Another Antidepressant Crashes & Burns

By Neuroskeptic | May 17, 2012 7:53 pm

Yet another “promising” novel antidepressant has failed to actually treat depression.

That’s not an uncommon occurrence these days, but this time, the paper reporting the findings is almost as rubbish as the drug: Translational evaluation of JNJ-18038683, a 5-HT7 receptor antagonist, on REM sleep and in major depressive disorder

So, Pharma giant Janssen invented JNJ-18038683. It’s a selective antagonist at serotonin 5HT-7 receptors, making it pharmacologically rather unusual. They hoped it would work as an antidepressant. It didn’t – in a multicentre randomized controlled trial of 230 depressed people, it had absolutely no benefits over placebo. A popular existing drug, citalopram, failed as well:

About the only thing JNJ-18038683 did do in humans was to reduce the amount of dreaming REM sleep per night. This REM suppressing effect is also seen with other antidepressants and this is evidence that the drug does do something – just not what it’s meant to. Being charitable you could call this a failed trial.

Ouch! But it gets better. Unhappy that JNJ-18038683 bombed, Janssen reached for their copy of the Cherrypicker’s Manifesto. This is a new statistical method, proposed by fellow Pharma company GSK in a 2010 paper, which consists of excluding data from study centres with a very high (or very low) placebo response rate.

Anyway, after applying this “filter” JNJ-18038683 seemed to do a bit better than placebo, but the benefit over placebo still wasn’t statistically significant - with a p value of 0.057, the wrong side of the sacred p=0.05 line (on page 33).
Yet Page 33′s “trend towards statistical significance” magically becomes “significant” – in the Abstract:

[with] a post hoc analyses (sic) using an enrichment window strategy… there was a clinically meaningful and statistically significant difference between JNJ-18038683 and placebo.

Well, no, there wasn’t actually. It was only a trend. Look it up.

That aside, the problem with the whole filter idea is that it could end up biasing your analysis in favour of the drug, leading to misleading results. The original authors warned that “data enrichment is often perceived as a way of improperly introducing a source of bias… In conventional RCTs, to overcome the bias risk, the enrichment strategy should be accounted for and pre-planned in the study protocol. They should know, as they invented it, but Janssen rather oddly say the exact opposite: “This methodology cannot be included in a protocol prospectively as it will introduce operational bias in that scheme.”

Hmm.

Anyway, even after the filter technique, citalopram didn’t work either… bad news for citalopram, except, was it citalopram at all? This is really unbelievable: Janssen don’t seem clear on whether they compared their drug to citalopram, or to escitalopram – a quite different drug.

They say “citalopram” in most cases, but they have “escitalopram” instead, in three places, including, mysteriously, in a “hidden” text box in that graph I showed earlier:

I’m not making this up: I stumbled upon a text box which is invisible, but if you select it with the cursor, you find it contains “escitalopram”! I have no idea what the story behind that is, but at best it is seriously sloppy.

Come on Janssen. Raise your game. In the glory days of dodgy antidepressant research, your rivals were (allegedly) concealing data on suicides and brushing whole studies under the carpet, to make their drugs look better. Despicable, but at least it had a certain grandeur to it.

ResearchBlogging.orgBonaventure, P., Dugovic, C., Kramer, M., De Boer, P., Singh, J., Wilson, S., Bertelsen, K., Di, J., Shelton, J., Aluisio, L., Dvorak, L., Fraser, I., Lord, B., Nepomuceno, D., Ahnaou, A., Drinkenburg, W., Chai, W., Dvorak, C., Carruthers, N., Sands, S., and Lovenberg, T. (2012). Translational evaluation of JNJ-18038683, a 5-HT7 receptor antagonist, on REM sleep and in major depressive disorder Journal of Pharmacology and Experimental Therapeutics DOI: 10.1124/jpet.112.193995

  • http://www.gustavoperezpsicologo.com Gustavo P

    Funny if it wasn't sad: all this cheating would feel so childish if it didn't have to do with people's health. Anyway always so eye-opening; great job. Not the same for reviewers at J of Pharm Exp Ther…

  • http://www.blogger.com/profile/01743182952112081912 Hapsci

    Oh my that is really, absolutely, shocking.

  • http://www.blogger.com/profile/05026223483117357541 usethebrains godgiveyou

    Frankly, I like citalopram. It makes me feel as if I am a wee bit drunk all the time. At $4 a month, cheaper than the time-tested poor mans antidepressant…booze. A little wine for what ails you!

  • Anonymous

    great post

  • Anonymous

    Anti-depressant medication research is a dirty business. I don't understand why the drug companies refuse to just farm this “research” out to the drug cartels in South America. There is no credibility, integrity or honesty in these trials.

  • http://www.blogger.com/profile/07368104387539222919 julia

    an insider in big pharma who actually cares about their expressed purpose needs to make a documentary about what goes on behind closed doors.

