Antidepressants and suicide: what is the balance of benefit and harm

August 20, 2004

BMJ 2004;329:34-38 (3 July), doi:10.1136/bmj.329.7456.34

Gunnell, professor of epidemiology1, Deborah Ashby, professor

of medical statistics2

1 Department of Social Medicine, University of Bristol, Bristol BS8

2PR, 2 Wolfson Institute of Preventive Medicine, Barts and the

London, Queen 's School of Medicine and Dentistry, University of

London, London EC1M 6BQ

Correspondence to: D Gunnell d.j.gunnell@...

Introduction

Top

Introduction

Is increased prescribing linked...

Time trends

Toxicity

Do antidepressants increase the...

Conclusions

References

Prescribing of antidepressants has increased greatly in England and

elsewhere in recent years.1-3 This increase has coincided with a

fall in rates of suicide, leading some researchers to suggest a

causal association.2 4-6 Meanwhile, others are concerned that

antidepressants may precipitate suicidal behaviour.7 8 A recent

review of evidence from paediatric trials by the Committee on Safety

of Medicines in Britain led to most selective serotonin re-uptake

inhibitors (SSRIs) being contraindicated in people aged younger than

18.9 So how safe are they? In this article, we assess the data on

the risks and benefits.

Is increased prescribing linked to reduced suicide rates?

Top

Introduction

Is increased prescribing linked...

Time trends

Toxicity

Do antidepressants increase the...

Conclusions

References

SSRIs and tricyclic antidepressants account for over 90% of

antidepressant prescribing in Britain. Systematic reviews confirm

that both these classes of antidepressant are effective in adults,10

although SSRIs are better tolerated by patients.11 The effectiveness

of antidepressants in childhood and adolescence is less clear.12

As depression is the main psychiatric condition leading to suicide,

it seems reasonable to infer that rises in antidepressant

prescribing, which indicate improved management of depression,

should have a beneficial effect on suicide rates. Indeed, an

intervention to improve general practitioners' management of

depression in a Swedish community resulted in increased

antidepressant prescribing and a short term reduction in suicide.13

Summary points

Concern is growing that serotonin reuptake inhibitors (SSRIs) may

precipitate suicidal behaviour, especially in children

Reassuringly, although antidepressant prescribing in Britain has

more than doubled in the past 15 years, population suicide rates

have fallen.

If the risks of SSRI associated suicidal behaviour seen in children

were to apply to suicide in adults, the number of " antidepressant

induced " suicides would be small enough to be masked by currently

favourable suicide trends

Long term studies are required to assess the risks and benefits to

population health of recent large scale rises in antidepressant

prescribing.

Surprisingly, direct evidence that antidepressants prevent suicide

is hard to find. A meta-analysis of data on the SSRI fluoxetine,

funded by its manufacturer, found no evidence that suicidal acts

were less frequent among adults taking antidepressants; the pooled

incidences were 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for

tricyclics.14 In the most comprehensive synthesis of data from

randomised trials, Khan and colleagues found no evidence of a

beneficial effect of antidepressants on suicide.15 These findings

are difficult to interpret as this was not a formal meta-analysis

and relative risks were not derived separately for each trial on an

intention to treat basis.

Suicide is rare, even among people with depression.16 Thus, most

clinical trials have insufficient power to provide clear evidence on

the effect of antidepressants on suicide.

Time trends

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Introduction

Is increased prescribing linked...

Time trends

Toxicity

Do antidepressants increase the...

Conclusions

References

In the absence of clear evidence from clinical trials, researchers

have investigated whether rises in antidepressant prescribing are

associated with reductions in population suicide rates.2-6 17-19

With some exceptions,3 17 18 such studies conclude that recent rises

in prescribing have contributed to falls in suicides. Interpretation

of these findings is not straightforward. A range of factors

influence population suicide rates.19 It is therefore challenging to

distinguish the discrete effects of increased antidepressant

prescribing from changes in other risk factors.

Furthermore, declining overall suicide trends may mask rises in some

age and sex groups.19 In Australia, recent rises in antidepressant

prescribing were associated with falls in suicide among some age and

sex groups but increases in others.4 In Britain, declines in suicide

preceded increases in prescribing (see fig A on bmj.com) and rises

in antidepressant prescribing since 1991 in different age and sex

groups do not consistently coincide with clear changes in previous

suicide trends (fig 1). The levelling out of suicide trends in young

men is probably due to a fall in suicide by self poisoning with car

exhaust because of reductions in the carbon monoxide content of

exhaust gases.20

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Fig 1 Trends in suicide and undetermined death rates (England and

Wales) and prescribing of antidepressants (United Kingdom) by age

and sex

Toxicity

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Introduction

Is increased prescribing linked...

