Sugar pills, antidepressants, and the miracle of the human brain

[drwex]

Chasing other links I stumbled across this:

As a proportion of the drug response, the placebo response was constant across different types of [antidepressant] medication (75%), and the correlation between placebo effect and drug effect was .90. [...] These data raise the possibility that the apparent drug effect (25% of the drug response) is actually an active placebo effect.

In English: it's possible that all reported effects of antidepressant medication are placebo effects. It's quite likely that 75% of reported effects are placebo.

More recently, these authors replicated the work using studies from the FDA database. FDA studies are done as part of drug approval processes. They're generally not published in refereed literature and there have been accusations that they're slanted in favor of the drugs. That is, the studies are done in order to speed drugs through the approval process and may overreport positive effects and underreport negatives. So in theory you'd see a larger effect for ADs if you analyzed these studies. In fact:

Kirsch et al. reported an 18% difference between drug and placebo.

The debate is actually fairly nuanced. There's been some good work recently looking (via MRI) at the neurochemical mechanisms triggered by placebos. There is some evidence that the difference between AD and placebo increases with the severity of depression, though that might be due to differences between active and inert placebos - people with serious depression are often familiar with the side effects of ADs and can recognize when given a sugar pill that doesn't have the expected side effects.

Nobody's claiming that ADs don't work. The claim is that they do work... and sugar pills work, too.

Title: "Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication."
Authors: Kirsch, Irving; Sapirstein, Guy
Publication: Prevention & Treatment. 1(1), Jun 1998
<http://content.apa.org/journals/pre/1/1/2>

Title: "The emperor's new drugs: An analysis of antidepressant medication data submitted
 to the U.S. Food and Drug Administration."
Authors: Kirsch, I., Moore, T. J., Scoboria, A., & Nicholls, S. S.
Publication: Prevention & Treatment, 5, art. 23
<http://journals.apa.org/prevention/volume5/pre0050023a.html>

Comments

[dpolicar]

I wonder what effect reading this study has on the effectiveness of antidepressants.

[drwex]

There's actually some commentary on that. In particular, a significant number of patients asked to be reassigned to the active arm of studies once they found they were in placebo arms (usually due to the use of inactive placebos). There was also a significant resurgence of depressive symptoms among people who discovered or were told that they were in the placebo arm.

Opens Up Entire New Approaches For Study

[daurdabla.livejournal.com]

It would be interesting to see what happened if they

--told people who are on the active arm that they're on the placebo arm.

--selected a group who were on the placebo arm and who benefited, and gave them counseling to see if they can gain the effects of the placebo without even the sugar pills.

Re: Opens Up Entire New Approaches For Study

[drwex]

I agree that it's possible to study placebo effects in more detail though I worry about a protocol in which patients are actively lied to.

[coraline]

...your pre-formatting on the cites atht ebottom is causing my page to scroll :}
(the title of the second paper is wider than my screen.)

[drwex]

Use a wider window :)

Seriously, I'll re-frob it. I played around a fair bit with the HTML in order to get it to handle the embedded blockquotes and paragraph spacing the way I wanted.

[coraline]

i know it's not your problem, it's mine, but i thought it would be something you'd prefer to be aware of :)

[drwex]

Bien sur. Is "fixed" now.

[mrw42.livejournal.com]

I'm not particularly surprised by this...

I suffer from some type of mild, periodic depression, and I've found that I can actively pull myself out of depressive periods by choosing to believe that something will fix it... More light, a vacation trip, finishing something that I've been working on, paying all of my bills, taking vitamins, taking a day off to clean up around the house, etc.

The interesting part is that, while I don't have a logical explanation for why some of these things work, I've had enough experience that they _do_ work that sometimes I'll start feeling better even before I complete them. So, just planning a vacation, picking up a bottle of vitamins at the store or scheduling a day off can make me feel better.

Go figure.

[drwex]

I would say that your methods are not placebos but are other techniques known to affect brain chemical balance and mood. I'm glad they're effective for you.

I'll start feeling better even before I complete them.

