Journal Article Annotations
2025, 1st Quarter

Women’s Mental Health

Annotations by Diana Punko, MD, MSc
March, 2025

Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3α and/or 3β-HSD neurosteroidogenic enzymes?

PUBLICATION #1 — Women’s Mental Health

Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3α and/or 3β-HSD neurosteroidogenic enzymes?

Lauren M Osborne, Semra Etyemez, Graziano Pinna, Rebecca Alemani, Lindsay R Standeven, Xin-Qun Wang, Jennifer L Payne.

Abstract: Neuropsychopharmacology. 2025 Jan 30. doi: 10.1038/s41386-025-02052-z. Online ahead of print.

Postpartum depression (PPD) affects ~10-15% of childbearing individuals, with deleterious consequences for two generations. Recent research has explored the biological mechanisms of PPD, particularly neuroactive steroids (NAS). We sought here to investigate associations between NAS levels and ratios during pregnancy and the subsequent development of depressive symptoms with postpartum onset. NAS levels and psychological scales were measured in individuals with and without mood disorders at up to eight visits across pregnancy and postpartum. Generalized linear mixed-effects regression models were used to assess relationships in euthymic pregnant individuals between each of the NAS biomarkers and ratios and subsequent PPD. Participants with a one-unit increase in the log isoallopregnanolone/pregnanolone ratio at the third trimester (T3) had higher odds (OR = 1.64, 95% CI: 1.13-2.37, FDR adjusted p = 0.038, C-index = 0.82), and those with a one-unit increase in the log pregnanolone/progesterone ratio at T3 had lower odds (OR = 0.64, 95% CI: 0.47-0.88, FDR adjusted p = 0.036, C-index = 0.82) of developing PPD; those with a one-unit increase in the log progesterone level at T3 had higher odds of developing PPD (OR = 4.00, 95% CI: 1.54-10.37, FDR adjusted p = 0.035, C-index = 0.80). We found key differences in the progesterone metabolic pathway at the third trimester, indicating likely decreased activity/expression of the 3α-HSD enzyme and/or increased activity/expression of 3β-HSD.

Annotation

The findings:
Osborne et al. investigated the role of neuroactive steroid (NAS) biosynthesis during pregnancy as a potential biomarker for predicting postpartum depression (PPD) in individuals who were euthymic during pregnancy. They found that a higher log isoallopregnanolone/pregnanolone ratio in the third trimester was associated with increased odds of developing PPD (OR = 1.64, 95% CI: 1.13-2.37), while a higher log pregnanolone/progesterone ratio in the third trimester was associated with decreased odds of PPD (OR = 0.64, 95% CI: 0.47-0.88). Elevated log progesterone levels in the third trimester were also linked to higher odds of PPD (OR = 4.00, 95% CI: 1.54-10.37).

Strength and weaknesses:
The sample size was relatively small (136 participants, 33 with postpartum depression) but adequately powered to identify statistically significant differences in progesterone metabolites that could ultimately be used for screening during the third trimester. The study’s strengths include its longitudinal design, well-characterized and prospectively monitored sample, and use of robust statistical methods, including adjustments for covariates and corrections for multiple testing. The inclusion of both negative (isoallopregnanolone and epipregnanolone) and positive (pregnanolone and allopregnanolone) allosteric modulators of the GABA receptor further strengthened the study’s findings. Weaknesses of the study include reliance on the self-report Edinburgh Postnatal Depression Scale (ESPD) rather than a clinical interview for their definition of PPD and limited generalizability due to the predominantly Caucasian, well-educated, and high socioeconomic status participant pool. This demographic homogeneity restricts the applicability of the findings to more diverse populations and highlights the need for future research to include more racially and socioeconomically diverse participants to enhance the inclusivity of the findings.

Relevance:
C-L psychiatrists are often the first mental health providers to evaluate women in late pregnancy and early postpartum. Screening with the EDPS and subsequent clinical diagnostic interview are currently the gold standard to identify women with PPD in the weeks following delivery; the potential for biomarkers measured during pregnancy to predict which women are at highest risk for developing PPD would allow for earlier intervention and direction of scare resources to those at increased risk. Further, these results offer insights into the biological underpinnings of this condition (in particular, differential activity/expression of 3α- and 3β-hydroxysteroid enzymes in the third trimester) and could lead to the development of target therapeutics which would be expected to improve outcomes for both vulnerable mothers and infants.