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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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February 27, 2008

Antidepressants: Depressing News or Not?

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Posted by Derek

There’s an interesting analysis in the latest PLoS Medicine on the clinical effectiveness of four modern antidepressant drugs: Prozac (fluoxetine), Effexor (venlafaxine), the partially discontinued Serzone (nefazodone), and Paxil (paroxetine). The authors compared all the published placebo-controlled studies on these drugs, and further included all the regulatory filing data. (Update: not so! See below). The result made headlines all over the place yesterday, because one of the things they found was that these drugs hardly seem, compared to placebo, to do anything at all.

Here’s the odd part: that shouldn’t have been such a big surprise. It wasn’t surprising to the authors of the paper – in fact, they started with the belief that this would be the case, because that analysis has been done before. Their interest was in seeing if there was some difference between different populations of depressed patients – is there some group for which the drugs really show efficacy or not?

As it turns out, there is, but perhaps not for the reasons you’d think. The most severely depressed cohort do seem to show a statistically meaningful response, but that seems largely because the placebo group’s response goes down. That’s been the difficulty with antidepressant clinical trials forever: there is a huge placebo response. This isn’t news; people have been studying this effect and trying to figure out what it means (or figure out a way around it) for years.

So, what does this do to the whole popular culture around the SSRI drugs – you know, “Listening to Prozac”, “Prozac Nation”, all that sort of thing? In this case, popular culture probably has it wrong. These drugs are not magical happy pills, but “Placebo Nation” just doesn’t have the same ring to it. The whole subject is too tangled to make for a catchy title.

It makes sense, though, that this is the area of drug discovery where the biggest placebo effect would turn up – you’d have to think that for depressed patients, a big step would have to be the thought that something can actually affect their condition. It’s bound to help for them to believe (correctly) that their moods aren’t necessarily part of the drab fabric of the universe, but depend instead on the (changeable) chemical weather inside their brains. Knowing those things, and the act of taking a medication that is supposed to work, is enough to help between a quarter and a half of depressed patients right there.

The actual mechanism of the placebo effect is a field of great interest and potentially great importance. (See here, here, here, and here). News like this makes a person wonder, though: if large parts of the public become convinced that antidepressant drugs don’t work, will they? And the question remains: do the SSRI drugs do anything at all through their supposed chemical mechanisms? (It's not like we know). One way to find out would be to run a placebo versus placebo trial. You could blind things at the start, even though everyone was getting the same sugar pills, and you’d presumably see the same response in each group. Then you unblind and cross everyone over, telling people that they’d been in one group and were now headed to the other. Careful work would give you four study arms: (1) people who responded to placebo, and who were then told they’d been taking sugar but were now getting the real drug, (2) people who responded and were told that they were taking a real drug but were now being switched off of it, (3) people who didn’t respond, but were told that this was because they’d been taking sugar, but help was now on the way, and (4) people who didn’t respond, and were told that they’d been getting (apparently ineffective) drug, but were now coming off even that. Fascinating stuff, but we’re going to have to wait for the North Koreans to set it up for us, because no other regulatory agency would let it through.

But from this latest analysis, we can conclude something interesting. The fact that the placebo effect diminishes in the most severely depressed patients, but that the drugs continue to show the same level of efficacy, suggests that they do have some effects of their own. To me, that’s the real news from this study. It reminds me of G. K. Chesterton’s line about journalism being the business of saying “Lord Jones Is Dead” to people who never knew he was alive. In this case, the headlines have been “Antidepressants Don’t Work”, but that should have been the headline years ago. This one should have come in as “Antidepressants Might Actually Do Something”.

Update: A closer look, as suggested in the comments section, shows that the trials included in the meta-analysis were mostly quite short (six weeks or less), when a good deal of evidence would suggest that these drugs take longer to become truly worthwhile. And there is only one study on moderate depressed patients, making it hard to draw conclusions about that group. See the comments page on the article here for more criticisms. So, do antidepressants work or not? You can find an answer that fits, no matter what you need it to be. . .

Comments (32) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System


1. LNT on February 27, 2008 9:57 AM writes...

One thing I have not seen pointed out yet is that IT MAKES SENSE that the most depressed patients have the lowest placebo response. Severely depressed people are unlikely to believe that anything will help them -- and that becomes a self-fulfilling prophesy.

