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Antidepressants and The Risk of Suicide Inypung Persons PDF
Antidepressants and The Risk of Suicide Inypung Persons PDF
he Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12160
Significant outcomes
• The ‘black box’ warnings for that antidepressants would carry an increased risk of ‘suicidality’
in young people were followed by an increase in suicide.
• The increase in suicide occurred among young persons without antidepressant treatment.
• This supports the a priori hypothesis that the warnings might be counterproductive.
Limitations
• The causes of variations in suicide rates can never be definitely proven.
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Antidepressants and suicide in young persons
ductive, because young suicides in USA showed a The Swedish Board of Health and Welfare
sudden 14% increase (girls 33%) in 2004, after provided aggregated data on the annual use of
previously having been continuously decreasing antidepressants in the 10- to 19-year age group in
since 1988 (3, 7, 8). This negative association on 1999–2010. These data originate from sales on pre-
the ecological level between the use of antidepres- scription in Swedish pharmacies regarding all spe-
sants and the incidence of suicide does not however cific antidepressant medications. The volume unit is
allow conclusions to be drawn regarding causality. defined daily doses per thousand inhabitants per
It is not known whether the increase in suicide had day (DDD/TIND). Each medication has a specific
occurred among persons treated with antidepres- defined daily dose corresponding to a ‘normal’ dos-
sants or among persons who were not treated. age of the drug (e.g. 1 DDD of fluoxetine is 20 mg,
Such knowledge is a prerequisite for an interpreta- while 1 DDD of sertraline is 50 mg), and this facili-
tion that the reason for the increase in suicide was tates the summation of drugs of different strengths.
that a number of depressed and suicide-prone Since 1 July 2005, all prescriptions filled at Swed-
young persons were not taking antidepressant ish pharmacies have been registered in an individ-
medication due to the ‘black box’. ual-based database run by the Swedish Board of
Health and Welfare, from which it was possible to
retrieve individual-level medication data for the
Aims of the study
period 2006–2010. The registered variables include
Because suicide among young persons in Sweden the patient’s personal identification number, which
had also increased since 2003, we decided to test the permitted linkage to the toxicology data, the ATC
hypothesis that this increase had occurred in indi- code of the prescribed drug, the amount purchased
viduals who were not treated with antidepressants. in defined daily doses, the date of purchase and
The rationale for the hypothesis was that depression other variables that are not considered in this analy-
is the main risk factor for suicide and consequently sis. We calculated from these a variable regarding
that, if depression is treated to a lesser degree, the dispensation in the last 6 months prior to suicide.
population at risk of suicide will increase and ulti- The three parameters we studied were the use of
mately also the occurrence of suicide. antidepressants in the population, the number of
suicides in the population and the use of antide-
pressants in individual suicides. As age has been an
Material and methods
important variable in the question of antidepres-
In the Swedish population, there are about 1.1 mil- sant-induced suicidality, we separately analysed
lion persons in the 10- to 19-year age group. the relatively few suicides in the 10- to 14-year age
The National Board of Forensic Medicine pro- group.
vided toxicological data relating to all individual The study period was divided into the baseline
suicide cases aged 10–19 years in the period 1992– time period before the warnings for an increased
2010 (N = 845). Apparently unnatural deaths in risk of suicidality 1992–2002, and the outcome per-
Sweden are investigated by forensic pathologists. iod 2003–2010.
Their investigation leads to a conclusion as to The statistical procedures included Poisson
whether the cause of death was homicide, suicide, regression for trends and the comparison of trends.
accident or natural. In some cases, the cause of If not otherwise specified, one-sided tests were con-
death cannot be determined. If investigated further, sidered, because it was an a priori-hypothesized,
the majority of these undetermined cases are often and actual, increase in suicide that should be
found to be probable suicides, mostly because of tested. Chi-squared test was used for comparing
poisoning (9). Such undetermined cases may prefer- the rates of suicide in the two periods.
ably be considered to be suicides and are so in the
present study (15.4%). A routine procedure in these
forensic investigations is to search for foreign sub- Results
stances in the body. All such toxicological analyses
Baseline period 1992–2002
are performed at the same laboratory in Link€ oping,
Sweden. In the analyses, around 200 substances are During this period, the use of antidepressants in
screened for. All antidepressants can be detected at the population aged 10–19 years increased from
therapeutic concentration levels. We consider in 3.5 DDD/TIND in 1999 to 7.3 DDD/TIND in
this study individuals in whom an antidepressant is 2002 (Fig. 1, Table 1).
detected in toxicology as ‘treated’ and the other as In the whole period, there were 407 cases of
‘untreated’. The date of the forensic investigation suicide (16.2% undetermined cases). The annual
was considered as the date of death. numbers varied in the range from 29 to 47
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Isacsson and Ahlner
Fig. 1. Group-level sales of antidepressants (1999–), numbers of suicides, numbers of suicides with toxicological detections of antide-
pressants and number of suicides who had purchased at least one prescription of antidepressants in their last 6 months prior to death
(2006–).
without any obvious trend (P = 0.18, two-sided Among the 52 cases in the 10- to 14-year age
test). Antidepressants were detected in group, antidepressants were detected in toxicology
post-mortem toxicology in 0–4 of these individ- in only one case during the whole period, and it
ual suicides per year. was uncertain whether suicide or accident.
