Thursday, March 18, 2010

Antidepressants are no more effective than a placebo and why that's great news

(updated seven times, please see below)

I finally read the Newsweek cover story, "The Depressing News about Antidepressants" by Sharon Begley. It's shocking. I highly encourage you to read the whole thing. Shortly thereafter, The New Yorker came out with a similar article entitled, "Head Case: Can Psychiatry be a Science" by Louis Menand that reports on a similar set of data (the article appears to be free right now but The New Yorker sometimes put things behind their subscription pay wall so check it out while you can). As is my style, I want to quote from both articles and then riff a bit at the end on what all of this may mean:

The number of Americans taking antidepressants doubled in a decade, from 13.3 million in 1996 to 27 million in 2005. [Basically 1 in 10 Americans.] -- Newsweek, January 29, 2010

In 1998, researchers examined 38 manufacturer-sponsored studies involving just over 3,000 depressed patients. The authors, psychology researchers Irving Kirsch and Guy Sapirstein of the University of Connecticut, saw—as everyone else had—that patients did improve, often substantially, on SSRIs, tricyclics, and even MAO inhibitors, a class of antidepressants that dates from the 1950s. This improvement, demonstrated in scores of clinical trials, is the basis for the ubiquitous claim that antidepressants work. But when Kirsch compared the improvement in patients taking the drugs with the improvement in those taking dummy pills—clinical trials typically compare an experimental drug with a placebo—he saw that the difference was minuscule. Patients on a placebo improved about 75 percent as much as those on drugs. Put another way, three quarters of the benefit from antidepressants seems to be a placebo effect....

Out of the blue, Kirsch received a letter from Thomas Moore, who was then a health-policy analyst at George Washington University. You could expand your data set, Moore wrote, by including everything drug companies sent to the FDA—published studies, like those analyzed in "Hearing Placebo," but also unpublished studies. In 1998 Moore used the Freedom of Information Act to pry such data from the FDA. The total came to 47 company-sponsored studies—on Prozac, Paxil, Zoloft, Effexor, Serzone, and Celexa—that Kirsch and colleagues then pored over. (As an aside, it turned out that about 40 percent of the clinical trials had never been published. That is significantly higher than for other classes of drugs, says Lisa Bero of the University of California, San Francisco; overall, 22 percent of clinical trials of drugs are not published. "By and large," says Kirsch, "the unpublished studies were those that had failed to show a significant benefit from taking the actual drug.") In just over half of the published and unpublished studies, he and colleagues reported in 2002, the drug alleviated depression no better than a placebo. "And the extra benefit of antidepressants was even less than we saw when we analyzed only published studies," Kirsch recalls. About 82 percent of the response to antidepressants—not the 75 percent he had calculated from examining only published studies—had also been achieved by a dummy pill.
The extra effect of real drugs wasn't much to celebrate, either. It amounted to 1.8 points on the 54-point scale doctors use to gauge the severity of depression, through questions about mood, sleep habits, and the like. Sleeping better counts as six points. Being less fidgety during the assessment is worth two points. In other words, the clinical significance of the 1.8 extra points from real drugs was underwhelming. Now Kirsch was certain. "The belief that antidepressants can cure depression chemically is simply wrong," he told me in January on the eve of the publication of his book The Emperor's New Drugs: Exploding the Anti-depressant Myth.

Even Kirsch's analysis, however, found that antidepressants are a little more effective than dummy pills—those 1.8 points on the depression scale. Maybe Prozac, Zoloft, Paxil, Celexa, and their cousins do have some non-placebo, chemical benefit. But the small edge of real drugs compared with placebos might not mean what it seems, Kirsch explained to me one evening from his home in Hull. Consider how research on drugs works. Patient volunteers are told they will receive either the drug or a placebo, and that neither they nor the scientists will know who is getting what. Most volunteers hope they get the drug, not the dummy pill. After taking the unknown meds for a while, some volunteers experience side effects. Bingo: a clue they're on the real drug. About 80 percent guess right, and studies show that the worse side effects a patient experiences, the more effective the drug. Patients apparently think, this drug is so strong it's making me vomit and hate sex, so it must be strong enough to lift my depression. In clinical-trial patients who figure out they're receiving the drug and not the inert pill, expectations soar. That matters because belief in the power of a medical treatment can be self-fulfilling (that's the basis of the placebo effect). The patients who correctly guess that they're getting the real drug therefore experience a stronger placebo effect than those who get the dummy pill, experience no side effects, and are therefore disappointed. That might account for antidepressants' slight edge in effectiveness compared with a placebo, an edge that derives not from the drugs' molecules but from the hopes and expectations that patients in studies feel when they figure out they're receiving the real drug.