A lot of people are up-in-arms over the fact that the drugs have little effect over placebo. However, those same people would cry foul if their doctor gave them a sugar pill and told them that it was an effective treatment for depression. It seems to me that placebo only works under the guise of deception. If patients were honestly told that they were receiving a sugar pill, then the placebo effect would likely no longer exist.

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2. Still Scared of Dinosaurs on February 27, 2008 10:55 AM writes...

I think that "the placebo effect" is as confounded a phrase as "the cure for cancer". There are many different "placebo effects" that need to be considered when interpreting trial data. One is that the presence of a placebo arm in a trial often changes the population of patients willing to enroll, especially when comparing trials conducted prior to the first approval for a new class such as SSRI's versus subsequent trials.
Another is that "placebo" really means "everything in the trial except the agent of interest" which in the context of a trial for an antidepressant could include talking to a nurse and/or doctor on a weekly basis. Also, since trials often include people who don't have adequate health coverage those talks may be the first in a substantial period of time. This can lead to a bolus of newly diagnosed conditions at the start of the participation that are nonetheless classified as treatment emergent events.

There are many more possibilities but in every case context is hugely important in interpreting what the relevant factors might be. The effects of patients' beliefs are only a part of what might be going on.

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4. MTK on February 27, 2008 11:00 AM writes...

First, a disclaimer, I haven't read the study only the commentaries and reports about it. Also the SRRI's treat more than depression. Anxiety, OCD, etc. and I don't know if the same conclusions hold for those indications.

One of the more interesting aspects of all this is reading people's responses to the popular press reports whose tone was generally that antidepressants don’t work. The responses essentially fell into 3 general categories. 1) "Bull. They've done wonders for me. I can tell you firsthand that they work.", 2) "Just another example of the pharma companies ripping us off.", and 3) "you don't need to take what pharma is feeding you, use Vitamin X instead." The irony of each of these is astounding given that the whole point is that the placebo effect is huge.

#2 is my favorite, because if anything the "joke" is on pharma for spending all the money to develop these things. The alternative to getting ripped off by pharma would be to get ripped off even more by a placebo maker who would have to charge pharma-like prices to make the placebo convincing.

BTW, anyone know how bad the side effects are in the placebo groups in these studies?

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5. Placebo Side Effects? on February 27, 2008 11:36 AM writes...

If these drugs dont have a measurable effect, a "Placebo only" homeopathic treatment would be more cost effective including ZERO side effects. For the patient, the effect counts, even if it is a Placebo one.
But big pharma seems to be interested in making big money, even with (Placebo?) side effects...

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6. DrSnowboard on February 27, 2008 11:57 AM writes...

Similar disclaimers as above but the placebo effect is also surprisingly high in pain trials. Not only for subjective scoring in antimigraine trials but also for other situations. I seem to recall there was a small but stoic placebo group for some of the COX-2 trials given post-double wisdom tooth extraction...

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7. Sigivald on February 27, 2008 1:06 PM writes...

#5: Placebos have side effects too. The same mechanism that makes them "work" sometimes also makes them cause side effects.

I've seen enough "placebo vs. medicine" side-effect charts to see that simply giving someone a pill will cause some side effects in a number of people.

Plus you neglect the real-world issue of giving people a placebo outside of a trial - the ethical issues are huge, as are the ones of not letting them ever find out it's a placebo. Because, you see, if they know the pill itself is doing nothing, the effect flies out the window.

(And yes, scary old "big pharma" wants to make money. Because if they don't, their shareholders sue them, and if that doesn't happen, they simply go out of business, and nobody gets anything, ever from them.

Side effects are inevitable with any drug that does anything, short of a radical and far-off improvement in our understanding of the entire human body's most subtle processes and interactions. (Assuming we bracket off placebo-induced side effects.)

Considering that we have only a gross and rough understanding of any but the most major and obvious processes, you can call back in a century, minimum. Maybe two.)

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8. Anon on February 27, 2008 2:27 PM writes...

Hi Derek,

I'm a bit surprised by your take on this study - I would take a closer look at the methods section of the paper/some of the comments the discussion page (for example this one and this one).

