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‘The Reports of My Death Are Greatly Exaggerated’: As Is the Correlation of Antidepressants With Suicide

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“The Reports of My Death Are Greatly Exaggerated.” ~ Mark Twain

You can always count on Mark Twain for a response, even in the most awkward of circumstances.

In 1897, Mark Twain failed to return to New York City as scheduled (I forget why, but, as one who has spent much time in New York, I can relate to a desire for some delay), and reporters scrambled to find a cause–and to find Twain himself. As august a paper as The New York Times speculated that he might have been “lost at sea.”

Twain–alive and acerbic as ever–responded that the ‘reports of my death are greatly exaggerated.’

I think it’s up there with his “Heaven goes by favor. If it went by merit, you would stay out and your dog would go in,” and “In the first place God made idiots. This was for practice. Then He made school boards,” for the top 3.

But the point remains that sometimes people get the facts wrong–and that sometimes (shall I say often?), the media runs with those facts and creates a false reality.

That may very well have been the case with what we all accept as a truism today: Antidepressants greatly increase the risk of suicide in children and young adults.

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The FDA strikes

By March, 2004, things were not looking good for the antidepressants, as far as their standing with the Food and Drug Administration (FDA) went.

March 22, 2004: FDA advisory: “Worsening Depression and Suicidality in Patients Being Treated With Antidepressants“:

“Today the Food and Drug Administration (FDA) asked manufacturers of the following antidepressant drugs to include in their labeling a Warning statement that recommends close observation of adult and pediatric patients treated with these agents for worsening depression or the emergence of suicidality. The drugs that are the focus of this new Warning are: Prozac (fluoxetine); Zoloft (sertraline); Paxil (paroxetine); Luvox (fluvoxamine); Celexa (citalopram); Lexapro (escitalopram); Wellbutrin (bupropion); Effexor (venlafaxine); Serzone (nefazodone); and Remeron (mirtazapine).”

Surely not what the drug companies wanted to hear.

Litle did they know that 5 months later the second shoe would drop, with another, sterner warning on the topic.

“FDA NEWS RELEASE For Immediate Release PO4-97 October 15, 2004:

The Food and Drug Administration (FDA) today issued a Public Health Advisory announcing a multi-pronged strategy to warn the public about the increased risk of suicidal thoughts and behavior (“suicidality”) in children and adolescents being treated with antidepressant medications.

The agency is directing manufacturers to add a “black box” warning to the health professional labeling of all antidepressant medications to describe this risk and emphasize the need for close monitoring of patients started on these medications. . . .” [emphasis mine]

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The Return of the FDA

The dreaded ‘black box’ warning. It’s not quite what you’d hope for if you were in the business of marketing a drug. In fact, it’s about as bad as it gets–before it’s curtains.The warning goes on the package insert. It is the strongest warning the FDA mandates–the strongest one a med can carry and still remain on the US market–and it communicates that research indicates that the drug carries risk of serious–even life-threatening–adverse effects.

It’s just not good PR.

Here’s what it look liked, that black-box warning–on every insert of every prescription of the lucky antidepressants:

 “WARNINGS: SUICIDALITY AND ANTIDEPRESSANT DRUGS

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Drug Name] or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. . . . Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. . . .”

But the warnings weren’t over.

In May 2, 2007, there was another:

“FDA NEWS RELEASE: For Immediate Release PO7-77:

The U.S. Food and Drug Administration (FDA) today proposed that makers of all antidepressant medications update the existing black box warning on their products’ labeling to include warnings about increased risks of suicidal thinking and behavior, known as suicidality, in young adults ages 18 to 24 during initial treatment (generally the first one to two months).”

That was about all that was needed to create some massive hysteria.

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The Antidepressant-Danger Story Takes On a Life Of Its Own–Not Necessarily For the Best

The warning’s words ‘suicidal behavior,’ meaning suicide attempts, morphed in the public mind with ‘suicides,’ and antidepressant use became connected firmly with both suicide attempts and completed suicides–although the risk of completed suicides was never supported by FDA data.

