Brexanolone was approved for medical use in the United States in 2019.[10][14] The U.S.Food and Drug Administration (FDA) considers it to be afirst-in-class medication.[15] The long administration time, as well as the cost for a one-time treatment, have raised concerns about accessibility for many women.[16]
Brexanolone is used to treat postpartum depression in adult women, administered as a continuousintravenous infusion over a period of 60 hours, and essential tremor.[10][17]
Women experiencing moderate to severe postpartum depression when treated with a single dose of intravenous brexanolone display a significant reduction inHAM-D scores which persisted 30 days post-treatment.[18]
Side effects of brexanolone include dizziness (10–20%),sedation (13–21%), headache (18%), nausea (10%), dry mouth (3–11%), loss of consciousness (3–5%), andflushing (2–5%).[6][10][8][19] It can produceeuphoria to a degree similar to that ofalprazolam (3–13% at infusion doses of 90–270 μg over a one-hour period).[6] Serious or severe adverse effects are rare but may includealtered state of consciousness,syncope, presyncope, fatigue, andinsomnia.[19]
In the US, the Food and Drug Administration requires aRisk Evaluation and Mitigation Strategy(REMS) to counteract the risks of excessive sedation and loss of consciousness. It requires that all patients be monitored for those symptoms every 2 hours in planned non sleep periods and that oxygen saturation be monitored with continuous pulse oximetry.[20]
Allopregnanolone is anendogenousinhibitorypregnaneneurosteroid.[9] It ismade frompregnenolone, and is apositive allosteric modulator of the action of γ-aminobutyric acid (GABA) atGABAA receptor.[9] Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as thebenzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.[9][32][33] Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.[34]
Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[9] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containingδ subunits exhibit the greatest potentiation.[35] Allopregnanolone has also been found to act as a positive allosteric modulator of theGABAA-ρ receptor, though the implications of this action are unclear.[36][37] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be anegative allosteric modulator ofnACh receptors,[38] and also appears to act as a negative allosteric modulator of the5-HT3 receptor.[39] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at otherligand-gated ion channels, including theNMDA,AMPA,kainate, andglycine receptors.[40]
Unlike progesterone, allopregnanolone is inactive at the classicalnuclearprogesterone receptor (PR).[40] However, allopregnanolone can be intracellularly oxidized into5α-dihydroprogesterone, which does act as anagonist of the PR, and for this reason, allopregnanolone can produce PR-mediatedprogestogenic effects.[41][42] (5α-dihydroprogesterone is reduced to produce allopregnanolone, and progesterone is reduced to produce5α-dihydroprogesterone). In addition, allopregnanolone was reported in 2012 to be an agonist of themembrane progesterone receptors (mPRs) discovered shortly before, includingmPRδ,mPRα, andmPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[43][44] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective andantigonadotropic properties.[43][45] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of thepregnane X receptor.[40][46]
Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as aninhibitor ofL-type voltage-gated calcium channels (L-VGCCs),[47] includingα1 subtypesCav1.2 andCav1.3.[48] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.[48] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[48] Also, allopregnanolone, along with several other neurosteroids, has been found to activate theG protein-coupled bile acid receptor (GPBAR1, or TGR5).[49] 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.[49]
Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety,irritability, andaggression.[50][51][52] 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 toluteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.[50][51] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[26][52] In accordance, acute administration of low doses ofmicronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[53]
The mechanism by which neurosteroid GABAA receptor positive allosteric modulators (PAMs) like brexanolone have antidepressant effects is unknown.[54] Other GABAA receptor PAMs, such asbenzodiazepines, are not thought of as antidepressants and have no proven efficacy,[54] althoughalprazolam has historically been prescribed for depression.[55][56] Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and subpopulations differently than benzodiazepines.[54] GABAA receptor-potentiating neurosteroids may preferentially target δ-subunit–containing GABAA receptors, and enhance both tonic and phasic inhibition mediated by GABAA receptors.[54] It is possible that neurosteroids like allopregnanolone may act on othertargets, including membrane progesterone receptors,T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.[54]
Allopregnanolone is a pregnane (C21)steroid and is also known as 5α-pregnan-3α-ol-20-one, 5α-pregnane-3α-ol-20-one,[1][2][3][4][5] 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is closely related structurally to5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers ofpregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers ofpregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers ofpregnanolone (3,5-tetrahydroprogesterone), with the other three isomers beingpregnanolone (5β-pregnan-3α-ol-20-one),isopregnanolone (5α-pregnan-3β-ol-20-one), andepipregnanolone (5β-pregnan-3β-ol-20-one).
A variety ofsyntheticderivatives andanalogues of allopregnanolone with similar activity and effects exist, includingalfadolone (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), andrenanolone (3α-hydroxy-5β-pregnan-11,20-dione).
The 21-hydroxylated derivative of this compound,tetrahydrodeoxycorticosterone, is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treatepilepsy and other conditions, includingpost-traumatic stress disorder.[9]
In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women,[10][14] the first drug approved by the U.S.Food and Drug Administration (FDA) specifically for PPD.[10]
The efficacy of brexanolone was shown in two clinical studies of participants who received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for four weeks.[10] 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.[58]
The FDA granted the application for brexanolonepriority review andbreakthrough therapy designations, and granted approval of Zulresso to Sage Therapeutics, Inc.[10]
Sage Therapeutics took Zulresso off the market in December 31 2024, citing need to focus onzuranolone.[59]
It has been suggested that allopregnanolone and its precursor pregnenolone may have therapeutic potential for treatment of various symptoms of alcohol use disorders by restoring deficits in GABAergic inhibition, moderatingcorticotropin releasing factor (CRF) signaling, and inhibiting excessive neuroimmune activation. Many co-occurring symptoms ofethanol addiction (e.g., anxiety, depression, seizures, sleep disturbance, pain) that are believed to contribute to the downward spiral of the addiction may also be controlled withneuroactive steroids.[63]
Exogenous progesterone, such asoral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[64] Due to this, it has been suggested that oral progesterone could be described as aprodrug of sorts for allopregnanolone.[64] As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy,[65] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to oral progesterone, oralpregnenolone has also been found to act as a prodrug of allopregnanolone,[66][67][68] though also ofpregnenolone sulfate.[69]
In animal models oftraumatic brain injury, allopregnanolone has been shown to reduce inflammation by attenuating the production of proinflammatory cytokines (IL-1β and TNF-α) at 3 h after the injury. It has also been shown to reduce the severity of brain damage and improve cognitive function and recovery.[70]
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Clinical trial numberNCT02942004 for "A Study to Evaluate Efficacy and Safety of SAGE-547 in Participants With Severe Postpartum Depression (547-PPD-202B)" atClinicalTrials.gov
Clinical trial numberNCT02614547 for "A Study to Evaluate SAGE-547 in Patients With Severe Postpartum Depression" atClinicalTrials.gov
Clinical trial numberNCT02942017 for "A Study to Evaluate Safety and Efficacy of SAGE-547 in Participants With Moderate Postpartum Depression (547-PPD-202C)" atClinicalTrials.gov
This article incorporates text from this source, which is in thepublic domain.
