The antidepressant suicide link - busted?

The Washington Post reports on the apparent jump in suicide rates since antidepressants got a black-box warning in 2004 after some reports suggested an increased suicide rate in youths after the initial prescription.

The article here (goddamn WaPo still can't figure out how to link anyone but themselves) shows a disturbing correlation:

METHOD: The authors examined U.S. and Dutch data on prescription rates for selective serotonin reuptake inhibitors (SSRIs) from 2003 to 2005 in children and adolescents (patients up to age 19), as well as suicide rates for children and adolescents, using available data (through 2004 in the United States 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.
RESULTS: SSRI prescriptions for youths decreased by approximately 22% in both the United States and the Netherlands after the warnings were issued. In the Netherlands, the youth suicide rate increased by 49% between 2003 and 2005 and shows a significant inverse association with SSRI prescriptions. In the United States, youth suicide rates increased by 14% between 2003 and 2004, which is 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.

This is disturbing. However, the I don't agree with the current interpretation of the problem.

NIMH's Insel said it is possible that antidepressants are lowering the risk of suicide overall, even as they increase the risk among a subset of patients. New research to be published soon examines genetic factors that may put some patients at particular risk, he added.

There is another explanation - a mixture of confirmation bias and post hoc ergo propter hoc reasoning. The main offender, yet again, is a meta-analysis.

The analysis pooling data from multiple clinical trials of anti-depressants found:

The overall risk ratio for selective serotonin reuptake inhibitors in depression trials was 1.66 (95% CI, 1.02-2.68) and for all drugs across all indications was 1.95 (95% CI, 1.28-2.98). The overall risk difference for all drugs across all indications was 0.02 (95% CI, 0.01-0.03).

Conclusion Use of antidepressant drugs in pediatric patients is associated with a modestly increased risk of suicidality.

It was a small effect observed, the CIs almost covered the RR of 1.00. The authors of the study also mentioned a prominent biases in such a study:

There has been a long-standing concern that antidepressant drugs might actually induce suicidality early in treatment. A textbook of psychiatry published more than 40 years ago, in referring to observations of depressed patients during initial treatment with tricyclic antidepressants, noted that, "With beginning convalescence, the risk of suicide once more becomes serious as retardation fades."

This is true, for a long time doctors observed that if a patient would commit suicide while under their care, it was usually right after prescription of an anti-depressant, rather than later on.

The data that I think illuminate the problem, are in yet another AJP paper, shows a possible reason for the result.

i-22b3d4eed692b777090f789d1a0374cc-R912F1.jpeg

In this figure you see a big drop after prescription of SSRI, but critically, in the first month after the prescription is given, suicidality is higher than at any other time during the course of treatment. Notice also the rate of suicidality is much higher among patients seeing a psychotherapist as opposed to a GP, don't worry though, this is likely referrer bias rather than pscyhotherapists causing suicides.

Now think about it. Doctors don't see patients in the months before the prescription and have knowledge of suicidality before they enter the medical system. What they see is a patient they've given a script for, and that suicides, if they happen, are usually right after prescription. But that doesn't mean the SSRIs didn't greatly reduce the overall risk. And even more likely, given the rapidity of the effect, that merely seeking help had an enormous influence on suicide risk (the study authors felt the effect on suicidality was too fast to be a result of pharmacologic intervention).

I think it will take more study to prove my hypothesis, but I suspect the problem was confirmation of an existing bias among clinicians, that was justifiable based on the time-window of their experience with depressed patients, but not reflective of the overall disease course. The data showing such a drastic jump in suicides after a substantial decrease in SSRI prescriptions is pretty shocking proof that removal of this intervention has cost lives, and that SSRIs are responsible for decreasing suicides. The long term decrease in suicide rates was attributed to SSRI prescriptions, although it has never been clear it was SSRIs or some other confounding variable. This convinces me at least, that SSRIs have had a significant impact on suicidality, and the long term decreases in suicidality have been from the introduction of these drugs.

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tags: researchblogging.org, mental health, suicide, depression, bipolar disorder, SSRIs, selective serotonin reuptake inhibitors, antidepressants, FDA black-box warning Prozac. Image: Tom Varco After a 2003 report linking selective serotonin reuptake inhibitors, or SSRIs, with increased suicide…
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Just when you thought there could not possibly be any more to say about the subject, given the uncertainties inherent in the area, there is yet another study.  This one is from analysis of a large patient registry in Finland.  A total of 15,390 patients were included in the analysis, over a period…

Question: is the decrease in SSRI prescriptions accompanied by a decrease in the numbers seeking help?

For a general summary of deaths see the CDC tables. Choose "violence related injuries only" at the bottom of the page.

Goodness, but there are many people offing themselves. I assume that when people hit 30+ age they reassess their lives and conclude that they might as well end it.

Very interesting. I wonder if we will see further upticks in suicide rates following this week's panicked announcement of "Zillions of kids on meds for bipolar disorder! They must be misdiagnosed!" (I'm paraphrasing, of course).