  • http://www.blogger.com/profile/18379669883853001278 TheCellularScale

    Wow, what a truly craptacular paper.
    At best this study could be useful in a pro 'reviewer transparency' argument.
    The Frontiers journals publish the names of the reviewers online right next to the paper. I am not sure I am for this reviewing method, but whoever reviewed this paper should be embarrassed. Maybe if their names were going to be attached to it, they would have been more careful. (Though I might say the same thing about the authors themselves)

  • Ivana Fulli MD

    Thank you Neuroskeptic for that post:

    Even you ,with your talent with words, couldn’t possibly write about the subject of your post tin a theater play, a novel, a movie scenario without the literary critics calling you weak for improbability and gross caricature of the drug industry and accomplices in your plot!

    May be it is about time that the USA justice system (or another one) take action against dishonest presentation of data in order to make money.

    Illegal marketing that is to my mind since it is the scope of it and illegal marketing is being prosecuted in the USA. To take a recent example I appreciate a lot thinking about all those young trusting female clients risking defects on their foetus with that drug:

    http://www.dddmag.com/news/2012/05/abbott-pleads-guilty-illegal-marketing

    ///Abbott Laboratories has pleaded guilty and agreed to pay $1.5 billion over allegations that it promoted the anti-seizure drug Depakote for uses that were not approved by the Food and Drug Administration.

    The case includes a criminal fine and forfeiture of $700 million and civil settlements with the federal government and states totaling $800 million. Deputy Attorney General James Cole said the settlement reflects the determination by government “to hold accountable those who commit fraud.”///

    One can hope that the determination of USA prosecutors “to hold accountable those who commit fraud.” could and will apply to falsifying data.

    It has to be said for the USA that to lie to the State is not taken lightly and fiscal fraud can send you to years in jail when in France or Italy you will pay a fine at most…Seing what happens right now with the mediator trials in France, I find safer to look to the USA prosecutors to protect us from that kind od illegal marketing.

    NB: of course the editors who let it pass where not “The Lancet ” editors and they might plead incompetence…

    May be our Andrew can explain to us why illegal marketing USA prosecutors stay out of the fraudulent clinical trials so far.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Gustavo P: Well in this case, it's not going to impact on anyone's health, I very much doubt this will ever make it to market.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    TheCellularScale: Yeah. To be fair to the reviewers, most of the paper seems fine, there's a ton of animal & preclinical work in there which looks OK. It's just the clinical trial that's dodgy but that's what reviewers ought to focus on, really.

  • http://petrossa.wordpress.com/ petrossa

    Well, citalopram and escitalopram are the same active metabolite afterwards. I personally always suspected they designed citalopram on purpose with the inactive part in the molecule so they could double the patent lifetime without much problems. As such they can be forgiven to mix them up. A kind of freudian slip.:)

  • Matthew Hankins

    Two further things about that paper:

    1. There's no such thing as a 'trend towards' significance: the result is significant or it isn't, whatever the threshold for the p value

    2. Why is the outcome 'Mean change from baseline'? It's a randomised trial. Why not compare outcomes directly?

  • http://www.blogger.com/profile/16203083806436919715 Bernard Carroll

    This is not the first time Janssen has fiddled the statistics in reporting clinical trials. They fudged on significance levels when they tried to position Risperdal as an add-on treatment for refractory depression. See PubMed ID: 18033236. After they were caught out that time, they abjectly retracted a claim of efficacy. At least on this occasion they went it alone with an all-Janssen cast of authors. The previous time, they used Mark Rapoport and Charles Nemeroff as fronts for the misleading infomercial. What is it with the culture at Janssen, and at JNJ in general, for that matter?

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    BC: Holy moly. I didn't know about that previous report – which seems even worse than this one, although they're pretty close in quality.

    One of the Corrigendums correcting that article said “We appreciate the assistance of a diligent reader in identifying this error.” Maybe we will get another one of those soon.

  • http://www.blogger.com/profile/16203083806436919715 Bernard Carroll

    Um, who could he have been? LOL.

  • Ivana Fulli MD

    “What is the difference between a doctor and a pilot?”

    Dr. David Healy asked during a recent talk at the CUNY Graduate Center.

    The answer? A doctor isn’t going to go down with you.

    (…) And because doctors, unlike pilots, are not going to be personally affected by every professional decision they make, they may be less critical of “evidence” put forth by pharmaceutical companies, and more willing to overlook potential risks associated with the drugs they prescribe.

    http://www.corporationsandhealth.org/news/307/62/Finding-a-Cure-for-Pharmacosis/d,Article

  • Anonymous

    From oil to tech, from real estate to the pharmaceuticals we are living in the world according to Ponzi.

