Do Antidepressants Work?

In 2002, the July 2002 Prevention and Treatment published a study by Irving Kirsch PhD of the University of Connecticut. The study analyzed the FDA database of 47 placebo-controlled short-term clinical trials involving six antidepressants. These included "file drawer" studies, ie trials that failed but were usually never published.

The study found that the mean difference between the drug and placebo was a "clinically insignificant" two points on the HAM-D depression scale.

In other words, going solely on these data, there is no rational basis for choosing to take an antidepressant, much less for doctors to be prescribing them.

There are two main arguments to rebut this conclusion, both raised in an editorial in this month's American Journal of Psychiatry. In the editorial, Sanjay Matthew MD and Dennis Charney MD (both of the Mount Sinai School of Medicine) use findings from the NIMH-underwritten STAR*D real world clinical trials in support, namely:

"Mean" data is misleading in that it fails to parse out those populations who truly benefit from an antidepressant as opposed to those who don't. Clinical observation reveals that for certain patients an antidepressant is a Godsend. The catch is we don't know in advance which patients are more likely to respond.

STAR*D made an attempt at this, finding, amongst other things, that depressed people with anxiety or substance use, those with melancholic features, and those with a certain gene variation fare less well on antidepressants.

STAR*D also demonstrated the value of switching to a second antidepressant if the first one fails. The study showed that while at least half those in the study did not achieve a good result on their first try, according to the AJP editorial: "Patients who completed all phases of the study had an overall cumulative remission rate of 67%."

The editorial, however, failed to point out a major catch, namely that the 67 percent remission rate is theoretical, fully acknowledged by STAR*D. In the words of STAR*D's authors:

"The theoretical cumulative remission rate is 67% ... Note that this estimate assumes no dropouts, and it assumes that those who exited the study would have had the same remission rates as those who stayed in the protocol."

Ah, drop-outs. In the words of Holly Swartz MD of the University of Pittsburgh addressing a symposium at the 2006 American Psychiatric Association annual meeting: "If a patient doesn't stay on it, it doesn't do any good, even if it works."

The Kirsh study found a mean drop-out rate of 63 percent in it's review or clinical trials. This finding corresponds to other studies. In STAR*D, of 3,671 who entered the study only 123 made it to Round Four (keeping in mind that those who did well exited at earlier rounds).

Commenting on STAR*D, in a recent blog, Nassir Ghaemi MD of Tufts University noted that:

"Even if antidepressants worked in the short term (2 months, which is also what the meta-analysis assessed), one-half of patients who stayed on them relapsed into depression within one year. At the one year outcome, only about 25% of patients actually had remained well on and tolerated an antidepressant, much below the levels most clinicians seem to feel occurs in their clinical experience."

So what can we learn from all this?

First, beware of the exaggerated claims of the pharmaceutical industry and psychiatry. Also, beware of those making negative claims. All sides in this debate excel at spinning data.

Second - assuming you are not suffering from bipolar or a depression that behaves like bipolar - it is rational to choose to go on an antidepressant. Antidepressants may not work for everyone, but you may be one of the lucky ones.

Further, if your first antidepressant fails, it is worth persevering with a second or even a third antidepressant. Assuming you do not give up, your theoretical chance of success is two in three.

But also keep in mind you may find these meds intolerable and that relapse rates are high. They work in some cases, but they also disappoint. To conclude with Dr Ghaemi:

"We could all wish that clinicians' beliefs about antidepressants were true, or even half true. And perhaps they are the latter, for these agents surely have some uses in some settings; they are just not the dream drugs they seemed to be. ..."

From mcmanweb:

When Your Second Antidepressant Fails

The paradox: Perhaps if we don’t expect much of our antidepressant, we can get much better results.

Clinical Trials - What the Drug Companies Don't Report

So what is the most meaningful figure in an antidepressant trial? Apparently not the response rate, not the remission rate, not the Hamilton Depression scores. It's the drop-out rate, way too high whether going by industry figures or the FDA database. Clearly we are sending an unequivocally strong message that our medications leave much to be desired. Are any drug companies listening?