Unless these studies were doing trials on a group of women already at high risk for postpartum depression, it seems quite likely that RCTs at n>200 would be futile at detecting any clinically meaningful effects at those sample sizes.

The Allen et. al. study is also a pilot study. The trouble with pilot studies is that they are usually not at all statistically powered to make negative statements [1]. While technically, pilot studies are meant to be for checking feasibility, one could optimistically use them to screen for potentially positive findings that warrant a larger study.

So taken together, I wouldn't treat the first 3 studies as negative findings because they are all seem pretty futile from the get go.

Regardless of the seemingly negative results in the past, it seems valuable to test efficacy of oral progesterone [2] definitively in a well designed study. The biological plausibility alone, coupled with what we seem to know anecdotally about its off-label use seem adequate "green flags" to do a study like this.

[1] https://www.nccih.nih.gov/grants/pilot-studies-common-uses-and-misuses

[2] https://astralcodexten.substack.com/p/zounds-its-zulresso-and-zuranolone/comment/5471185?s=r

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Thanks for the interesting post!

Progesterone does seem to have complex effects on mood, some of which I guess are upstream to allopregnanolone. I’m cautious about it’s potential as an antidepressant. Dysphoria is a recognised side effect of progesterone, and the progesterone only pill seems to be more associated with subsequent depression than the combined contraceptive pill https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2552796

For conditions like PMDD, progesterones on their own do not seem to be an effective treatment https://iapmd.org/treatment-guidelines - although I’m not sure if there is a dose-related issue here as well!

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Katharina Dalton was a quack. Her progesterone treatment for premenstrual syndrome was shown to be ineffective through clinical trials. You know where she is now? She's in hell having hot pokers stuck up her cunt.

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