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Relative Mortality from Overdose Ofantidepressants

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Relative Mortality from Overdose Ofantidepressants 12 Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI. Pharmacokinetic 16 Forrest ARW, Marsh I, Bradhaw C, Braich SK. Fatal temazepam overdoses. determinants of dynamic differences among three benzodiazepine Lancet 1986;ii:226. hypnotics. Arch Gen Psychiatr 1989;46:326-32. 17 Martin CD, Chan SC. Distribution oftemazepam in body fluids and tissues in 13 Mitler MM. Evaluation of temazepam as a hypnotic. Pharmacotherapy lethal overdose. JAnal Toxicol 1986;10:77-8. 1981;1:3-13. 18 Buckley NA, Dawson AH, Whyte IM, McManus P, Ferguson N. Correlations 14 Alexander B, Perry PJ. Detoxification from benzodiazepines: schedules and between prescriptions and drugs taken in self-poisoning: Implications for strategies.JSubstAbuse Treat 1991;8:9-17. prescribers and drug regulation. MedJAust (in press). 15 Crome P. The toxicity oif drugs used for suicide. Acts Psychiaer Scand 1993;371(suppl):33-7. (Accepted 23 November 1994) Relative mortality from overdose ofantidepressants John A Henry, Carol A Alexander, Ersin K Sener Abstract due to acute poisoning by a single antidepressant.4' Objective-To compare the fatal toxicities of The statistics and research division of the Department antidepressant drugs in 1987-92. of Health supplied data on the number of anti- Design-Retrospective epidemiological review of depressant prescriptions for general medical practices prescription data of the Department of Health, within the NHS for England, Wales, and Scotland for Scottish Office Home and Health Department, and 1987-9 and for England for 1990-2; for 1990-2 the Welsh Health Common Services Authority (exclud- Scottish data were provided by the Scottish Office ing data from most private general practices and Home and Health Department and the Welsh data most hospitals), and mortality data from the Office by the Welsh Health Common Services Authority. of Population Censuses and Surveys and General Private general practice and most hospitals were Register Office in Scotland. excluded; figures for 1991 and 1992 include dispensing Setting-General practice, England, Scotland, practices. About three quarters of all drug prescrip- and Wales. tions are written by general practitioners.6 7 Most Main outcome measures-Deaths per million pre- patients with psychiatric disorders, however, are scriptions and deaths per defined daily dose. treated by general practitioners rather than by psy- Results-816% (1310/1606) of deaths from anti- chiatristsS" (90% to 98% ofdepressed patients"`). The depressant overdose were due to two drugs, amitrip- exclusion of hospital prescriptions from our analysis tyline and dothiepin. The overall average of deaths should not, therefore, appreciably affect the outcome per million prescriptions was 30-1. The overall ofthis study. rate for tricyclic drugs was 34-14 (95% confidence We calculated the number of deaths per million interval 32*47 to 38-86; P<0-001), monoamine prescriptions during the six years for all the drugs oxidase inhibitors 13*48 (6-93 to 22-19; P<0.001), taken together; for each of the four groups of anti- atypical drugs 6-19 (404 to 8*80; P<0-001), and depressants; and for each drug individually. The X2 test selective serotonin reuptake inhibitors 2.02 (0.64 to was applied to the groups of antidepressants. The 4*17; P<0-001). The numbers of deaths- per million expected numbers of deaths are given for the indi- prescriptions of amoxapine, dothiepin, and ami- vidual drugs, with Fisher's exact test (one tailed) triptyline were significantly higher than expected, applied to the data. Confidence limits are calculated as while nine drugs had a significantly lower number of x± 196 SD(x). deaths per million prescriptions than expected. Using the prescribed data, we considered each Analysis of deaths per defined daily dose showed a preparation of each drug analysed, multiplied the similar pattern. strength of the preparation by the quantity prescribed, Conclusions-Safety in overdose should be con- and divided this by the defined daily dose values sidered in risk-benefit and cost-benefit consider- (obtained from the World Health Organisation)."'3 ations of antidepressants. A switch in prescribing, We calculated the number of defined daily doses per from drugs with a high number ofdeaths per million prescription for each drug and the number of deaths prescriptions to drugs with a low number, could per million defined daily doses prescribed. reduce the numbers of deaths from overdose. Although this form of suicide prevention can be Results implemented easily and immediately, its intro- duction needs to be considered against the higher The mean annual number of deaths due to overdose costs ofsome ofthe newer drugs. with a single antidepressant