Even though the study seemed to suggest that changes in diagnostic criteria and past under-diagnosis were likely the reason, I suppose that many parents responded by taking their kids off the meds. Yet another reason I don't like Dr. Sanjay Gupta's "journalism."

This would assume that suicide is one of the expected outcomes of BPD as it is for plain ol' depression, which I think is true (but do not know for sure).

Tammy,
I'm not sure the two situations are comparable. It sounded to me that the bipolar prescriptions were an example of extreme overprescription - giving antipsychotics to kids under 10 is a little bit nuts. I don't think there's a strong basis for the diagnosis at those ages, and the paper describing the large increases in bipolar disorder concluded the same thing.

What I suspect is happening here is that having patients stop taking the medication triggered a nocebo effect.

If the antidepressants really lowered the risk of suicide, this should've been detected by the case-control studies, unless there was a big confound in those.

What about the nocebo effect? You know, where listing it as a possible symptom in big type is likely to cause people to consider it a little bit more than they would otherwise?

By Adam Cuerden (not verified) on 08 Sep 2007 #permalink

Is it just me or are SSRIs actually safer to use than all meds combined (RR 1.66 vs. 1.95)? The CIs overlap, but even so. Imagine the headlines: "SSRIs safer than average meds" Not gonna happen, is it?

It is difficult to discuss anything in this area without confronting the reality of cheating in many SSRI studies. Unfortunately the pharmaceutical industry bears much of the responsibility for the uncertainty, and that uncertainty relates to a lot more than uncertainties over data interpretation and confounders.

There is abundant evidence of deception in many SSRI RCT's. We have to operate under the banner of science or join the quacks - can't have it both ways. Cheating has included
i) innovative recoding of events
ii) non-disclosure of whole studies with unwanted results
iii) misallocation of events to the placebo arm (events post treatment, run-in, and washout).

One random example of innovative patient coding
http://scientific-misconduct.blogspot.com/2007/05/on-redefinition-of-re…

Scrutiny of GSK's actions leading to the infamous study 329
http://clinpsyc.blogspot.com/2007/07/jaacap-strikes-again.html

and a slew of internal GSK documents revealing what they knew and when
http://tinyurl.com/2whsgv

all depressing reading, and the routine way of doing business.

It is therefore not entirely clear why scientists would accept the findings of scientifically weaker epidemiological studies without questions that go beyond the obvious.

Having had raw data in clinical trials hidden from me (as a scientific "author" of ghostwritten material) and knowing what those data actually showed when finally revealed, I have a healthy skepticism ( http://scientific-misconduct.blogspot.com/search/label/Procter%20and%20… ).

Its a case of "Fool me once, shame on you. Fool me twice, shame on me." We are happy to see Eric Poehlman in prison for scientific misconduct. We won't ever believe any future Poehlman research and quite rightly. Applying that principle more widely seems too uncomfortable.

It is sad that this science has reached such a low point, and even sadder that our own actions give the cranks and hucksters out there a field day. It is also hardly surprising that our patients don't trust much of the good science either, but perhaps we have ourselves to blame.

Aubrey Blumsohn

Joseph said: "Is it just me or are SSRIs actually safer to use than all meds combined (RR 1.66 vs. 1.95)?"

No thats a doubling of risk (RR 1.95) over all indications for SSRI use, not other medicines.

There are a few other things to say here (apart from the fraud aspect in the RCT).

Your first sentence needed an additional word.

You say "jump in suicide rates since antidepressants got a black-box warning in 2004"

You should have said

"jump in suicide rates since antidepressants got a black-box warning in OCTOBER 2004"

That leaves 10 weeks of 2004 to account for the supposed black box induced jump. So what was the distribution of suicide during 2004 vs the distribution in other years? Furthermore, since the CDC just reported suicide data for 2005, and that showed a fall, in fact there is if anything a drop in rate in the year post black box vs the year before (not using whole years that is). Furthermore the journalists neglected to mention that the reduction in SSRI use is because SSRI's are replaced by something else -- antipsychotics. The journalists quietly forgot to mention these little tidbits. Aren't pharma funded science journalists and epidemiology great.

To comment on one statistical point you make. You say:

"It was a small effect observed, the CIs almost covered the RR of 1.00."

There is a not so subtle difference between effect size and P value. A RR of 2 is a RR of 2 - that is the best estimate. The CI (or P) has nothing whatever to do with effect size.

You have a great blog here, but this posting was not one of the best science-wise. The RCT's are the best we have and we have to stick with them even though we know they have not been all that kosher (and even with the manipulation they raise lots of concerns). The first step is to get the raw data from those trials, and go back to scrutinize the records. That is far more important than epidemiology or any new trials.

Barbara P

By Barbara Ironside (not verified) on 12 Sep 2007 #permalink

I tell ya Barbara, I just don't know about these meta-analyses. Seems like they just keep turning up nonsense.