Dr. Norman Sussman, psychiatrist at NYU Medical Center in New York City said FDA issued black box warning for antidepressants and risk of suicide in children and adolescents was “ill-conceived.”

It was a finding of an increased rate of ideation [suicidal thoughts] and attempts during some clinical trials that formed the entire basis for the FDA black box warning. Yet. . .no actual suicides occurred in these [trials].

Anthony J. Rothschild, M.D., director of the Center for Psychopharmacologic Research and Treatment in the Department of Psychiatry at the University of Massachusetts Medical School, emphasized the point once again that suicidal ideation and suicide attempts were different from completed suicides in an editorial in January of this year. He wrote,

although the FDA used the concept of “suicidality” as a proxy for completed suicide, they are not the same. “Suicidality” has been criticized as grossly overestimating the risk of suicide and as not being as clinically useful as more specific terminology such as ideation, behavior, attempts, and suicide.

But the point was too subtle, once fear took hold. Separating out completed suicides from suicidal behavior became an issue of confusing people with the facts.

With the FDA warnings was born a story that the media nursed from its infancy to, really, a form of adulthood.

The article, “News Coverage of FDA Warnings on Pediatric Antidepressant Use and Suicidality,” found that the tide turned against antidepressants after the FDA warnings. The situation was exacerbated by the news media’s tendency to use anecdote over a presentation of the statistics, which somewhat obfuscated the facts, and played into parental fears.

The authors found that, after the FDA advisory,

News stories, in particular television news, were more likely to include anecdotes of children harmed by antidepressants than children helped, whereas expert source quotations were more likely to emphasis the benefits of antidepressants over their risks. Given evidence that patients may weigh anecdotal versus statistical evidence disproportionately, the news coverage use of anecdotes of children harmed might have led to larger decreases in pediatric antidepressant use than would have occurred otherwise.

So it is no surprise that prescriptions decreased, between the FDA warnings and the media fear frenzy.

What some may be surprised to learn, though, is just how that decrease impacted youth suicide rates.

In a fascinating paper entitled, “Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents,” Robert Gibbons, from the University of Chicago, notes that from 1998-2003, there was a 91% increase in prescription rates for SSRIs [the newer, at the time, antidepressants, such as Prozac, Zoloft, or Paxil] in America–and a 33% decrease in suicide rates.

The trends reverse markedly after the FDA advisory.

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.

These findings, they believe, emphasize the protective properties of SSRIs when it comes to suicide, even in youths. Their statistics lead them to conclude that

If the FDA’s conclusion that there may be a causal link between suicide and antidepressants (which was the basis for the black box warning) were correct, we would have expected to see decreases in the suicide rate during the period of declining SSRI prescription rates, but instead we saw an increase in suicide rates, and the increase was greatest in the age range most affected by the decline in SSRI prescription rates. This finding. . .suggests that SSRIs confer a protective effect. [emphasis mine]

One more tidbit. According to Suicide Awareness Voices of Education (SAVE), suicide in young adults nearly tripled between 1952 and 1995, really before the newest antidepressants got their real start in treating children. If from 1998 suicide rates began showing a decline, might it very well have something to do with the introduction of these new meds?

It seems, based on statistics and numbers, you can score one point for the reviled pharmaceutical companies after all when it comes to youth suicide and its connection to antidepressants like Prozac and Paxil.

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Don’t Forget: The Greatest Risk for Suicide is Untreated Depression

As Gibbons’ study shows, questions about the accuracy of the FDA’s assertions have plagued the boxed warning all along–and recent research may be close to another nail in the coffin.

Before we get to that piece-de-resistance, though, let’s take a look at what clinicians thought at the time of the FDA advisory.

In 2007, in the New England Journal of Medicine, Richard Friedman, M.D. and Andrew Leon, Ph.D., published an editorial which questioned the very underlying beliefs of the FDA warning.

Their point? Yes, certain youths with depression–whether on or off antidepressants–will suicide, and their rates of suicide are higher than for the adult and geriatric population. BUT. . . Untreated depression is a suicide risk–and a far more serious one—than taking an antidepressant.

