the defined daily dose or deaths/DDD/100years) and CF (12.4% 95%CI 11.0-13.9). Fentanyl, methadone and morphine had the highest relative fatal toxicity within this class. Tricyclic antidepressants had the highest relative fatal toxicity of all antidepressants (FTI 14.5 95%CI 9.7-19.3 deaths/DDD/100years and CF 7.1% [95%CI 4.8-9.3]) and benzodiazepines appeared to be more associated with multiple agent deaths than single. Of the illicit drugs, heroin had the highest CF (26.4%, 95%CI 19.1-33.7). Knowledge of relative lethal toxicity is useful to prescribers and medicines and public health policy makers in restricting access to more toxic drugs and may also assist coroners in determining cause of death.

Fatal toxicity index of medicinal drugs based on a comprehensive toxicology database.

The fatal toxicity index (FTI) is the absolute number of fatal poisonings caused by a particular drug divided by its consumption figure. Consequently, it is a useful measure in evaluating toxicity of the drug and its relevance in fatal poisonings. In this study, we assessed the FTI of medicinal drugs in 3years (2005, 2009, and 2013) in Finland. As the measure of drug consumption, we used the number of defined daily doses (DDD) per population in each year. There were 70 medicinal drugs in Finland for which the mean FTI expressed as the number of deaths per million DDD over the three study years was higher or equal to 0.1. The Anatomical Therapeutic Chemical (ATC) classification system was used for the classification of the active ingredients of medicinal drugs according to the organ or system which they act on. Of these 70 drugs, 55 drugs (78.6%) acted on the nervous system (denoted by ATC code N), 11 (15.7%) on the cardiovascular system (C), three (4.3%) on the alimentary tract and metabolism (A), and one (1.4%) on the musculoskeletal system (M). The nervous system drugs consisted of 20 psycholeptics, (ATC code N05), 20 psychoanaleptics (N06), eight analgesics (N02), six antiepileptics (N03), and one other nervous system drug (N07). The highest individual FTIs were associated with the opioids methadone, dextropropoxyphene, oxycodone, tramadol, and morphine; the antipsychotics levomepromazine and chlorprothixene; and the antidepressants doxepin, amitriptyline, trimipramine, and bupropion. Buprenorphine was not included in the study, because most of the fatal buprenorphine poisonings were due to smuggled tablets. A clearly increasing trend in FTI was observed with pregabalin and possibly with bupropion, both drugs emerging as abused substances.

Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose

Self-poisoning is a common method of suicide and often involves ingestion of antidepressants. Information on the relative toxicity of antidepressants is therefore extremely important. To assess the relative toxicity of specific tricyclic antidepressants (TCAs), a serotonin and noradrenaline reuptake inhibitor (SNRI), a noradrenergic and specific serotonergic antidepressant (NaSSA), and selective serotonin reuptake inhibitors (SSRIs). Observational study of prescriptions (UK), poisoning deaths involving single antidepressants receiving coroners' verdicts of suicide or undetermined intent (England and Wales) and non-fatal self-poisoning episodes presenting to six general hospitals (in Oxford, Manchester and Derby) between 2000 and 2006. Calculation of fatal toxicity index based on ratio of rates of deaths to prescriptions, and case fatality based on ratio of rates of deaths to non-fatal self-poisonings. Fatal toxicity and case fatality indices provided very similar results (rho for relative ranking of indices 0.99). Case fatality rate ratios showed greater toxicity for TCAs (13.8, 95% CI 13.0-14.7) than the SNRI venlafaxine (2.5, 95% CI 2.0-3.1) and the NaSSA mirtazapine (1.9, 95% CI 1.1-2.9), both of which had greater toxicity than the SSRIs (0.5, 95% CI 0.4-0.7). Within the TCAs, compared with amitriptyline both dosulepin (relative toxicity index 2.7) and doxepin (2.6) were more toxic. Within the SSRIs, citalopram had a higher case fatality than the other SSRIs (1.1, 95% CI 0.8-1.4 v. 0.3, 95% CI 0.2-0.4). There are wide differences in toxicity not only between classes of antidepressants, but also within classes. The findings are relevant to prescribing decisions, especially in individuals at risk, and to regulatory policy.

