Friday, April 18, 2014

Antidepressants and Suicide: A History

Do antidepressants prevent suicide, or do they cause it?

Yes.

Well, maybe.

It's a no-brainer, right?  People who commit suicide are depressed.  Take away the depression, and how better than with an anti-depressant, and you decrease the risk of suicide.

So what's with the question?  Here is the story:

History of Antidepressants

The first modern medications used to treat depression were imipramine and its imitators, developed in the 1950s.  Nortriptyline is a currently prescribed example.  They worked great, but had harsh side effects, plus one major draw-back.  Overdoses are lethal.  A lot of doctors were reluctant to hand them to people who had announced their intention to off themselves.

Then came Prozac.

Debuting in 1987, Prozac had less severe side effects and was deemed safer.  An overdose might make you sick, but was not fatal.

It was soon followed by a host of other medications that worked the same way (for us brain geeks: by inhibiting the reuptake of serotonin).  These include Celexa, Lexapro, Zoloft, Paxil, and Luvox, and half siblings Cymbalta, Effexor, and Pristiq.

Over the next 20 years, antidepressant use increased by 400%.

Today, 11% of people in the US, aged 12 years and older, take antidepressants.  Among women in their forties and fifties, 23%.

Evidently, a lot of doctors overcame their reluctance.

Bad News and Prozac

However, an occasional news story began to appear.  People on Prozac claimed the medication was responsible for irrational behavior, even violent crime.


The Prozac Defense in court was usually rejected out of hand.  But troubling claims about suicide, particularly among teenagers, would not go away.

Suicide and Statistics

Research about suicide risk for antidepressants is plagued by problems with method.  The biggest issue is that clinical trials, designed to determine whether a medication works, do not enroll enough participants to yield significant results about suicide risk, either positive or negative.  (Significant in research lingo means that the results reach a certain level of probability, that they didn't happen by chance.)  It doesn't take as many participants to establish efficacy.

Researchers record what they call Adverse Events, AE.  Suicide would be a Serious Adverse Event, SAE.  Ya think?  person with clinical depression has a 10-15% risk of suicide over a lifetime.  But pick any random two-month period out of that whole lifetime, say April and May, and chances are really good that person will survive to June.  That's as long as a clinical trial lasts.  So the odds are friendly to drug companies who do not want people to die while they are testing their newest money maker.

In 2003 the British equivalent of the FDA (Medicines and Healthcare Products Regulatory Agency - MHRA) conducted a meta-analysis -- they put together the data from several clinical trials.  With these greater numbers, they did establish a significant risk of suicide for teenagers taking antidepressants, and banned the use of all antidepressants except Prozac for teens and children.  Prozac dodged this particular statistical bullet, though in the US, the FDA would later find against them.

Well, you can imagine how that went over among doctors who want to prescribe these drugs, not to mention the drug industry that wants to sell them. 

FDA Weighs In

After the MHRA raised the alarm, the FDA conducted its own meta-analysis, addressing objections raised to how the MHRA counted suicidal events.  They came to similar conclusions as the MHRA, but stopped short of banning anything.  Instead, in 2004 they required that a black box warning be added to the prescribing information.

All medications have risks, even when prescribed by doctors who know what they are doing.  A doctor (should) educate the patient about risks and the more frequent side effects.  Some doctors are more conscientious about this responsibility than others.

A black box warning is the strongest caution the FDA gives for a medication that it allows to be sold.  It tells the doctor to inform the patient about the risk included in the warning.  In addition, the box is printed right up top on the paper that comes with the medicine bottle from the pharmacist.  So patients (might) see it, even if their doctor fails to provide adequate information.

Here is the template for the current version:


Again, you can imagine how that went over.

Why a Black Box Warning?

The value of these black boxes might reasonably be questioned.  Patients do not see them until they have the medication in their hands.  The simpler one-sheet that lists what it is for, how to use it, and what its potential side effects are begins with another line, something like: This information should not be used to decide whether or not to take this medicine or any other medicine.  Only your health care provider has the knowledge and training to decide which medicines are right for you.


Well, okay.

Meanwhile, the patient's ten minutes with the doctor are over, and the doctor is no longer available for further discussion.

And even assuming that anybody is reading any part of what has become a several page insert in tiny print, what does clinical worsening, suicidality, or unusual behavior mean, anyway?

John Grohol of psychcentral.com summarizes the medical profession's problem with this warning by suggesting that shallow reporting of the issue scares people off of effective treatments, and leaves them no better informed about their specific risks and benefits.


And with that we move next week to what doctors and drug companies have to say, Defending Prozac, and after that what I wish doctors and the FDA were saying, Collateral Damage.  Stay tuned...


The Death of Chatterton by H. Wallis, in public domain
photo of Prozac by Tom Varco, used under creative commons license
photo of pancakes by Jacks and Jason's Pancakes, used under creative common license
photo of gavel from Luke Air Force Base by Airman 1st Class Grace Lee, in the public domain
image of black box warning in public domain
flair from facebook.com

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