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The antidepressant reboxetine: A “headdesk” moment in science


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Every so often there comes a truly "headdesk" moment in science. A moment where you sit there, stunned by a new finding, and thinking, blankly…"OK, now what?"

For psychiatry and behavioral pharmacology, one of those moments came a few weeks ago with the findings of a meta-analysis published in the British Medical Journal (Eyding et al., 2010). The meta-analysis showed that an antidepressant, reboxetine (marketed by Pfizer in Europe, but not in the U.S., under the names Edronax, Norebox, Prolift, Solvex, Davedax or Vestra) doesn’t work. Not only does it not work, it really doesn’t work, and it turns out that Pfizer hadn’t published data on the putative antidepressant from 74% of their patients. Some people have reported that the study found that reboxetine was even "possibly harmful," but that’s not quite true. What the study did find is that reboxetine produced more side effects (noted as "adverse events") than placebo (as might be expected), but with no positive effects at all. While many antidepressants on the market today are not great, most are effective in around 60% of patients; reboxetine turns out to be even worse than that.

It turns out that publication bias was rampant. Pfizer and Lundbeck, the two companies running the studies, didn’t publish a lot of their data, especially the data showing no effect and unfortunate side effects. A bit nefarious, that. But bad science will out.

While sales of reboxetine never compared to sales of more traditional antidepressants like citalopram and fluoxetine, the study still puts a major kink in the pharmacotherapies currently available for depression. Whereas drugs like citalopram and fluoxetine primarily target the neurotransmitter serotonin, reboxetine targets the neurotransmitter norepinephrine. So it was hoped when drugs like reboxetine came on to the market that the different chemical focus might prove more effective or change the side-effect profiles normally associated with antidepressants. But obviously the side effects got worse, and reboxetine turns out to not be so effective in patients after all.

And this is a rough moment for scientists studying depression. Why? Because reboxetine works beautifully in our animal models. It’s practically a poster-child antidepressant. It produces acute effects in tests such as forced-swim tests and tail-suspension tests (which use changes in struggle as a measure of antidepressant efficacy). It produces neurogenesis in the hippocampus, which is thought to be correlated with antidepressant effects. When behavioral pharmacologists are doing comparisons between older antidepressants and newer ones, reboxetine is often used as a positive control, a drug known to have an effect in the behavioral test of choice.

But it doesn’t work in patients. And patients are what matters. Now, scientists are stuck with a difficult question: What went wrong? This is more than just an issue with an antidepressant that didn’t work, it’s an issue with the tests we are using to study depression. How effective are they, really? Are we in fact modeling the right things? Do the tail-suspension test and forced-swim test detect antidepressant activity after all? And if they aren’t detecting antidepressant activity, what are they actually doing? What does this mean for both the neurochemical theory of depression and the neurogenesis theory? Reboxetine affects both but still has no clinical effect. Does this mean that both of these theories are wrong? Or does it mean that they are incomplete? And where, exactly, do we go from here?

We may need new models to study depression, or we may need to simply redefine and reexamine the ones that we have. But the latest findings on reboxetine raise more questions than those about pharma companies, scientific conduct and efficacy in patients. They raise questions about the way we study depression and what it is we need to measure to come up with the therapies that patients need. And it makes it more important than ever to study the possible mechanisms behind depression and other mental disorders, to understand how they work and what behaviors and changes we need to detect, to gain new insights into how to combat depression with more success and less…reboxetine.

References:

Eyding et al. “Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials.” British Medical Journal, 2010; 341:c4737. DOI: 10.1136/bmj.c4737

Kobayashi et al. “Neurochemical responses to antidepressants in the prefrontal cortex of mice and their efficacy in preclinical models of anxiety-like and depression-like behavior: a comparative and correlational study.” Psychopharmacology, 2008; 197(4):567-80. DOI: 10.1007/s00213-008-1070-6

Sacchetti et al. “Studies on the acute and chronic effects of reboxetine on extracellular noradrenaline and other monoamines in the rat brain.” British Journal of Pharmacolology, 1999; 128(6):1332-8. DOI: 10.1038/sj.bjp.0702926

Dziedzicka-Wasylewska et al. “Effect of antidepressant drugs in mice lacking the norepinephrine transporter.” Neuropsychopharmacology, 2006; 31(11):2424-32. DOI: 10.1038/sj.npp.1301064

Malberg et al. “Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.” The Journal of Neuroscience, 2000; 20(24):9104-9110. PMID: 1112498

About the Author: SciCurious has a Ph.D. in Physiology, a Bachelor of Arts in Philosophy and a Bachelor of Science in Biology. She is currently a postdoctoral researcher. Her professional interests are in neurophysiology, specifically the interactions of neurotransmitter systems. Her writing has appeared at ScienceBlogs, the Guardian and the New York Times, and she has been published in two editions of The Open Laboratory: The Best of Science Blogging. She blogs at Neurotic Physiology (and can also be found on Twitter) .