Basically, the meta-analysis is potentially flawed because quite a bit of the data came from very short trials. It's pretty well known that SSRIs don't 'kick in' right away (usually two-four weeks) and patients often need to try a few different SSRIs before they find one that 'works' for them - so I think people need to approach this particular meta-analysis with a bit more skepticism. (I'd actually approach all meta-analyses with quite a bit of skepticism...)

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9. confused on February 27, 2008 2:35 PM writes...

I'm confused... why can't the trial be run in the following way. Give everyone a placebo and after a given time x swap a proportion over to the actual drug. That way the people who would have had the 'placebo effect' could be accounted for in the study and of those who showed improvement on placebo any additional effect of the trial drug would reveal itself?? I don't think the ethics here are any worse than a double-blind study, but could be on the wrong track here and it seems more simple than the plan proposed in the post.

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10. MTK on February 27, 2008 3:19 PM writes...


It's unethical to give patients who could receive treatment, no treatment. In fact it is forbidden by the Helsinki human rights protocols of 1964. That's why Dinosaur's reminder of what is meant by placebo is important and that's why Derek mentioned a non-signatory country.

In the case of depression, however, the placebo treatment is psychotherapy alone, so one might be able to do it. I'm not an ethicist, so don't take my word. In other indications, the double-blind is compared to a standard of care. One of the challenges in formulations and clinical development is devising ways to make the pills and protocols so you don't provide a tell.

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11. Mac on February 27, 2008 5:19 PM writes...

Sometimes ethics just goes against the best means of scientifically achieving useful results. One of those annoying realities of life.

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12. sroy on February 27, 2008 7:07 PM writes...

Just my 2 cents,

As some one above has pointed out meta-analysis of clinical trials by a group known to have a bias against SSRIs need to be taken with some skepticism.

Having said that it is important to understand why this particular result is possible.

SSRIs not only take a few weeks to work, but they also do not treat depression as such. They reduce the anxiety, intense emotions, repetitive behavior and thought patterns caused by depression. The best evidence for a therapeutic effects of SSRIs are in treating anxiety and OCD. SSRIs dampen all emotional response by raising serotonin (and have sexual side effects + delay ejaculation).

The brain had particularly good feedback loops to reinforce behavior and emotions. SSRIs essentially trick the brain into working as if it were not depressed. If you remove the negative emotion feedback loop, things cannot get worser than they were and the depression will eventually improve.

However if your cause of depression was too bad, your brain will recover pretty quickly on it's own. Most SSRI prescriptions are for mild reactive depression (life events), rather than a strong medical history of severe depression.

Noradrenaline and Dopamine reuptake inhibitors (Bupropion and Methylphenidate) on the other hand improve mood and motivation and dampen the negative emotion feedback loop by 'raising the bar' required for a negative emotion to have any effect. That is why they do not have sexual side effects (do not dampen emotion). Infact they seem to help with desire issues in non-depressed people. They also work much faster - often within 3 days for methylphenidate (ritalin).

I have always believed that NA and Dopamine reuptake inhibitors are the way to go for treating most cases of depression (especially the mild ones).

Non-selective MAO inhibitors are even more effective, but have issues with safety due to interactions with dietary tryptophan. Given that the first MAO inhibitor was discovered because of unexpected happiness in TB patients treated with an analogue of isoniazid (iproniazid), I do not doubt that it works. Non-selective MAO inhibitors such as phenelzine and tranylcypromine are still the last hope for severely depressed patients before ECT.

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13. Skeptic on February 27, 2008 7:42 PM writes...

"Considering that we have only a gross and rough understanding of any but the most major and obvious [biological]processes, you can call back in a century, minimum. Maybe two."

Probably never in North America. With all of academia kissing corporate butt in a last ditch attempt to keep overinflated stock prices of pharma from collapsing I wonder who is going to have the foresight to attack the protein interacterome with a novel viewpoint(meaning no more nodes and links, computationalism, holism)

Surely the medicinal chemists are in way over their heads?

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14. Polymer Bound on February 27, 2008 8:17 PM writes...

