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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 8 of 8. This is the beginning of the thread.
Posted by SLS on November 10, 2011, at 6:42:27
Hi.
I found this extremely disappointing.
I don't know what pre-clinical tests were used to indicate antidepressant activity for this drug. Perhaps these tests ought to be re-appraised.
- Scott
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J Psychopharmacol. 2011 Nov 6. [Epub ahead of print]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.
Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, Zamuner S, Evoniuk G, Ratti E.
SourceNeurosciences Discovery Medicine, Research Triangle Park, NC, USA; Neurosciences Discovery Medicine, Verona Italy.
AbstractGSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- and active-controlled, double-blind studies examined the efficacy and safety of GSK372475 in outpatients (aged 18-64 years) with a diagnosis of major depressive episode associated with major depressive disorder (MDD). Patients were randomized 1:1:1 to placebo, GSK372475 (1-2 mg/d), or active control (Study 1: venlafaxine XR 150-225 mg/d; Study 2: paroxetine 20-30 mg/d). GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS) in either study. Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints. The most common adverse effects (AEs) with GSK372475 were dry mouth, headache, insomnia, and nausea. AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related, gastrointestinal, and tachycardia events. Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups. Completion rates were lower for GSK372475 (49%, 58%) compared with placebo (67%, 74%), venlafaxine XR (63%), or paroxetine (77%). GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies.
Posted by Chairman_MAO on November 10, 2011, at 7:37:49
In reply to Triple reuptake inhibitor GSK372475 fails., posted by SLS on November 10, 2011, at 6:42:27
> Hi.
>
> I found this extremely disappointing.
>
> I don't know what pre-clinical tests were used to indicate antidepressant activity for this drug. Perhaps these tests ought to be re-appraised.
>I'd have to read more about the drug's mechanism of action. How much is actually getting to the brain? How did they determine the effective dose?
If you have more information, I'll give you my opinion and/or get the opinion of someone who knows a lot more than I do.
If it is, at that dose, actually significantly blocking monoamine uptake, I think another study is in order. I just don't see how it could be any other way unless there is something else going on.
Posted by BrainDamage on November 11, 2011, at 2:45:43
In reply to Re: Triple reuptake inhibitor GSK372475 fails. » SLS, posted by Chairman_MAO on November 10, 2011, at 7:37:49
More Bad News..............
I don't mean to sound negative, but whether the failure was a fair or not, doesn't make much difference
Its gone :(
Posted by ed_uk2010 on November 11, 2011, at 5:44:38
In reply to Triple reuptake inhibitor GSK372475 fails., posted by SLS on November 10, 2011, at 6:42:27
>AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related...
I wonder whether sleep and anxiety adverse effects disguised any beneficial effects that it may have had on depressive symptoms.
Still, it was not very well tolerated, and this does not surprise me.
Posted by europerep on November 11, 2011, at 14:08:54
In reply to Re: Triple reuptake inhibitor GSK372475 fails. » SLS, posted by ed_uk2010 on November 11, 2011, at 5:44:38
Is there any reason to believe that a TRI is actually more effective than a combination of, say, venlafaxine and bupropion?
Ok, I get it, combining agents may produce synergistic side effects and having to take several different meds decreases patient compliance, so I probably shouldn't bash those agents, but still... I don't think TRIs have a significantly greater antidepressant potential than the combination of agents that add up to triple reuptake inhibition.
I don't think the solution for treatment-resistant depression lies in drugs like vilazodone or TRIs. They may be more tolerable for those remit on "old" monoaminergic drugs, which is great, but they won't make the number of TRD patients go down a lot.
Posted by psychobot5000 on November 14, 2011, at 11:53:23
In reply to Re: Triple reuptake inhibitor GSK372475 fails., posted by europerep on November 11, 2011, at 14:08:54
> Is there any reason to believe that a TRI is actually more effective than a combination of, say, venlafaxine and bupropion?
>
> Ok, I get it, combining agents may produce synergistic side effects and having to take several different meds decreases patient compliance, so I probably shouldn't bash those agents, but still... I don't think TRIs have a significantly greater antidepressant potential than the combination of agents that add up to triple reuptake inhibition.
>
> I don't think the solution for treatment-resistant depression lies in drugs like vilazodone or TRIs. They may be more tolerable for those remit on "old" monoaminergic drugs, which is great, but they won't make the number of TRD patients go down a lot.I'm forced to agree--though I would note that TRIs would partly deal with the deficiency in drugs affecting dopamine pathways (bupropion, if I remember right, has only modest overall effects, and the stimulants aren't really a fabulous substitute), overall they're not really very innovative drugs. I guess the opposing view hopes that, by sustained action on all three monoamine systems, you'd have a modestly stronger effect, but, sadly, I'm guessing we'll need to look elsewhere, anyway.
In my (extensive, though individual) experience, the S/E of drugs that substantially inhibit the reuptake of noradrenaline or serotonin are not really very tolerable anyway.
Posted by psychobot5000 on November 14, 2011, at 11:58:32
In reply to Re: Triple reuptake inhibitor GSK372475 fails., posted by psychobot5000 on November 14, 2011, at 11:53:23
P.S. - I guess that was kind of a downer... But buck up, Scott! There are steady advances being made in the area of therapeutic neuromodulation! CES! TMS! VNS! DBS! Cortical stimulation! RFuECT (I admit to grimacing a bit as I write that last one). They work! And insurance will have to cover them eventually.
Posted by B2chica on November 15, 2011, at 11:28:30
In reply to Triple reuptake inhibitor GSK372475 fails., posted by SLS on November 10, 2011, at 6:42:27
off the top the one thing i noticed that i didnt like was the 10-week limit.
ah-hem makers of pristiq....
lets see i think it was 12 weeks this go around before i even noticed any effects from it.so lets hope for second go around rather than trashing the whole study and restart with drug alterations.
and i am ALL FOR a TRI.
its about time they start clinical trials on this!
thats promising. and normally scott where there is one TRI study there are many more to follow!
keep that in mind. always competition.Best
b2c.
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