Time trends

Toxicity

Do antidepressants increase the...

Conclusions

References

The possible benefits of increases in SSRI prescribing are not

limited to their effect on depression. Self poisoning accounts for

around a quarter of suicides in England; 20% of these deaths are

antidepressant overdoses.21 Tricyclic antidepressants are

considerably more toxic in overdose than SSRIs.21 Consequently, it

has been estimated that a switch from tricyclics to SSRIs as first

line treatment for depression could prevent 300-450 overdose deaths

a year through restricting access to the more toxic

antidepressants.22 Of note, increased SSRI prescribing has not been

accompanied by a fall in use of tricyclics (fig 2).

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Fig 2 Trends in the number of antidepressant prescriptions issued

1980-2002, England

Do antidepressants increase the risk of suicide?

Top

Introduction

Is increased prescribing linked...

Time trends

Toxicity

Do antidepressants increase the...

Conclusions

References

Soon after the launch of fluoxetine, the most commonly prescribed

SSRI, a series of reports were published suggesting worsening of

depression and emergence of suicidal thoughts in some people.23 24

The issue has been hotly debated.7 8 Disentangling the evidence is

problematic as much of the research is sponsored by the

pharmaceutical industry.25 Review of data from paediatric trials of

SSRIs shows that published findings present a more favourable risk-

benefit profile than unpublished trials sponsored by industry.12

Table 1 summarises the evidence from clinical trials on the adverse

effects of SSRIs on suicidal behaviour in children, abstracted from

information recently released by the Medicines and Healthcare

Products Regulatory Agency.26 No suicides occurred in these trials.

The pooled estimate of increased risk of suicidal thoughts or

behaviour from these data is 1.66 (95% credibility interval 0.83 to

3.50). Interpretation of this apparent increase in risk is

problematic as people taking SSRIs may be more likely to report

adverse effects, perhaps because the drugs could have a

disinhibiting effect. In addition, response to treatment may lead to

reactivation among people whose depression previously prevented them

from acting on suicidal impulses.27 Furthermore, any increased risk

may be counterbalanced by a longer term reduction in suicidal

behaviour; such benefits would not detected in the trials as they

generally lasted 10 weeks or less, whereas the mean duration of

treatment in clinical practice is three to four months.28

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Table 1 Risk of suicidal behaviour associated with use of SSRIs

to treat depression in children and adolescents26

Reassuringly, time trends for suicide (England and Wales)29 and non-

fatal self harm (Oxford)30 in children and adolescents provide no

consistent evidence of adverse trends paralleling increased

prescribing in the 1990s, although there is some evidence of a rise

in non-fatal self harm in young females. Furthermore, in the United

States, recent research suggests that areas with the largest

increases in antidepressant prescribing to 10-19 year olds

experienced the greatest falls in suicide.6

Modelling the effect

There are two reasons why an adverse effect of antidepressants on

suicide risk may have been overlooked in adult clinical trials.

Firstly, self harm, and fatal self harm in particular, is relatively

rare, and most clinical trials lack power to detect any increased

risk. Secondly, as it seems counterintuitive that treatments for

depression might increase suicide risk, the possibility may not have

been specifically investigated in the clinical trials. The increased

risk in children may have been detected either because of the

increased prevalence of suicidal thoughts and self harm in young

people (giving greater power) or because the absence of beneficial

effects12 meant that adverse effects dominated the clinical picture.

If rare adverse effects of antidepressants on suicide exist, recent

large scale increases in prescribing might be expected to affect

suicide trends. But, as detailed above, recent suicide trends have

generally been favourable, and so it is likely either that benefits

outweigh the risks in adults or that any excess risk is small.

Nevertheless, antidepressants may have precipitated some suicides in

susceptible individuals, and it is important to estimate the number

of such deaths. Table 2 outlines a model to estimate the number of

excess deaths that may have occurred in 2002 compared with 1991 as a

result of their increased use in England.

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Table 2 Model of possible excess suicides in 2002 compared to

1991 as a result of increased antidepressant prescribing (assumes

findings from paediatric trials apply to adults and additional

assumptions listed in text)

The model is based on the worst case scenario that the findings in

relation to non-fatal self harm in paediatric trials are applicable

to suicide deaths in adults. Under the model's assumptions (see

bmj.com) an excess of 388 suicides (95% credibility interval-202 to

704) (233 men and 155 women) may have occurred in 2002 compared with

1991 as a result of increased anti-depressant prescribing. This is

equivalent to an annual increase of around 35 suicides since 1991

(0.8% of the roughly 4500 annual suicides in England). Such a small

increase may have been masked by other favourable influences on

suicide.

