Antidepressants reduce the risk of suicide in depressed youths, despite fears to the contrary, writes consultant psychiatrist Dr Cian Denihan
Data from the US revealed that suicide was the third leading cause of death in the 15-24 year old age group in 2006. For the population as a whole, suicide was the 11th leading cause of death. The US National Institute for Health estimates that between 12-25 suicide attempts occur per every suicide death.
In the 15-19 age-group, some 8.2 per 100,000 ended their lives by suicide in 2006; and the rate was 12.5 per 100,000 in 20-24 year olds. Marked gender differences were found in suicide among young people, with over four times as many males as females aged 15-19 years dying by suicide and more than six times as many males as females aged 20-24 dying by suicide.
Over 90 per cent of suicides in the US are associated with psychiatric illness, with mood disorders accounting for approximately 60 per cent of all suicides. Most depressed persons who eventually commit suicide seek professional help within one month of their death. The evidence is that most are not on antidepressant medication at the time of death, which suggests that lack of treatment contributes to suicide risk and that more widespread anti-depressant treatment might reduce suicide rates.
Antidepressant prescription in adolescents and young adults has been the source of considerable controversy, due to a putative increase in suicidal ideation and behaviour associated with antidepressant usage. The Food & Drugs Administration (FDA) issued a public health advisory warning in October 2003 regarding several reports of children and teenagers taking antidepressants, who attempted or committed suicide.
A similar warning was issued in the UK in December 2003 and also by the European Medicines Agency during the same month. In October 2004, the FDA ordered pharmaceutical companies to add a ‘black box’ warning to the labelling of all antidepressants used in child and adolescent patients regarding a possible increased risk of suicidality in paediatric patients taking antidepressants.
This FDA action was based on data from randomised controlled trials suggesting a twofold increase in suicidal ideation and behaviour when antidepressants, including selective serotonin reuptake inhibitors (SSRIs), were prescribed to adolescents who were not actively suicidal.
In December 2006, the FDA reviewed the Agency’s data from randomised controlled trials with adults and concluded that the ‘black box’ warning should be extended to young adults. A major limitation of the studies in the FDA’s database was that no suicides were reported in the child and adolescent studies. Only eight suicides were reported in the adult studies: two of 36,049 patients receiving placebo, five of 53,030 patients receiving the test drug, and one of 11,217 patients receiving the active control drug.
Even the combination of 372 studies involving nearly 100,000 patients provided no real evidence of a heightening effect of antidepressants on suicide.
Study findings
Gibbons et al observed that the FDA’s findings for children and adolescents appeared to be inconsistent with psychological autopsy studies of suicide victims suggesting that few paediatric suicide victims have been exposed to SSRIs, and with ecological studies on completed suicides and suicide attempts that indicate an overall protective effect of SSRIs in children and adolescents. Their research found a significant inverse relationship between US county-level SSRI prescription rates and adult suicide rates, both within counties over time and between counties.
Ludwig & Marcotte found an inverse association between SSRI prescription rates and suicide rates from 1980 to 1999 in 26 European countries; and Grunebaum et al found similar results in the US.
More recently, Bramness et al confirmed a significant inverse association between SSRI sales and suicide rates from 1980 to 2004 in a county-level analysis in Norway. Isacsson conducted a naturalistic study, which found that a 3.5-fold increase in antidepressant prescriptions in Sweden was associated with a 19 per cent suicide decrease.
Gibbons et al noted these ecological data on suicide rates suggested that a decrease in the number of prescriptions written for the newer anti-depressants (SSRIs and non-serotonergic-specific antidepressants — non-SSRIs) would lead to an increase in the suicide rate. They set out to examine if the public health warnings in the US and Europe led to decreases in SSRI prescription rates for children and adolescents in the US and the Netherlands, and if such decreases were associated with increases in suicide rates in children and adolescents.
They examined US and Dutch data on prescription rates for SSRIs from 2003-2005 in children and adolescents (≤ age 19), as well as suicide rates for children and adolescents, using available data (through 2004 in the US and through 2005 in the Netherlands). They used Poisson regression analyses to determine the overall association between antidepressant prescription rates and suicide rates, adjusted for sex and age, during the periods preceding and immediately following the public health warnings.
They found SSRI prescriptions for youths decreased by approximately 22 per cent in both the US and the Netherlands after the warnings. In the Netherlands, the youth suicide rate increased by 49 per cent between 2003 and 2005 and showed a significant inverse association with SSRI prescriptions.
In the US, youth suicide rates increased by 14 per cent between 2003 and 2004, which was the largest year-to-year change in suicide rates in this population since the Centers for Disease Control and Prevention began systematically collecting suicide data in 1979.
