SEPTEMBER 30, 2007


Did we get it all wrong about SSRIs and youth suicide?

New data shows suicide spike after warnings.
Kids undertreated

Black box warnings imposed by the FDA to flag suicide risk in adolescents who take the commonest class of antidepressants may have backfired badly, suggests new research that finds suicides rose as prescriptions fell.

Reporting in the September American Journal of Psychiatry, researchers found that in 2004, a 22% decrease from the previous year in prescriptions of selective serotonin reuptake inhibitors to patients aged under 19 coincided with a 14% increase in youth suicides. The research also looked at Holland, where prescriptions fell by 22% in the period 2003-5. This was accompanied by a startling 49% increase in suicides among the young.

Even the smaller rise in US rates is highly significant, representing the largest single-year change since nationwide suicide reporting began in 1979. It reverses a long-term decline in suicides among the young, which had previously fallen 28% since 1990.

A total of 4,599 Americans aged under 24 took their own lives in 2004, making it the third leading cause of death in this age group. The overall US suicide rate is about 32,000 in a typical year.

Professor Robert Gibbons, PhD, of the University of Illinois at Chicago, lead author of the study, says he's anxiously awaiting 2005 prescribing and suicide data. The FDA only announced its decision to put the warnings on SSRIs in March of 2004. He fears an even bigger effect will be seen in the following year's data. "The really major fall in prescribing came just after the period we studied," he says.

He notes that in Holland, the rise in suicides was proportionately much greater than the decline in SSRI prescriptions. "My conjecture is that patients deemed most at risk of suicide were those most likely to be taken off the drug, leading to a selection effect," he says.

The data appears to knock major holes in what had rapidly become conventional wisdom on SSRIs, particularly since it is based on actual suicides in the population. No young person actually killed themselves in any of the studies which led the FDA to link SSRIs and suicides. Rather, the agency found a consistent pattern of increased suicidal ideation, self-harming behaviour and other surrogate markers for suicidality.

But the researcher who first proposed a link between SSRIs and suicidality in the young, Professor David Healy of the University of Cardiff, is not willing to call it quits yet. He begins by challenging the accuracy of the data, noting that suicides are only recorded when a coroner says it's suicide.

"As suicide rates have fallen in recent years, autopsy rates have also fallen and have fallen so dramatically that it is quite plausible that this is the reason for fewer diagnoses," he says. "Against a background of recognition of SSRI adverse effects, leading possibly to suicide, it's conceivable that deaths formerly noted as uncertain or accidental have been appropriately coded instead as suicides now, where they weren't before."

Professor Healy has always maintained that SSRI treatment involves two periods of sharply elevated risk - the beginning of treatment, and withdrawal. The new data leaves open the possibility, he notes, "that there are in fact no fewer people on SSRIs. A drop in the script rate may stem primarily from those on treatment chronically — 80% of those being treated - and a constant or even increased rate of new patients being put on the drugs." These new patients would be at high suicide risk, he says.

Then there are withdrawals. It is actually quite consistent with Professor Healy's theories that a large number of people coming off SSRIs would translate into a bump in suicides.

Finally, he says, "there has also in the last two or three years been a huge switch from antidepressants to antipsychotics. The antipsychotic 'mood stabilizers' have just as great an increase in suicide risk as antidepressants - if not greater."

Professor Gibbons counters: "I understand where Professor Healy is coming from but I don't think the data supports it." He points to research published last month in the American Journal of Psychiatry by his co-author Dr Robert Valuck of the University of Colorado, which found no corresponding increase in antipsychotic prescriptions as SSRI prescriptions fell.

He adds that SSRI prescriptions continued to rise in 2003-4 in one age group - the over-60s - and this was the only age group in which suicides fell.

Professor Gibbons also notes that Dr Valuck's data shows "that the FDA warnings were followed by a fall in the number of actual diagnoses of depression among the young." This raises a third possibility not yet discussed - that the rise in suicides may not be a pharmacological effect at all. Could it be that the FDA's questioning of the most obvious tool for treating depression led doctors to undertreat their patients, leaving the vulnerable young feeling more helpless and abandoned than ever? That kind of effect can be very hard to measure.

If there is a pharmacological effect, help may be on the way. Thomas Insel, director of the National Institute of Mental Health (NIMH), suspects that SSRIs are beneficial in most patients, but are causing suicidality in a small minority who may be genetically differentiated from the rest of the population. Research sponsored by NIMH has already found a gene test that can predict response to the SSRI citalopram, and more results are on the way.

In the meantime, the FDA is watching the situation closely, and plans a big review later this year. Canada's Therapeutic Products Directorate, which issued similar warnings, told NRM they have no plans to change the monograph, which they consider to be up to date.

For the record, Canada's youth suicide rate actually fell slightly in 2004, the most recent year for which statistics are available.



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