Friday, May 2, 2014

Antidepressants and Suicide: Defending Prozac

It amazes me how many research scientists seem to have flunked statistics.  Or ought to have.  Me, I majored in the liberal arts.  But at Reed, even those who took Science for Poets would be required to rewrite some of the scientific papers I have read on the subject of antidepressants.

So the vocabulary terms for the week are observer bias and confounding variables.  No worries -- lots of pictures.

Clinical Experience in Defense of Prozac

Let's say you are a doctor treating 100 patients with severe depression.  You give them all antidepressants.  It seems irresponsible not to, doesn't it.  Thirty of them get better.  Fifteen do not make a follow-up appointment.  You switch the fifty-five who are still trying to another antidepressant.  Another fifteen get better.  And another fifteen do not make a follow-up appointment.

Over the course of a year, you get up to fifty whose depression is remission and ten who are still struggling.  You don't know what happened with the forty who are no longer seeing you. They couldn't afford treatment; they didn't like your face; they couldn't find parking; they got worse on your medication. You have no idea.  But you have fifty patients who think you saved their lives.  You feel pretty good about yourself, don't you.

Now the FDA comes along and tells you that you have to tell your patients that antidepressants may cause them to feel suicidal.

Following the FDA requirement of the black box warning, lots of news stories appeared with quotes like this one: "I've seen the SSRIs help people immensely," said Helen Stavros, a clinical social worker... "I've never seen anyone become suicidal as a result of being on antidepressants."  That is clinical experience talking.

Another word for clinical experience is anecdote.  They call it anecdote when patients are reporting and clinical experience when clinicians are reporting.  But it is the same story.

Commentary on Clinical Experience

Individual clinicians, in particular, are hindered by observer bias.  They do know, theoretically, that of those fifty people in remission, forty-five might have gotten better if they had been taking tic tacs (the placebo effect).  They do know, theoretically, that a depressive episode is self-limiting and usually goes away with no intervention whatsoever in six to nine months.  They do know, theoretically, that one cannot draw conclusions about those who drop out of the experiment.  And yet, they will ascribe an 80% success rate to their antidepressants in this hypothetical, because they prescribed them, expecting their patients to get better, and because the patients they still see did.

How many of their patients stopped seeing them because they got worse on the treatment?  They have no idea.  They do not observe them.

But it's not just clinical social workers like Stavros who get blind-sided by observer bias. A friend of mine heads the mood disorder section of the psychiatry department of a reputable research facility.  He tells me that he asks his colleagues why they get so agitated about non-compliance, when research shows that 90% of the efficacy rate for antidepressants is due to the placebo effect.  They respond with a blank stare.

Anecdotes have their place in research.  Their place is to suggest areas of investigation.  Is Stavros' six years of experience universal?  Is it even typical?  The FDA started looking at the suicide issue because of testimony by parents whose children had a very different experience of antidepressants.  -- Anecdotes, very powerful anecdotes that led the FDA to examine the experience of 77,000 patients in clinical studies, including the ones that the drug companies did not publish.

Among the many ways used to establish cause and effect, anecdote is the weakest.  Well-constructed clinical studies have the highest level of reliability.  But are 77,000 subjects enough?

Epidemiological Defense of Prozac

After the FDA mandated the black box warning, population-based (epidemiological) studies that crunched even bigger numbers were marshaled in defense of antidepressants.  One type of study would chart suicide rates for ten or twenty years before and ten years after the introduction of Prozac and other SSRIs.  In nation after nation, suicide rates rose in the 1980s until the introduction of Prozac, and then fell in the 1990s as the sales of these new antidepressants rose.

Dr. Julio Licinio, co-author of the much reported Depression, Antidepressants and Suicidality: A Critical Appraisal, said, I don't see how these drugs could be causing suicide if these rates [of suicide] are actually going down.

Commentary on Epidemiological Studies

Defenders of antidepressants don't publish these charts any more.  The charts do show that suicide rates fell steadily for a decade after the introduction of SSRIs.  But that trend ended at the start of the 21st century.  Suicide rates bottomed out in 2000, and started climbing again in 2001, before the black box warning, while antidepressant sales were still sky-rocketing.  Suicide rates have climbed steadily since 2001, especially in people of working age.  Meanwhile, more people are taking antidepressants than ever.

You see, if you chart suicide rates beginning in the 1920s through the current day, and then examine business conditions and the unemployment rate in the same frame, you establish a 90-year correlation between suicide rates and the condition of the economy.

Population-based studies run afoul of confounding variables.  If two things happen at the same time (antidepressant sales go up; suicide rate goes down), that does not mean that one caused the other.  [For science geeks, correlation ≠ causation.]  There might be a third issue responsible for the data.

