Progesterone for Postpartum Depression

Maybe it's all about dosage

Scott Alexander recently posted that progesterone megadoses might be a cheap alternative to the new, hyper-expensive postpartum depression drug Zulresso. Zulresso is the brand name of allopregnanolone, a natural metabolite of progesterone. Administering progesterone to women raises allopregnanolone levels, just as you’d expect. So perhaps, Scott speculates, administering progesterone should also be effective as a postpartum depression treatment?

We don’t have to speculate though; it’s been tried.

Back in 1984¹, Van der Meer et al conducted a crossover randomized trial of rectal suppositories containing 200 mg of progesterone on 10 women with postpartum depression. There was no significant difference in symptom scores between weeks on progesterone vs. weeks on placebo.

Tsai & Schaffir, conducting a retrospective study on 247 pregnant women given depot medroxyprogesterone acetate (Depo-Provera injections) as birth control immediately after birth, or no hormone treatment, found no statistically significant difference in the incidence of postpartum depression, indicating that the progesterone injections neither caused nor prevented postpartum depression.²

Allen et al, in a randomized controlled study of progesterone on postpartum smoking relapse in 46 women, also measured depressive symptom scores as a secondary outcome; there was no significant difference in rates of postpartum depression between women taking 200 mg oral progesterone 2x daily vs. women taking placebo.³ Again, this suggests that progesterone has no preventative effect on postpartum depression in the general population.

Now, it’s possible that both these studies are using too little progesterone to have an effect; Barak & Glue⁴ estimate that it would take 300 mg every two hours to produce the same amount of allopregnanolone as the effective dose of Zulresso.

Back in the 1970s-1980s, Katharina Dalton, the doctor who first defined premenstrual stress syndrome (PMS) treated⁵ a self-selected series of 100 patients who had previously experienced postpartum depression with much higher doses of progesterone (400 mg suppositories, 2-6 times daily), and found that only 10% had a relapse, compared to 68% relapse on subsequent pregnancies in a series of 221 untreated women who had postpartum depression.⁶

Is this a case of the More Dakka heuristic, where most studies find a treatment ineffective merely because few of them try adequately high dosages?

Dalton’s reports of the effectiveness of high-dose progesterone should be viewed skeptically, because they are uncontrolled studies on a self-selected patient population.

But in my opinion, there are a couple of “green flags” about the findings:

1. They’re old reports, from before the influx of vast quantities of unreplicable studies into the biomedical field.

2. Dalton was a pioneering clinician-researcher; she was the first to observe PMS as a syndrome, and the first to report that women commit violent crimes and suicide at higher rates during the premenstrual period.

3. Dalton proposed a simple and coherent theory: that rapid declines in progesterone levels (such as after birth or during the premenstrual period) cause a “withdrawal” effect associated with psychiatric symptoms, which can be treated (or prevented) by administering enough progesterone to produce a gradual taper rather than a sudden drop.

4. “Only very high-dose oral progesterone treats postpartum depression” is consistent with the Barak & Glue dosage conversions and the hypothesis that the mechanism of action is through progesterone being metabolized to allopregnanolone.

High-dose progesterone has to be tested experimentally to see if it works, of course, but I have a good feeling about it.

1. Van der Meer, Y. G., E. W. Loendersloot, and A. C. Van Loenen. "Effect of high-dose progesterone in post-partum depression." Journal of Psychosomatic Obstetrics & Gynecology (1984).

2. Tsai, Rita, and Jonathan Schaffir. "Effect of depot medroxyprogesterone acetate on postpartum depression." Contraception 82.2 (2010): 174-177.

3. Allen, Sharon S., et al. "Progesterone and postpartum smoking relapse: A pilot double-blind placebo-controlled randomized trial." Nicotine & Tobacco Research 18.11 (2016): 2145-2153.

4. Barak, Yoram, and Paul Glue. "Progesterone loading as a strategy for treating postpartum depression." Human Psychopharmacology: Clinical and Experimental 35.3 (2020): e2731.

5. Dalton K. (1985) Progesterone prophylaxis used successfully in postnatal depression. Practitioner, 229, 507 – 508.

6. Dalton, Katharina. "Depression after childbirth." British Medical Journal (Clinical research ed.) 284.6325 (1982): 1332.