In an analysis of six large experiments [published in the Journal of the American Medical Association in January 2010] in which, as usual, depressed patients received either a placebo or an active drug, the true drug effect—that is, in addition to the placebo effect—was "nonexistent to negligible" in patients with mild, moderate, and even severe depression. Only in patients with very severe symptoms (scoring 23 or above on the standard scale) was there a statistically significant drug benefit. Such patients account for about 13 percent of people with depression. "Most people don't need an active drug," says Vanderbilt's Hollon, a coauthor of the study. "For a lot of folks, you're going to do as well on a sugar pill or on conversations with your physicians as you will on medication. It doesn't matter what you do; it's just the fact that you're doing something."

Right about here, people scowl and ask how anti-depressants—especially those that raise the brain's levels of serotonin—can possibly have no direct chemical effect on the brain. Surely raising serotonin levels should right the synapses' "chemical imbalance" and lift depression. Unfortunately, the serotonin-deficit theory of depression is built on a foundation of tissue paper. How that came to be is a story in itself, but the basics are that in the 1950s scientists discovered, serendipitously, that a drug called iproniazid seemed to help some people with depression. Iproniazid increases brain levels of serotonin and norepinephrine. Ergo, low levels of those neurotransmitters must cause depression. More than 50 years on, the presumed effectiveness of antidepressants that act this way remains the chief support for the chemical-imbalance theory of depression. Absent that effectiveness, the theory hasn't a leg to stand on. Direct evidence doesn't exist. Lowering people's serotonin levels does not change their mood. And a new drug, tianeptine, which is sold in France and some other countries (but not the U.S.), turns out to be as effective as Prozac-like antidepressants that keep the synapses well supplied with serotonin. The mechanism of the new drug? It lowers brain levels of serotonin. "If depression can be equally affected by drugs that increase serotonin and by drugs that decrease it," says Kirsch, "it's hard to imagine how the benefits can be due to their chemical activity."

Antidepressants had sales of $9.6 billion in the U.S. in 2008.

The New Yorker article also cites the studies on the placebo effect by Kirsch and then for good measure questions the scientific basis for the entire field of psychiatry. About midway through a long article he drops this bombshell of a paragraph:

Later studies have shown that patients suffering from depression and anxiety do equally well when treated by psychoanalysts and by behavioral therapists; that there is no difference in effectiveness between C.B.T., which focuses on the way patients reason, and interpersonal therapy, which focuses on their relations with other people; and that patients who are treated by psychotherapists do no better than patients who meet with sympathetic professors with no psychiatric training. Depressed patients in psychotherapy do no better or worse than depressed patients on medication. There is little evidence to support the assumption that supplementing antidepressant medication with talk therapy improves outcomes. What a load of evidence does seem to suggest is that care works for some of the people some of the time, and it doesn't much matter what sort of care it is. Patients believe that they are being cared for by someone who will make them feel better; therefore, they feel better. It makes no difference whether they’re lying on a couch interpreting dreams or sitting in a Starbucks discussing the concept of “flow.” --The New Yorker, March 1, 2010

Okay so here's what we know:

* Most people do recover from depression.

* The effect of anti-depressants is almost entirely due to the placebo effect -- which is substantial.

* The 13% of depressed patients who are severely depressed, do seem to benefit from antidepressants for reasons that aren't clear.

* For everyone else, just sitting down and talking with someone who cares about you is as effective as any clinical treatment.

* The serotonin theory of depression is bunk and always has been (in spite of being repeated hundreds of millions of times a year by doctors, nurses, and mental health professionals around the world.)


So let me just take a moment to explain why I think this is good news, fantastic news even.

Basically, the effectiveness of psychopharmaceuticals was a bubble -- just like the bubble at the end of the 1990s and just like the housing and financial services bubbles that popped in 2008. Big Pharma is basically in the branding business -- no different than Nike, Starbucks, or Tommy Hilfiger. Big Pharma was selling a lifestyle brand -- PERMANENTLY HAPPY -- but in order to keep their huge profits going, they had to keep hyping the value of their product and pushing it on more and more people. And now that bubble has popped. It's not that there was never any value there. It's just that the value was not as great as advertised.

