Prescriptions

Data on antidepressant prescriptions dispensed in the community in the form of quarterly estimates for years 2000 to 2006 for the UK were obtained from the Medical Data Index and supplied by IMS Health Inc (www.imshealth.com). Data were for people of all ages. Mid-year population estimates for the UK for 2000–2006 were obtained from the Office for National Statistics. ¹¹ Rates of prescribing were calculated per 100 000 population, for people of all ages, for the years 2000–2006 combined.

Deaths

Information on drug-poisoning deaths receiving a verdict of suicide or death of undetermined intent that involved the antidepressants under investigation was provided by the Office for National Statistics, based on death registrations during 2000–2006 in England and Wales. In England and Wales it has been customary to assume that the majority of injuries and poisonings of undetermined intent are cases where the harm was self-inflicted but there was insufficient evidence to prove that the deceased intended to kill themselves. ^{Reference Adelstein and Mardon12,Reference Brock, Baker, Griffiths, Jackson, Fegan and Marshall13} We have restricted our analyses to deaths involving single drugs or single drugs and alcohol. Data were obtained for males and females separately for all drugs. Mortality rates were calculated as the number of deaths per 100 000 population in England and Wales, for people aged 10 years and over.

Self-poisoning

Self-poisoning data came from three centres currently involved in the Multicentre Monitoring of Self-harm project (see Hawton et al ^{Reference Hawton, Bergen, Casey, Simkin, Palmer and Cooper2} for a description of the first phase of this project). Data were collected on all people who presented with self-harm to emergency departments at general hospitals in Oxford (one hospital), Manchester (three hospitals) and Derby (two hospitals) during the study period. Self-harm is defined as intentional self-poisoning or self-injury, irrespective of motivation. ^{Reference Hawton, Harriss, Hall, Simkin, Bale and Bond14} Self-poisoning includes the intentional ingestion of more than the prescribed amount of any drug, or other non-ingestible substance, whether or not there is evidence that the act was intended to result in death. Data were collected on gender, age, date of self-harm and method of self-harm, including which drug(s) were ingested in overdoses. The analyses for non-fatal self-poisoning were based on all non-fatal overdoses of the antidepressants, including those with other drugs (with or without alcohol).

Episodes of self-poisoning involving the antidepressants for people aged 10 years and over for the defined population areas of Oxford City (mean annual population 128 411), Manchester City (381 236) and Derby Unitary Area (204 032) were included in the study. Mid-year population estimates for these areas for 2000–2006 were obtained from the Office for National Statistics. ¹¹ Rates of self-poisoning per 100 000 population were calculated for these areas combined.

Statistical analysis

Ethical approval

Oxford and Derby both have approval from local health/psychiatric research ethics committees to collect data on self-harm for local monitoring and multicentre projects. Self-harm monitoring in Manchester is part of a clinical audit system, and has been ratified by the local research ethics committees. All monitoring systems are fully compliant with the provisions of the Data Protection Act of 1998. All centres also have approval under Section 251 of the National Health Service Act 2006 (formerly section 60 of the Health and Social Care Act 2001) regarding the use of patient identifiable information.

Fatal toxicity index (mortality to prescriptions ratio)

There was significant heterogeneity in fatal toxicity within the TCA group (χ² = 365.02, d.f. = 6, P<0.001). The mortality to prescriptions rate ratio was considerably higher for dosulepin and doxepin than for amitriptyline (Table 2). This is reflected in the toxicity ratios relative to amitriptyline for these drugs (dosulepin 3.2, doxepin 2.5). The fatal toxicity ratios were generally far higher in males than females but the relative toxicity indices were mostly similar in males and females.

Table 2 Fatal toxicity: rate ratios and relative toxicity indices for individual antidepressants based on rates of death (suicide and undetermined intent) in England and Wales, and prescription rates in the UK

