In short
Brexanolone is a neuroactive steroid that acts as a positive modulator of the GABA A receptor. It is authorised in the United States as Zulresso for treating postpartum depression (PPD) in patients 15 years and older. One completed Phase 1 trial in 24 healthy male participants evaluated its central nervous system effects using transcranial magnetic stimulation.
Key points
- Brexanolone is a neuroactive steroid GABA A receptor positive modulator authorised as Zulresso for postpartum depression in patients 15 years and older.
- It is given as a continuous intravenous infusion over 60 hours in a medically supervised setting.
- One Phase 1 trial completed in 24 healthy male participants evaluated its central nervous system pharmacodynamic activity.
- The trial compared brexanolone with lorazepam and placebo using transcranial magnetic stimulation and electromyography.
- Brexanolone carries a boxed warning for excessive sedation and sudden loss of consciousness during administration.
- The trial measured change from baseline in TMS-induced motor evoked potentials as its primary endpoint.
What is brexanolone?
Brexanolone is a chemically synthesised neuroactive steroid. It is the same molecule as allopregnanolone, a naturally occurring steroid in the brain that influences mood and stress responses. The substance is marketed under the trade name Zulresso and was first approved by the US Food and Drug Administration (FDA) in 2019. In the EU Clinical Trials Information System, the product records list brexanolone as an authorised medicine and as the test substance in one trial. The drug has been discontinued in the United States according to a professional monograph.
How does brexanolone work?
Brexanolone acts as a positive modulator of the gamma-aminobutyric acid type A (GABA A) receptor. GABA is the main inhibitory neurotransmitter in the brain, meaning it reduces the activity of nerve cells. By enhancing the effect of GABA at the GABA A receptor, brexanolone increases inhibitory signalling in the central nervous system. This mechanism is thought to help restore the balance of brain activity that can be disrupted in postpartum depression, a condition that may be linked to sharp changes in neurosteroid levels after childbirth.
Which conditions is brexanolone used or studied for?
- Postpartum depression (PPD) — a serious depressive episode that can begin during pregnancy or after childbirth. Brexanolone is authorised for the treatment of PPD in patients 15 years and older.
- Central nervous system pharmacodynamic activity in healthy volunteers — one Phase 1 trial investigated how brexanolone affects brain excitability in healthy male participants, using transcranial magnetic stimulation.
How is brexanolone given?
Brexanolone is administered as a continuous intravenous infusion over 60 hours (2.5 days). The product information describes a stepwise dosing schedule: 30 micrograms per kilogram per hour for the first 4 hours, then 60 micrograms per kilogram per hour from 4 to 24 hours, and 90 micrograms per kilogram per hour from 24 to 52 hours. In the Phase 1 pharmacodynamic trial, brexanolone was given intravenously at a dose of 90 micrograms per kilogram. Because of the risk of excessive sedation, administration requires continuous monitoring by a healthcare provider and continuous pulse oximetry.
What do the clinical trials show?
The EU Clinical Trials Information System lists one completed Phase 1 trial of brexanolone. The trial enrolled 24 healthy male participants and was designed to evaluate the central nervous system pharmacodynamic response to brexanolone compared with placebo and lorazepam, a benzodiazepine used as an active comparison.
The primary endpoint was the change from baseline in transcranial magnetic stimulation-induced motor evoked potentials (TMS-MEPs) measured by electromyography. Motor evoked potentials are electrical signals recorded from a muscle after the motor cortex of the brain is stimulated with a magnetic pulse; their amplitude reflects how excitable the motor pathways are. The trial compared brexanolone at 90 micrograms per kilogram intravenously with lorazepam 2 milligrams orally and with placebo.
What side effects are known?
The prescribing information for Zulresso carries a boxed warning for excessive sedation and sudden loss of consciousness during administration. Patients must be monitored continuously with pulse oximetry, and they must be accompanied during interactions with their children while the infusion is running. Because of these risks, brexanolone is available only through a restricted program called the Zulresso Risk Evaluation and Mitigation Strategy (REMS). The professional monograph confirms that the risk of excessive sedation or sudden loss of consciousness applies during administration of the drug.