Anticipatory cycle is a moderately freaky thing. When I was an undergrad there was a prof studying this effect in addicts, who would begin to demonstrate "high" behaviors and responses during the preparation prior to injecting. Even when they knew they weren't going to get any drug (e.g. they had agreed to show researchers how they shoot up and were demonstrating things) their bodies still responded.

[halleyscomet.livejournal.com]

I remember seeing something similar with alcohol when I was in college. I think all of us knew someone who started acting drunk and exhibiting signs of inebriation, even when all they'd had was the first half of a beer.

My Father tells the story of a frat brother of his who was known as "Neck." Neck would always drink about enough of the beer to empty the neck of the bottle, and then abandon the rest. He would be stumbling and slurring after a few sips.

The thing his frat brothers found most infuriating about Neck was his tendency to drink the "Neck" of a bottle, and then proceed to drink the "Neck" of four or five more, leaving the mostly full bottles in random places at the party.

[okelle.livejournal.com]

I've heard about this before, and while it may show up in academic medical studies, my personal experience with psychotropic medications indicates that there *is* in fact a difference in the effects of different medications.

The human brain is a strange and wondrous creation about which we still know very little. It is possible through a combination of thought and behavioral modification to affect our own brain chemistries and to reroute our neural pathways. That is why a combination of Cognitive Behavioral Therapy (CBT) and antidepressants has been proven by other studies to be the MOST effective treatment for depression. This does not change the fact that medications designed to act on particular neurotransmitters are effective.

It is my fear that these widely publicized studies will lead people to conclude that psychotropics, and antidepressants in particular, are completely ineffective. True, some of the marketing tactics of the pharm industry are complete hooey. Untrue, that the proper balance of medications--a balance which sometimes needs to be fine-tuned on a regular basis--can make a marked difference in the life of someone with persistent, chronic mental illness.

[drwex]

my personal experience with psychotropic medications indicates that there *is* in fact a difference in the effects of different medications.

I'm not trying to debate your (or anyone else's) personal experience. What this research is saying is that it's quite likely that you could have gotten the same effect without taking the particular pill involved.

CBT+drugs has been shown to be more effective than either alone. What has NOT been shown is how CBT+placebo compares, and that's the point here.

I'm not going to shed any tears for big pharma. If people decide they can get by without drugs and do so, then more power to 'em.

the proper balance of medications--a balance which sometimes needs to be fine-tuned on a regular basis--can make a marked difference in the life of someone with persistent, chronic mental illness.

Yes, and so can placebos. As I said in the posting, nobody's arguing that ADs don't work. What's at issue is the method by which they work. If their primary path of operation is placebo effect (which it sure looks like) then we're doing people a disservice by giving them chemicals that have serious side effects when other methods might be as effective but do less collateral damage.

[darkrosetiger.livejournal.com]

CBT+drugs has been shown to be more effective than either alone. What has NOT been shown is how CBT+placebo compares, and that's the point here.

I somehow missed the definition of CBT in the above post. I was kind of confused.

[drwex]

Hee. I love that the abbreviation causes that. Of course, some people think I'm talking about Computer-Based Training. Though in this case, the reference is to Cognitive-Behavioral Therapy (aka "talk" therapy).

[keyne.livejournal.com]

What this research is saying is that it's quite likely that you could have gotten the same effect without taking the particular pill involved.

I'm a big believer in the power of the human mind, but it's a little difficult for me to believe that so many folks taking Effexor are inventing "brain shivers" independently. Or that anybody taking placebos would want to. :/

[drwex]

No one is claiming anything is "invented." The claim is that the effect on depression in patients with mild to moderate symptoms is almost entirely placebo effect.

The point of differentiating active vs passive placebos is to produce more accurate simulations of the effects of ADs. I can't say whether Effexor was particularly studied or not.

[hlmt.livejournal.com]

Whoo! Let me be first in line to tell ya that maybe in some cases it might be placebo effect, but when my SO forgets to take his meds? MAJOR (unlivable) difference. Major. Major, major, major.

And it's taken different meds to achieve the liveable effect. I guess you could argue that it's a white versus brown sugar pill, but prior self-medication did not work, either (or CBT). What we have now, works now. Don't know how things will evolve in the future, of course...

[drwex]

I'm glad it works for you, dear.