over the six years was 268 (range 238 to 288). The tricyclic drugs were implicated in most deaths (table I), with two drugs- Introduction amitriptyline and dothiepin-accounting for 81-6% of While little demonstrable difference exists between all deaths. Tables II and III show the figures for antidepressants in terms of efficacy,' toxicity in over- mortality and data for prescriptions for deaths per dose varies widely.' We compared the fatal toxicities of million prescriptions for the four groups of drugs for National Poisons Unit, the six years. The tricyclic antidepressants as a group Guy's Hospital, London antidepressants currently available in Britain individu- SEI 9RT ally and by group during 1987-92, during which time TABLE i-Mean yearly numbers of deaths from tricyclic and other John A Henry, consultant the selective serotonin reuptake inhibitors were intro- antidepressants, 1987-92 physician duced. Carol A Alexander, research Death from Death from assistant tricyclic non-tricyclic Ersin K Sener, research Methods Cause ofdeath drugs drugs fellow Antidepressants were assigned to four classes: Suicide with single antidepressant 150 4 Suicide with more than one substance, including Correspondence to: monoamine oxidase inhibitors, tricyclic antidepres- antidepressants 240 10 Dr Henry. sants, selective serotonin reuptake inhibitors, and the Overdose with single antidepressant 260 12 Overdose with more than one substance, so called "atypical"3 antidepressants. We obtained including antidepressants 424 24 BM7 1995;310:221-4 numbers of deaths in England, Wales, and Scotland BMJ VOLUME 310 28jANuARY 1995 221 had a significantly higher number of deaths per million drugs (mianserin and trazodone) had a significantly prescriptions than expected compared with all the lower number of deaths per million prescriptions. antidepressants taken together (P < 000 1). The mono- Three of the selective serotonin reuptake inhibitors amine oxidase inhibitors as a group had a lower than (fluoxetine, fluvoxamine, and paroxetine) had a lower expected number of deaths per million prescriptions number of deaths per million prescriptions. No deaths (P < 000 1). The groups ofatypical antidepressants and were recorded for five drugs, all of which had low selective serotonin reuptake inhibitors each had the prescription figures (table III). Calculation ofdata with lowest number of deaths per million prescriptions defined daily doses showed a pattern that was broadly (P<0-001). Tables IV and V list each drug in each similar to the data derived from deaths per million group with its number of deaths per million prescrip- prescriptions. tions, which is used to rank them within groups, and shows that three of the tricyclic agents (dothiepin, amitriptyline, and amoxapine) had a significantly Discussion higher number of deaths per million prescriptions than The atypical antidepressants form a heterogeneous expected. A further three drugs from this group group of drugs, while the other antidepressants fall (lofepramine, clomipramine and trimipramine) had into three pharmacologically homogeneous groups. a significantly lower number of deaths per million The selective serotonin reuptake inhibitors share a prescriptions than expected when compared with all common mechanism of action, despite their remark- antidepressants. One monoamine oxidase inhibitor ably differing chemical structures (fluvoxamine is (phenelzine) had a significantly lower number of a monocyclic agent, fluoxetine a bicyclic agent, sertra- deaths per million prescriptions. Two of the atypical line a naphthylamine derivative, and paroxetine a phenyl piperidine derivative). They also had the lowest TABLE iI-Fatal poisonings and deaths per million prescriptions for deaths from single antidepressant, by toxicity in overdose of the groups of drugs studied groups ofdrug. Values in parentheses are 95% confidence intervals here. This accords with clinical experience.'"'7 The numbers of deaths per million prescriptions of anti- No of Observed Expected prescriptions depressants have been shown to be inversely related to deaths deaths (millions) Deaths per million their serotonin reuptake inhibition activity,'8 but this Antidepressant 1987-92 1987-92 1987-92 X2value prescriptions 1987-92 relation may be coincidental with their structural Tricyclicdrugs 1563 1378 45-78 24-80 4 14 (34-47 to 35-86)* properties. Monoamine oxidase inhibitors 12 27 0-89 8-17 13-48 (6-93 to 2219)* Shortcomings of a study of this nature include Atypical drugs 26 126 4-20 79-78 6-19 (4 04 to 8 80)* Selective serotonin reuptake inhibitors 5 75 2-48 64-99 2-02 (0-64 to 4-17) systematic error in prescription or mortality data, or All antidepressants 1606 1606 53-35 30-10 both; confounding by prescriber biases or patient *P < 0-05 P < 0-001 (difference from all by test). biases-such as, an inability
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