[Listen to parts of an interview with Andrew Leon on the FDA’s expanded black-box warning for antidepressants.]

In fact, according to SAVE, the strongest risk factor for suicide is depression. Thus not treating depression is what increases risk of suicide.

The point, and it’s a good one, got lost on the media coverage when the FDA announced its warning. Write Friedman & Leon,

There may be controversy about the risk posed by antidepressants, but there is none about the risk associated with untreated depression: estimates of the lifetime risk of suicide in depressed persons range from 2.2 to 15%, depending on the population under study — not to mention the considerable suffering and functional impairment caused by this illness. In contrast, the FDA meta-analyses reveal an absolute risk of suicide in patients taking investigational antidepressants of 0.01%. [emphasis mine]

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Prozac Is Redeemed–and Redeems Others With It

And then, just three months ago, came a new study refuting the correlation of antidepressants and suicide. Gibbons (from the University of Chicago, if you recall) and his colleagues reviewed over 40 controlled trials of well-known antidepressants Prozac and Effexor. In short? Suicidal ideation decreased with the two meds in adults, including the elderly, and did not increase in children and teens, according to the trials.

Results . . .across published and unpublished placebo-controlled RCTs of fluoxetine [Prozac] (adult, youth, and geriatric patients) and venlafaxine [Effexor] (adults) revealed that there was no evidence of increased suicide risk with treatment. Except for youths, the level of suicide risk for most subjects in these trials was low, and for all groups there was a major reduction in risk over time. Most events were suicidal ideation. . . . .For all adult trials, depression severity mediated the effect of antidepressant medication on suicide risk. . . .For youths, depression severity was strongly related to suicide risk and depression responded to treatment, but no effect of treatment on suicide risk was found. [emphasis mine]

It’s of course quite unfortunate that youths don’t seem to get the same suicide-relief that older adults do; but lack of relief is a far cry  from increasing suicidality.

[It does remain to address why suicide rates are so much higher among adolescents and young adults than among older adults. The authors suggest some other psychopathology is indicated here, such as aggressive impulsive traits. That seems quite possible, and indicates that even if antidepressants treat a number of the depressive symptoms in teens, the adolescents still have a risk for suicidal ideation and attempts.]

After surveying all the studies, however, the authors found that the rate of risk for such was

not significantly greater than that found for youths randomized to placebo. It was the finding of an increased rate of ideation and attempts using AERs that formed the entire basis for the FDA black box warning, and notably, we do not find such a signal. . .

The Gibbons study has a serious limitation, though, being that it focused on Prozac’s effect above all others. But Prozac was a med that took some very heavy heat in the antidepressant-suicide wars, one of only 10 antidepressants required to carry the initial FDA warning. It has become somewhat symbolic in the antidepressant wars–and is similar in biochemical makeup to a number of other drugs. As such, the relevance of the study remains strong.

Seems to leave the FDA with “some ‘splaining to do,” as Desi used to tell Lucy.

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Neither More Suicides, Nor More Suicidal Behavior

But for those who aren’t content to leave Prozac standing in as emblematic of ‘the antidepressant,’ an earlier 2006 study actually serves as mop-up. In “Suicide Risk During Antidepressant Treatment,” researchers analyzed records of 65,103 patients with 82,285 episodes of antidepressant treatment between January 1, 1992, and June 30, 2003.

Just as warnings had claimed, in some cases the risk of serious suicide attempt was in fact higher in the month after starting antidepressant treatment than in the subsequent 5 months. BUT. . .

The highest risk, however, was seen in the month before starting treatment. Although the total number of events in adolescents was much smaller. . ., the pattern of risk over time was generally similar to that in adults, with the highest risk in the month before starting treatment, a sharp decline immediately after starting treatment, and a gradual decline over the next 6 months.

The authors explain the spike in suicide attempts in the mont preceding treatment as most likely due to the fact that a suicide gesture or attempt often prompts treatment.

