10 à 15 % des parturientes développent une dépression du post-partum (DPP). Une physiopathologie propre la distinguerait des autres formes de dépression. La prise en charge médicamenteuse repose sur des traitements non spécifiques. La fluctuation des taux de neurostéroïdes durant la grossesse et après l’accouchement, et leur action sur le récepteur GABA-A sont des mécanismes étudiés.

Décrire l’émergence et évaluer la pertinence de la cible GABAergique dans la dépression du post-partum.

Revue systématique de la littérature clinique et pré-clinique à partir de la base de données MEDLINE et des termes : « postpartum depression », « GABA », « ganaxolone », « brexanolone », « allopregnanolone », avant septembre 2019.

Les modèles animaux montrent une fluctuation du fonctionnement GABAergique durant la gestation et après la mise bas et une corrélation entre l’allopregnanolone (AP) et la plasticité des GABA-A-r. Les modèles KO pour la sous-unité δ-GABA-A-r présentent des symptômes de dépression et d’anxiété en post-partum. Les études cliniques confirment la cinétique des taux de neurostéroïdes et la modification GABAergique durant la grossesse et après l’accouchement. Les femmes avec antécédent de DPP ont une sensibilité supérieure à la diminution brutale des neurostéroïdes. Plusieurs essais contrôlés randomisés font la preuve d’une efficacité des injections de brexanolone, forme injectable d’allopregnanolone, avec une réponse rapide et prolongée.

La DPP semble associée à une dysrégulation de l’expression des GABA-A-r durant la grossesse et des difficultés à rétablir leur fonctionnement en post-partum. L’approche GABAergique constitue une cible thérapeutique prometteuse.

Prevalence of postpartum depression (PPD) ranges from 10 to 15 % of parturients. The impact of the PPD is major on the maternal bond and the health of both mother and child. Its physiopathological mechanisms appear to differ from other types of depression. Today, pharmacotherapy is based on nonspecific treatment, and recent therapeutic advances in this field require a comprehensive approach of the implication of the GABAergic system in the development of PPD. Neurosteroid levels during pregnancy and after parturition and the GABA-A-r modulation are thought to be involved in PPD.

To evaluate if the GABAergic approach is relevant in postpartum depression management.

We conducted a systematic review of literature based on the MEDLINE database with the following Medical Subject Headings (MeSH): “postpartum depression”, “GABA”, “ganaxolone”, “brexanolone”, “allopregnanolone”, prior to September 2019. We selected articles in English: preclinical and clinical studies, literature review, observational and therapeutic studies.

Preclinical models (mouse and rat) show changes in GABAergic inhibition in the peripartum period and correlation between allopregnanolone and GABA-A-r plasticity. This plasticity in the peripartum period maintains levels of inhibition adapted despite increased neurosteroid levels. KO models for the GABA-A-r δ subunit develop depression and anxiety symptoms in the postpartum period, and a change in the expression of the gene coding for the GABA-R alpha-4 subunit was found. Artificial inhibition of progesterone metabolism during post-partum increased depression symptoms. GABAergic fluctuation seems to be interrelated with other systems such as those of oxytocins. A synthetic neurosteroid (SGE-516) was tested on mouse models of PPD, KO for δ-GABA-A-r or KCC2, and showed decreased depressive symptoms and better mothering. Clinical studies confirm neurosteroid fluctuation and changes in the GABAergic system during the peripartum period. Allopregnanolone is the neurosteroid the most studied in PPD, and it is elevated in the brain during the pregnancy. Studies disagree on the presence of significant differences in allopregnanolone plasma levels during pregnancy or postpartum between women with PPD or not. Women with a history of PPD have greater susceptibility to neurosteroid withdrawal. Imagery and genetical data also show a link between allopregnanolone and PPD. The GABA-A-r may not recover in time following a reduced number during pregnancy, and this mismatch between neurosteroid levels and their receptor may trigger PPD. Several randomized controlled trials investigated brexanolone administrated IV, a synthetic formulation of allopregnanolone, and demonstrated a rapid and well tolerated reduction in depressive symptoms. In March 2019 brexanolone obtained FDA approval in PPD indication under the name Zulresso. However, there are differences in the time of beginning of PPD, which could constitute different subgroups of this disease, and which physiopathology could respond to different mechanisms. Prenatal depression does not respond to a GABAergic approach, but women without any risk factor or previous mood disorder developing PPD in the weeks following childbirth could be particularly responsive to this kind of treatment.

Disability to modulate GABA-A-r expression during pregnancy and restore its previous state after parturition appears to trigger PPD. The GABAergic system is a promising pharmacotherapy target. From preclinical to clinical studies for about twenty years the GABAergic system has been incriminated and targeted in this challenging mental disease.