However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain. Biphasic actions at the GABAA receptor
Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression. This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nmol/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it. This seems to be a common effect of many GABAA receptor positive allosteric modulators. In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect. Antidepressant effects
The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown. Other GABAA receptor PAMs, such as benzodiazepines, are not thought of as antidepressants and have no proven efficacy, despite clinicians prescribing Alprazolam for depression in the past. Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and sub-populations differently than benzodiazepines. As examples, GABAA receptor-potentiating neurosteroids may preferentially target δ subunit-containing GABAA receptors, and enhance both tonic and phasic inhibition mediated by GABAA receptors.
Derivatives
A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione). The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD). History
In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women, the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for PPD.The efficacy of brexanolone was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for four weeks. The FDA approved allopregnanolone based on evidence from three clinical trials, conducted in the United States, (Trial 1/NCT02942004, Trial 3/NCT02614541, Trial 2/ NCT02942017) of 247 women with moderate or severe postpartum depression.The FDA granted the application for brexanolone priority review designation, breakthrough therapy designation, and granted approval of allopregnanolone to Sage Therapeutics, Inc.

Society and culture
Names
Allopregnanolone is the name of the molecule commonly used in the literature when it is discussed as an endogenous neurosteroid. Brexanolone is both the INN and the USAN in the context of its use as a medication.Zulresso is a brand name of the medication. Legal status
In the United States, brexanolone is a Schedule IV controlled substance.