Fatal venlafaxine poisonings are associated with a high prevalence of drug interactions

Venlafaxine (VEN) is an antidepressant found to possess a higher fatal toxicity index (FTI, i.e., deaths in proportion to consumption) than other newer antidepressants and selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to elucidate using post-mortem cases whether the apparent high toxicity of VEN is associated with adverse drug interactions, pharmacogenetic factors and/or the manner of death. Within a 2-year period, a comprehensive post-mortem database and death certificates were searched for cases with laboratory findings of VEN, findings of other drugs, associated background information and the cause and manner of death. In 123 cases, the concentrations of VEN and its two metabolites, O-desmethylvenlafaxine (O-VEN) and N-desmethylvenlafaxine (N-VEN), and the CYP2D6 genotype were determined in post-mortem blood. The median concentrations of VEN, O-VEN and N-VEN were 560, 420 and 49µg/l, respectively. A prominent feature of the VEN-positive cases was the high abundance of interacting drugs (46%), being more common with higher VEN concentrations. Compared to other common antidepressants, VEN-positive cases showed the highest suicide frequency, but also the proportion of suicidal VEN poisonings of all suicides was substantially higher than that of mirtazapine or SSRIs. Relative CYP2D6 activity did not predispose to high VEN concentrations, and the frequency of the extreme phenotypes followed the general population. In conclusion, the high suicide potential of VEN in combination with the high prevalence of drugs causing adverse interactions could be the reason for the observed high FTI.

John Anthony Henry

John Anthony Henry

Reference Concentrations of Antidepressants. A Compilation of Postmortem and Therapeutic Levels

In approximately 95% of all medicolegal autopsies performed in Sweden between 1992 and 2005, femoral blood samples were collected and screened for antidepressant drugs. A total of 8591 cases were identified and used for detailed analysis and interpretation. The present compilation provides information about 15 antidepressant drugs determined in femoral blood from certified fatal intoxications and in postmortem "control cases". The postmortem data were subjected to a previously proposed strategy, based on strictly standardized conditions regarding collection, handling and toxicological analysis of the samples. The postmortem data were compared with a therapeutic drug monitoring material (Group T; n = 16,809). The strict inclusion criteria meant that only 2737 postmortem cases were included in the survey. Accordingly, Group A (n = 330) were certified as deaths involving intoxication with a single antidepressant drug; Group B (n = 864) were deaths involving intoxication with more than one drug and/or with a significant concentration of ethanol; and Group C (n = 1800) were deaths under circumstances not involving incapacitation by drugs. In addition to providing reference levels for each drug, the results may also be used to assess risk of toxicity and supply supplementary information to the standard fatal toxicity index.

Carisoprodol intoxications: a retrospective study of forensic autopsy material from 1992–2003

Carisoprodol is commonly prescribed as a centrally acting muscle relaxant, but it is also subject to abuse. The literature describing fatal intoxications with the drug is limited to a relatively small number of cases, and there are inconsistencies with regard to which concentration levels that are toxic. We therefore investigated all forensic autopsies at the Norwegian Institute of Public Health during the period 1992-2003 where carisoprodol was detected. The median concentrations of carisoprodol in intoxication with carisoprodol only or with only minor other analytical findings was 36 mg/l (range 8-65 mg/l; n=5). In the rest of the intoxications, the relevance of carisoprodol relative to the other drugs detected was variable (n=93). When the number of intoxications with carisoprodol each year were divided by the number of defined daily doses (DDD) sold, a fatal toxicity index between 5.6 and 6.9 deaths/1 million DDD was obtained. The total number of cases where carisoprodol was detected increased during the period studied, which correlated to sales figures for the drug. We conclude that carisoprodol can be fatal in concentrations below those indicated in some of the previously published literature. There were, however, only a small number of cases where the cause of death can be attributed to use of carisoprodol alone.

