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Oral zuranolone (ZURZUVAE) approved for postpartum depression

Generic name: zuranolone

Trade name: ZURZUVAE

Pronunciation: zu RAN oh lone / zur ZOO vay

Mascot / mnemonic phrase: "Zu Zu Zu ran alone"

How to remember zuranolone  Zurzuvae visual mnemonic.
The mascot for zuranolone is derived from the brexanolone mascot, shown below. The rain cloud means the medication is approved for treatment of depression. Note the actual spelling is -olone, not -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:

Zuranolone ZURZUVAE is a CYP3A4 substrate.  Interactions apply.
CYP3A4 substrate (fish)

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”

how to remember the name of brexanolone zulresso
Mnemonic mascot for brexanolone

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).





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