The patterns [we found] appear more consistent with a decline in risk after initiation of treatment than with a medication-induced increase. This trend in suicide attempts probably reflects improvement in depression rather than a specific effect of treatment on suicidality. The decline in suicide attempts shown in closely parallels the trend in depressive symptoms seen in patients who receive new antidepressant prescriptions

After running the numbers, researchers found that the risk of serious suicide attempt fell by more than 1/2 in the month after starting medication, and declined progressively after that.

In terms of completed suicide, the risk of death by suicide was stable during all 6 months after initiation of treatment with an antidepressant. It was not significantly higher during the first month.

Ironically, for their study, there were too few teen suicides to support analysis of time trends.

[In a second irony, all this held true for the ‘new classes’ of drugs, for example the SSRIs, just the ones first hit with the FDA warnings. Among ‘older’ antidepressants, the ‘myth’ of the danger of increased suicidality in first month held true: “Among those treated with older drugs (mainly tricyclic antidepressants), risk was highest in the first month of treatment, and risk in the first month of treatment was significantly higher than in months 2–6.” ]

In fact, in a paper as early as 2004, while the FDA was still passing out warnings, results were indicating that suicidal behavior was not related to antidepressants. “Antidepressant Treatment and Risk of Suicide Attempt by Adolescents with Major Depressive Disorder: A Propensity-Adjusted Retrospective Cohort Study” studied  24,119 adolescents suffering from Major Depressive Disorder, between the ages of 12-18.

And there, in the thick of the questions about suicidality and its association with antidepressants, the authors conclude:

 Antidepressant medication use had no statistically significant effect on the likelihood of suicide attempt in a large cohort of adolescents across the US after propensity adjustment for treatment allocation and controlling for other factors.

From One Great Name in Publishing (Over a Century Later) to the Next: Time For Backtracking

So it may be time for the media to change its tune.

In 2006, The New York Times ran a story Antidepressant May Raise Suicide Risk. Right in the thick of the FDA advisory warnings, the Times as frontrunner, as it so often is.

But by 2007, they had caught wind of a potential change, and ran “Suicide Findings Question Link to Antidepressants.”

Its equal, only in a different media, NPR published in February of this year, “A Fresh Look At Antidepressants Finds Low Risk Of Youth Suicide,” and The Atlantic, who can hold her own in this company, just recently ran a piece in March with the subtitle, “The FDA’s decision to require strong warnings about risk of suicide in kids on antidepressants could have been misguided, new study finds.“

So it seems the media’s onto it–they’re pushing the belief that antidepressants don’t cause suicidality.

And, given the studies coming out, I’m all for believing that in this case the media’s much more ‘with it’ this time than they were regarding Mark Twain’s untimely–and greatly exaggerated–death announcement.

REFERENCES

Barry CL, Busch SH. News Coverage of FDA warnings on Pediatric Antidepressant Use and Suicidality. Pediatrics 2009; 125:88-95.

Friedman, R.A. & Leon, A.C. (2007). NEJM — Expanding the Black Box — Depression, Antidepressants, and the Risk of Suicide. New England Journal of Medicine, 356:2343-2346.

Gibbons RD, Brown CH, Hur K, et al. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Archives of General Psychiatry Feb 2012 (ahead of print).

Gibbons RD, et al. Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents. American Journal of Psychiatry 2007; 164:1356-1363.

Rothschild AJ. Do Antidepressants Cause Suicide? Psychiatric News January 6, 2012; 47(1):17b.

Sharp IR, Chapman JE. Antidepressants and increased suicidal behavior: The media portrayal of the controversy. Scientific Review of Mental Health Practice 2004; 3:71-75.

Simon GE. Suicide Risk During Antidepressant Treatment. American Journal of Psychiatry 2006; 163:41-47.

Valuck RJ, et al. Antidepressant Treatment and Risk of Suicide Attempt by Adolescents with Major Depressive Disorder: A Propensity-Adjusted Retrospective Cohort Study. CNS Drugs 2004; 18(15):1119-1132.

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