Smooth Pebbles

Slippery Ground: SSRI-Study Fallout Spreads

photo © iStockPhoto/AnikaSalsera

The ripples from the PLOS Medicine antidepressants-don't-work study by Kirsch et alia, which I covered below, just keep spreading. Those who want to follow it can do well by visiting or bookmarking this search I did (an ingenious Google News search for "Kirsch SSRI"). It seems to be tracking the press coverage pretty well. Note that the heavier and higher-profile coverage comes mainly from UK. As far as I can tell, none of the top 3 or 4 US papers have yet covered it.

This blog search should help as well.

Some of the more notable responses since yesterday:

Science weighs in. The Times Online (UK), with a hat top to SSRI as antidepressant, opines that "If it's all in the mind, fine."

The searches above will find more.

As many have noted, that antidepressants barely best placebo is not big big news; other studies have found that the drugs barely best placebo. But the starkness of Kirsch's "no effect" finding -- and the paper's assertion that there seems no reason to prescribe except for the deeply, dangerously depressed -- seems to have sparked a deeper examination of this issue than previous studies have. The anguish you see in many posts and comments, especially by doctors and depression sufferers, is that of an entire discipline and patient base having to confront the profound ambivalence of the data and the plain wierdness of the way in which psychiatric drugs work. Many drugs depend heavily on a placebo effect, of course. But the mind-body mystery raised by placebo effects in antidepressants presses itself more insistently, since "the body" doesn't seem so much in play.

This is slippery territory; not surprising that many are having trouble finding their footing.

Drug Bust Paper Blowback: Responses and implications to the Kirsch antidepressant study

The Kirsch study I wrote about a couple days ago, which found that antidepressants seem to have no more effect than placebo, has generated a wide variety of reactions in the blogosphere and press. Several things of note here:

1) In a pattern I've noticed repeatedly of late about other types of stories about things in the U.S., this story got much more attention in the British press than it did here in the U.S. (The authors were from the UK, but the paper was published in a U.S.-based journal, and antidepressant use is a huge issue in the U.S.)

2) The responses -- some by bloggers, writers, and other critics, some by doctors -- are a fascinating mix of hard-line rhetoric (from both sides) and more nuanced points about the difficulties of drawing definite conclusions from meta-analyses that are by their nature heavily statistical. Pointers to a few are below. Most intriguing is the exchange on the the PLOS Medicine site itself (where the paper was published), which involves mainly doctors. My thoughts on that are at bottom, below a far-from-complete annotated list of responses here and there

My thoughts on that are at bottom, below this shorter list of worthwhile responses:

Ben Goldacre, who writes the column "Bad Science" for the UK's Guardian, points out some of the more troubling implications of this study.

The Washington Post's Kevin Drum drew brief notice to it. His post is notable mainly for the lively and long string of reader comments it produced -- an exchange that suggests reader interest in the U.S. is perhaps more intense than editorial interest.

The journalist/blogger James Hrynshyn, of North Carolina, wrote a thoughtful post on his blog at Seed, as did Jonah Lehrer at his Seed blog The Frontal Cortex.

The Socratic Gadfly takes a shot at some of the study's limitations.

PsyBlog takes a measured, educational approach.

Among posts noting the study's limitations, the most damning I came across is perhaps that of Henry Gee, an editor at Nature. Gee is one of several writers who point out that a major caveat of this study is that it is limited to patients taking the drugs over only about 8 weeks or less, thus missing anyone who would have benefited from taking the drug for a longer period. He finds this completely damning:

This will affect the conclusions of the study, as every doctor (and patient) knows, antidepressants are drugs for the long haul. It takes weeks for them to have much effect, and this study seems to have had a cutoff before any such effect could be manifested. The results of this study are therefore compromised, and people who have been distressed by it have, I think, been misled....

So, shame on PLoS Medicine for touting what looks like a sensationalist story that grabs headlines on the distress of others; and shame (as usual) on the hog-whimperingly low standards of science news editing and reporting that have failed to pick up on this important flaw.

