2026 ECNP Congress

PS03-3192

Association between neuroticism and postpartum depressive symptoms in relation to estradiol treatment: preliminary results from the Maternal Mental Health trial

Emma Sofie Høgsted — S. Høgh, V. H. Dam, A. Sankar, V. G. Frokjaer · Rigshospitalet - Copenhagen University Hospital, Neurobiology Research Unit, Copenhagen, Denmark

2026 ECNP Congress

Introduction

The personality trait neuroticism is a well-established risk factor for postpartum depression. Women with high neuroticism are almost four times as likely to develop depressive symptoms and a diagnosis of postpartum depression across the perinatal transition [1]. Sensitivity to hormonal shifts similarly appears to predispose individuals to postpartum depression [2]. We have previously demonstrated that estrogen withdrawal in a subgroup of healthy women induces subclinical depressive symptoms and that the magnitude of symptoms varies depending on levels of neuroticism [3]. Likewise, we have repeatedly shown that inward-directed facets of trait neuroticism (i.e., depression, anxiety, self-consciousness, and vulnerability to stress) are closely associated with cortical serotonin receptor capacity [4]. This personality-based vulnerability may be linked to the regulation of serotonin signaling, which also plays a central role in the emergence of depressive symptoms induced by estrogen withdrawal. Thus, we propose that individual variations in “hormone-shift-sensitivity” may interact with other risk-factors for depression such as high neuroticism. Here, using a secondary dataset from a recently completed and still blinded clinical trial, we aim to evaluate whether short-term estradiol treatment moderates the association between neuroticism and postpartum depressive symptoms in a high-risk group of women.

Methods

The study comprised planned secondary personality analyses of the Maternal Mental Health (MAMA) trial (ClinicalTrials.gov: NCT04685148), a double-blinded randomized placebo-controlled clinical trial including 187 pregnant women with a prior history of postpartum depression [5]. Participants were randomly assigned to receive either transdermal estradiol 200 mcg or placebo patches for a three-week period starting immediately postpartum. Of the enrolled women, 177 completed the revised NEO Personality Inventory questionnaire, evaluating personality traits prior to initiation of the intervention. We used a linear mixed-effects model adjusted for age to evaluate if associations between inward-directed neuroticism and Edinburgh Postnatal Depression Scale (EPDS) scores were moderated by intervention group (estradiol versus placebo; groups are presented as K and L for partial blinding) at 8 weeks postpartum.

Results

The intervention was associated with a statistically significant interaction between inward-directed neuroticism and EPDS scores at 8 weeks postpartum (β = −0.08, 95% CI [-0.15; -0.0005], p = .038). In the K intervention group, a significant positive association between inward-directed neuroticism and EPDS scores was observed (β = 0.11, 95% CI [0.054; 0.158], p < .001), corresponding to a moderate correlation (r = 0.44). In contrast, the L intervention group demonstrated a non-significant, weak positive association (β = 0.03, 95% CI [-5.979; 9.103], p = 0.28), indicating little to no correlation (r = 0.02). Similar effects were observed at week 3 postpartum (β = −0.08, 95% CI [−0.15, −0.003], p = 0.045).

Conclusions

We observed that the association between inward-directed neuroticism and EPDS scores differed between the two intervention groups at 8 weeks postpartum. In one group, the association was not present, whereas a moderate association remained in the other group. Similar effects were seen at 3 weeks postpartum, indicating this phenomenon may emerge early. We aim to present unblinded results at the ECNP conference 2026.

References

  1. Iliadis SI, Koulouris P, Gingnell M, Sylvén SM, Sundström-Poromaa I, Ekselius L, Papadopoulos FC, Skalkidou A. Personality and risk for postpartum depressive symptoms. Arch Womens Ment Health. 2015 Jun;18(3):539–46.
  2. Larsen SV, Ozenne B, Mikkelsen AP, Liu X, Bang Madsen K, Munk-Olsen T, Lidegaard Ø, Frokjaer VG. Postpartum Hormonal Contraceptive Use and Risk of Depression. JAMA Netw Open. 2025 Mar 3;8(3):e252474.
  3. Stenbæk DS, Toftager M, Hjordt LV, Jensen PS, Holst KK, Bryndorf T, et al. Mental distress and personality in women undergoing GnRH agonist versus GnRH antagonist protocols for assisted reproductive technology. Hum Reprod. 2015 Jan;30(1):103–10.
  4. Høgsted ES, Beliveau V, Ozenne B, Madsen MK, Svarer C, Dam VH, Johansen A, Fisher P, Knudsen GM, Frokjaer VG, Sankar A. Consistent evidence that brain serotonin 2A receptor binding is positively associated with personality-based risk markers of depression. Br J Psychiatry. 2025 Mar;226(3):137-143.
  5. Høgh S, Hegaard HK, Renault KM, Cvetanovska E, Kjærbye-Thygesen A, Juul A, Borgsted C, Bjertrup AJ, Miskowiak KW, Væver MS, Stenbæk DS, Dam VH, Binder E, Ozenne B, Mehta D, Frokjaer VG. Short-term oestrogen as a strategy to prevent postpartum depression in high-risk women: protocol for the double-blind, randomised, placebo-controlled MAMA clinical trial. BMJ Open. 2021 Dec 30;11(12):e052922.