I was always deeply skeptical of the claims made by Big Pharma. It seemed to me that life is just a series of peaks and valleys. But Big Pharma pathologized the human condition to boost their profits (which is all kinds of messed up when you think about it). Furthermore, it seemed to me that the massive proliferation of antidepressants in the culture was too often just a (happy!) mask to hide the corporate power that has been strip mining our society for the last 40 years. Wages have been stagnant for 40 years, living standards are declining, and huge monopolies control an ever greater share of our lives (between Big Insurance, Big Energy, and Big Finance people have fewer discretionary dollars to spend each month -- most dollars are already allocated for survival before the paycheck ever arrives). PEOPLE HAVE REASON TO BE DEPRESSED BECAUSE THINGS ARE REALLY MESSED UP IN OUR SOCIETY. But Big Pharma came along and patted us all on the heads and said, no, no, it's just YOU who's messed up, society is JUST FINE!

But that quote from The New Yorker is really the big one:

patients who are treated by psychotherapists do no better than patients who meet with sympathetic professors with no psychiatric training.... it doesn't much matter what sort of care it is. Patients believe that they are being cared for by someone who will make them feel better; therefore, they feel better. It makes no difference whether they’re lying on a couch interpreting dreams or sitting in a Starbucks discussing the concept of “flow.”

Here's what that means -- if another human being cares about you and shows that he/she cares, you are likely to get better.

So much of our current moment -- the collapse of the global financial system, the decline in trust in corporations, elected official, and elites -- is pointing us to a return to modesty. To a return to what we know in our gut is true. To a return to living within our means. Furthermore, the evidence that human interaction plays such a large role in healing also points us to something much more important -- the return to community; the return to actually giving a shit about each other instead of trampling over each other in search of ever greater paper wealth. Which is really great news when you think about it.

Look, nature's antidepressants are sleep, exercise, natural food, community, and touch. All of those are almost free (natural food costs money -- but the profit margins on real food are substantially lower than on processed foods). But corporations sell us on the virtues of coffee, cubicles, fast food, and individuality -- because all of those are extremely profitable. And then corporations sell us the "solutions" to the problems they created. I think the way forward then, is for us to step away from the corporatist distortions that have come to permeate society over the last 40 years and to return to what we know to be true -- getting plenty of rest, moving our bodies, eating right, and most importantly, being really good to each other in community.

Update #1: This post is slightly modified from an earlier version. In a post I wrote earlier this week, I accused Niall Ferguson of letting his politics preceed his facts and yet I see that I did some of that in this post too so I went back and rewrote several sentences. Also, I should be clear to point out that all of the discussion above is in reference to depression and antidepressants. This research, by Kirsch and others, is only talking about the placebo effect in connection with antidepressants. Their research says nothing about other classes of psychopharmaceuticals including mood stabilizers, anti-convulsants, or anti-psychotics. Likewise, their research says nothing about the placebo effect in connection with other mental health issues like bipolar disorder, ocd, schizophrenia, etc.

Update #2: For folks interested in learning more about these issues, check out the Carlat Psychiatry Blog.

Update #3: Absolute genius: "how to be happy, a flow chart"

Update #4: Talk Deeply, Be Happy? from the NY Times. (hat tip AR for the link.)

Update #5:  It seems to me that based on the data above, we don't actually know whether the thing that is working is the 1. placebo, 2. the antidepressant drug, or 3. neither -- whether depression just remits on its own with time. Because even the placebo group in the control is still getting something -- no one in these studies is getting no treatment are they?  So isn't there still a third possibility out there -- that depression sometimes goes into remission on its own?

Update #6: A friend (who also happens to be a pharmacist) pointed out that antidepressants are both underprescribed and overprescribed at the same time.  Many of those with severe depression (the population actually helped by these drugs) are not on antidepressants whereas millions of middle class and wealthy people with good health insurance and milder symptoms are overprescribed these drugs.

