4 ms·

> We need better treatments for PPD It was compared to placebo. People are rightly highly suspicious of Big Pharma. I like the idea of a novel class but I wo

> We need better treatments for PPD It was compared to placebo. People are rightly highly suspicious of Big Pharma. I like the idea of a novel class but I won't pay attention to this new, expensive drug until it proves significant efficacy over older cheaper drugs (like Alprazolam and Zolpidem/Zopiclone). Technically it's a Z-drug (like Zolpidem/Ambien) which are non-benzodiazapine positive allosteric modulators of GABA_A However, since it's a neurosteroid most will probably not think of it as such. (It's name does begin with Z though... And end in -one like a steroid).[Note below] Anyways, it's licensed for 2 weeks only, side effects are drowsiness, sleepiness and cognitive impairment. You mustn't drive within 12 hours of a dose. It's best effects are where the depression is associated with insomnia and anxiety. It was compared to placebo not Alprazolam (Xanax) which has some antidepressant activity. That's just how you seek market Auth when nothing else is licensed. That's just smart. But you have a GABA agonist you must only use for the short term with primary anxiolytic and hypnotic effects. That will be widely used because otherwise you need off license script and will likely put even more people on the path to SSRI. [0] this is a reckless insightless cognitive impairment think Roseanne Bar racist tweet.

haldujai 3y ago
> People are rightly highly suspicious of Big Pharma. Absolutely, but that should only trigger scrutiny which in this case would provide several answers for why this is a good thing and not a BigPharma scam. > efficacy over older cheaper drugs (like Alprazolam and Zolpidem/Zopiclone). This drug, and the IV formulation it is based on (Zulresso), are not the same as and have different mechanisms from sedative-hypnotics which as an aside are not indicated as monotherapy for PPD (or any depression, don't give a downer to someone down). The mainstay of treatment is SSRIs. This class (which is the only FDA approved drug class for PPD) is an analogue of the endogenously produced metabolite of progesterone and the mechanism is not fully understood. To your point of head to head trials, you are correct they do not exist at this time and will eventually be done however all of these are still new. What we have right now are indirect comparative analyses which while limited show stronger magnitude effects than SSRIs. https://www.frontiersin.org/articles/10.3389/fphar.2022.950004/full#B2 https://www.frontiersin.org/articles/10.3389/fphar.2022.9500...
- psychphysic 3y ago
  I don't think we disagree the more arrows in a quiver the better. But the network meta analysis did not show zuranolone beating placebo due to wide effect size. I'm old enough to remember the studies in the 90s where we so the saw the same thing with benzos and TCAs and SSRIs. Alprazolam beats SSRI for depression with significant anxiety and insomnia with faster onset but treatment must be time limited. That's uncanny to me esp as both are PAM for GabaA
  - haldujai 3y ago
    > But the network meta analysis did not show zuranolone beating placebo due to wide effect size. It did not, using 1 of the studies, but my optimism is that the drug it was based on (brexanolone) was significant and is unfortunately only available IV (so difficult to access and expensive), so the hope is that this will play out similarly and why I feel is sufficient reason to give Big Pharma the benefit of the doubt that this isn't purely a money making play. > Alprazolam beats SSRI for depression with significant anxiety and insomnia with faster onset but treatment must be time limited. Sure, for anxiety-predominant scenarios but as you're alluding to there are significant dependence and abuse risks and hence why they're used as adjuncts. If this turns out to work in the same pathway but safer that would be a huge win. If it turns out to work in the same pathway but not safer than non-benzo sedatives then you're right it's a scam. With that said: > That's uncanny to me esp as both are PAM for GabaA My clinical pharmaceutical resource lists mechanism not fully known. This is getting outside of my comfort zone to comment on validity or fully understand but this editorial (citing for my own accessibility) suggests a different mechanism from benzodiazepines: Antonoudiou et al. (6) offer key insights into the potential mechanisms of rapid affective switching following brexanolone treatment of postpartum depression, despite the use of male subjects for all the studies. The remarkable discoveries include the parallels in human and rodent brain network dynamics associated with depression that are responsive to GABAergic analogs of allopregnanolone, the role of δ-subunit–containing receptors in some of these effects in mice, and the lack of effect of benzodiazepines on the electroencephalographic network dynamics, consistent with the lack of antidepressant efficacy of these compounds. https://www.sciencedirect.com/science/article/pii/S0006322321017467 https://www.sciencedirect.com/science/article/pii/S000632232... Antonoudiou et al: https://www.sciencedirect.com/science/article/pii/S0006322321014700 https://www.sciencedirect.com/science/article/pii/S000632232...
vGPU 3y ago
It’s supposed to be an oral version of Allopregnanolone. I’d definitely be a little bit more comfortable with it than with zolpiderm, which we tried to transition everyone off of if possible.

