A paper just out reveals that the snappily-named GSK372475 doesn't work and has lots of side effects. It's a report of two clinicals trials in which Glaxo's contender was pitched against placebo and against older antidepressants in the treatment of depression.
GSK372475 failed to improve depression any better than placebo, even though the trials were large (393 and 504 patients respectively) and twice as long as most antidepressant trials (10 weeks whereas 4 or 6 is more usual)which ought to have given it plenty of room to shine.
The comparison drugs, the widely used venlafaxine and paroxetine, did work. A bit.
In terms of side effects it caused dry mouth, insomnia, and nausea serious enough to make many people quit the study early. But even worse, it raised heart rate by almost 10 beats per minute on average, which is really never a good sign.
So, overall, it was an utter flop. In one sense this is not surprising. New "antidepressants" that don't work in trials have been all too common recently. Just last week we learned about the failure of "Serdaxin" in a Phase II trial. Actually Serdaxin isn't a new drug but an old antibiotic called clavulanic acid that a company was trying to rebrand as a mood lifter.
However the failure of GSK372475 is a bit of a mystery. The drug is a potent triple reuptake inhibitor (TRI) which acts on the neurotransmitters serotonin, noradrenaline and dopamine. By contrast, venlafaxine is a double reuptake inhibitor which doesn't hit dopamine, and paroxetine only targets serotonin. I've written about other TRIs before.
Now it seems surprising that venlafaxine worked, but a TRI didn't, in the same trial. That would imply that blocking the reuptake of dopamine makes you more depressed, enough to cancel out the other actions which are shared with venlafaxine. Which is not what I'd have predicted.
There are other differences between the drugs though. Venlafaxine has a very short half-life - it's broken down in the body in a matter of hours. But GSK372475 has a halflife of 8-10 days. Could this be the problem?
Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, Zamuner S, Evoniuk G, & Ratti E (2011). Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials. Journal of psychopharmacology (Oxford, England) PMID: 22048884
19 comments:
Do you know, do other TRIs and SNRIs (anything that inhibits reuptake of norepinephrine, basically) also tend to raise heart rates?
Bupropion is a dopamine reuptake inhibitor. Granted it isn't really an anti-depressant but is widely prescribed as such.
But it doesn't depress, rather the opposite. The effect is more as if you took amphetamines.
I'd go for too much of a good thing. Just more isn't usually better. That other tri's work surprises me actually.
Lindsay: Venlafaxine an SNRI is well known to raise blood pressure slightly, but I don't think it's meant to raise heart rate, and in this study it didn't. Only the new drug did.
As for other TRIs, another TRI that I blogged about raised heart rate slightly but much less, just 1.5 beats per minute as opposed to 8-10 beats in this case.
Venlafaxine is known to raise heart rate in some people. Any noradrenaline reuptake inhibitor would be expected to do this to some extent.
@pj - That's what I thought; you'd think that since norepinephrine (or noradrenaline, whatever you're used to calling it) activates the sympathetic nervous system, and tends to make people physiologically aroused, you'd think anything that had the effect of raising the amount of noradrenaline in circulation would potentially have that side effect.
Which is why I wanted to know if any other, similar drugs were known to raise heart rates.
Now it seems surprising that venlafaxine worked, but a TRI didn't, in the same trial. That would imply that blocking the reuptake of dopamine makes you more depressed, enough to cancel out the other actions which are shared with venlafaxine.
That's a pretty big leap I'd say. Depression isn't a simple three-switch system.
As one example, different drugs may have different tendencies to affect certain brain regions more than others, so it could be a matter of which receptor is blocked in which area.
And there could be many, many other possibilities.
Please do not forget the new dogma believing that anti-depressants work by promoting an increase of new cells in the hippocampus although I heard C.B. Nemeroff saying publicly in the last World Psychiatric Association meeting that it is a bit premature since for one he never succeed in reproducing the findings even by sending one PhD candidate of his to Yale…
To use only the clinical results to judge any anti-depressant effect ( studying a drug or of any talking, sport or whatever therapy effects) is the only serious option- if you are interesting in science or in patients benefits that is.
Sorry, Neuroskeptic, about my bad English.
I meant to write yesterday:
"To use only the clinical results to judge any anti-depressant efficacy in relieving depressive suffering ( studying a drug or of any talking, sport or whatever therapy effects) is the only serious option- if you are interesting in science or in patients benefits that is."
Of course I welcome with all my mind and heart the efforts to understand any mecchanism involved in that therapeutic effect.
On the condition that Big Pharma marketing do not continue to polute the minds of drugs prescribers and premature neuroscientists claims do not result in not paying attention to good possible clinical outcomes of some molecules not responding to false science dogma.
@Ivana Fulli: That hippocampal neurogenesis is a necessary component of SSRI efficacy is hardly unsupported dogma. It has been repeatedly demonstrated in rodents, and by Tarique et al. (PLoS One, 2011) in non-human primates as well.
To Anonymous 14/11/11 15:16 who wrote "That hippocampal neurogenesis is a necessary component of SSRI efficacy is hardly unsupported dogma."
I wrote about it :
" (...)although I heard C.B. Nemeroff saying publicly in the last World Psychiatric Association meeting that it is a bit premature since for one he never succeed in reproducing the findings even by sending one PhD candidate of his to Yale…(...)"
I admire C.B. Nemeroff but would not less admire you - no doubts in my mind if I knew your name and credentials-
I just thought it was worth listening when C.B. Nemeroff said very publicly last 22 of September that he even send a PhD candidate of his to spend a long time in a Yale lab to master the methodology used and has been unable to reproduce the findings.
Anonymous, do rodents or non-human primates get depression? Do antidepressants help?
An animal model is just that, a model.
Thank you pj
May I had on that topic that:
A rodent pharmacologists'model of relief from depressive symptoms had been depression using the time a rat will keep swimming before letting go and die of asphyxia with water in his little lungs.
The longer the rats swim the less depressed they are considered.
To my mind it would be more interesting if we had the scope of improving the survival rate of persons swimming for their lives ( from a wreck ship in a calm ocean for example).
Calling that model "learned helplessness" or whatever doesn't make it more relevant to science or relieving human suffering from depression.
Of course more reasonable rodent models do exist in neuropsychiatry like in learning capabilities under several chemical impregnation and /or environment modifications.
Considering it works on noradrenaline and dopamine, I wonder how long it'll be before they trial it as a treatment for ADHD?
Goldie: Good idea, but they're way ahead of you, they already tried that. It didn't work. Judging by the fact that the trial was completed in 2004 and they didn't follow it up.
And the grand social experiment that is psychiatric medicine rolls onward.
nice post
nice post
So, is there anyone left in the field of developing TRIs?
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