I think Gee goes too far. SSRIs do sometimes take weeks to kick in; but in most cases, they kick in inside of 8 weeks -- and some users get an initial lift then that then fades. So this time limit (created primarily by the drug companies who nevertheless repeatedly claimed to find high benefit during that period) strikes me as one of several limitations on the study rather than a fatal flaw. And the criticism ignores the fact that the drug companies repeatedly claimed to find a significant therapeutic effect inside that 6- to 8-week window. I'm not sure why we're supposed to accept on one hand that the drugs have proven themselves effective within an 8-week window ... but reject a study that finds they were not effective in that window because the drugs supposedly aren't effective till later. If they're not effective till later, how did the drug companies ever find an effect inside of 6 or 8 weeks? Strange logical territory.

As Gee notes, however, quite a few people, many of them doctors, lodged similar critiques at the PLOS Medicine "responses" site, as well as other objections more substantive. This is the juiciest reading on the paper I've found -- well worth perusing to get a sense of the debate and an education in the problems with meta-analyses, especially as applied to placebo effects. It's a serious debate even among doctors.

One doctor, for instance, says the study is a needed wake-up call to doctors who have been essentially falling for a placebo effect themselves; another doctor argues that "dozens of clinicals trials plus decades of clinical practice plus millions of content patients can't be that wrong. Whatever the bias in whatever the study, common sense clearly says: the sum of the parts attesting antidepressants efficacy blatantly outnumbers the evidence showing the opposite. The use of these antidepressants is now deeply rooted and well-established in medical society worldwide, it's safe, it works, and there's no shadow of doubt about it. Instead, this study insists in a different truth."

Overall, the discussion among doctors on the PLOS Medicine Responses page is The meta-analysis is a strange animal, in some ways more reliable than individual studies, since it looks at many; but problemmatic for the same reason, because it has to use some sometimes sophisticated (even obscure) statistical methods to extract (hopefully) reliable, consistent information from studies that may differ in structure and method.

How this all sugars out (no pun intended), I'm not quite sure myself. Two paradoxes jump to my mind, however. One is that the drug companies, with nods from the FDA, dug much of this hole themselves by structuring studies and often filtering results in ways designed to highlight advantages and minimize disadvantages. The short timespan of these studies is an example: When psych drugs work, they generally work their best early on, and the 6- or 8-week drug trial took advantage of that. That's just one way in which the drug companies created a clinical trial system that pretty much begs for harsh criticism; it worked for a while, but now it has cast the industry's credibility into question, making it extremely difficult to ferret out what really works and what does not.

The other paradox, even more painful, is that many, many people, both clinicians and patients, have found these drugs genuinely helpful. In a highly limited but important sense, whether these drugs help through biological mechanisms or through placebo effect is almost a moot point for those they help: They've given quite a few people the buoyancy to float atop life again instead of getting tugged under. The question I tried to raise in my earlier post remains: If these drugs lack a genuine biological effect (or if they have that effect only for a very few) but work well as placebos, how the heck do we replace them?

*update later 2/28/08: Another interesting thread of comments from doctors is this one at the Herald (the one from the UK).

How Jazz Players Get into the Zone

A jazz player's brain: Brain activation while improvising. Blue areas are deactivated comparable to normal, orange and read are ramped up. From PLOS One.

An intriguing finding: While improvising, jazz players seem to turn OFF the part of the brain that (to quote a new study just published in PLOS One) "typically mediate self-monitoring and conscious volitional control of ongoing performance." They're in what athletes call the zone, where they navigate the oncoming musical terrain by a sort of flexible trained instinct, like boulder-hopping downhill: Think about it and you stumble. Lovely stuff. But what part of the brain, then, is monitoring and responding? The sensorimotor areas, which are the same ones an athlete would use.