haldujai 3y ago

> People are rightly highly suspicious of Big Pharma. Absolutely, but that should only trigger scrutiny which in this case would provide several answers for why this is a good thing and not a BigPharma scam. > efficacy over older cheaper drugs (like Alprazolam and Zolpidem/Zopiclone). This drug, and the IV formulation it is based on (Zulresso), are not the same as and have different mechanisms from sedative-hypnotics which as an aside are not indicated as monotherapy for PPD (or any depression, don't give a downer to someone down). The mainstay of treatment is SSRIs. This class (which is the only FDA approved drug class for PPD) is an analogue of the endogenously produced metabolite of progesterone and the mechanism is not fully understood. To your point of head to head trials, you are correct they do not exist at this time and will eventually be done however all of these are still new. What we have right now are indirect comparative analyses which while limited show stronger magnitude effects than SSRIs. https://www.frontiersin.org/articles/10.3389/fphar.2022.950004/full#B2 https://www.frontiersin.org/articles/10.3389/fphar.2022.9500...

psychphysic 3y ago
I don't think we disagree the more arrows in a quiver the better. But the network meta analysis did not show zuranolone beating placebo due to wide effect size. I'm old enough to remember the studies in the 90s where we so the saw the same thing with benzos and TCAs and SSRIs. Alprazolam beats SSRI for depression with significant anxiety and insomnia with faster onset but treatment must be time limited. That's uncanny to me esp as both are PAM for GabaA
- haldujai 3y ago
  > But the network meta analysis did not show zuranolone beating placebo due to wide effect size. It did not, using 1 of the studies, but my optimism is that the drug it was based on (brexanolone) was significant and is unfortunately only available IV (so difficult to access and expensive), so the hope is that this will play out similarly and why I feel is sufficient reason to give Big Pharma the benefit of the doubt that this isn't purely a money making play. > Alprazolam beats SSRI for depression with significant anxiety and insomnia with faster onset but treatment must be time limited. Sure, for anxiety-predominant scenarios but as you're alluding to there are significant dependence and abuse risks and hence why they're used as adjuncts. If this turns out to work in the same pathway but safer that would be a huge win. If it turns out to work in the same pathway but not safer than non-benzo sedatives then you're right it's a scam. With that said: > That's uncanny to me esp as both are PAM for GabaA My clinical pharmaceutical resource lists mechanism not fully known. This is getting outside of my comfort zone to comment on validity or fully understand but this editorial (citing for my own accessibility) suggests a different mechanism from benzodiazepines: Antonoudiou et al. (6) offer key insights into the potential mechanisms of rapid affective switching following brexanolone treatment of postpartum depression, despite the use of male subjects for all the studies. The remarkable discoveries include the parallels in human and rodent brain network dynamics associated with depression that are responsive to GABAergic analogs of allopregnanolone, the role of δ-subunit–containing receptors in some of these effects in mice, and the lack of effect of benzodiazepines on the electroencephalographic network dynamics, consistent with the lack of antidepressant efficacy of these compounds. https://www.sciencedirect.com/science/article/pii/S0006322321017467 https://www.sciencedirect.com/science/article/pii/S000632232... Antonoudiou et al: https://www.sciencedirect.com/science/article/pii/S0006322321014700 https://www.sciencedirect.com/science/article/pii/S000632232...

vGPU 3y ago

It’s supposed to be an oral version of Allopregnanolone. I’d definitely be a little bit more comfortable with it than with zolpiderm, which we tried to transition everyone off of if possible.