Peer Review, SSRIs, Suicide, and Booze

The recent study in the American Journal of Psychiatry by Gibbons, Mann, and colleagues regarding the relationship between SSRI usage and suicides reads more like an exercise for undergraduate students to find obvious errors than it does a real peer-reviewed study. Sounds mean, but keep reading.

The abstract of the study includes the following...

"In both the Unites States and the Netherlands, SSRI prescriptions for children and adolescents decreased after U.S. and European regulatory agencies issued warnings about a possible suicide risk with antidepressant use in pediatric patients, and these decreases were associated with increases in suicide rates in children and adolescents."

So less SSRIs = more suicides, according to the authors. Let’s see if this study actually shows such a relationship…

Look closely at the above graphs (click to enlarge) from the article. Note that the decrease in SSRI prescriptions from 2003 to 2004 was very slight across the 0-10, 11-14, and 15-19 age groups, which is the timeframe in which suicide rates for those aged 5-19 increased notably. The larger declines in SSRI prescribing for youth occurred from 2004-2005, which happens to be when the suicide rate for those aged 15-24 appears to have decreased from 10.3 per 100,000 (see Table 9; page 28 here) to 9.8 per 100,000 (see Table 7 here). Yes, I know I am comparing data for ages 15-24 to data on ages 5-19, but I think this makes sense when one considers that the suicide rate for those 14 and under is much lower than for those aged 15-24. Actually, grouping suicide data for ages 5-19 makes little sense to me given the vast differences in suicide rate within this age group.

It is important to note that the authors of the paper did not have data from 2005, but there is nothing from the 2003-2004 U.S. SSRI prescription data cited in their paper that even suggests a relationship between decreased SSRI use in youth and an increased suicide rate, as the decrease in prescriptions was minimal. Pay close attention: The authors ran a total of zero statistical analyses to examine the relationship between SSRI prescription rates and suicide rates in the United States. That’s right, zero. So they put up a couple of figures without a single shred of statistical evidence, then claim that declining SSRI prescriptions are associated with an increase in suicide rates. Any peer reviewer who was not drunk or on a high dose of Seroquel should have noticed this gigantic flaw.

In the discussion, the authors state: “While only a small decrease in the SSRI prescription rate for U.S. children and adolescents occurred from 2003 to 2004, the public health warnings may have left some of the most vulnerable youths untreated.” This is unadulterated speculation, which as I just mentioned is not supported by a single statistical analysis in their paper. It is also hard to imagine how an FDA warning in mid-October could make suicides earlier in the year increase. One can only wonder to what magical time-traveling extent an FDA warning in October could have increased suicide rates earlier in the year. This is so mind-bogglingly obvious that, again, the peer reviewers were possibly inebriated during the review process, or the editor published the paper over the objections of the reviewers. Am I being too nasty? I'm just trying to figure out how it got published and "good science" is not the answer.

The authors then proposed the following:

…we estimate that if SSRI prescriptions in the United States were decreased by 30% for all patients, there would be an increase of 5,517 suicides per year…

In addition…

In children 5 – 14 years of age, a 30% reduction in SSRI prescriptions would lead to an estimated increase of 81 suicides per year… Given that SSRI prescriptions for children under age 15 already underwent a reduction of approximately 17% from 2003 to 2005, we expect an increase of .11 suicides per 100,000 children in this age group. Since there are approximately 40 million children in this age group, we would expect 44 additional deaths by suicide in 2005 relative to 2003, or an increase of 18% in this age group.

Preliminary 2005 suicide data indicate a suicide rate in 5-14 year olds of .7 per 100,000, holding steady from 2004. This does not support the predictions of Gibbons and colleagues. Granted, the 2005 data are preliminary, but I’d be surprised if they showed a large change in the direction that Gibbons, Mann, and their team predicted.

Again, let me state that these are only correlational data and that data from clinical trials as well as other sources trumps these types of studies in any case. At the very least, when doing correlational research, try to control for covariates (other variables of interest), examine trends over a longer time period than one year, and maybe actually run some statistics. Oh, and avoid conclusions that require belief in time travel. There are even more potential problems, but the authors missed so many glaring basic issues that it makes no sense to go any deeper.