Update #7:  Louis Bayard writing in reflects on this new data in a compelling and deeply personal post entitled, "My antidepressant gets harder to swallow: As studies shed doubt on certain psychiatric drugs, I wonder: Do I really need my little white pill?"  It's very very well done (and many of the comments are fascinating too).  Money quote:
It's bracing to see how depression is treated in other countries, where the relationship between drug manufacturers and physicians isn't quite so hand-in-glove. Great Britain's National Institute for Health and Clinical Excellence, for example, recommends that, before taking antidepressants, people with mild or moderate depression should undergo nine to 12 weeks of guided self-help, nine to 12 weeks of cognitive behavioral therapy, and 10 to 14 weeks of exercise classes.


Beth said...

Yeah, community's great, talking with someone is also great, no doubt. But there are those who need - NEED - to be on medications in order to get well. I tried for years to get better using all of the "natural" means, and I didn't get better. I just felt bad about myself because I couldn't cure myself.

Nothing worked until I was properly medicated, and that *isn't* a placebo effect. So I think your line of thinking can also be really dangerous for people who truly need to be medicated and decide NOT to because they feel like getting exercise should be enough or eating good food should be enough. For lots of people it's NOT enough, and then they can feel like failures or freaks.

I do think perhaps there's an overmedication of America going on right now, but as I personally thank god every single day of my life for Big Pharma and the medication that saved me life - and I will continue to do that every day for the rest of my long, happy, healthy life....the life that is now available to me thanks for the right medication!!

RFK Action Front said...

Yes, indeed, you are correct. That's what's so fascinating about these findings. Antidepressants really do work -- just not for the reasons that scientists think that they do (and a lot of other things work just as well). And for a certain subset of the depressed population -- about 13%, it seems the drugs actually DO work chemically to make things better. It's like quantum mechanics: antidepressants are sometimes a particle (placebo) and sometimes a wave (chemically effective) and no one is sure when it will behave as a particle and when it will act like a wave. But again, you are correct to point out the side of the story that I neglected to tell.

Jeanne said...

I have to comment on the line that actually made me laugh out loud: "Patients apparently think, this drug is so strong it's making me vomit and hate sex, so it must be strong enough to lift my depression."

I think drugs that would do that to me would ADD to depression rather than alleviate it. Just sayin'.

On a serious note, this article does offer a lot to think about...

RFK Action Front said...

Thanks Jeanne! Yeah that is a funny line. Two thoughts:

1. These studies (and this post) point to the power of the mind, the power of belief, and the power of caring for one another. The placebos don't work because they are placebos, they work because they activate that place inside us that makes us know that we are cared for and can get well. BUT, by the same token then, if the gosh dang doctors would say instead, "I have the remedy for your affliction -- but you have to follow it to the letter. Here's what you do: exercise 1 hour every day, never eat processed sugar or white flour, and hug your friends at least once a day and tell them you love them" then the evidence suggests that about as many people would get well from that too.

2. As you point out, many of the things people take for depression, and indeed the whole way that we've set up our society, seems to increase the problem rather than to help.

Josh said...

This truly is great news. The antidepressant bubble will be fizzling out and that could mean that research dollars will be diverted to new areas of study. It would be nice to see more research done into the placebo effect itself.

Does it seem like EVERY advertisement on TV is selling you happiness? Doesn't matter what the product is, just buy it and your life will change forever! It's no surprise that you can cook up a pill that barely outperforms placebos in alleviating depression and then market it to the masses like Red Bull.

What makes this story more twisted is how the marketing is part of the cure. So I find myself in the position of criticizing something that helps cure depression. Our marketing devices have the potential to heal too, imagine that.

RFK Action Front said...

Hi Josh:

Yep, you've hit the nail on the head! Three thoughts (following up on the reply I posted on twitter).

1. Alas, I'm not sure more research dollars will go towards the sorts of humanistic approaches that really deserve our attention because the sorts of things that might prevent depression -- exercise, community, touch, etc. are basically free. I think Big Pharma and their allies in government only want to research in those areas that are likely to generate huge profits. However, it is interesting to note that just in the last year Facebook overtook Google to become the most frequently visited website in the world. Basically Facebook has figured out how to position itself as the intermediary for (electronic) community and they are working hard at monetizing that.

2. Fun fact about Red Bull -- one of the key ingredients in Red Bull is inositol which is a mineral that is recommended for people suffering from anxiety disorders. Basically the massive doses of sugar and caffeine in Red Bull get one amped up -- but it's the inositol that takes away the jitters and leaves folks feeling hyped but calm.

3. Yes indeed, marketing has a huge impact on how these drugs work. Last summer Wired Magazine did a completely fascinating article on this topic titled, "Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why."