Brexanolone is a type of neurosteroid that has been studied for the treatment of postpartum depression (PPD) treatment and major depressive disorders (MDD). To date, brexanolone is the first PPD-specific antidepressant with rapid action that has been approved by the United States Food and Drug Administration (FDA).

A new paper in Neuropsychopharmacologyexplores the mechanisms of action of brexanolone.

Study: Novel neurosteroid therapeutics for postpartum depression: perspectives on clinical trials, program development, active research, and future directions. Image Credit: christinarosepix / Shutterstock.com

What causes PPD?

PPD affects many new mothers and may lead to adverse outcomes for both the mother and infant. Notably, one of the significant contributors to maternal deaths is maternal suicide.

Fluctuations in estrogen and progesterone levels during and after pregnancy and childbirth can be between 10- and 50-fold that of the non-pregnant healthy woman. This subsequently affects the hypothalamic-pituitary-adrenal (HPA) axis, which, in turn, alters cortisol levels.

Neurological processes are fundamentally dependent for their regulation of these steroid hormones and play a key role in the origin of depression in women. Cortisol levels can affect various neurotransmitters, including dopamine, norepinephrine, serotonin, glutamate, and gamma-aminobutyric acid (GABA), in addition to regulating the stress-HPA link at many stages.

PPD is treated with the same drugs used for MDD outside pregnancy and childbirth, the most common of which include selective serotonin reuptake inhibitors (SSRIs). However, these drugs are neither specific to PPD nor effective in all cases and have a slow effect.

PPD may arise due to various factors, including increased sensitivity to sex hormones during pregnancy and perinatal period, poorly regulated HPA activity, altered immune function, as well as changes in neural network activity and GABA-mediated synaptic transmission.

Brexanolone is currently approved for intravenous infusion over 60 hours in human new mothers. This treatment has been shown to rapidly and chronically relieve PPD symptoms in treated women.

What did the clinical trial show?

Brexanolone was approved following an open-label trial in 2019. The trial included mothers diagnosed with MDD during or after the third trimester of pregnancy up to 12 weeks postpartum. Each of the patients was prescribed stable doses of antidepressants for at least two weeks at the time of inclusion.

Brexanolone was infused at titrated doses, increasing to reach the maintenance dose over 12 or 24 hours and then sustained for 36 hours. Brexanolone treatment was subsequently tapered off over the next eight to 12 hours in Phase I and Phase II/III trials, respectively, during which the change in depression symptoms was measured.

In three Phase III trials including 375 women, the mean change in depression scores was significantly greater in the treatment group as compared to the placebo group and remained higher for the next 30 days. The response to the placebo was also robust, as expected from earlier studies on MDD. However, brexanolone still caused a significant improvement as compared to the placebo, with a rapid onset of action.

The side effects included autonomic symptoms like flushing, hot flashes, dry mouth, and sometimes, brief unconsciousness or, more commonly, excessive sedation, which required dose reduction in 4-5% of treated women. This was often linked to the simultaneous use of benzodiazepines.

These symptoms led the FDA to require a Risk Evaluation and Mitigation Strategy (REMS), including medical supervision during the period of administration, to monitor oxygenation and sedation levels.

What is the clinical experience?

The University of North Carolina (UNC) created a Clinical Brexanolone Program for PPD treatment. All participants must stop or reduce benzodiazepine use by 50% or more before beginning brexanolone treatment, which has been shown to reduce excessive sedation in these patients.

The UNC program is conducted on a medical floor rather than in the perinatal psychiatry inpatient unit (PPIU). This location change has provided patients with more freedom during their treatment; however, it also requires additional training for staff to manage psychiatric patients, which may involve acute safety or suicidal threats.

Over 55% of treated women experienced symptom remission, while 94% had clinically significant improvement at the 90-day follow-up visit. Notably, about 30% of women do not respond to this treatment.

The mechanism of action of brexanolone

Progesterone is converted to allopregnanolone, which acts on neurons in the brain to modulate GABA_A receptors. These are the major inhibitors of brain neuronal activity and the stress response.

GABA signals may be altered by genetically determined sensitivity to changes in sex hormone levels, as demonstrated in mouse models. Previous in vivo studies have demonstrated that genetically susceptible female mice during delivery exhibit symptoms of stress and depression with poor maternal behavior. This may be due to reduced allopregnanolone levels in the brain at the time of delivery.

Allopregnanolone reduces inflammatory pathways in cell models, primarily through toll-like receptors (TLRs) that detect a wide range of potentially dangerous molecules and agents. These include pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and xenobiotics (XAMPs).

Allopregnanolone reduces the production of several inflammatory mediators through its action on TLR2, TLR4, and TLR7 in rodent brains. In vitro, brexanolone reduces inflammatory markers in correlation with improved depression symptoms.

Brexanolone also prevents blood cells from reacting to the presence of lipopolysaccharide (LPS) and other activators of the inflammatory immune system, thereby preventing the activation of TRL4 and TLR7, a response that has been predictive of symptomatic improvement. The duration of inhibition of systemic inflammation remains unknown but may explain why infusion remains effective at 90 days.

Other neurosteroids

Zuranolone is an oral neurosteroid that modulates synaptic and extrasynaptic GABA_A receptors allosterically, which is unlike benzodiazepines that only act on synaptic receptors. Additionally, zuranolone acts fast and has been approved as the first oral drug for PPD.

Currently, zuranolone is being studied for non-pregnant MDD, which has produced mixed results. Sedation is a major side effect of zuranolone, which is otherwise well-tolerated.

Ganaxolone is a methyl-allopregnanolone analog with a similar mechanism of action; however, this agent does not affect estrogen or progesterone receptors. The efficacy of ganaxolone in PPD is still being studied; however, one study has not shown efficacy in post-traumatic stress disorder (PTSD) among veterans.

Pregnenolone and dehydroepiandrosterone (DHEA) are also potential candidate neuroactive steroids being investigated in depression and other psychiatric conditions.

What are the implications?

The efficacy of brexanolone as a rapid therapeutic for PPD has been demonstrated; however, further studies are needed to understand how and which inflammatory pathways are impacted by this drug.

The effect of brexanolone on GABA_A receptors may be enhanced by its anti-inflammatory activity. However, continued inflammation could overcome its GABA-ergic effects.

We propose that pleotropic actions of allopregnanolone are essential to its therapeutic potential in PPD and possibly other forms of depression and inflammatory brain disease.”