If data based on correlations is going to be trotted out to scare physicians into prescribing more SSRIs, then it should be examined whether the correlations provide even preliminary support for the idea that SSRIs might reduce suicide. I've criticized many studies on this site for a variety of concerns (like here and here, among many examples), and I think the present study is among the worst offenders of basic research methodology. Until we clean up the "science," don't expect much real progress in the mental health treatment world.

Background here and here.

Major Hat Tip: Furious Seasons.

Less SSRI's, More Suicide -- Apparently Not

Now that the 2005 suicide data are available from the CDC (as mentioned yesterday), one can see that despite SSRI prescriptions falling, there was apparently a very slight decrease in suicides. That does not lend credence to the story that decreased SSRI use leads to more suicides. The New York Times (Alex Berenson and Ben Carey) has some nice reporting on the story, including some telling quotes. Here's what Thomas R. Ten Have, a biostatistics professor at the University of Pennsylvania had to say regarding the latest study that claimed to show a link between decreased SSRI usage and increased suicide rate:

There doesn’t seem to be any evidence of a statistically significant association between suicide rates and prescription rates provided in the paper.

Yet here's what Dr. John Mann, one of the "experts" on the topic and coauthor of the previously mentioned study had to say:

The most plausible explanation is a cause and effect relationship: prescription rates change, therefore suicides change

Too bad the "most plausible explanation" just got shot down. This is just the tip of the iceberg regarding SSRIs and suicide. More to come at a later date. In the meantime, always be wary when someone notes that two variables are related, then claims that one variable causes another. Be especially wary when it turns out that the correlation is inconsistent or does not even exist, or may perhaps even go in the other direction. More to come another time.

Hat Tip: Furious Seasons.

SSRIs, CDC, and Suicide

Though some people have been asserting with confidence that a decline in SSRI prescriptions has led to an increase in the suicide rate, Furious Seasons has the story that, um, suicide rates were slightly down in 2005 according to data from the Centers for Disease Control. Link to the CDC document here and link to an excellent post at Furious Seasons here.

Many researchers, bloggers, and others have been slamming the FDA for daring to put a black box warning on SSRI's that links the drugs to potential increased suicidal ideation. If fewer people take SSRI's, more people die. Or so the argument goes.

There is indeed some correlational data linking decreased SSRI prescription with increased suicide rates, as well as some correlational data finding no such relationship. Mind you, there is a reason that we all learn in introductory research methods that correlation does not prove that change in one variable causes change in another variable. There are much stronger sources of evidence, which will be discussed at a later date. For now, it is interesting that the suicide rate appears to have fallen slightly in 2005 despite estimates that SSRI prescriptions fell significantly.

FDA Testimonies on SSRIs and Suicide

You may recall the FDA's meeting on SSRI's and suicide. You can now access the presentations of the speakers, including David Healy, Robert Gibbons, Sara Bostock, Vera Sharav, Robert Valuck, and many more.

Transcripts of the meeting (part 1 and part 2) are also available. Kudos to the FDA for their willingness to post all this material online.

Hat Tip: ShrinkRap.

Suicide Update

Psychiatric News, the newspaper of the American Psychiatric Association, has caused me a traumatic brain injury. How? Well, after reading the following, I hit my head against a wall so hard that I probably damaged at least 85% of my brain. Why?

The paper is beating the drum over the supposed relationship between a) the FDA placing a warning about the link between suicidality and SSRI usage and b) the subsequent increase in teen suicides. To arouse the ire of its audience, the piece stated:

"This is very disturbing news," said David Fassler, M.D., an APA trustee-at-large and a child and adolescent psychiatrist in Vermont. "The current data suggest that the decreased use of these medications is, in fact, associated with an increase in actual deaths attributable to suicide."

David Shern, Ph.D., president and CEO of Mental Health America, echoed Fassler's concern.

In the article, nobody was interviewed who took an opposing view. Better yet, there was no data presented in the article that the FDA warning actually led to a decrease in SSRI prescriptions for youth. As I have attested to in two prior posts on this issue, the data do not actually support that SSRI prescriptions for youths declined when the FDA issued its warning. So if prescription rates did not go down, kinda hard to say that declining prescriptions led to more suicides.

Yet note how the mainstream psychiatric press and the mainstream media have reported this issue -- it's a pro-drug circus where science is omitted so that a panic can better be created. Funny how there are never a lack of "key opinion leaders" who are willing to step up and opine on these issues despite having no data to back their assertions.

