Are antipsychotic drugs becoming less effective?

According to a report published today at Reuters, antipsychotic drugs appear to be losing their efficacy.  This is supposedly because there is a rise in the affect of the placebo effect.  The Reuters story is well-written (go and read please), but is missing a “Part II”.  If the data are correct and there is a narrowing gap between drug effect and placebo effect, what are the most likely explanations? Is it true that placebo responses are rising? Or that drugs are becoming less effective?

Let’s step back and examine the question being asked, and the possible answers.

When clinical drug trials are done, the drug in question (the test drug) is usually compared to a placebo, an inert substance designed to look, taste, and feel the same as the test drug. This is one way of separating the true effect of the drug from other effects, such as simply being involved in a study.  Example time (skip if you already know this stuff).

Hypothesis: Oral Wonderflonium increases scrotal volume in human adult males. This is based on a mouse model that showed some promising results.  Aspiring Academic Medical Center (AAMC) decides to test the hypothesis. They recruit 400 human adult males and measure their scrotal volumes on entry into the study (up to you to imagine how it’s done). They treat the males with Wonderflonium for six months and then re-measure the scrotal volumes. Lo and behold, the average scrotal volume of the group increases by 20%.  The folks at AAMC submit the paper to Second Tier Medical Journal.

Two of the reviewers at STMJ love it.  Increased scrotal volume! Wonderflonium! Twenty percent!  The final reviewer is less enthusiastic. “How do we know it was the Wonderflonium? After all, we’re not comparing these people to anyone else.  Maybe the drive two and from the center increased their scrotums.  Maybe there’s something at the coffee cart. Go back and re-work this.”

The AAMC folks want to re-do the study, but ran out of money, as Wonderflonium is very hard to come by. But over at Major Academic Medical Center (MAMC), there’s a guy with a big grant who grabs the whole idea by the, um, reins and sets up a new study.  This time another 400 men are recruited, but half receive Wonderflonium and half receive a placebo that is outwardly identical to Wonderflonium.

This time, the results are published: Wonderflonium increased scrotal volume by 18% over placebo.  Woo. Hoo.

The potential market is huge, especially among a certain set of inadequate-feeling, ‘roid-raging gym rats.  Several more studies are designed by academics and by drug companies (sometimes indistinguishably).  Wonderflonium is flying off the shelves as the studies continue to give positive results.

A few years later, someone goes back and looks at the data.  The  most recent studies are showing that scrotums among gym rats aren’t actually getting much bigger, something expected given the wide use of the drug.  He goes back and finds recent studies have shown that scrotal size is only up by about 3-4% vs. placebo..  WTF?

The researcher notes that scrotums in the placebo groups in the latest study are up more than in the original, and that this increase in placebo response is responsible for what seems like a decrease in the drug’s efficacy.

His colleague has a different idea, one examined in detail by Dr. David Gorski at Science-Based Medicine.  His colleague looks at the trend, and she sees something familiar: new drugs seem to work better right after their discovery. She proposes the Scrotum Problem is due to the “decline effect”, a mixture of factors that better explains the trend.  The early studies of the new drug may have captured a less random moment in time.  As more and more people are treated, there is a “regression toward the mean”, with more studies giving us more accurate (and less impressive) numbers.  There may also have been some publication bias, in which studies with interesting positive results were more likely to be submitted and published.

What is less likely is that something about placebos has changed.  While placebo scrotum volumes increased, there may be many explanations for this. Study design can affect placebo response considerably, as can measurement biases.  But since placebos don’t change, they’re not to blame.

So before we all get too excited about the increasing placebo effect killing off new drug development we need to ask smarter questions: are we looking at the right end points and doing it correctly? Are we allowing expectations to trump good study design? Are we jumping the gun on new drugs by relying on initial small studies? Are we moving the goal posts in our original studies by hunting for statistically significant effects that we didn’t lay out in our hypothesis?

All could be true. But a sugar pill is still a sugar pill.