Table 1. Use of antidepressants (AD) and suicide in the total population of 10–19 years of age in 1992–2010
The annual numbers of individuals aged 10–19 years in the total Swedish population in 1992–2010, the use of antidepressants in this age group (1999–), as well as the actual
prevalence of treatment (2006–), the total number of suicides, the number of suicides that had at least one or more than one purchase of antidepressants in the last 6 months
prior to death (2006–), the number of suicides with antidepressants detected in post-mortem toxicology, and the annual suicide rates. (DDD TIND, defined daily doses per 1000
individuals per day; TIN, per 1000 inhabitants) .
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Antidepressants and suicide in young persons
299
Isacsson and Ahlner
a risk factor leading to suicide in children or in ple do not form a homogeneous group. Some might,
adolescents. The 2.1-fold increase in the use of for example, have expressed suicidal thoughts and
antidepressants during 1999–2002 was not paral- others not. The readiness of physicians to prescribe
leled by any significant change in the annual num- antidepressants to children and adolescents in these
ber of suicides. two categories might have differed. The warnings in
There is a possibility that the increase in suicide 2003 might have prompted a rapid withdrawal of
was caused by other factors than lack of treatment the medication in young depressed patients with
with antidepressants, but to our knowledge, no overt suicidal ideation, resulting in an immediate
such alternative causal factor has been proposed. increase in suicide, while the prescribing to children
By demonstrating that the increase in suicide and adolescents not expressing suicidality or judged
occurred among individuals who were not treated not to be at risk might have been relatively unaf-
with antidepressants, however, this study goes one fected by the ‘black box’.
step beyond the correlation in time on the ecologi-
cal level. It, therefore, provides further support for
Comparison with other studies
the conclusion that the increase in suicide after the
‘black box’ was actually a result of the limited pre- Our result is consistent with the time series analy-
scribing of antidepressants thereafter. The fact that ses of Gibbons et al. and Bridge et al. in the USA
the study was a test of an a priori hypothesis based and by Katz et al. in Canada (3, 7, 8). They all
on a plausible biological mechanism and that it is demonstrated prominent increases in suicide after
consistent with previous US and Canadian findings the black box. Several cross-sectional studies
also lends support to this interpretation. The effect further demonstrate that suicide in young people is
of the ‘black box’ seems, however, to have come to not associated with treatment with antidepres-
an end in 2007, because the steeply increasing sants, but with no treatment. Jick et al. (12) analy-
trend in the use of antidepressants then recovered. sed all individuals in the UK General Practice
Thereafter, the annual number of suicides Research Database who in 1993–1999 were pre-
decreased and in 2010 approached prewarning lev- scribed one of the antidepressants fluoxetine, par-
els. Therefore, we find it sound to exclude 2010 oxetine, amitriptyline or dothiepin. Among the
from the Poisson analyses of trends. 6976 studied in the 10- to 19-year age group, none
There is, however, also a trend over the two dec- had committed suicide during the study period (at
ades for antidepressants to be more often detected least 2 years) and the risk of non-fatal suicidal
in the toxicology of suicides. This is to be expected behaviour decreased continuously during antide-
regardless of any influence of antidepressants on pressant treatment. Leon et al. investigated youth
the risk of suicide, as the use of antidepressants in suicides in New York City in 1993–1998 and 1999–
the population increased by 240% between 1999 2002(13, 14). They found 66 and 41 cases, respec-
and 2010. As a consequence, the number of failed tively, below the age of 18. Toxicological analyses
treatments must have increased because antide- were carried out in 58 and 36 of them, and among
pressant medication is not 100% effective. We have these, antidepressants were found in four and one
actually in a previous study shown that the case respectively (6.9% and 2.8%). Leon et al. fur-
increase is far less than expected, and we have ther investigated prospectively 757 mood disorder
interpreted this as evidence for a suicide-preventive patients with 6716 time periods being either
effect of antidepressants (11). Actually, any drug exposed to an antidepressant or not exposed dur-
that becomes more common in the population ing a time period of up to 27 years. They found
must also be become more common among sui- that, although those with more severe affective syn-
cides. Our estimation of treatment from toxicology dromes were more likely to initiate treatment,
is an overestimation, however, because the pre- antidepressants were associated with a significant
scription data for the period 2006–2010 showed reduction in the risk of suicidal behaviour (15).
