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Zuranolone is a neurosteroid that is inching its way toward FDA approval in depression. In some ways it’s similar to brexanolone (Zulresso) – the IV therapy approved in 2019 for postpartum depression – and in other ways it’s different.

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Published On: 04/04/2022

Duration: 12 minutes, 20 seconds

Related Articles: “Brexanolone: A New Treatment for Postpartum Depression,” The Carlat Psychiatry Podcast, August 2019

“Brexanolone (Zulresso) for Postpartum Depression,” The Carlat Psychiatry Report, June 2019

“Brexanolone: A New Treatment for Postpartum Depression,” The Carlat Psychiatry Report, January 2019

Chris Aiken, MD, Kellie Newsome, PMHNP, and Margaret Chisolm, MD, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

Transcript:

When you think about it, the meds we have available today are not too different from the ones we had 50 years ago: Antipsychotics, antidepressants, mood stabilizers, stimulants, and sedatives. But a new classification is about to disrupt that. In fact, it already has: The neurosteroids.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: “First in class” is a designation the FDA gives to medications that bring a novel mechanism of action into the treatment arena. It’s a mixed honor – “first in class” therapies bring new possibilities but carry uncertain risks.

Brexanolone justly earned this status, as the first neurosteroid to gain FDA approval in psychiatry. Branded as Zulresso, Brexanolone was FDA approved for postpartum depression in 2019. It is a synthetic version of allopregnanolone, a naturally occurring hormone that has activity on GABA and serotonin receptors. 

Brexanolone’s main advantage is speed. The drug works within a few days, an advantage that is amplified in the setting of postpartum depression, because every month of depression in the mother has a measurable effect on the infant’s development.

Brexanolone may be a breakthrough, but it’s just barely broken through, gathering about 6 million on sales annually. Those are small numbers for the pharmaceutical industry, especially for a drug that costs $36,000 per treatment – it translates to about 166 treatments a year. What has held brexanolone back is cost and convenience. The $36,000 treatment has to be given intravenously – over 2 and a half days. 

Today we’re going to tell you about a new medication that may overcome at least one of those hurdles: Zuranolone. But first, a preview of the CME quiz for this podcast.

Zuranolone and brexanolone are structural analogues of which naturally occurring hormone?

A. DHEA

B. Prednisone

C. Allopregnenolone

D. Progesterone 

CHRIS AIKEN: In most respects, zuranolone is the same medication as brexanolone. What sets it apart is its bioavailability. Zuranolone can be given orally, while brexanolone must be delivered intravenously because it’s barely absorbed in the gut. Another rapid-acting antidepressant – esketamine – is beset with the same problem. Esketamine has such poor bioavailability that it has to be given intranasally, although an oral version is being developed. 

Zuranolone is also under development, but in the past half-year a string of favorable studies have increased its chances of getting FDA approved. Things are going to change if it does, in several ways:

1. We’ll have a practical, fast-acting option for postpartum depression
2. We’ll have two rapid-acting antidepressants – esketamine and zuranolone. And unlike esketamine, zuranolone doesn’t seem to have an abuse liability and probably won’t need to be given in a controlled setting.
3. We’ll have an option for depression with a totally unique mechanism of action.

Like intravenous brexanolone, oral zuranolone is also fast-acting. It treated depression within 3 days in two clinical trials – the CORAL and WATERFALL trials. “Treated” may be an overstatement, however, as so far it only reduced the Hamilton depression score by 2-4 points in the data we’ve seen. However, it did improve anxiety in addition to depression, so the difference may be clinically meaningful to patients.

KELLIE NEWSOME: So far zuranolone is being planned as an acute treatment for rapid relief from depression – something you might use while waiting for a traditional antidepressant to kick in. That’s particularly useful for severe, suicidal patients, where rapid relief can keep them out of the hospital. We don’t have any reason to think zuranolone will have much use beyond acute relief. In some of the trials, its benefits tapered off a bit by day 15 compared to day 3, although in others it continued to keep patients in remission up to 45 days after it was dosed.

Those details should become more clear as the full trials are published – which include studies in postpartum depression and general depression, as monotherapy, augmentation, or as a co-initiated treatment started alongside an antidepressant.

Zuranolone appears safe and well tolerated. Its main side effects are fatigue, dizziness, and headache.

CHRIS AIKEN: Zuranolone and brexanolone are analogues of the hormone allopregnanolone. Presumably their effects are similar to those of the natural hormone, but being synthetic analogues allows them copyright protection. As far as we know, allopregnanolone has not been used on its own in medicine, but many patients have probably taken it indirectly through the related hormone pregnanolone has. 

Pregnanolone was used to treat rheumatoid arthritis in the 1950’s, but is no longer used for that anymore. Today, it’s a popular over the counter treatment, promoted for cancer, arthritis, and multiple sclerosis without much evidence to help any of them. Pregnanolone is preferentially metabolized into allopregnanolone, so if your patient is taking pregnanolone they are probably getting a good dose of allopregnanolone as well.

But just what constitutes a good dose is not a straight-forward question. Allopregnanolone has paradoxical effects that vary by its dosing – and we expect zuranolone and brexanolone will as well. The effects at the GABA-A receptor follow a U-shaped curve. At low and high doses – the tail ends of the U-shape – allopregnanolone stimulates the GABA-A receptor, relieving anxiety. At medium doses, however, it inhibits GABA-A, potentially causing anxiety. Those medium doses are equivalent to the natural levels seen in women during the luteal phase of the menstrual cycle. 

KELLIE NEWSOME: If zuranolone gains FDA approval, it could happen anytime in the next year, with a possible launch in 2023. In the meantime, if your patient needs brexanolone for postpartum depression, you can locate a provider by calling 844-472-4379. And if you need CME credit for this podcast, follow the link in the show notes.

Now for the word of the day….  Cyclooxygenase-2

CHRIS AIKEN: Cyclooxygenase-2, or COX-2, is an enzyme involved in inflammation and pain. This enzyme converts arachidonic acid to prostaglandin H2, a precursor of the prostacyclin, an inflammatory prostaglandin that dilates the blood vessels and inhibits platelet activation. COX-2 inhibitors like celecoxib (Celebrex) are NSAIDs that block this enzyme, thereby reducing inflammation and pain, and – as we’ll see in the next episode – possibly even treatment resistant depression.

KELLIE NEWSOME: If you like audio learning, check out Dr. Aiken’s new audiobook on bipolar II disorder, Bipolar, Not So Much, available on Amazon or Audible.com from WW Norton. The book is written for patients and professionals and covers the diagnosis, medication, and lifestyle approaches to bipolar. Here’s what Dr. David Dunner – the psychiatrist who developed bipolar II back in the 1970’s wrote about it: “This informative book is easy to read and provides practical information for patients and families. . . . I would also recommend it to mental health trainees.” Or as an Amazon Reviewer put it, “A must-read for all psychiatrists and therapists… Honestly, I’m addicted to this book.”