I'm not sure why people are acting like I'm trying to shoot their dog or something...

[hlmt.livejournal.com]

*giggles*

[drwex]

You're giggling, which is good. But my girlfriend is so mad she won't talk to me and at least one other commenter in this thread seems to think I'm advising everyone to go off their meds.

gah.

[hlmt.livejournal.com]

Well, I don't think you should be surprised at ppl being mad, since your plain English -seems- to lead to the corollary that 75%, and possibly 100%, of mental illness (or at least mental illness that is relieved by the use of antidepressants) is (pun aside) in the users' head.

I'm sure you can see why that would piss someone off. =)

[drwex]

As I said, I didn't write these studies. I did translate the abstract, but that is in fact what the abstract says. People may take offense at "placebo effect" but that's what it is. What the studies show is that if you give people with mild to moderate depression a non-AD (placebo) you get effective treatment, just as if you'd given them an AD.

I can't stop people thinking "placebo effect" means "is in your head" because... well that's what it DOES mean. It doesn't mean you're a fool or dupe. If people want to get offended over their own implications associated with the phrase I can't stop that either.

As I said, there's starting to be MRI work tracing the neurochemical bases for placebo effects. I found a reference to Mayberg's article titled The functional neuroanatomy of the placebo effect but you might not want to read that because, among other things, she found that there were some significant similarities in brain chemistry changes between placebo and SSRI groups. There were also significant differences. What we don't know is whether one matters more than the other.

[ariesd.livejournal.com]

What the studies show is that if you give people with mild to moderate depression a non-AD (placebo) you get effective treatment, just as if you'd given them an AD.
That is B.S. personally. You can pretty much change your diet in any way, eat all fat, eat all carbs, eat all protein, etc and you will lose weight for a short period of time.

How long did these studies go on for?

Most researchers with a clue would I hope know that AD and CBT work is a long term approach, not something that is over in the span of a month or what could be tested for in a trial of this type.

I think this is bad science in general. SSRI's and eating Carbohydrates will do the same thing. SO sugar pills don't surprise me. Hell if you know what an SSRI does you will know there are many ways to achieve that effect w/o the pill.

Sorry, this is a bad study, I would like to see it researched for a much longer period of time and on drugs and I think actual lying to some and telling them they are getting a placebo when they are not would be extremely valuable to see if the efficacy is impacted.

[drwex]

How long did these studies go on for?

The study periods I saw were six weeks and six months. I believe that under six weeks you may not get the full effect of an AD. Can't say why the six month period was picked.

what could be tested for in a trial of this type.

That was one of the reasons for replicating the work with the FDA database. If you wish to say (as the Feds do) that the FDA study criteria are sufficient to establish the safety and effectiveness of a drug that is to be prescribed to patients then it's a very strange claim to then say "well those studies are no good."

That said, you're not the first one to say this. Certainly there's a body of objection to Kirsch that says "if you measure in a properly constructed study you do see significant differences." Fair enough, but then the onus is on the claimant both to state what a proper study would be and to say why a study is sufficient to get a drug approved and onto the market but somehow is not sufficient to distinguish its effect from a placebo effect.

actual lying to some and telling them they are getting a placebo when they are not would be extremely valuable to see if the efficacy is impacted.

There are two problems with that. One, as I mentioned earlier, is that you have a very hard time getting approval for a study protocol that bald-faced lies to people. You can mislead or conceal, but lying it pretty much right out because it destroys informed consent. Two, it messed with the notion of double-blind. The point is that not only does the patient not know what pill they're getting, the administering person doesn't know either. That removes effect and observational biases. (Or at least reduces them; again, see the discussion of active vs inert placebos.)

[sweetmmeblue.livejournal.com]

> I would like to see it researched for a much longer period of time and on drugs and I think actual lying to some and telling them they are getting a placebo when they are not would be extremely valuable to see if the efficacy is impacted.

But that can't be done. Not with the ethical considerations. There was a big tadoo after the Tuskeegee trials and others of the 60's and 70's where peole were lied to, harmed and in some cases, allowed to die in the name of research.