Newer antidepressants: evaluation of fatal toxicity index and interaction with alcohol based on Finnish postmortem data

Finnish postmortem toxicology data from 1995 to 2002 was analyzed to obtain improved estimates of fatal toxicity indices for the newer antidepressants and to evaluate their interaction with alcohol. Altogether 284 fatal poisonings were attributed to 12 different newer antidepressants. Venlafaxine, mianserin, moclobemide, and mirtazapine were responsible for significantly more deaths than expected from their sales. Their fatal toxicity indices were higher than those of selective serotonin reuptake inhibitors (SSRIs) but lower than those of tricyclic antidepressants. In fatal poisonings involving alcohol in combination with venlafaxine, mianserin, moclobemide, or mirtazapine, the median blood alcohol concentration (BAC) ranged from 2.35 to 2.7 mg/g, whereas in those involving alcohol in combination with citalopram or fluoxetine the median BAC was 2.9 and 3.4 mg/g, respectively. The BAC was significantly lower in venlafaxine-related deaths than in those involving fluoxetine or citalopram. We conclude that among the newer antidepressants differences are present both in toxicity and in interaction potential with alcohol. The SSRIs appear to present a low risk of fatal poisoning when taken alone or in combination with alcohol, whereas venlafaxine is associated with an elevated risk.

Changes in Fatalities Due to Overdose of Anxiolytic and Sedative Drugs in the UK (1983???1999)

To establish the frequency with which anxiolytic and sedative drugs result in fatal poisonings and to examine longitudinal changes in poisoning deaths. The number of fatal poisonings between 1983 and 1999 in England, Scotland and Wales due to a single anxiolytic or sedative drug was obtained from the Department of Health in the UK. This was divided by the number of prescriptions for these drugs in England and Scotland to derive a fatal toxicity index (FTI) of deaths per million prescriptions. Chloral hydrate, clomethiazole, barbiturates, and related sedatives had much higher FTIs than benzodiazepines, buspirone, zolpidem and zopiclone. There has been a substantial reduction in the annual number of deaths from sedative drug poisoning between 1983 and 1999. This has been due to a sustained reduction in prescriptions for high toxicity drugs and more recently a major reduction in temazepam deaths that coincided with the withdrawal of gelatin capsule formulations. Deaths would be expected to be further reduced if there were reduced prescriptions of high toxicity drugs--and the continuing need for short-acting barbiturates, clomethiazole and chloral hydrate should be questioned.

Interaction of alcohol and drugs in fatal poisonings.

In Finnish data from 1995-2000, 1006 fatal poisonings due to alcohol (ethanol), a single drug or both were statistically analysed in retrospect to evaluate the interaction between alcohol and drugs. In 53% of these cases, low concentrations of some common benzodiazepines were present. The median postmortem blood alcohol concentration (BAC) was 3.3 percent per thousand (w/w) in the 615 alcohol poisonings, but significantly lower, ranging from 1.3 to 1.7 percent per thousand, when promazine, doxepin, amitriptyline or propoxyphene were found together with alcohol. When levomepromazine, temazepam or zopiclone were present, the median BAC was also significantly lower, 2.5-2.7 percent per thousand. Citalopram and diltiazem did not exhibit a significant effect. The median BAC was significantly lower in cases with high concentrations than in those with low concentrations of a drug (excluding citalopram), suggesting a positive concentration-effect relationship. Fatal toxicity indices (FTIs) were calculated by relating the number of deaths caused by a drug to the corresponding sales figures. Promazine had an extremely high FTI, followed by levomepromazine, propoxyphene, doxepin and amitriptyline. The other drugs had relatively low FTIs. The results reflect not only the acute toxicity of a given drug-alcohol combination but also the manners of use and abuse of these drugs.

Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data

Several studies over the past 15 years have compared the number of fatal poisonings due to antidepressant drugs in the United Kingdom with drug use statistics to derive a fatal...

A mortality index for postmarketing surveillance of new medications

The rate of introduction of new pharmaceuticals is growing as a result of advances in molecular pharmacology and targeted drug development. The Fatal Toxicity Index (FTI) has been proposed as a means for monitoring drug toxicity through post-marketing surveillance. The FTI requires data regarding the general availability of a particular agent in the community which, in the US, is proprietary. The authors propose a Mortality Index as an alternative method for calculating relative lethality that does not rely on proprietary information for postmarketing surveillance. Using data from the Toxic Exposure Surveillance System (TESS) a Mortality Index was calculated from the proportion of deaths occurring among all patients who present to a health care facility with an overdose on the same agent or class of agents. The average Mortality Index for various drugs or drug classes for the years 1989 to 1997 is reported. Because the Mortality Index for desipramine appeared much greater than that for the other tricyclics, a chi-squared analysis was performed. The authors conclude, based on this analysis, that desipramine is significantly more likely to lead to death after overdosage than any other tricyclic antidepressant in the study. Also, the Mortality Index appeared to identify the impact of pediatric formulations on overdose lethality. We conclude that the Mortality Index may be a useful tool for determining the safety of agents during the postmarketing surveillance phase.

Antidepressants and suicide mortality

Background: This paper presents a nationwide analysis of suicide mortality in Finland from 1990 to 1995, when the total use of antidepressants, especially that by selective serotonin reuptake inhibitors (SSRIs) expanded in the country. Methods: Suicide rate was analysed by various methods including that by intake of antidepressants. Various antidepressants were compared by calculating fatal toxicity indices (FTI) by relating number of fatal poisonings by a drug to its consumption. Results: The expanded use of antidepressants coincided with an increased number of deaths caused by these drugs. The proportion of suicides committed by use of antidepressants among all suicides increased from 5.6% to 8.4%. The total suicide rate, however, declined significantly. This was mainly accounted for by the reduced suicide rates by hanging and carbomonoxide poisoning, which outnumbered the increased figures of suicides by poisoning. On the whole, 82% of suicides by antidepressants were committed by use of tricyclics. Use of doxepin and amitriptyline remained steady, and their FTIs were constantly high. The lowest FTIs were associated with fluoxetine, citalopram, mianserin and moclobemide. Limitations: The method ignores causality between the increased use of SSRIs and suicide mortality. Various factors affecting risk of suicide or choice of a method remain outside the scope of the data. Conclusion: The increased use of SSRIs coincided with a significant decline in suicide mortality. However, suicides by use of antidepressants showed an upward trend. Therefore, in suicide prevention, risks and benefits of antidepressants should be considered in choosing treatment for depressive patients.

Can the fatal toxicity of antidepressant drugs be predicted with pharmacological and toxicological data?

