Allopregnanolone

DEA Schedule IV Controlled Substance -> Depressants

Pharmaceuticals -> Listed in ZINC15

Breastfeeding; Lactation; Milk, Human; Antidepressants; Antidepressive Agents; GABA Agents; Hormones; Progesterone Congeners

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Brexanolone has a rapid onset of action within 60 hours of infusion and has a sustained response for up to 30 days after infusion. Patients in clinical trials were not followed after a 30-day follow-up period, limiting data on toxicity from long-term use. Long-term efficacy of brexanolone, when compared with other antidepressants, is unknown and needs further research.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Brexanolone

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

N - Nervous system

QN - Nervous system

Brexanolone potentiated GABA-mediated currents from recombinant human GABA(a) receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits. Moreover, it was determined during a Phase 1 randomized, placebo and positive-controlled, double-blind, three-period crossover thorough QT study in 30 healthy adult subjects that brexanolone use did not prolong the QT interval to any clinically relevant extent when administered at 1.9-times the exposure occurring at the highest recommended infusion rate (90 mcg/kg/hour).

Brexanolone is a neuroactive steroid that occurs naturally (referred to as natural allopregnanolone) in the body when the female sex hormone progesterone is metabolized. This steroid compound is also believed to exhibit activity as a barbiturate-like, positive allosteric modulator of both synaptic and extrasynaptic GABA(a) receptors. In doing so, brexanolone can enhance the activity of GABA at such receptors by having GABA(a) receptor calcium channels open more often and for longer periods of time. Furthermore, it is believed that brexanolone elicits such action on GABA(a) receptors at a binding site that is distinct from those associated with benzodiazepines. Concurrently, GABA is considered the principal inhibitory neurotransmitter in the human body. When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors. With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons, like those involved in neuronal pathways that may be in part responsible for eliciting certain traits of PPD like stress, anxiety, etc. Postpartum depression (PPD) is a mood disorder that can affect women after childbirth. Women with PPD experience feelings of extreme sadness, anxiety, and exhaustion that can make it difficult or even dangerous for them to perform various daily activities or care for themselves or for others, including newborn. Although the exact pathophysiology of PPD remains unknown, it is believed that altered profiles and rapid, unpredictable fluctuations in the blood concentrations of neuroactive steroids like endogenous brexanolone (among others), GABA, and GABA receptors occur in women who are at risk of PPD after childbirth. In particular, within the context of PPD, it is proposed that endogenous brexanolone levels can quickly drop or fluctuate variedly after childbirth and that GABA(a) receptor levels and expression are decreased and down-regulated throughout pregnancy. Such fluctuations and decreases may consequently leave women susceptible to the possibility of PPD. As a medication, synthetic brexanolone can subsequently facilitate a return of positive allosteric modulator GABA(a) modulation while GABA(a) receptor levels and expression gradually return to normal in the time following postpartum. As such, studies suggest the potential for the development of brexanolone as a new mechanism for treatment of PPD that is directly related to the underlying pathophysiology as opposed to many other antidepressant medications whose pharmacological actions are usually entirely unrelated.