On August 4, 2023, the FDA approved zuranolone (Zurzuvae, “zur-ZOO-vay”) for postpartum depression (PPD). The medication is an oral version of IV brexanolone (Zulresso), which was approved for the same indication in 2019. Brexanolone stalled, with just over 1,000 women receiving it, because of its high cost and requirement for overnight monitoring. Both drugs bring a novel mechanism to the table, and in this article I’ll look at what that means for depression in postpartum and beyond.

Rapid action

Zuranolone works quickly. It is given as a two-week course, and the benefits are seen within three days. This kind of rapid onset is particularly important in PPD, where every day of active symptoms takes a measurable toll on infant development. 

On the other hand, we don’t know how long those benefits will last. Zuranolone’s approval was based on two randomized trials that followed patients for four weeks after their last dose. No decline was seen at that point, but this was a select group where active psychosis, suicidality, and bipolar were excluded. In practice, patients with PPD often have more complex histories and high levels of recurrence. In these trials, 89% were in their first postpartum episode (Deligiannidis KM et al, JAMA Psychiatry 2021;78(9):951–959; Deligiannidis KM et al, Am J Psychiatry 2023;180(9):668–675).

Non-postpartum depression

While both postpartum trials were positive with a respectable effect size (0.5), zuranolone’s course in general depression has been uneven. The manufacturer, Sage Therapeutics, first tested it in treatment-resistant depression. Failing there, they moved on to major depressive disorder (MDD) and found success in a small controlled trial. However, the large, follow-up MOUNTAIN study was negative, prompting the company to try again at a higher dose of 50 mg instead of 20–30 mg (Clayton AH et al, J Clin Psychiatry 2023;84(2):22m14445). 

What followed were two large controlled trials that are often presented as positive but did not convince the FDA. Zuranolone surpassed placebo, but only for a few days. Over the two-week course of treatment, it fizzled out before the treatment was over in the CORAL study and just after the final dose in the WATERFALL study (Carvalho T, Nat Med 2023;29(5):1032–1033). Zuranolone’s mechanism of action may explain these conflicting results.

How it works

Like the benzodiazepines, zuranolone is a positive allosteric modulator of the GABA-A receptor. Unlike the benzodiazepines, it binds to a different area of GABA-A, upregulates the receptor, and has broader effects on GABAergic transmission (Stahl S et al, CNS Spectr 2023;28(2):260–261). 

These actions mimic the effects of allopregnanolone, a hormone that rises during pregnancy and falls after delivery. The sudden fall in allopregnanolone contributes to the pathophysiology of PPD. Brexanolone (approved as an IV treatment for PPD) is chemically identical to allopregnanolone, and zuranolone is a slightly modified version designed to enhance oral absorption. In theory, they treat PPD by easing allopregnanolone withdrawal.

No such elegant mechanism exists for zuranolone in MDD. Until proven otherwise, it’s hard to see how this drug is any different in MDD from a benzodiazepine.

Besides sharing a common mechanism with the benzos, zuranolone shares in their anxiolytic, hypnotic, and rewarding effects. One study asked subjects with a history of sedative misuse to compare zuranolone, alprazolam, and placebo. Zuranolone made them feel euphoric and drunk, and they found it just as rewarding as alprazolam, according to FDA data cited in PDR.

It is not surprising that a medication with benzo-like properties would improve depression, if only temporarily. Benzodiazepines have robust short-term data in MDD, particularly alprazolam, which earned an initial FDA approval in MDD (Van Marwijk H et al, Cochrane Database Syst Rev 2012;2012(7):CD007139). That approval was downgraded to “anxiety associated with depression” upon alprazolam’s release in 1981, in part due to concerns about tolerance and drug misuse. 

Because of these similarities, zuranolone is classified along with the benzodiazepines as a Schedule IV controlled drug, as is its IV cousin brexanolone.

Bipolar disorder, psychosis, and ­suicide

While zuranolone is praised as a breakthrough for PPD, we have to acknowledge that the most severe forms of this disorder were excluded from the trials: bipolar depression, psychotic depression, and patients with an elevated suicide risk. 

PPD is more common in bipolar disorder, and postpartum episodes should raise suspicion for bipolarity. Whether zuranolone will work in these cases is unknown, but there was no sign of manic switching in the depression trials. Studies are underway in bipolar depression, and so far they have produced a small open-label trial where 45% of the subjects responded to a two-week course of zuranolone (Meshkat S et al, J Affect Disord 2023;S0165-0327(23)01003-0).

Side effects and drug interactions

Zuranolone’s main side effects are drowsiness, dizziness, and diarrhea. One in four women experienced significant fatigue, although unlike brexanolone, it did not cause loss of consciousness. Zuranolone can impair driving for up to 12 hours after the dose. It is not recommended in breastfeeding because its safety is untested. Women who intend to breastfeed should pump during the treatment in order to maintain their lactation ability.

Zuranolone is vulnerable to drug interactions at CYP3A4. Patients will need a higher dose to adjust for CYP3A4 inducers (eg, carbamazepine and the ­modafinils) and a lower dose for CYP3A4 inhibitors (eg, nefazodone, fluvoxamine, and grapefruit juice). Otherwise, it can be taken with other antidepressants, as it was for one in five women in the trials. However, other GABAergics like benzos, z-hypnotics, and alcohol were not allowed in the trials, so use caution until we have more clarity on those interactions.

How to use it

Zuranolone is dosed once at night for two weeks. It needs to be taken with a high-fat meal of at least 400 calories in order to be absorbed. The starting and treating dose is 50 mg, and this can be lowered if it causes problematic side effects like fatigue. The two postpartum trials found similar benefits with the 30 and 50 mg doses.

The FDA has not addressed the issue of repeated trials, but this strategy was tested in a large open-label study of MDD. In the year following treatment, 55% of patients required a second two-week course of zuranolone, and 16% required three or four additional courses (Meshkat et al, 2023).

CARLAT VERDICT