As for the long term vs short term, with mild to moderate depression there is a long term benefit even with plecbos. In my work, once a client has called to make an appointment there is always a lift in some of the depression. It's called the "hope effect". What happens is that once a person knows they are going to get help they relax a bit, find more strangth cause help is about to be there, find more cope and remember coping mechanisms. One of the things I always do with new clients is ask them how much better things got from the time they made the hone call to the time they came in. Same numbers as the plecebo trials, about 75% say things got noticebly better. I then talk to them about what they did and what made them better. 10% of those where things got better don't stay in therapy long or, when it comes time for the first appointment, don't show because they no longer need the help.

The 25 where things don't get better usually need something more than just hope. Many of those benifit from some chemical assistance because the combination of therapy (and it may not be CBT) and drugs is much more useful to that group than any other and better than drugs alone.

I read studies like these when I was in school as a way of keeping in mind that drugs are over-used and over-emphasised and a person's strengths were downplayed.

All that said... are anti-depressants and other drugs useful? Yes, when used correctly. The person who trained me on anti-depressants said there are 3 kinds of people that benifit from the drugs. 1) use for a year and get off them to set the chemical balance back on track. 2) may use short term every so often (4-6 months) across a life time. 3) on them all the time becasue the chemicals in the brain need that extra help. She also said that accounted for about 40% of the people being prescribed anti-depressants. The other 60% may not need them for as long as they are being given them, were given them by laze doctors and therapists, may have asked for them and think they need a magic fix pill, may be addictted to them, may have fogotten how to cope off of them and are uninterested in learning....

Everyone is different. Studies are not designed to account for the individual. Studies are designed to try and put everyone into boxes. As with all things YMMV. That does not make the study any less valuable to the mental health community in general. It may just make it less valuable to you.

[ariesd.livejournal.com]

yes but Tuskeegee was purposefully to harm patients and observed the results.

In a study people know they may or may not get a placebo. All I am saying is tell the group that is getting the placebo they are getting the real drug and vs versa. See if that knowledge actually skews the results.

I think we are always surprised when the placebo works because it is just that a placebo. I'm curious if the drug wouldn't work if they thought they weren't getting it. The reverse of the placebo effect.

[halleyscomet.livejournal.com]

I suspect some folks will see this kind of research as implying they could just "Snap out of it" if they "really wanted to." Given the fact that there are still people who see mental illness as a sign of a weak mind, and not a disease in need of treatment, some folks are probably a bit edgy about the whole topic.

[drwex]

Sure, I get that people are feeling personally attacked. But I didn't write the papers, nor do the studies. I actually was not aware of the research until I stumbled across the initial link.

I suppose it falls into the "inconvenient truth" department.

[earthling177.livejournal.com]

Take this with a huge amount of salt if you need to, but I'd just like to add that the results don't affect me one way or another, having never been on anti-depressants in my life, or read the paper(s).

But I wonder what they mean by "placebo".

Why, might you ask?

Because eons ago, when Zantac became OTC, I bought a box. When I opened the box, there was a nice insert explaining what the drug does etc, and among the data was how effective it was complete with a chart. The chart claimed that the drug was (I forget the real number, but it was on the order of) 30% more effective than the placebo, so I was telling Dave how nuts it was that I could just take a sugar pill and it could be just as nice, and I was making up stuff like "wouldn't it be funny if in 30 years we found out that sugar *is* actually a remarkably good medicine?" when I noticed they had a URL (less common back then) so I went to their web site, where they actually explained the whole protocol. Well, darn, wouldn't you know it, it's considered unethical to give placebos to certain classes of patients, like people with heart conditions and, apparently, people with acid reflux. So the protocol is that the "placebo" is a very well known medicine that is known to work and the new medicine is compared to that one, so, no, sugar pills are not just 30% less efficient as an acid-reflux drug, sugar pills are nearly zero effect.

After that, I try to find out about the protocols and what the "placebos" were in studies. It's important. For example, for the continuous-wear (30 days, 29 nights) contact lens studies, the "placebos" are typically Accuvue, which compare poorly to the Night&Day (silicone hydrogel) contacts, of course, given that they can only be worn for 7 days, and very poorly to Menicon Z (which behave better because they are rigid gas-perm contacts).

YMMV.