Antidepressant drugs are among the most common drugs involved in fatal poisoning and large variations between antidepressant drugs have been noted. Despite the fact that a large number of studies have calculated a fatal toxicity index (FTI) for antidepressants, no serious attempts have been made to compare the differences in fatal toxicity against known pharmacological and toxicological differences in receptor affinity. It is potentially from such data that screening of drugs during their pre-clinical development can be facilitated. We examined correlations between the FTI and noradrenaline (norepinephrine)/serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibition selectivity, the dose that is lethal to 50% of animals (LD50), lipid solubility, and antagonist activity at cholinergic, histaminergic, alpha-adrenergic and gamma-aminobutyric acid (GABA)A receptors or sodium and potassium channel blocking effects. We obtained data on the number of fatal poisonings between 1983 and 1992 in England and Wales caused by a single antidepressant drug from the Department of Health in the UK. This number was divided by the number of prescriptions in England for these drugs over this time to derive a FTI of deaths per million prescriptions. The highest FTIs were for amoxapine, viloxazine, desipramine and dothiepin. Lofepramine, paroxetine and fluoxetine had very low FTIs. Using Poisson regression, there was a significant positive relationship between the FTI of antidepressant drugs and their lethal toxicity in animals, and measures of their cardiac effects. The relative noradrenaline/serotonin reuptake inhibition, lipid solubility and their potency at histamine H1, muscarinic and alpha 1-adrenergic receptors had no substantial association with the FTI. Limited data suggest that some cardiac effects and potency as a GABAA antagonist may be important predictors of significant toxicity. Further data using standardised bio-assays are needed to compare the direct cardiac effects of antidepressants. Thus, the best current pre-clinical indicator of fatal toxicity in humans is the LD50 in animal studies. Clearly, there are humane and practical reasons for developing a better pre-clinical indicator of toxicity in overdose for this rapidly expanding group of drugs.

Moclobemide Safety

Moclobemide is a reversible and selective inhibitor of monoamine oxidase subtype A with a wide spectrum of antidepressant activity. To fully evaluate product safety, Roche Drug Safety has collected data on adverse events (AEs), regardless of causality, from all sources worldwide through the product development phase and after launch. This effort has included analyses of reports from clinical trials, regulatory authorities, the literature, observational studies, and the marketplace. Roche Drug Safety has also carefully examined all cases where moclobemide was taken in overdose, whether with or without other substances. This article presents the safety profile of the product after 3 years on world markets. In clinical trials, moclobemide appeared only slightly less well tolerated than placebo. In comparative trials, moclobemide was largely devoid of the anticholinergic effects associated with tricyclic antidepressants. To the end of June 1993, with an estimated 780,000 subjects exposed, AEs had been reported by less than 0.2% of users. The most frequently reported AEs were psychiatric, neurologic, and gastrointestinal disorders. Hepatobiliary AEs were rare, suggesting that moclobemide is largely devoid of hepatotoxic potential. Cardiovascular AEs reflected the prevalence of cardiovascular disease in the population treated. This safety profile is largely unchanged from those observed at 1 and 2 years postlaunch, when the estimated exposed populations were 168,000 and 328,000, respectively. It is of great significance that the fatal toxicity index of moclobemide is zero. A review of single-drug intoxications with moclobemide at doses of up to 20.55 g revealed no deaths due solely to moclobemide overdose. All patients recovered fully within 1 to 7 days without residual hepatic or cardiovascular toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative toxicity of benzodiazepines in overdose

To assess the sedative effects in overdose of temazepam and oxazepam compared with other benzodiazepines to determine if this explains reported differences in fatal toxicity. Cohort study of patients admitted with benzodiazepine poisoning. Newcastle, Australia. 303 patients who had ingested benzodiazepine alone or in combination with alcohol and presented to a general hospital which served a well defined geographical area. Degree of sedation: Glasgow coma score, McCarron Score, and whether patients were stuporose or comatose. Oxazepam produced less and temazepam more sedation than other benzodiazepines. Unadjusted odds ratios for coma with oxazepam and temazepam compared with other benzodiazepines were 0.0 (95% confidence interval 0.0 to 0.85) and 1.86 (0.68 to 4.77) respectively, chi 2 = 7.08, 2df, P = 0.03. After adjustment for potentially confounding effects of age, dose ingested, and coingestion of alcohol, the odds ratios were 0.22 (0.0 to 1.43) for oxazepam and 1.94 (0.57 to 6.23) for temazepam. Similar results were obtained for other measures of sedation. These results were in accordance with fatal toxicity indices derived from coroners' data on mortality and rates of prescription. The relative safety of benzodiazepines in overdose should be a consideration when they are prescribed.