that not all individuals with antidepressants in tox- Moskos et al. (16) found no antidepressants in the
icology had been dispensed an antidepressant. toxicology of 49 suicide cases aged 13–21 in Utah
Thus, the portion of treated suicides was in fact in 1996–1998. Sondergard et al. (17) found in a
even smaller than that on which we based our con- Danish nationwide prescription database that
clusion. ‘Among 42 suicides nationally aged 10–17 years at
It might somewhat obscure the correlation in time death, none was treated with SSRIs within 2 weeks
that the use of antidepressants after the warnings in prior to suicide’. Dudley et al. (18) found in six
2003 did not decrease but became stationary and studies that 9 of 574 (1.6%) adolescent suicides
started to increase again already in 2007. A proba- had recent exposure to SSRIs. We have previously
ble explanation for this is that depressed young peo- demonstrated with toxicological evidence that
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Antidepressants and suicide in young persons
SSRIs were less associated with young suicides and adolescents might be more beneficial than it
than were other antidepressants (19). appears to be in RCTs. To our knowledge, no
In England and Wales, Wheeler et al. (20) study has presented empirical evidence confirming
found no association between the notable reduc- an inference from the RCTs that antidepressants
tion in the prescription of antidepressants after might increase the risk of suicide in
the black box and changes in suicide in the 12- to youth, although Ghaemi et al. (31), based on
17-year age group. This is at variance with our several assumptions, recently estimated that
Swedish findings, but does not support the ratio- ‘antidepressants can be said to be, at the popula-
nale for the ‘black box’. Wheeler et al. (21) also tion level, neutral in their effects on suicide’.
investigated suicide rates in 23 countries during
the period from 1990 to 2006 and concluded that
Strengths and limitations
there was no evidence for a change in trend in
relation to the time for the warnings, although The strength of this study is that it included all
suicide in young women had increased by 8.1%. young suicides in Sweden during the eleven years
The study had, however, no data on the use of an- before the warnings for increased risk of suicidality
tidepressants in the different countries. It might and the 8 years thereafter. Individual data on pre-
also be that girls more than boys were actually scriptions of antidepressants and post-mortem tox-
vulnerable for the decrease in prescribing as the icology were available, as well as reliable data on
US data indicate (3). This study thus does not the use of antidepressants in the whole Swedish
contradict our results. Hammad et al. (22) con- population. It is a limitation that observational
cluded from a meta-analysis that the use of an- study cannot establish causality, and this study
tidepressants in paediatric patients is associated goes only one step beyond ecological study when
with a modestly increased risk of suicidality. This illuminating the actual use of antidepressants
might be true if it is accepted that ‘suicidality’ is among young suicides.
not necessarily a risk factor for suicide, which the
term unfortunately implies. The TADS showed a Conclusion
two-fold risk of ‘harm-related events’ but not ‘sui-
cide-related’ in the children treated with fluoxetine Youth suicide increased remarkably in Sweden in
compared with those without antidepressants (23). the 5 years after the ‘black box’ warnings. The
Whittington et al. (24) meta-analysed data from cause of this increase cannot be determined. The
RCTs of SSRIs in the 5- to 18-year age group and fact that the increase in suicide occurred in young
concluded that, with the exception for fluoxetine, persons without antidepressant medication, how-
SSRIs had ‘unfavourable risk-benefit profiles’, and ever, is consistent with our hypothesis that these
particularly so when including data from non- truly suicidal persons might have been denied
published trials in the meta-analysis. This conclu- antidepressants, or abstained from them, due to
sion was based on the limited evidence for antide- the ‘black box’ and then committed suicide
pressants being effective against paediatric because of untreated depression. Thus, the study
depression. The scarcity of evidence of efficacy supports the notion that antidepressants prevent
may be due to the many weaknesses in the way suicide in youth and contradicts the rationale for
RCTs are actually conducted, which is far from the ‘black box’. The prevalence of antidepressant
the ideal experimental situation (25–27). These treatment is still low in young persons compared
weaknesses decrease the probabilities of demon- with the prevalence of depression. It is a prospec-
strating possible effects of antidepressant drugs tively testable hypothesis that increasing treatment
because of a statistical type II error (i.e. the statisti- with antidepressants would correspond with fur-
cal power is insufficient). Gibbons et al. recently ther decreasing numbers of suicides. As antidepres-
reanalysed 20 RCTs of fluoxetine or venlafaxine, sant treatment is not 100% effective, however, a
however, and found that both were more effective greater proportion of the persons who commit sui-
in young people than they were in older patients cide would be expected to have antidepressants
and without evidence of increased suicide risk (28, present post-mortem.
29). Recently, it has also been demonstrated that
shortcomings of the universally used Hamilton Acknowledgement
Depression Rating Scale (HDRS-17) further
Karolinska Institutet and Stockholm County Council are
increase the risk of false-negative results (type II acknowledged for providing funding (ALF grants). Ulf Bro-
error; 30). Because ‘efficacy not demonstrated’ is din, MSc in Medical Statistics, at the Department of Learning,
not the same as ‘non-efficacy demonstrated’, Informatics, Management and Ethics (LIME), is acknowl-
antidepressant medication in depressed children edged for statistical advice.
301
Isacsson and Ahlner
302