This strengthens my long-held conviction that playing sports and playing an instrument (I play tennis, baseball, ski, and play the violin -- the sports better than the violin, as family and neighbors can attest) are processes very much alike. Thus, among other things, the psychically cleansing effect that playing either tennis or the violin well produces: You are, in some senses, quite out of your mind for a while.

My bet is that if you could get Roger Federer in the scanner -- playing tennis, that is, -- you'd find similar brain-activation patterns. Time will come.

The study, by Charles Limb and Allen Braun at the NIH, is online and free at PLOS, is "Neural Substrates of Spontaneous Musical Performance: An fMRI Study of Jazz Improvisation." Abstract:

We found that improvisation (compared to production of over-learned musical sequences) was consistently characterized by a dissociated pattern of activity in the prefrontal cortex: extensive deactivation of dorsolateral prefrontal and lateral orbital regions with focal activation of the medial prefrontal (frontal polar) cortex. Such a pattern may reflect a combination of psychological processes required for spontaneous improvisation, in which internally motivated, stimulus-independent behaviors unfold in the absence of central processes that typically mediate self-monitoring and conscious volitional control of ongoing performance. Changes in prefrontal activity during improvisation were accompanied by widespread activation of neocortical sensorimotor areas (that mediate the organization and execution of musical performance) as well as deactivation of limbic structures (that regulate motivation and emotional tone). This distributed neural pattern may provide a cognitive context that enables the emergence of spontaneous creative activity.

Fish can count!

The amazing counting mosquitofish. Image courtesy Wikipedia

Eight years ago I published a book about a fight over how to count fish. Now it turns out that fish themselves can count. The account below comes from the BBC's natural history site, loveearth.com -- which is a well worth visiting anyway, full of visual and scientific wonders. The original paper is in Animal Cognition -- unfortunately, behind the usual absurdly expensive firewall ($32 for this article). Luckily there are science writers at the BBC to write this up:

Researchers find fish that can count up to four

Fish can count. We know that fish are able to tell big shoals from small ones, but now researchers have discovered that fish can actually count how many other fish are nearby.

'We have provided the first evidence that fish exhibit rudimentary mathematical abilities,' says experimental psychologist Christian Agrillo of the University of Padova in Italy, who made the discovery while studying a group mosquitofish (Gambusia holbrooki).

.... [The reseachers found that] the fish ... have a rudimentary ability to count, and that they appear to do so using similar cognitive mechanisms as other, higher vertebrates. 'They show a performance very similar to what is observed in apes, monkeys and dolphins,' Agrillo says.

The article then goes on to describe the clever experiments used to ferret out the counting ability:

[The research] team first conducted a series of experiments to see whether a lone mosquitofish would prefer to join a shoal of between two and four others. Females preferred to join shoals that were larger by just one fish significantly more often; consistently preferring shoals of four fish rather than three fish, and consistently preferring shoals of three fish over those containing just two. This means the fish were clearly able to count up to four and demonstrates that fish have a rudimentary mathematical ability to visually count how many items are present if the number is small.

A second series of experiments revealed the fish’s ability to process larger numbers. The fish were not able to directly count over four, but they were able to distinguish between larger numbers if they differed by a ratio of 2:1. For example, the fish could distinguish between a shoal of 16, compared to a shoal of eight others. But they could not tell the difference between a shoal of 12 compared to a shoal of eight, a ratio of 3:2. This demonstrates that fish are able to visually estimate larger numbers - but not very accurately.

I am fascinated to read of this testing for 2:1 ratios, for it is very similar to experiments that Harvard cognitive psychologist Liz Spelke and others have used to explore the numerical awareness, or "numerosity," as Spelke calls it, of human infants. I described Spelke's work in a profile for Scientific American Mind a while back. I'd love to know if the fish researchers took this method from Spelke and similar work.

The Drug Bust II: Big New Study Shows Antidepressants Have No Significant Effect

[This is a revised, expanded version of the original heads-up I put up last night.]