Update: Turns out there were data indicating a decline in SSRI prescriptions, though this information did not become public knowledge until much later. But, it appears that despite decreased SSRI usage, suicide rates fell slightly in 2005.

Bipolar in Kids: The BS Train Keeps Running

Earlier in this week, I wondered how Charles Nemeroff, "key opinion leader" in psychiatry at Emory University could make the following statement with a straight face...

"The concerns about antidepressant use in children and adolescents has paradoxically resulted in a reduction in their use, and this has contributed to increased suicide rates."

Note that the data do not actually show a decrease in SSRI prescription for teens during the timeframe when suicides increased, and that even if it did, such a relationship could have just been a coincidence.

But now, I believe that Nemeroff's statement does not even make for the least-supported (i.e., most fictional) statement of the week in psychiatry. The award instead goes to (extended drum roll, please...)

Jean Frazier of Harvard University. The New York Times quoted her as follows:

Dr. Jean Frazier, director of child psychopharmacology at Cambridge Health Alliance and an associate professor at Harvard, said that up to three-quarters of children who exhibit bipolar symptoms become suicidal, and that it is important to treat the problem as early as possible.

"We’re talking about a serious illness with high morbidity, and mortality," Dr. Frazier said, "and for some of these children the medications can be life-giving."

NICE! To my knowledge, there is little to no data to show that bipolar disorder is a valid diagnosis in young children, nor that early treatment is helpful, nor that treatment reduces risk of suicide for "bipolar" children, nor that 75 percent of "bipolar" children become suicidal. This is absolute nonsense, the type of statement that leads to unnecessary medication and leads people to falsely believe that bipolar disorder is a terrible epidemic among youth.

It gets even more detached from reality when we consider the case of Rebecca Riley, a four year old who was prescribed a very high dose of Clonidine, as well as being prescribed Seroquel and Depakote, and who died, reportedly due to the effects of her meds (clonidine seems to be the leading suspect).

Hat tip: Furious Seasons, who has been absolutely on fire as of late.

SSRI's and Suicide: Updated Update

I found more information regarding SSRIs and suicide in youth. I'm going to present two sets of statistics from an article and then illustrate how it is impossible to say that decreasing rates of SSRI prescription led to more suicides, contrary to what many "experts" are saying. From the Seattle Times:

The suicide rate climbed 18 percent from 2003 to 2004 for Americans under age 20, from 1,737 deaths to 1,985. Most suicides occurred in older teens, according to the data — the most current to date from the federal Centers for Disease Control and Prevention.

--SNIP--

Data from Verispan, a prescription tracking firm, show that 3 million antidepressant prescriptions were written for kids through age 12 in 2004, down 6.8 percent from 2003. Among 13- to 19-year-olds, the number dropped less than 1 percent to 8.11 million in 2004.

So, SSRI prescriptions were essentially unchanged in 2004 (less than 1% decrease) among older teens, who are much more likely to commit suicide than youger children. Logically, how could a less than one percent decrease in SSRI prescriptions among older teens lead to a significant increase in suicides? Seriously, folks!

I thank the Seattle Times for at least presenting some data, as other sources (such as ABC News) have just taken it as fact that SSRI prescriptions plummeted without presenting any information.

See a prior post on this topic here, which cites somewhat different data, but essentially comes to the same conclusion that there is no scientific data that link the 2004 increase in suicides to decreasing SSRI prescriptions.

Note: Please see the comments. A couple of readers provided some additional information that was very interesting. Note that my conclusion on this matter remains unchanged.

Less SSRI's, MORE Suicide (?)

Some "key opinion leaders" were in the papers again last week stating that the increase in suicide rates for teens was related to a lower prescription rate of SSRIs. Of note, in the news stories I've seen on the topic, no data have actually been provided to show that antidepressant prescription rates went down when the suicide rate increased. The lack of data, naturally, did not prevent the media from running with the story, much in the same way that children sometimes run with scissors.

For examples of reporting on the topic in the media, try MedPage, or ABC for example. The AHRP blog dug up information from the American Psychiatric Association that stated:

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.

The point here is that antidepressant prescription rates were actually rising when suicide rates were rising, so it is a bit hard to see how FDA warnings were leading to fewer prescriptions which were, in turn, leading to more suicides.