The credibility intervals of our estimated increase in suicides (-

202 to 704) include the possibility of a null or beneficial effect

of SSRIs. Furthermore, some of our model assumptions are likely to

result in us overestimating possible SSRI associated suicides.

Firstly, there is no evidence that the findings from the paediatric

trials can be extrapolated to adults, nor indeed that the strength

of associations are the same for fatal and non-fatal self harm.

Furthermore, the relative risk we used in our main model is based on

findings from trials generally lasting 10 weeks or less, whereas the

recommended duration of treatment is six months or more.32 Any

increased suicide risk early in treatment may be offset by longer

term improvements in suicide risk.

Secondly, we will have overestimated person time at risk because not

all dispensed prescriptions are used and we have not taken account

of the fact that (any) antidepressant associated increased risk of

suicide may be concentrated in the early weeks of treatment. A

sizeable proportion of people prescribed the drugs are long term

users or have been taking antidepressants for two months or more and

may therefore not be at risk of side effects.

Lastly, we assumed that suicide rates among those receiving

antidepressants in 2002 are similar to those in the late 1980s and

early 1990s.16 Recent increases in prescribing are likely to have

occurred among people with less severe depressive illness and

therefore a lower absolute suicide risk. The balance of risk and

benefits may be different in this patient group. Our estimate of

suicide rates among those treated with antidepressants is, however,

some five times lower than that reported in one study.15 A

sensitivity analysis of our model assumptions is presented on

bmj.com.

Conclusions

Top

Introduction

Is increased prescribing linked...

Time trends

Toxicity

Do antidepressants increase the...

Conclusions

References

There is no strong evidence that increases in antidepressant

prescribing lie behind recent reductions in population suicides.

Furthermore, data from paediatric trials suggest that SSRIs are

associated with an increased risk of suicidal behaviour and most

SSRIs seem to be ineffective for childhood depression. However,

current concerns about the safety of SSRIs come from clinical trials

both of too short duration (< 10 weeks) to identify longer term

beneficial effects and are carried out in children and adolescents,

among whom suicide is rare.

From the population perspective, the balance sheet of risks and

benefits of SSRIs is unclear. Any antidepressant induced suicides

may be offset by the beneficial effects of antidepressants on

depression and long term suicide risk associated with untreated

depression. The low toxicity of SSRIs in overdose will have

prevented some suicides. The balance of risks and benefits may vary

depending on an individual's underlying suicide risk. For patients

with conditions that have a high risk of suicide, such as severe

depression,33 the risk-benefit balance may be more favourable than

for patients with conditions such as anxiety and mild depression, in

which suicide is rare. It is in these lower risk conditions,

however, that much of the recent rise in prescribing has probably

occurred.

Depression is a common and disabling condition, and so the safety of

drugs used in its management is crucial. Future trials of

antidepressants should be of sufficient duration to detect longer

term benefits of this class of drug and balance these against

possible risks. They should also systematically collect data on

suicidal thoughts and behaviour. Long term studies are required to

assess the effect on population health of recent rises in

antidepressant prescribing.

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A figure showing trends in suicide and prescribing plus further data

on the model are on bmj.com

We thank Ian Weller and Davey for critical comments on

the paper, IMS Health for the age specific prescribing data, the

Department of Health for prescribing data, Lesley Wise for critical

comments and helpful discussions on our model, and Shahrul Mt Isa,

for help with calculating the confidence intervals.

Contributors and sources: DG has a longstanding research interest in

the epidemiology and prevention of suicide. DA has a longstanding

research interest in drug safety and bayesian modelling. The idea

for the paper arose from their joint work on the Medicines and

Healthcare Products Regulatory Agency's Expert Working Group on

SSRIs. DG wrote the first draft of the article and undertook

literature reviews; DA performed the statistical modelling. Both

authors contributed to the final content of the paper and will act

as guarantors.

Competing interests: DG and DA are members of the Medicines and

Healthcare Products Regulatory Agency's expert working group on the

safety of SSRIs and DA is a member of the Committee on Safety of

Medicines. We act as independent advisers, receiving travel expenses

and a small fee for attending meetings and reading materials in

preparation for the meeting. DA has spoken on the methodology of

adverse drugs reactions in HIV at a scientific meeting attended by

several pharmaceutical companies, and sponsored by GlaxoKline.

An honorarium was paid to her department.

References

Top

Introduction

Is increased prescribing linked...

Time trends

Toxicity

Do antidepressants increase the...

Conclusions

References

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(Accepted 11 June 2004)

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[Full Text]

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G. Aldred and D. Healy

Antidepressants and suicide: Rising prescription rate does not mean

rising rate of new users

BMJ, August 21, 2004; 329(7463): 461 - 461.

[Full Text]

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