A large new meta-analysis of SSRI antidepressant trials concludes that the drugs have essentially no therapeutic effect at all. The study, in PLOS Medicine today, comes on the heels of another study published a few weeks ago (I blogged on it here) showing that SSRIs have little therapeutic effect if you include the (unflattering) clinical trials the industry had previously hidden.

The PLOS study is a meta-analysis of 47 clinical trials that account for almost all full data on clinical trials of SSRIs such as Prozac and Paxil. It showed that "compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression" -- and that (as the editors write) "the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective."

If this holds up, this is a huge development. Many people who take SSRIs say they help them, and they know they have a physiological effect because of subtle or more blatant side-effects -- everything from itching, dry mouth, and sexual problems to slight tingling or numbing of the lips or a sort of spacey feel. Those things often kick in within a few days. Then, for those who do feel better, the improvement follows 3 to 6 weeks later. But is the improvement a placebo effect and/or the result of attentive treatment via psychotherapy? The association of the felt physiological changes with improvement makes it seem clear the drug helps. This study appears to argue -- adamantly -- otherwise -- or, at best, that SSRIs work because the drug's felt physiological side-effects strengthen the placebo effect.

This is a profoundly consequential finding. Millions of people take these drugs, spending billions of dollars to do so. And many feel they are helpful. Are they being hoodwinked? Fooling themselves? All of the above? The finding that the drugs have no statistically significant effect is not necessarily the same as saying they don't help anyone. It is saying that the drugs help about the same number of people as placebos do. And placebos help a fair number -- generally between 30 and 50 percent in antidepressant trials. What's producing the placebo effect? The power of expectancy comes into play here, as does the value of even a little bit of official attention to one's despair. Back in 1963, Claude Levi-Strauss proposed some mechanisms behind the magic of placebo:

First, the sorcerer’s belief in the effectiveness of his techniques; second, the patient’s or victim’s belief in the sorcerer’s power; and, finally, the faith and expectations of the group, which constantly acts as a sort of gravitational field within which the relationship between sorcerer and bewitched is located and defined.

Whatever the mechanism, it's clear that placebos have an effect. If SSRIs are helping some people -- and they are, though apparently no more than placebo does -- then they may be helping via a placebo effect. THis is valuable, of course. But is it worth the side-effects (and incredible expense)? An SSRI makes a pricey placebo whether from a medical or an economic perspective. But it carries the placebo's effectiveness, which in depression seems to run about a third to a half.

Be nice, of course, if doctors could just prescribe placebos. But hoodwinking patients -- telling the they're getting a drug when they're getting a placebo -- violates informed consent, at least if the patient asks very many questions. A few years back, a NY Times Magazine article explored just this question -- If placebos work so well, why can't doctors use them?

This is not to suggest we should keep prescribing physiologically powerful, side-effect-heavy drugs just for a placebo effect. That's not conscionable. But most therapists feel it's clear that SSRIs, precisely BECAUSE they were so hyped and create such positive expectancy, have provided a tool that has helped many patients feel better and saved quite a few lives. What do we replace that with? This won't be an easy question to answer.

It'll be interesting to see how this plays out.

Some of the editors' summary is below. The paper itself is here, and free.

What Did the Researchers Do and Find?

The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.

What Do These Findings Mean?

These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.

Meta-Analysis Shows Antidepressants Have No Significant Effects

I've not had time to thoroughly read this yet. But on the heels of another study published a few weeks ago (I blogged on it here) showing that SSRIs have little therapeutic effect if you include the (unflattering) clinical trials the industry had previously hidden, PLOS Medicine now publishes a larger study -- a meta-analysis of all available data on clinical trials of SSRIs -- that shows that "compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression" -- and that (as the editors write) "the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective."