  • http://www.blogger.com/profile/07273444395675262783 Alexander Riccio

    The whole “escitalopram”/”citalopram” thing sounds ALOT like the Kitzmiller v. Dover Area School District case, where a textbook was systematically revised to “Intelligent Design” from “creationism”. The truly damning evidence was in one of the revisions, where “Creationists” was mistakenly replaced with “cdesign proponetsists”. (see link)

    Did somebody manipulate the data here? was the data completley fabricated? It sounds like this paper was rushed in the same way that Pandas was?

    This can't be good.

    Neuroskeptic, this could be major.

    http://www.pbs.org/wgbh/nova/evolution/intelligent-design-trial.html – begin at 1hr:26min

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Alexander: A botched Find&Replace… interesting idea. Maybe we'll find out soon when the inevitable correction appears in the Journal.

  • http://www.blogger.com/profile/11702516173987835066 Zigs

    It's hard to get excited by a 5-HT7 antagonist. Many second generation antipsychotics already have this property. (See http://en.wikipedia.org/wiki/5-HT7_receptor). Therefore it is not a “novel mechanism of action.”

    I'm holding my breath for the round of glutamate modulating drugs.

  • Ivana Fulli MD

    Zigs,

    ///
    I'm holding my breath for the round of glutamate modulating drugs.///

    One just hopes you had not been previously holding your breath for the” original” melatonine modulating drug agomelatine.

    PS: I am holding my middle-aged little lungs capacity for honest and thorough research about whom benefit from the antidepressant drugs doctors -and sadly to my mind many non MD persons in the USA I was told-are prescribing.

    Because those drugs are dangerous and should be prescribed when you are reasonably confident that it might help the person better than homeopathy.

    To my poor mind, this is the real medical emergency-and it applies also to neuroleptics.

    NB: I also hold my breath for the French judges not taking twelve years to judge the 90 years old Jacques Servier in the Mediator trial- but yesterday, we learn that a sort of “legal shortcut” by a dedicated and clever lawyer was rebuked!

    http://www.marianne2.fr/Mediator-un-long-calvaire-jusqu-au-proces_a218538.html

    That NS post was about dishonesty of the drug maker wasn't it Zigs?

    (Sorry about my English but my computer wants me to write in French and underlines every word in red on the NS's blog little window.)

  • http://nuaccumbens.myopenid.com/ nuaccumbens

    Alexander Riccio said…
    The whole “escitalopram”/”citalopram” thing sounds ALOT like the Kitzmiller v. Dover Area School District case

    Really… please help explain
    the former seems like type or botched find and replace as neuroskeptic says, the other is a fundamental devine belief in the origin of humanity..

  • http://www.blogger.com/profile/07273444395675262783 Alexander Riccio
  • Ivana Fulli MD

    nuaccumbens,

    “Creationists” was mistakenly replaced with “cdesign proponetsists”

    In “cdesign proponetsists”, “c” and “ists” might be the telling tale of “creationists” having been replaced by “intelligent design”.

  • http://www.blogger.com/profile/17570337436614983225 Zanaprin

    Anti depressants are prescribed by doctors for the treatment of many different kinds of mental disorders such as depression and anxiety.

  • http://www.blogger.com/profile/14904212911961735296 williamsmarkseo

    Really great research on antidepressant medication. Keep it up.

  • http://www.blogger.com/profile/02728664681563684404 babydocmd

    A couple of issues:

    1) Synthetic organic chemistry processes always yield racemic compounds (citalopram). It costs more money to make pure enantiomers (escitalopram). So there was no conspiracy. These are NOT different compounds. There's a reason why the clinically equivalent dose of escitalopram is EXACTLY 50% of citalopram. It's because citalopram is composed of exactly 50% escitalopram. You can have gin and tonic (citalopram) or just gin.

    2) Neither citalopram nor escitalopram (same compound) undergo significant hepatic metabolism (at least compared to other SSRIs). They are NOT metabolites. It's one of the reasons they are favored treatments in the elderly and those on complicated medication regimens . . . fewer drug-drug interactions.

    3) The UK and Australia did not approve escitalopram on the grounds you cannot patent the same compound twice. Unfortunately, corporate interests prevailed in the US.

    4) Yet on the treatment side, FDA approved pediatric indications for escitalopram on the grounds that citalopram (which does not have a pediatric indication) is sufficiently bioequivalent that previous pediatric studies with citalopram could be included with labelling studies of escitalopram to justify approval.

    5) Change scores are used in clinical trials because change can occur for a host of reasons. Some people get better for $50, the clinic visit gets them out of the house/school every two weeks or your staff is attractive. Other than the PI and me, every person in my research group is 22-29 years-old and easy on the eyes. Further, if your randomization doesn't produce identical groups, a change score still provides an opportunity to show differential effects (treatment vs control).

    6) While several antipsychotics have 'some' activity at 5HT7, the actual affinity and intrinsic activity (what it does) is EXTREMELY low for virtually all compounds with the exception of clozapine and maybe lurasidone.

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Neuroskeptic

No brain. No gain.

About Neuroskeptic

Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.

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