Although one might expect that decreases in SSRI prescriptions would have led to increases in alternative antidepressant treatments, this was not the case: similar decreases were seen in paediatric and young adult prescription rates for alternative antidepressant types (approximately 20 per cent in 5-14 year olds and approximately 10 per cent in 15-19 year olds).
An alternative explanation that has been proposed for the decrease in US child and adolescent suicide rates from the late 1980s to 2003 is a drop in substance use during this period. However, the fact that US national rates of illicit drug use continued to decline from 2003 to 2004, while suicide rates increased, makes this unlikely.
Further support for the findings of Gibbons et al was provided by Libby et al in 2007, to the effect that US SSRI prescription fills were 58 per cent lower than predicted by pre-2004 data and that paediatric diagnoses of major depression were more than 30 per cent lower than predicted for paediatricians and primary-care physicians based on pre-2004 historical trends.
They found no evidence of a significant increase in use of treatment alternatives, including psychotherapy, in the child and adolescent age group. These effects spilled over to the adult population, where a significant decrease in the percentage of adults diagnosed with new depressive episodes was observed since the ‘black box’ warning was introduced, despite the advisory warning not applying to adults at the time.
They found there was a significant increase in the percentage of community-based depressed patients who did not receive antidepressants (from 20 per cent before the policy action to 30 per cent after). Of concern is the fact that both antidepressant prescription rates and diagnosis of new episodes of depression fell in both paediatric and adult populations.
It is reasonable to conclude significant numbers of depressed children and adults went undiagnosed and untreated in the aftermath of the advisory on SSRI prescription in the paediatric population. It is therefore easy to see why suicide rates started climbing.
Extended warning
In December 2006, the FDA recommended that the warning be extended to include young adults. In May 2007, the FDA asked drug manufacturers to revise labels accordingly. This recommendation was based on the results of a meta-analysis of data on nearly 100,000 patients from 372 randomised controlled trials of SSRIs and new-generation non-SSRIs.
The analysis indicated a protective effect of antidepressants on suicidal ideation and behaviour (odds ratio=0.83). When the data were stratified by age, antidepressants were associated with a significantly lower risk of suicidal ideation and behaviour in patients ≥ 65 (odds ratio = 0.37) and in patients in the 25-64 age range (odds ratio=0.79), but a higher risk in adult patients under 25 years (odds ratio=1.62), although the latter fell short of statistical significance.
Even in this large sample, there were only eight suicides: two of 27,164 placebo subjects, five of 39,729 subjects on test drug, and one of 10,489 subjects on the active control drug. Given the established favourable inverse relationship between SSRI prescription rates and suicide rates seen in adults, older adolescents and young adults, and younger adolescents and children, the FDA findings seemed contradictory and simply likely to further increase suicide rates.
To elucidate this, Gibbons et al examined the relationship between antidepressants and suicide attempts in adult patients in the Veterans Administration healthcare system. They analysed data on 226,866 veterans who received a diagnosis of depression in 2003 or 2004, had at least six months of follow-up, and had no history of depression from 2000 to 2002. Suicide attempt rates overall, as well as before and after initiation of antidepressant therapy, were compared for patients who received SSRIs, new-generation non-SSRIs, tricyclic antidepressants, or no antidepressant. Age group analyses were also performed.
The results showed that suicide attempt rates were lower among patients who were treated with antidepressants than among those who were not, with a statistically significant odds ratio for SSRIs and tricyclics. For SSRIs versus no antidepressant, this effect was significant in all adult age-groups. Suicide attempt rates were also higher prior to treatment than after the start of treatment. These findings suggest that SSRI treatment has a protective effect in all adult age groups and do not support the hypothesis that SSRI treatment places patients at greater risk of suicide.
The FDA’s ‘black box’ warning policy directive in May 2007 on SSRI and new-generation antidepressant usage and suicide risk in young adults is particularly puzzling in light of the finding of Simon et al in January 2006 that the risk of suicide attempt was highest in the month before starting antidepressants and declined progressively after starting medication (see figure).
When the 10 newer antidepressants included in the FDA advisory were compared to older drugs, an increase in risk after starting treatment was seen only for the older drugs, possibly due to the slower timescale to achieve therapeutic dosage.
The essential message is that the evidence indicates that antidepressant usage reduces the risk of suicide in depressed child, adolescent and young adult patients.
The highest rate of suicide in depressed individuals occurs in the month before initiation of SSRI and new-generation non-serotonin-specific antidepressants and declines progressively thereafter. Obviously, depressed individuals commencing antidepressant therapy need careful monitoring for risk of suicide, but this issue is integral to the depressive state and not the treatment prescribed.
l References on request
l Dr Cian Denihan is a Consultant Psychiatrist at Saint John of God Hospital, Stillorgan, Co Dublin and UCD Student Health Service
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