If this holds up, this is a huge development indeed. Many people who take SSRIs say they help them, and they know they have a physiological effect because of subtle or more blatant side-effects -- everything from itching, dry mouth, and sexual problems to slight tingling or numbing of the lips or a sort of spacey feel. Those things often kick in within a few days. Then, for those who do feel better, the improvement follows 3 to 6 weeks later. But is the improvement a placebo effect and/or the result of attentive treatment via psychotherapy? The association of the felt physiological changes with improvement makes it seem clear the drug helps. This study appears to argue -- adamantly -- otherwise -- or, at best, that SSRIs work because the drug's felt physiological side-effects strengthen the placebo effect.

It'll be interesting to see how this plays out.

Some of the editors' summary is below. The paper itself is here, and free.

These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.

Now THIS is bringing the war home

Yesterday's NY Times Magazine carried one of the best stories I've seen yet on our military efforts in Afghanistan in Iraq -- "Battle Company is Out There," a riveting and deeply informative piece by Elizabeth Rubin about the difficulties (to put it lightly) faced by a company of soldiers trying to win the war on terror (and keep mind and body together) in the remote highlands of Afghanistan. Simply stunning reporting -- relevant, compassionate, and frightfully immediate. This is reporting and writing on the level of Michael Herr's Dispatches. (And I do not say this just because I sometimes write for the Magazine.)

Check it out at:

Battle Company Is Out There
by Elizabeth Rubin

There is also an excellent slide show of photographs by Lindsey Addario. (Warning: Some are a bit bloody.)

The story's opening:

WE TUMBLED OUT of two Black Hawks onto a shrub-dusted mountainside. It was a windy, cold October evening. A half-moon illuminated the tall pines and peaks. Through night-vision goggles the soldiers and landscape glowed in a blurry green-and-white static. Just across the valley, lights flickered from a few homes nestled in the terraced farmlands of Yaka China, a notorious village in the Korengal River valley in Afghanistan%u2019s northeastern province of Kunar. Yaka China was just a few villages south and around a bend in the river from the Americans%u2019 small mountain outposts, but the area%u2019s reputation among the soldiers was mythic. It was a known safe haven for insurgents. American troops have tended to avoid the place since a nasty fight a year or so earlier. And as Halloween approached, the soldiers I was with, under the command of 26-year-old Capt. Dan Kearney, were predicting their own Yaka China doom.

NeuroImage of the Week: Pretty stuff in the rat brain

Neuroimage of the day:

Rat hippocampus neurons:

From Dissociated culture of rat hippocampal neurons on Flickr - Photo Sharing!]

Fabric may make the first real power suit : Nature News

Clothes that produce power. Who ever thought?

Fabric may make the first real power suit

From Fabric may make the first real power suit : Nature News

The fibres, covered with 'hairs' of zinc oxide, can be wired up for power.The fibres, covered with 'hairs' of zinc oxide, can be wired up for power.Z.L. Wang and X.D. Wang, Georgia Institute of Technology.

Mobile phone battery running out mid-conversation? One day you might be able to make a few vigorous arm movements while wearing a nanowire electricity-generating shirt to keep the battery going.

This is power-dressing in the real sense: nothing to do with shoulder pads or 1980s office dramas. Zhong Lin Wang and his colleagues at the Georgia Institute of Technology in Atlanta have made a yarn out of nanofibres that produce charge when they are rubbed against one another. Materials woven from these yarns could be used for self-powering clothes, shoes or biological implants such as pacemakers.

...

Wang took standard synthetic Kevlar fibres and coated them with tetraethoxysilane, onto which they stuck a layer of zinc oxide. Crystals of zinc oxide grew outwards, forming crystalline rods protruding from the fibres like the hairs on a brush. The power comes from the zinc oxide, which is piezoelectric: when mechanical stress — such as bending, crushing or stretching — is applied to a piezoelectric material, it produces a voltage.

Japan scientists make paper planes for space (Reuters)

And this:

Japan scientists make paper planes for space (Reuters)

Reuters - A spacecraft made of folded paper zooming through the skies may sound far-fetched, but Japanese scientists plan to launch paper planes from the International Space Station to see if they make it back to Earth.

I am sad that I can find no pictures.