I'm not convinced of an effect yet. And while the studies you link are examples of misconduct - ghostwriting is an under-recognized problem in the literature, I'm not convinced yet. I think this does require a new RCT specifically designed to uncover such an effect.

Doctors don't see patients in the months before the prescription and have knowledge of suicidality before they enter the medical system. What they see is a patient they've given a script for, and that suicides, if they happen, are usually right after prescription.

Bingo Mark.
The data line starts with the initial consultation. That's t=0. The only thing you can know for sure is that the longer the patient undergoes treatment, the lower the risk of suicide.
Unfortunately, that doesn't fit wit hthe paranoid narrative:

1) depression is not a disease or a symptom of disease, its (*life experience/ spiritual/doesn't exist/ good for you*) etc.
2) evil drug companies are taking advantage of poor little depressed people through gullible doctors
3) just like an episode of the x-files, the drug that they claim will cure you, actually makes you worse and can even make people take their own life
4) there is a massive scientific cover-up to stop the truth getting out.

On the other hand, maybe SSRI's help with depression and suicide.

Unfortunately, that doesn't fit wit hthe paranoid narrative:

1) depression is not a disease or a symptom of disease, its (*life experience/ spiritual/doesn't exist/ good for you*) etc.

2) evil drug companies are taking advantage of poor little depressed people through gullible doctors

3) just like an episode of the x-files, the drug that they claim will cure you, actually makes you worse and can even make people take their own life

4) there is a massive scientific cover-up to stop the truth getting out.

On the other hand, maybe SSRI's help with depression and suicide.

Boy that's a whole litany right there.

1. Re: point 1 -- Who said that? I'd like to evaluate the credibility.
2. Re: point 2 -- There's no history of SSRI overprescription?
3. Re: point 3 -- who is the "you". Someone specific or users in general? A subgroup? For how many does it need to be true in order to be true for some?
4. Re: point 4 -- Seeing that there's no money in SSRIs, I doubt it; scientists are as pure as the driven snow. If only scientists had a code of ethics to protect them from marketing...because it's those bastards over in marketing that are engineering the cover up. (Same link as above (those bastards(!) in marketing read Forbes).

So who's behind this outrageous theory that SSRIs cause suicides in some? What conspratorial axe are they grinding? Is it the greedy lawyers that are driving the research. Apparently Forbes readers again.

Help a brother out and break it down for me.

'The authors examined U.S. and Dutch data on prescription rates for SSRIs from 2003 to 2005 in children and adolescents (patients up to age 19), as well as suicide rates for children and adolescents, using available data through 2004 in the United States ...In the United States, youth suicide rates increased by 14% between 2003 and 2004, which is the largest year-to-year change in suicide rates'

Could rise in suicidality be because FDA data showed an INCREASE of 8% percent antidepressant prescriptions to children in the first 6 months of 2004, according to an article by the American Psychiatric Association the same year:

http://www.psychservices.psychiatryonline.org/cgi/content/full/55/10/11…

��In 2003, U.S. physicians wrote 15 million antidepressant prescriptions for patients under age 18, according to FDA data. In the first six months of 2004, antidepressant prescriptions for children increased by almost 8 percent, despite the new drug labeling��

I'm very surprised that the fact that antidepressant use in children INCREASED by 8 percent in the same year that it is now reported that there was an increase in suicides, was NOT reported by the authors in the recent study. It is extremely important data and should not have been omitted in research. The that fact that such pertinent data WAS omitted would indicate the research was NOT conducted in a scientific way, and therefore the results are NOT based on science. Unscientific research in medicine can cost many lives.

Apologies for html errors (I should have previewed before posting), to clarify the link in the previous comment:

http://www.psychservices.psychiatryonline.org/cgi/content/full/55/10/11…

"...In 2003, U.S. physicians wrote 15 million antidepressant prescriptions for patients under age 18, according to FDA data. In the first six months of 2004, antidepressant prescriptions for children increased by almost 8 percent, despite the new drug labeling..."

As the APA stated in 2004 that antidepressant prescriptions had risen in the first 6 months of 2004 according to FDA data, it makes the following assertion with regard to the recent studies surrounding the issue (http://ajp.psychiatryonline.org/cgi/content/full/ajp;164/9/A36 ):

"Suicides by children and adolescents increased as antidepressant prescriptions for them decreased after public health warnings in 2003-2004..."

quite clearly - a LIE.

Which in my view makes everything that follows that initial example of 'economy with the truth' quite clearly also suspect.

Thats the way genuine science works. Or in this particular instance - the lack of it. The publications should clearly be dismissed by the scientific medical community as simply unscientific, because they fail to adhere to including the established facts and are therefore not worthy of scientific consideration.

Perhaps studies should now be done by (independent?) scientists capable of including and studying ALL the established facts alongside new information. Isn't that the necessary criteria for any genuine research in any field of science?

The basic rules of science and research CANNOT be bent to suit a particular field, in this case one of psychiatry/psychopharmacology. Its either scientific or it is not. And this particular research quite obviously is not.