	Both genders		Males		Females
	Rate ratio (95% CI)	Relative toxicity indexa	Rate ratio (95% CI)	Relative toxicity indexa	Rate ratio (95% CI)	Relative toxicity indexa
TCAs
Amitriptyline	11.4 (10.3-12.6)	1.0	20.3 (17.7-23.2)	1.0	7.5 (6.5-8.7)	1.0
Clomipramine	14.1 (10.0 -19.3)	1.2	15.9 (8.4-27.1)	0.8	13.3 (8.7-19.5)	1.8
Dosulepin	36.3 (33.4-39.3)	3.2	70.5 (62.9-78.8)	3.5	23.3 (20.6-26.2)	3.1
Doxepin	28.1 (17.6-42.6)	2.5	60.1 (32.0-102.7)	3.0	15.9 (7.3-20.1)	2.1
Imipramine	12.4 (8.1-18.4)	1.1	17.0 (8.5-30.4)	0.8	10.2 (5.6-17.2)	1.4
Nortriptyline	9.9 (3.2-23.2)	0.9	0	—	13.3 (4.3-31.0)	1.8
Trimipramine	15.0 (8.0-25.6)	1.3	35.1 (15.2-69.2)	1.7	7.8 (2.5-18.1)	1.0
All seven TCAs	18.8 (17.7-20.0)	1.7	33.7 (31.0-36.5)	1.7	12.6 (11.6-13.8)	1.7
SNRI: venlafaxine	5.3 (4.2-6.6)	0.46	8.7 (6.4-1.6)	0.43	3.5 (2.5-4.9)	0.47
NaSSA: mirtazapine	3.6 (2.1-5.7)	0.32	4.1 (1.8-8.1)	0.20	3.3 (1.6-6.0)	0.44
SSRIs
Citalopram	1.7 (1.3-2.3)	0.15	3.3 (2.2-4.7)	0.16	1.0 (0.6-1.6)	0.14
Fluoxetine	0.5 (0.3-0.9)	0.05	0.6 (0.2-1.3)	0.03	0.5 (0.3-1.0)	0.07
Fluvoxamine	0	0	0	0	0	0
Paroxetine	0.5 (0.2-0.9)	0.04	1.1 (0.4-2.2)	0.05	0.2 (0.05-0.6)	0.03
Sertraline	0.7 (0.3-1.3)	0.06	1.1 (0.3-2.7)	0.05	0.5 (0.1-1.2)	0.06
All five SSRIs	0.9 (0.7-1.1)	0.08	1.6 (1.2-2.1)	0.08	0.6 (0.4-0.8)	0.08

The relative toxicity index for venlafaxine (0.46) was approximately half that for amitriptyline but over five times higher than that for the SSRIs (0.08). The relative toxicity index for mirtazapine (0.32) was slightly lower than that of venlafaxine.

There was significant heterogeneity in fatal toxicity within the SSRI group (χ² = 28.76, d.f. = 4, P<0.001). The fatal toxicity index for citalopram was three times higher than that for the other SSRIs (1.7, 95% CI 1.3–2.3 v. 0.6, 95% CI 0.4–0.8), with a threefold higher relative toxicity index (0.15 v. 0.05).

Case fatality (mortality to self-poisonings ratio)

There was significant heterogeneity in the relative toxicity within the TCA group (χ² = 123.01, d.f. = 6, P<0.001). The mortality to self-poisonings rate ratio was significantly higher for dosulepin and doxepin than amitriptyline (Table 3). The relative toxicity indices for both dosulepin and doxepin suggest that these are two to three times more toxic than amitriptyline. There was a particularly high relative toxicity index for doxepin in females and for trimipramine in males (although the 95% CIs for the rate ratios were wide).

Table 3 Case fatality: rate ratios and relative toxicity indices for individual antidepressants based on rates of death (suicide and undetermined intent) in England and Wales, and rates of non-fatal self-poisoning in three centres

	Both genders		Males		Females
	Rate ratio (95% CI)	Relative toxicity indexa	Rate ratio (95% CI)	Relative toxicity indexa	Rate ratio (95% CI)	Relative toxicity indexa
TCAs
Amitriptyline	8.6 (7.8-9.5)	1.0	11.0 (9.5-12.5)	1.0	6.9 (5.9-8.0)	1.0
Clomipramine	12.5 (8.9-17.0)	1.4	20.3 (10.8-34.7)	1.9	10.3 (6.7-15.1)	1.5
Dosulepin	23.3 (21.4-25.2)	2.7	29.6 (26.4-33.1)	2.7	18.6 (16.5-21.0)	2.7
Doxepin	22.5 (14.1-34.0)	2.6	18.5 (9.8-31.6)	1.7	33.9 (15.5-64.3)	4.9
Imipramine	12.8 (8.3-18.9)	1.5	19.1 (9.5-34.2)	1.7	10.0 (5.5-16.8)	1.5
Nortriptyline	11.0 (3.6-25.5)	1.3	0	-	18.8 (6.1-43.9)	2.7
Trimipramine	14.2 (7.8-24.3)	1.7	62.5 (27.0-123.1)	5.7	6.3 (2.0-14.6)	0.9
All seven TCAs	13.8 (13.0-14.7)	1.6	17.7 (16.3-19.2)	1.6	11.1 (10.2-12.1)	1.6
SNRI: venlafaxine	2.5 (2.0-3.1)	0.29	4.0 (2.9-5.3)	0.36	1.7 (1.2-2.3)	0.25
NaSSA: mirtazapine	1.9 (1.1-2.9)	0.22	2.4 (1.0-4.7)	0.20	1.6 (0.7-2.9)	0.23
SSRIs
Citalopram	1.1 (0.8-1.4)	0.12	1.8 (1.2-2.5)	0.12	0.7 (0.4-1.1)	0.10
Fluoxetine	0.3 (0.2-0.5)	0.03	0.3 (0.1-0.6)	0.02	0.3 (0.2-0.5)	0.04
Fluvoxamine	0	0	0	0	0	0
Paroxetine	0.3 (0.1-0.5)	0.03	0.5 (0.2-1.0)	0.05	0.1 (0.03-0.4)	0.02
Sertraline	0.4 (0.2-0.8)	0.05	0.6 (0.2-1.5)	0.05	0.3 (0.08-0.7)	0.04
All five SSRIs	0.5 (0.4-0.7)	0.06	0.8 (0.6-1.1)	0.07	0.4 (0.3-0.5)	0.05

