The interaction between progesterone and catatonia is also very interesting. There was once a patent application to use RU486 in catatonia, but as far as I know it never went anywhere.
Oestrogen also seems to modulate ADHD symptoms -
Roberts B, Eisenlohr-Moul T, Martel MM. Reproductive steroids and ADHD symptoms across the menstrual cycle. Psychoneuroendocrinology. 2018 Feb;88:105-114.
Baker AS, Freeman MP. Management of attention deficit hyperactivity disorder during pregnancy. Obstet Gynecol Clin North Am. 2018;45(3):495-509.
Good question, to which I don't have a great answer.
So the negative RCT I cited was actually for sepranolone (isoallopregnanolone), a GABAA receptor modulating steroid antagonist - it's a stereoisomer of allopregnanolone which (confusingly) has antagonistic effects to allopregnanolone at the GABAA receptor.
The rationale was that fluctuations in allopregnanolone results in symptoms of PMDD due to its action at GABAA receptors so blocking this will treat symptoms.
Some possible explanations for the negative RCT:
1. Dosing issues. The timing of dosing was complicated, sub/cut administered injections every 48 hours during the luteal phase, up to a maximum of 14 days. Perhaps the timings were off. 10mg also seemed to work better than 16mg - the pharmacokinetics of these drugs are complicated.
2. Power issues. The trial retained slightly less than they had anticipated for their power calculation - 143 vs 150. Maybe a bigger phase III trial would show statistically significant effects?
3. Is sepranolone doing what we want it to do in vivo? A phase II trial in menstrual migraine also failed to beat placebo.
4. Maybe there are other mechanisms at play rather than allopregnanolone. After all, adding back oestradiol in PMDD leads to a recurrence of symtpoms, so it can't be the full story.
Final thought - getting new drugs to market is hard!
With oestrogen, and the reproductive hormones more generally, change is more important than dose as regards mental health. The complicated dosing for Qlaira is a case in point: while I can understand the attempt to mimic natural rhythms, those same rhythms are, for some people, difricult to navigate. I wonder if this may speak to your point #4?
Hi Thomas, any thoughts on underlying psychopathology? Could it be related to ASD? I have a son with Asperger’s Disorder as it was called when he was diagnosed and share some traits. My PPDD includes alcohol abuse, I want to drink and when I do I drink a lot. Don’t want to drink rest of the month, but always that few days before. When I was taking Zoloft I also had a much higher desire to drink daily. I also get a rebound high sex drive at onset of menstruation (when I make up with my partner after being horrible). Also when I stopped breastfeeding I got anxiety and depression, after both my children but worse with first one, I couldn’t drive the car at all, it was weird.
There’s been some research into how alcohol affects the menstrual cycle and also how consumption of alcohol varies across the cycle - https://helloclue.com/articles/cycle-a-z/alcohol-cycle
I’m not aware of much research linking ASD and PMDD but it’s an interesting thought!
The interaction between progesterone and catatonia is also very interesting. There was once a patent application to use RU486 in catatonia, but as far as I know it never went anywhere.
Oestrogen also seems to modulate ADHD symptoms -
Roberts B, Eisenlohr-Moul T, Martel MM. Reproductive steroids and ADHD symptoms across the menstrual cycle. Psychoneuroendocrinology. 2018 Feb;88:105-114.
Baker AS, Freeman MP. Management of attention deficit hyperactivity disorder during pregnancy. Obstet Gynecol Clin North Am. 2018;45(3):495-509.
Thanks, this is really interesting.
Do you have any thoughts on why allopregnanolone failed in trials?
Good question, to which I don't have a great answer.
So the negative RCT I cited was actually for sepranolone (isoallopregnanolone), a GABAA receptor modulating steroid antagonist - it's a stereoisomer of allopregnanolone which (confusingly) has antagonistic effects to allopregnanolone at the GABAA receptor.
The rationale was that fluctuations in allopregnanolone results in symptoms of PMDD due to its action at GABAA receptors so blocking this will treat symptoms.
Some possible explanations for the negative RCT:
1. Dosing issues. The timing of dosing was complicated, sub/cut administered injections every 48 hours during the luteal phase, up to a maximum of 14 days. Perhaps the timings were off. 10mg also seemed to work better than 16mg - the pharmacokinetics of these drugs are complicated.
2. Power issues. The trial retained slightly less than they had anticipated for their power calculation - 143 vs 150. Maybe a bigger phase III trial would show statistically significant effects?
3. Is sepranolone doing what we want it to do in vivo? A phase II trial in menstrual migraine also failed to beat placebo.
4. Maybe there are other mechanisms at play rather than allopregnanolone. After all, adding back oestradiol in PMDD leads to a recurrence of symtpoms, so it can't be the full story.
Final thought - getting new drugs to market is hard!
With oestrogen, and the reproductive hormones more generally, change is more important than dose as regards mental health. The complicated dosing for Qlaira is a case in point: while I can understand the attempt to mimic natural rhythms, those same rhythms are, for some people, difricult to navigate. I wonder if this may speak to your point #4?
Yes, completely agree
Hi Thomas, any thoughts on underlying psychopathology? Could it be related to ASD? I have a son with Asperger’s Disorder as it was called when he was diagnosed and share some traits. My PPDD includes alcohol abuse, I want to drink and when I do I drink a lot. Don’t want to drink rest of the month, but always that few days before. When I was taking Zoloft I also had a much higher desire to drink daily. I also get a rebound high sex drive at onset of menstruation (when I make up with my partner after being horrible). Also when I stopped breastfeeding I got anxiety and depression, after both my children but worse with first one, I couldn’t drive the car at all, it was weird.