Skeptic, we're waiting for you to descend on our industry and show us the light. I'm a fan of Nature Reviews Drug Discovery... how about an opinion piece?

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15. MTK on February 27, 2008 8:48 PM writes...


A very reasoned response. Only one thing. It doesn't address the large placebo effect.

So while your analysis of SSRI's vs NA vs. dopamine, etc all sounds great, it won't mean much in treating less than severe cases of depression if the placebo effect requires clinical trials of any drug in the 100,000's to see significance.

Maybe a clinical protocol needs to be written where the doctor providing the drug or placebo has to whisper to the clinical trial patient "I think this drug is a load of crap, but hey, you never know."

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16. OrgChemPostdoc on February 27, 2008 9:30 PM writes...

Drug development is based on lottery (screening). Then voodoo (biology) is coming in. Finally, the holy council (FDA) decides whether Lottery x Voodoo = Drug.
Within Pharma, this process is called "scientific". And the integrity of the system is out of question, since it is all ethical...

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17. Skeptic on February 28, 2008 12:28 AM writes...

Polymer Bound,

I will take your advice and do so.

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18. milkshake on February 28, 2008 1:26 AM writes...

roy: dietary tyramine, not tryptophane.

With some MAOs you cannot consume large quantity of aged cheese, fava beans and Chianti, Clarice.

Deprenyl (selegiline) being somewhat MAO-subtype selective has fewer complications than other MAOs, it can be used in elderly patients for exmple.

The problem with SSRIs is that they are known to be "safe" in sense that it is hard to overdose on them. So we end up with every goddamned psychologist hired by HMO instead of a real doctor "treating" patients by behavioural therapy. And of course he has a nurse who can write prescriptions for SSRI to augment the therapy. Then we get a bipolar patients misdiagnosed as being depressed. You put them on short-acting SSRI like Citalopram and you turn them into fast cycling between frank mania and depression.

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19. sroy on February 28, 2008 1:26 AM writes...


The strong placebo response for pain, anxiety, depression meds is the result of the your brain's neuron net filters readjusting the effect of
feedback loops. It will happen by itself in most people unless the condition is severe. The human brain is an incredibly flexible,versatile and self-equilibrating emergent system

Antidepressants merely help the process. However if I wanted an antidepressant I would go for bupropion or methylphenidate. Methylphenidate is somewhat harder to obtain though. If some company
made a longer lasting analog of methylphenidate and pushed it properly they would score big . Think about it - works in less than 3 days, no
significant anxiety (bupropion), no sexual dysfunction (SSRIs), no real tolerance or abuse potential (amphetamines). It is very effective in mild to moderate atypical depression, which accounts for the vast majority of depression.

Methylphenidate is overused in kids and vastly underused in adults. And it is quite safe in overdoses (treat with haloperidol and phenytoin).

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20. emjeff on February 28, 2008 8:18 AM writes...

The fact that all of the trials used in this study were of only 6 weeks duration is reason enough to discount it. I wonder when the journals are going to stop publishing this meta-analysis nonsense from groups with a political axe to grind?

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21. MTK on February 28, 2008 9:50 AM writes...


I would agree with you. In fact, my first thought was that the reason why these studies weren't published in journals was not some sinister selective publication by pharma, but that the investigators reasoned they weren't publication-worthy due to their short duration. The follow-up to that is why plan and run them in the first place? Or were these studies that were halted for one reason or another, which would also make them non-publishable.

Maybe someone out there who has been involved in the clinical part of anti-depression program can help answer that for us.

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22. Don B. on February 28, 2008 10:38 AM writes...


My wife of many decades had a father who had a heart attack when she was twelve.

As far as I can tell she has been worrying abaout a heart attack since she passed 40.

We used to visit the ER about twice a year with her complaining of "chest pains" or "chest pressure". After giving her a baby aspirin, the MDs would run through the usual tests showing no problem.

A few years ago her internist prescribed 10mg of Zoloft(TM), one pill every morning. We have not been back to the ER since.

The major side effect that I have seen is that it turned off the connection between her brain and mouth.
She will say things to people that she did not used to say. I have explained this to our sons and relatives so they would not be offended by accurate but possibly insulting comments.

I realize this is an N of one. It has convinced me "that in a couple