  1. aaah, but placebos *do* change. or, at least there are unintentional thumbs on the scale that change.

    Clinical trials tend to expand, especially when you are talking about the behavioral disorders. I’m talking about assessments and instruments and re-visits and follow-ups and…. etc. Most are *intended* to be only dependent measures or necessary features to satisfy IRBs. But they end up having (one might hypothesize) the effect of an independent variable. So it may be that case that while the inert pill itself is not changing, the overall treatment of all the subjects is changing over time. Changing in ways that might affect the underlying disorder. Psychosis is maybe a bit hard to grasp but take depression. All the extra intervention and personal interaction and getting-out-of-the-house and assessment and research assistant visits and educational materials and consent forms and blah, blah, blah might possible have a clinical benefit. Same dealio for testing medications for drug abuse, I will note.

    So it is possible that a change in study design has a big enough effect to swamp out the marginal gains that the medications can provide.

  2. agreed.

  3. The trouble is that medications that would have clinical effect might be overlooked- naturally real world care wouldn’t be so intensive on the other particulars.

  4. Is it too obvious to think that study inclusion criteria have probably migrated/loosened over time? If one looks at the history of SSRI use as any guide (reasonable?) a drug-class initially studied in more severely-ill patients gains acceptance and is gradually used for patients less likely to benefit (including the seemingly ridiculous but all-too-common indication of “I’m sad because Grandma died this week”). As I’ve seen antipsychotics gain wider use, I can’t help but wonder if the diagnostic criteria used have broadened as they have with SSRIs. This could result in apparent reduced efficacy, also increased placebo efficacy if there is overlap of mood disorder patients (ie depression/anxiety) in this pool; (see DrugMonkey’s discussion above.)

  5. Thanks for posting this vital information.
    The Eli Lilly company made an astounding $65 BILLION on Zyprexa that they PUSHED on the elderly and underage children (*Viva Zyprexa* Lilly sales rep slogan) with wanton disregard for the side effects

    *FIVE at FIVE*
    The Zyprexa antipsychotic drug,whose side effects can include weight gain and diabetes, was sold to Veterans,children in foster care, elderly in nursing homes.
    *Five at Five* was the Zyprexa sales rep slogan, meaning *5mg dispensed at 5pm would keep patients quiet*.

    *Tell the truth don’t be afraid*– Daniel Haszard

  6. Necandum

     /  June 22, 2012

    Just a hunch, but could the acceptance of certain drugs as having efficacy alter how patients respond to a placebo when told they are taking that drug, as their expectations are higher?

    • Samantha

       /  June 22, 2012

      That’s exactly what I was thinking.

  7. There’s also if the diagnosis is even accurate. Psychiatric diagnoses are far more nuanced than other diagnoses. Someone who is emotional isn’t necessarily bipolar, and that kid with no friends isn’t necessarily Asperger’s.

  8. Barbarella

     /  June 25, 2012

    This comment may be interesting to those who are under the burden of prescribing such medications but have no personal experience in taking the medications themselves. As DrugMonkey said, psychosis, big subject, no clear end in sight. But depression: when it is experienced as a chronic and disabling illness, and the patient has had many (let’s say 15) episodes in their lifetime, all lasting over a year each time, then the idea of discontinuing the medication becomes much more worrisome for both patient and doctor. The current prescribing practice (and possibly, unfortunately, mythology) is that after a certain number of episodes of very severe, chronic depression, it is possible that the medication will no longer work if you stop using it, so you continue to need to take it. Forever. No one wants to take a medication forever, especially for a psychiatric condition, but for people who have become housebound and spiraling downward for a period of more than ten years (raise hands, okay, one of us), then making the decision to stop taking the drug and convince our doctor that quitting is a good idea, rather than self-destructive? So, when speaking of antipsychotic medications, rather than scrotal volume (we women scoff), and granting that psychiatric diagnoses are necessarily highly subjective, deciding if the drug is really working is crucial, real and terrifying to those who are taking that drug.

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