Fatal toxicity of serotoninergic and other antidepressant drugs

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http://bmj.com/cgi/content/full/325/7376/1332

 

BMJ 2002;325:1332-1333 ( 7 December )

 

PapersFatal toxicity of serotoninergic and other antidepressant drugs: analysis

of United Kingdom mortality data

Nicholas A Buckley, associate professor a, Peter R McManus, pharmacist b.

a Department of Clinical Pharmacology and Toxicology, Canberra Hospital, PO Box

11, Woden, ACT 2606, Australia, b Pharmacy Department, Canberra Hospital

Correspondence to: N A Buckley nick.buckley

 

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 toxicity index: deaths per million prescriptions. 1

2 Greater than 10-fold differences in the index have been shown between

tricyclic antidepressants and even larger differences between some tricyclics

and newer antidepressants. Explanations have focused on preference for

noradrenaline or serotonin reuptake blockade, although only weak correlations

have been observed2 and the explanation is toxicologically implausible.1 In the

late 1990s the use of newer serotoninergic antidepressants increased

dramatically. Some data show that venlafaxine in particular may not be as safe

in overdose as other serotoninergic drugs, with reports of deaths, arrhythmias,

and seizures.3 We aimed to establish the relative frequency with which

venlafaxine and other new antidepressants result in fatal poisoning.

 

 

View this table:

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Fatal toxicity index (deaths per million prescriptions) for antidepressants

ranked within British National Formulary classes

 

 

 

 

Methods and results

 

We obtained the number of deaths in Scotland, England, and Wales due to acute

poisoning by a single drug, with or without co-ingestion of alcohol, from the

General Register Office for Scotland and the Office for National Statistics for

the years 1993-9. We used the number of prescription items for England, Wales,

and Scotland supplied by the respective departments of health for these years as

a measure of relative drug use. Use in hospital is not included, but prescribing

of antidepressants overwhelmingly occurs in general practice. For each drug we

calculated a fatal toxicity index expressed as deaths per million prescriptions.

We calculated the lower and upper 95% confidence limits for the index by using

exact confidence intervals for the deaths.1

 

The table lists the drugs in descending order of fatal toxicity index within

British National Formulary drug classes. The serotoninergic drug class overall

had a much lower index than the tricyclic antidepressants and monoamine oxidase

inhibitors, but venlafaxine had a higher index than the individual and combined

results of other serotoninergic drugs.

 

 

Comment

The most striking new observation is that the fatal toxicity index for

venlafaxine is higher than those for other serotoninergic antidepressants and

similar to those for some less toxic tricyclic antidepressants. This raises the

question of whether venlafaxine should continue to be a first line drug in

patients with suicidal ideation. Our results also confirm previously reported

large differences in fatal toxicity index between other antidepressant drugs. 1

2

 

This sort of analysis is open to several criticisms.1 Using the fatal toxicity

index as a measure of lethality in overdose makes some assumptions, including

that mortality data are not influenced by previous literature and that drugs are

taken in overdose with similar frequency and in similar amounts. The perceived

risk of overdose has the potential to confound by altering several variables.

For example, " less toxic " drugs may be preferentially prescribed to patients at

higher risk of poisoning and suicide,4 but they are also less likely to be

listed as the sole cause of death from overdose.

 

Toxicity in overdose should be an important consideration in the choice of first

line treatment but should be based on data for each individual drug and not on

the therapeutic class or on measures such as serotonin or noradrenaline

selectivity that do not directly lead to toxicity in overdose. Poisoning with

antidepressants accounts for only about 4-7% of all suicides, but the proportion

of suicides from antidepressant poisoning in people prescribed antidepressants

is much higher.5 Assuming that an average prescription is for one month's

treatment, the fatal toxicity index of venlafaxine suggests that it will cause a

death from poisoning about every 6000 patient years of use. Clinicians need to

consider whether factors in their patients reduce or compensate for this risk

before prescribing venlafaxine.

 

Acknowledgments

We thank Zoe Uren of the Office for National Statistics; Graham Jackson of the

General Register Office for Scotland; Bill Gold of ISD, Primary Care Information

Unit, Scotland; Andy Savva of the Statistics Division of the Department of

Health, England; and Sandra Hennefer, information officer at Health Solutions,

Wales, for supplying the data on which this analysis is based.

 

Contributors: NB drafted the paper and performed the statistical analyses. Both

authors performed data extraction, wrote the paper, and agreed on the final

version. NB is the guarantor.

Footnotes

Funding: None.

 

Competing interests: None declared.

 

References

1. Buckley NA, McManus PR. Can the fatal toxicity of antidepressant drugs be

predicted with pharmacological and toxicological data? Drug Saf 1998; 18:

369-381[iSI][Medline]. 2. Henry JA, Alexander CA, Sener EK. Relative mortality

from overdose of antidepressants. BMJ 1995; 310: 221-224[Abstract/Free Full

Text]. 3. Sarko J. Antidepressants, old and new: a review of their adverse

effects and toxicity in overdose. Emerg Med Clin North Am 2000; 18:

637-654[iSI][Medline]. 4. Isacsson G, Redfors I, Wasserman D, Bergman U. Choice

of antidepressants: questionnaire survey of psychiatrists and general

practitioners in two areas of Sweden. BMJ 1994; 309: 1546-1549[Abstract/Free

Full Text]. 5. Owens D, Dennis M, Read S, Davis N. Outcome of deliberate

self-poisoning: an examination of risk factors for repetition. Br J Psychiatry

1994; 165: 797-801[Abstract].

 

 

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