The views expressed are those of the author and are not necessarily those of Scientific American.

 






Comments 8 Comments

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  1. 1. EricMJohnson 2:50 pm 11/30/2010

    Thank you for pointing this out. Pfizer and Lundbeck’s activities seem tantamount to fraud. As you highlight, the focus needs to be placed on patients. Using animal models is the first stage of testing but it can’t provide conclusive results in people suffering from depression. These negative clinical results are important because now researchers can reexamine earlier studies and adopt novel approaches to understanding the neurochemistry of depression. If a PI was found guilty of the same behavior as these companies there would be an investigation and, quite possibly, a retraction of their related publications. Why are these companies held to a different standard?

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  2. 2. Peterbart 4:12 pm 11/30/2010

    What this study confirms is what many have suspected for quite some time – that despite impressive advances in basic and applied neuroscience, we still do not understand the molecular mechanisms underlying depression. The truth is that neither the serotonin hypothesis nor the neurogenesis hypothesis have been compelling, and the field has maintained a sense of joyous ignorance about the matter for far too long. That the animal models are not really appropriate models of depression just adds fuel to what should now be a raging fire. Hopefully, the outcome will be better science which will lead to a truly profound insight about the underlying mechanisms.

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  3. 3. ormondotvos 5:23 pm 11/30/2010

    Gawd. You think rats get depressed? I’ve always thought depression was a combination of thought processes PLUS a molecular level misfire of some sort.

    If you’re interested in the basics, look up Bertil Hille’s work over the last forty years, examining the shape and polarity filtering mechanisms in the nerve cell. There’s a million things that can go wrong in nerve transmission.

    And the toxicity of this society induces plenty of reasons to be depressed.

    And St. John’s Wort has some SERIOUS proven side-effects. Beware the snake oil hucksters.

    Link to this
  4. 4. ormondotvos 5:59 pm 11/30/2010

    St John’s Wort, from wikipedia:

    "recent studies concluded that the extract reacts with light, both visible and ultraviolet, to produce free radicals, molecules that can damage the cells of the body. These can react with vital proteins in the eye which, if damaged, precipitate out causing cataracts."

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  5. 5. Connectivist 11:47 pm 12/5/2010

    Sci, you argue that we need to rethink the neurogenesis model of depression because this study indicates that a drug that improves depression scores and causes hippocampal neurogenesis in rodents doesn’t help depression in humans. Later, though, you suggest that we must reconsider the validity of animal models of depression. I agree with you on the latter point, we need to be very careful in interpreting our findings in model organisms, particularly when we are putting a drug based on those findings on the market. However, given that we need to be careful when translating back and forth between humans and models organisms, shouldn’t we also consider that a drug leading to neurogenesis in mice might not necessarily do the same in humans? My point is that the neurogenesis hypothesis isn’t put to rest by the failures of reboxetine, nor does the study suggest we should pay more attention or try harder to disprove it; we shouldn’t need another big pharma flop to instigate that – its a hypothesis, by definition we should be trying to disprove it.

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  6. 6. MichaelS 5:56 pm 12/15/2010

    Hey Sci,

    Nice post and thanks for the link to my earlier blog post about the reboxetine case. (http://www.goodbadandbogus.com/bad-science/another-day-another-drug-company-cover-up) I just wanted to point out, however, that I don’t think I was wrong to report that the study showed that reboxetine was ineffective "and possibly harmful".

    Firstly, adverse effects are a form of harm. So, if you’re taking something that is ineffective and has adverse effects, your taking something that might harm you.

    Secondly, it’s exactly what the authors conclude themselves. Here’s their conclusion:

    "Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data."

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  7. 7. JacobMandelson 8:05 pm 01/17/2011

    "OK, now what?" Maybe we can turn this problem around?
    If reboxetine works in animals, but our brains ignore it, this seems like it might mark a path toward discovering what could be an important difference between our brains and animals’.

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  8. 8. Eneidawas 12:09 pm 01/31/2013

    Perhaps I can even use this study as ammunition with my own shrink who insists that the SNRI she has me on HAS to work better than a plain SSRI for my depression and OCD.
    It wasn’t broken. Why did she have to fix it? Oh, yeah. My husband died. I grieved longer than two months. Can’t have that. It was a mental illness in the DSM-IV, you know. If this were the Victorian era, I would just now be looking forward to wearing lavender and silver/gray in my wardrobe, entering into half mourning. Now, to shake that pesky laudanum habit.

    Link to this

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