So how does this kind of story gain traction?

Enter Chuck. According to ABC News, Dr. Charles Nemeroff, a "key opinion leader" in psychiatry, (background here and here) said that

"I have no doubt that there is such a relationship," said Dr. Charles Nemeroff, chairman of the department of psychiatry and behavioral sciences at the Emory University School of Medicine.

"The concerns about antidepressant use in children and adolescents has paradoxically resulted in a reduction in their use, and this has contributed to increased suicide rates."

It would appear that Nemeroff has either seen some data nobody else has seen or that he is making things up. Given his cozy relationship with a plethora of drug companies, I'm guessing it's the latter. Even if there were data showing a decrease in SSRI prescriptions as suicide rates increased, surely Nemeroff would know that there could be numerous other factors involved. As is stated in every introductory research class, correlation does not imply causation. Of course, this point appears to be moot, as I've yet to see any evidence that SSRI prescription rates went down as youth suicide rates increased.

It would appear that this latest scare over SSRI deficiency causing suicide is another case of pseudoevidence based medicine.

Hat Tip: AHRP, Hooked.

Update: Nemeroff indeed had some data indicating that SSRI prescriptions have fallen. Yet it now appears that while SSRI usage fell, suicides did not increase. Nemeroff's statement above thus appears incorrect.

Then What Happens...

Recently, a reader had an excellent comment to which I responded. The content of these comments seemed like they may be of general interest, so they is reposted below, with very slight trimming of both the reader's comment and my response. All emphases are added in this version...

nab said...

The next logical step from Healy's accurate description:

For all of those patients who have been betrayed - directly or indirectly - or any of us who are on the "outside" should/do not really care whether this was complicity or whether many were (as I think) hoodwinked.

Accountability must be demanded from the entire system (academic - research - clinical): we don't care how you do it, you just need to not have these results. If you are a clinician and you get fooled, then I don't feel you to be gaining personally, but I would like to see the scrutiny that people like you are demanding, or else, how do we know this sort of thing won't keep happening.

That trust is fragile, and that is why (a) I truly appreciate the outrage we can from you - CL Psych and the likes of Healy, Avorn, etc., and (b) am completely frustrated and disturbed by the general lack of such a response from the mainstrean medical community.

For a profession that demands - and is mostly granted - autonomy in its decision-making, I don't really care - to a large extent - how or why bad knowledge was propagated. Obviously those directly responsible should individually be held to account, but at the institutional or professional level, these are examples of a systemic failure.

I feel that many doctors reach Healy's conclusion, shrug their shoulders, and say, "damn, those bastards fooled us, but I didn't do anything personally wrong so whatayagonnado?" Why do we not hear more outrage? Where is the outrage about Vioxx for example?

Regardless, I know Healy means well, but it is quite an indictment of the entire system - not just the pharmaco. or specific academics and clinicians involved. I feel that organized medicine (and doctors generally), love to point the finger at the insurance companies, the pharmaceutical companies, hospitals, anyone besides themselves.

Unfortunately, this causes them to ignore the obvious fact that the practicing doctors on the frontline and the honest and honorable academics researchers have the most power and could be the most effective at remedying these problems. And they ignore this at their own peril because if they don't demand accountability then ultimately soneone has to.

My reply

More scrutiny from practitioners would indeed be a good step. I suspect that a large majority of clinicians have no idea of the degree to which the system has been corrupted.

How can anyone practice Evidence Based Medicine when the Evidence Base is full of half-reported data that is often sold like a used car in such forums as industry-sponsored consensus guidelines, continuing medical education, journal supplements, doctor dinners, and conferences which resemble Disneyland more than a scientific learning environment?

My thoughts: Med schools need to step up their ethics training. Likewise, when the vast majority of of physicians are not trained in research design or statistics during med school, they are not well trained to sniff out the BS in studies.

I believe, perhaps naively, that a class in research/stats and a class that details the numerous examples of what can go wrong when industry and science mix would really awaken med students. That would allow them to have a chance at bucking the system. Reforming the infomercial continuing medical education system would also be a nice touch.

There are surely other ways to go about this, but those are my initial thoughts.

Feel free to add your two cents. Someone has to come up with some answers.