The relative toxicity index for venlafaxine (0.29) was much lower than for the TCAs (1.6). However, it was considerably greater than for the SSRIs (0.06). The relative toxicity index for mirtazapine (0.22) was slightly lower than that of venlafaxine, although no different in females.

There was significant heterogeneity in relative toxicity in the SSRI drug group (χ² = 33.88, d.f. = 4, P<0.001). Citalopram had a higher case fatality than the other four SSRIs (1.1, 95% CI 0.8–1.4 v. 0.3, 95% CI 0.2–0.4), which was reflected in a threefold greater relative toxicity index (0.12 v. 0.04).

Comparison of fatal toxicity and case fatality

There was a very high correlation between the rankings of the results of the fatal toxicity and case fatality approaches to estimating relative toxicity of the specific antidepressants (Spearman's rho = 0.99, P<0.001).

Limitations and strengths of the study

One limitation is that data for different factors were derived from different areas: prescribing for the UK, deaths for England and Wales, and non-fatal poisonings for three local centres. We have made the assumption that they are all reasonably representative of the UK. This may be a particular limitation for the data on non-fatal self-poisonings, especially as the catchment areas used in this study are cities. We have commented elsewhere about differences in self-poisoning rates relative to prescribing patterns in the three centres. ^{Reference Bergen, Murphy, Cooper, Kapur, Stalker and Waters19} These were limited and unlikely to substantially bias our overall findings. The populations of all three centres include people from a wide range of socioeconomic backgrounds.

For fatal self-poisoning we have focused on single antidepressant overdoses (with or without alcohol), in order to avoid cross-contamination of the results with other drugs. However, certain antidepressants may be more toxic in overdose when combined with other drugs (e.g. doxepin and amitriptyline). ^{Reference Koski, Ojanperä and Vuori20} Also, we have not been able to take account of the size of overdoses, which may be influenced by local prescribing practices and use of antidepressants for indications other than depression (especially when lower doses may be used). For non-fatal self-poisonings we included both episodes of single drugs and those involving other drugs. The non-fatal self-poisonings are based on episodes that resulted in presentation to hospital. There are likely to be other cases where self-poisoning does not result in hospital presentation, ^{Reference Hawton, Rodham, Evans and Weatherall21} so that the case fatality rates may be overestimated. The prescription data we used were only available for all ages.

One factor that could influence the findings is differential use of specific antidepressants in overdoses, which is likely to reflect differences in indications used when they are prescribed. Elsewhere we have confirmed that this is the case for venlafaxine; which tends to be more often prescribed for, and taken in overdose by, people with longer-term psychiatric disorders and a history of self-harm. ^{Reference Bergen, Murphy, Cooper, Kapur, Stalker and Waters19}

The international applicability of the findings may be limited because of differences in regulatory advice, availability of specific antidepressants and prescribing practices between countries. Therefore country-specific and international comparative studies are warranted.

A major strength of the study is that we have used two approaches to assessing relative toxicity, the findings of which are remarkably similar. The data on non-fatal self-poisoning have come from three well-established monitoring systems. Also, by using 7 years of data the study has considerable statistical power.

Implications

Of the TCAs, dosulepin and doxepin have the greatest toxicity based on overdose deaths both relative to prescriptions and relative to non-fatal self-poisonings. Venlafaxine appears to be far less toxic that the TCAs but more toxic than the SSRIs and slightly more toxic than mirtazapine. Of the five SSRIs that we examined, citalopram appears to be more toxic than the other four. When prescribing antidepressants the clinician should take account of the risk that may be associated with an overdose, especially in someone judged to be at risk of self-poisoning, as well as relative efficacy, acceptability and possible interactions with other medication and alcohol, and concurrent physical morbidity. We suggest that the assessment of the relative toxicity of antidepressants should continue as new antidepressants are marketed and that international comparisons are warranted in view of differences between countries in prescribing practices.