Generic name: zuranolone
Trade name: ZURZUVAE
Pronunciation: zu RAN oh lone / zur ZOO vay
Mascot / mnemonic phrase: "Zu Zu Zu ran alone"
❖ Neurosteroid
❖ GABA-A receptor positive allosteric modulator
FDA-approved for:
❖ Postpartum depression
FDA-approved for:
❖ Postpartum depression
On August 4, 2023 the FDA approved zuranolone (Zurzuvae) as the first oral treatment for postpartum depression. Zuranolone follows brexanolone, a similar medication approved in 2019 for intravenous administration.
Mechanism of zuranolone
Zuranolone is a modified version of allopregnanolone (“all pregnant and alone”), an endogenous neurosteroid made from progesterone that is increased during pregnancy.
It is theorized that withdrawal from allopregnanolone after childbirth can lead to postpartum depression and anxiety.
There are two distinct allopregnanolone binding sites on the GABA-A receptor (Hosie et al, 2006). Conventional antidepressants are known to raise levels of endogenous allopregnanolone.
Zuranolone acts at the GABA-A receptor complex, as do several classes of drugs that calm down the central nervous system, including benzodiazepines and barbiturates (although at different binding sites). Unsurprisingly for something that works through the GABA-A receptor, zuranolone has anxiolytic, sedative, and anticonvulsant properties.
Details / Risks / Side effects of zuranolone
It can be used "-alone" or as an adjunct to other antidepressant therapy.
There is no Risk Evaluation and Mitigation Strategy (REMS) program for zuranolone (like there is for brexanolone, which is given by IV infusion over 60 hours in the hospital).
Zuranolone has a BOXED WARNING of impaired driving ability due to CNS depressant effects. Patients should not to drive for at least 12 hours after taking zuranolone.
Due to risk of fetal harm. Females of reproductive potential should use contraception during treatment and for one week after the final dose.
In clinical trials side effects reported by subjects included: somnolence 36% (vs 6% placebo), dizziness 13% (vs 9%), diarrhea 6% (vs 2%), memory impairment 3% (vs 0%), and abdominal pain 3% (vs 0%). Dosage reduction due to side effects occurred in 4% of subjects.
Dosing of zuranolone
Available in 20 mg, 25 mg, and 30 mg capsules
Administer with fat-containing food. Recommended dosage is 50 mg PO HS x 14 days. Reduce dose to 30 mg for severe hepatic or moderate/severe renal impairment. Avoid use in end stage renal disease (ESRD). No driving for 12 hours post dose. See CYP3A4 interactions.
Zuranolone interactions
Pharmacodynamic interactions:
❖ Sedation / CNS depression
Pharmacokinetic interactions:
❖ CYP3A4 substrate (fish)
● Use 30 mg with a strong 3A4 inHibitors
● Avoid concomitant use with a strong 3A4 inDucer (because zuranolone levels will be too low)
Zuranolone interaction mnemonic:
The fishy 3A4 mnemonic framework is explained here.
Now about brexanolone (ZULRESSO)
Generic name: brexanolone
Trade name: Zulresso
Pronunciation: brex AN oh lone / zul RESS o
Mascot / mnemonic phrase: “Zulu resigns (to) Brex (feed) alone”
Mechanism: Same as zuranolone
FDA approved for: Same as zuranolone
Brexanolone was the first medication FDA-approved for postpartum depression, (2019). Brexanolone is structurally identical to allopregnanolone (“all pregnant and alone”), an endogenous neurosteroid made from progesterone that is increased during pregnancy.
Brexanolone costs $34,000, not including the cost of hospitalization, and must be given as an IV infusion over 60 hours!
Dosing of brexanolone
Given intravenously over 60 hours; Start 30 mcg/kg/hr for 4 hours, then 60 mcg/kg/hr for 20 hours then 90 mcg/kg/hr for 28 hours, then 60 mcg/kg/hr for 4 hours, then 30 mcg/kg/hr for 4 hours = 60 hours total
Brexanolone Interactions
Unlike zuranolone, brexanolone is not a sensitive substrate. The label does not advise dose adjustment of brexanolone with concomitant CYP3A4 inhibitors or inducers. In Cafer's Psychopharmacology, brexanolone was represented "in a bubble" to indicate lack of relevant kinetic interactions. In the 2nd edition of the book, brexanolone will not be shown in a bubble because the mascot is essentially the same as for zuranolone, which we need to remember as a fish (CYP3A4 substrate).