Brexanolone, a GABAA Modulator, in the Treatment of Postpartum Depression in Adults: A Comprehensive Review

Abstract

Postpartum depression (PPD) is one of the three major categories on the spectrum of postpartum psychiatric syndromes. Postpartum psychiatric syndromes are classified as either postpartum blues, postpartum depression, or postpartum psychosis. Postpartum depression is important to recognize clinically because of the effect it can have on the mother-child bond. The neurosteroid allopregnanolone, a progesterone derivative, is important for its role in positively modulating GABAA receptors. GABA-mediated signaling has been previously implicated in major depressive disorder. Allopregnanolone-mediated signaling has been identified as an important therapeutic target. Treatment with an allopregnanolone-analog, brexanolone, has been shown to improve depression scores in trials for the treatment of PPD. Brexanolone is a positive allosteric modulator of GABAA and is the first drug approved by the FDA to treat postpartum depression. Brexanolone enhances the inhibitory effects of GABAA, restores dysfunctional GABAA transmembrane channels, and mimics a naturally produced progesterone metabolite that fluctuates during pregnancy and postpartum. One open-label study and two phase two studies have some significant reduction in HAM-D scores after treatment and that the effect was still there 30 days post-treatment. Per the data reported, intravenous infusion of brexanolone could be efficacious and safe for the treatment of women suffering from postpartum depression.

Behavioral Despair Is Blocked by the Flavonoid Chrysin (5,7-Dihydroxyflavone) in a Rat Model of Surgical Menopause

“…In support, it has been previously reported that pretreatment with picrotoxin, bicuculline and flumazenil, antagonists of the GABA A receptor, block the anxiolytic- and antidepressant-like effects of chrysin [ 30 , 32 , 35 ]. In this sense, it is to possible suggest that the GABA A receptor is therefore a molecular target to the substances tested in the present experiment, chrysin [ 30 , 31 ], allopregnanolone [ 37 , 87 ], and diazepam [ 88 ], without discarding the participation of other systems of neurotransmission.…”

Prospective Investigation of Glutamate Levels and Percentage Gray Matter in the Medial Prefrontal Cortex in Females at Risk for Postpartum Depression

“…ALLO is a potent positive allosteric modulator at the level of the synaptic and extrasynaptic GABA A receptors; thus, it contributes to the GABA-mediated inhibitory activity and inherently opposes glutamatergic excitatory activity [ 43 ]. Brexanolone, an exogenous formulation of ALLO, is rapidly effective in the treatment of PPD and is FDA approved for the treatment of PPD [ 44 ]. HRW are suspected of having maladaptive biological adjustments to physiological fluctuations of female hormones and their metabolites, especially ALLO [ 45 ].…”

Molecular pathways of major depressive disorder converge on the synapse

“…Additionally, ketamine enhances the mTOR complex 1 signaling and increases the number and function of synapses in the prefrontal cortex [ 42 ] independently of NMDA receptor inhibition [ 43 ]. Further drug developments include brexanolone, an analog of the neurosteroid THP, for the treatment of postpartum depression, as THP levels drop after pregnancy [ 44 ]. THP also affects the hypothalamus-pituitary-adrenal (HPA) axis as a positive allosteric modulator for specific subunits of extrasynaptic GABA A receptors (GABAARs) expressed in the paraventricular nucleus of the hypothalamus [ 40 ].…”