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Re: Zuranolone (SAGE-217) Update. undopaminergic

Posted by SLS on April 25, 2020, at 9:00:25

In reply to Re: Zuranolone (SAGE-217) Update., posted by undopaminergic on April 22, 2020, at 6:30:22

> > Hi.
> >
> > I am pleased that Sage Therapeutics has continued to pursue FDA approval of zuranolone, despite the irresponsible 15-day trial performed by an ignorant group of investigators. (Even if zuranolone proves to be ineffective, that doesn't excuse such a flawed study).
> >
> I agree, but I don't see what is exciting about it. According to Wikipedia, it "acts as a positive allosteric modulator of the GABAA receptor.". That's just what benzodiazepines, barbiturates, and even alcohol, do.
> -undopaminergic

I think zuranolone affects exclusively chloride influx at GABA-A receptors while alchohol also attaches to GABA-B receptors and thereby inhibits the influx of potassium ions. Chloride ions and potassium ions function as opposites. I don't know where that fits in.

I'm interested in zuranalone because it is novel and is reported to work for both Major Depressive Disorder and Bipolar Depression. Of course, the studies might be flawed or biased, but at least they weren't designed to fail by employing a 15-day trial.

Remember, some neural tracts are actually *overactive* in depression. Perhaps having specific GABA pathways become activated results in suppressing pathological overactivity. Just a wild guess.

From what I understand, zuranolone (and other progesterone-like neurosteroids) are far more potent than alcohol and benzodiazepines as positive allosteric modulators of GABA-A receptors. In addition, the activity of benzodiazepines is self-limiting. (I haven't looked into this). Zuranolone affects some GABA receptors that benzodiazepines miss. Somewhere, somehow, these differences might explain the reported greater efficacy of zuranolone to treat MDD and post-partum depression. A study found it effective in bipolar depression, too. Alcohol and Valium make poor treatments for chronic depression, despite their being used to self-medicate. (Alprazolam exerts some antidepressant-like effects, but I haven't looked into mechanisms).

The sister drug of zuranolone, brexanolone, is administered IV, and is already approved to treat post-partum depression. Of course, the ability to take zuranolone orally is appealing. I haven't seen anything that would indicate that these drugs were preferentially effective in females.

I'm not really *excited* about zuranolone as if it were the messiah of antidepressants. It's just different and apparently safe. Different is different. I've run out of different.

I'm currently taking Nardil. One wouldn't think that there are any contraindication for taking zuranolone along with it, but I'm not sure my doctor would go along with it.

- Scott

Some see things as they are and ask why.
I dream of things that never were and ask why not.

The only thing necessary for the triumph of evil is that good men do nothing.




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