Unemployment rate is the confounding variable here, at least one of them.  It turns out that SSRIs came along just as the boom years began. Their apparent success rode the business cycle up, and now rides it down.

Observational Cohort Study

An interesting twist on population-based studies is one from Denmark that bored in on the specific population that had purchased antidepressants in 1995-99.  Those who refilled their prescription had a lower suicide rate than those who filled it only once.  And the more refills, the lower the suicide rate.

The authors published this study under the title Do Antidepressants Prevent Suicide?  They conclude, Continued antidepressant treatment... is found to be associated with a reduced risk of suicide.  They aren't going to trip on that correlation ≠ causation thing.  So they leave it to the reader to answer the question in the title.

Well, don't answer too fast.  There was no effort to determine why those who quit did so.  Admittedly, with almost half a million patients, that would take a Herculean effort.  But here your confounding variable might be adverse events.  If the reason people failed to refill their prescriptions is that something bad happened when they took the medication, then we are comparing two different groups, those who can tolerate antidepressants and those who, for some reason, cannot.  These two groups might naturally have different suicide rates.

So there is your vocabulary lesson for the week, observer bias and confounding variables.  Put them together and you get a lot of research driven by wishful thinking.

Coming up, we look more closely at that Danish confounding variable, adverse events.

photo of diploma by author
flair from
clip art from Microsoft Office

Friday, April 18, 2014

Antidepressants and Suicide: A History

Do antidepressants prevent suicide, or do they cause it?


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 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
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Thursday, April 3, 2014

How To Tame Your Mind -- Ruby Wax

It's like training a dragon, only harder.

Ruby Wax nails depression: when your personality leaves town, and suddenly you are filled with cement.

She nails the problem: our brains don't have the band width for the 21st century.  Nobody's brain does.  Yours doesn't, either.

And she nails the solution: learning how to apply the brakes.

Monday, March 24, 2014

Richie Cox, Rest Easy Now

Any story worth telling is worth improving.

Richie had a fisherman's philosophy when it came to story telling.  He inspired, or provoked, or was co-conspirator in many of the Bar Tales of Costa Rica.  The following excerpt is my tribute to this cowboy/hippie/mystic who will be sorely missed.


There is one particular table at the Pato Loco where deals get made over American breakfast.  Mama, who has overheard a lot of deals being made, said, “It gets so you can tell the real ones from the ones who are all talk.  Paul, he never talks about his deals.  He’s one of the real ones.  But that Jerry who reneged on the house, you could tell he was all blow.”

Saturday, March 8, 2014

Christina the Astonishing!

Basil the Great vs. Christina the Astonishing – Lent Madness begins.

Saints and Lent – is Prozac Monologues straying from its mission, reflections and research on the mind, the brain, mental illness and society?  Hardly.  First, note the Madness in Lent Madness.  Then wait ‘til you see the saints.

Lent Madness

The forty days before Easter are traditionally a time to focus on one’s spiritual growth.  But there is a looniness built in from the start.  Ash Wednesday to Holy Saturday – count them – 46 days.  Oh yeah, Sundays don’t count.  Does that mean I can smoke and eat chocolate on Sunday?  Opinions vary.

And once you are debating whether you can smoke on Sunday (does it depend on what you’re smoking?), you have already leaned in the direction of madness.  Leaning, leaning…

Wednesday, March 5, 2014

Suicide Is Not a Choice

I peered over this very overpass on the Eisenhower Expressway.  Years ago, there was no the fence along the top, just a rail.  It was pie that brought me there.  Yes, pie.  It was Thanksgiving night, and the holiday was ending without pie.

Of course, it wasn't a reason to commit suicide.  Of course, suicide is a permanent solution to a temporary problem.  Don't treat me like an idiot with your clever lines.

No, pie brought me there, but that was not why I would jump.  Pie was a match, a tiny little three letter match.  My problem was a brain filled with gasoline.  And one tiny match, that I should have been able to snuff with my fingers, threatened to ignite it and send me over the edge.  The shame of being powerless over one tiny match poured on more gasoline.

Wednesday, February 26, 2014

Suicide Immoral? WTF?

Guilty pleasure: Eavesdropping on psychiatrists talking with each other about us loonies.  Like many guilty pleasures, it is not always good for my well-being.  But I am endlessly curious.  And it has yielded a number of blogposts in the OMGThat'sWhatTheySaid thread.

My go-to source for blog material is Psychiatric Times.  It reports the latest news and research in Loony Land.  It reflects on the practice of psychiatry.  Sometimes it turns to mud wrestling.  Oh, the good ol' DSM days!

A couple months ago, one of the editors, Ron Pies wrote a brave (foolhardy?) editorial inspired by Jennifer Michael Hecht's book, Stay: A History of Suicide and the Philosophies Against It.  Intending to provoke, he titled it, Is Suicide Immoral?  Let the rumble begin.