I posted on May 17th. On May 23rd, a new version of the offending article quietly appeared on the journal's website: here it is. But the old version is still up, although I'm not sure it's intended to be, because the link is gone, so I think the only way to find it is from this blog.
Interestingly, the new manuscript corrects those two issues I noted. As far as I can see those are the only changes. Coincidence?
The original paper was a "Fast Forward" online accelerated publication manuscript, and it's common for these to be corrected in minor ways when they're officially published (i.e. when they appear in print), but that's not what happened here, because the new version is still a Fast Forward. This kind of revision is unusual.
So it seems that someone at Janssen is reading this blog!
If so: Hey. Believe it or not, I'm on your side, I want you to succeed. I suffer from depression, and I've love it if you came up with an actually good new antidepressant. But your industry hasn't released one in at least 10 years (be honest), and you're not fooling anyone with clever statistical tricks.
Forget that, and invest in some proper science. For example, ketamine is clearly the most exciting potential antidepressant right now, and glutamate could be the next serotonin. But because no-one has tested it against an active placebo, no-one, including you, knows whether it's really working. Run a really serious trial of ketamine, if it does work, then that's your next generation of antidepressants right there. If not, better to know that now than later when you've sunk billions into the idea.
19 comments:
As ketamine is not patentable, I won't hold my breath for the stampede.
Patentable is irrelevant. Come up with another drug that acts in a similar way on the Glu system without as many unpleasant side effects.
The failure to run proper trials on ketamine is horrific when one considers both the wasted man hours and wasted rodent lives.
Anonymous: Well... I'm not sure it should be patentable, but apparantly it has been patented; according to Carlos Zarate's papers
"A patent application for the use of ketamine in depression has been submitted listing Drs Zarate and Manji among the inventors; they have assigned their rights on the patent to the US government."
anyway, Pharma will probably not be able to make money out of ketamine itself but if it really works they'll be able to invent some related compound with fewer side effects, and sell that.
Sometime someway somehow.... someone is going to realise that the cure for depression is not a fracking drug. Please I beg you............
Depression is cured by leucotomy? Do me a favour....
Although I am not saying that whisky does not help sometimes....
Psychiatry is a pseudoscience. Period.
Dirk, psychiatry and psychology might not be "real science" as many in the hard sciences like to say so, but in all fairness, the human mind is much more complex than the liver, the sun, or nuclear fission.
There are currently over 20 RCTs underway studying ketamine for depression, some of which are using active placebos (usually midazolam).
Having used ketamine for my depressed patients, I think that the active placebo avenue is not entirely necessary, as no other treatment available (medications, ECT, psychotherapy) give as rapid robust immediate effects on dysphoria and suicidality. It is extremely unlikely that the benefits seen are entirely due to placebo response. We have actually tried administering ketamine using alternate routes such as nasal spray. It was not absorbed as well and it did not work as well as the IV, suggesting that there is a definite dose related drug effect.
More relevant is the question of how we can mimic ketamine's effects using treatments that are easily administered. I am very interested in the possibility of using dextromethorphan (another NDMA antagonist) combined with a 2D6 inhibitor for depression. This combination has already been studied and proven safe in the Nuedexta trials for pseudobulbar affect. Dextromethorphan has been around since the 50s and is dirt cheap. It would be very easy to study it in MDD.
Really and seriously?!? Why are we testing ketamine when so many other street drugs work just as well? We all know that cocaine will work, right?
Usually there are reviewers of the articles. That's why the journals are called peer-reviewed ;)
@Eric Charles: Cocaine may make you feel good for a few minutes while you are high, but the effect does not last once you are no longer intoxicated. The antidepressant effect of ketamine lasts a few days after the intoxication state wears off.
In your opinion the last useful antidepressant launched was Escitalopram?
What about agomelatine? In my practice it works very well.
I've got no personal experience with agomelatine & don't know anyone who's taken it, but as I understand, at best it is as effective as an SSRI without the side effects.
Nice to have perhaps but it's hardly revolutionary. It's no game changer in the way fluoxetine was, or ketamine might prove to be.
"Having used ketamine for my depressed patients, I think that the active placebo avenue is not entirely necessary, as no other treatment available (medications, ECT, psychotherapy) give as rapid robust immediate effects on dysphoria and suicidality."
Conversely I've not seen great results from it - say 20% showing a good response - and that doesn't compare brilliantly with ECT. The benefit also seems to wear off quite quick in a lot of people, which is what you might expect if there's a big placebo element.
No that you can realistically conduct a placebo control for ketamine.
@pj: I'm surprised at your observations. We have been seeing results very similar to those described in the clinical trials - about 70% of patients benefit significantly (for periods of about 3-5 days). Those that do benefit all say that it has been more effective than any other treatment that they have tried (and they have all tried >10 medications as well as psychotherapy).
Were you using the 0.5 mg/kg infusion over 40 minutes? We have not had much success with alternate dosing regimens.
Re: agomelatine
Is this drug used as an antidepressant in bipolar conditions also?
Thanks.
@Anonymous: There are no published randomized trials of agomelatine in bipolar depression. A small pilot open-label study suggested possible benefit as an add-on to lithium or valproate and larger RCTs are planned.
@Zigs:
Thank you very much for the information. The challenge is to draw extrapolate from RCTs to this:
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Molecular Psychiatry , (29 May 2012) | doi:10.1038/mp.2012.55
The road not taken: life experiences in monozygotic twin pairs discordant for major depression
K S Kendler and L J Halberstadt
Abstract
In an effort to understand how environmental experiences contribute to risk for major depression (MD), we conducted joint autobiographical interviews with 14 pairs of monozygotic twins (mean age 51.2) rigorously discordant for a lifetime history of MD. Twelve of the pairs could be sorted into four broad categories. In two pairs, discordance was associated with a single traumatic event occurring to the affected twin. In seven pairs, the well twin had one stable, long-term, successful romantic relationship, whereas the affected co-twin had romantic reversals one or more of which precipitated depressive episodes. These pairs varied in the degree to which the romantic problems seemed to arise from bad luck or poor choices. In one pair, occupational difficulties were strongly related to discordance in experiences with MD. In two pairs, several mechanisms seemed to be at work. Discordance in the quality of intimate love relationships was the most common etiological factor revealed by interview in these discordant pairs, with single dramatic events and occupational problems being considerably rarer. Even in this best of natural experiments, the causal interrelationship between personality, environment and depressive episodes was not always clear. Many pairs illustrated the protective effects of planfulness and the malignant effect of cumulative continuity where early difficulties in relationships shaped the subsequent life course. These results speak both to the importance of environmental influences on human well-being and psychopathology, and the complexity of the causal paths underlying their effects.
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