Zuranolone (Zurzuvae) is newly approved for postpartum depression, but does it work in regular depression? And why did they put so many “Zs” in the name?

Published On: 08/17/2023

Duration: 22 minutes, 54 seconds

Last week the FDA approved the first oral medication for postpartum depression. Zuranolone will hit the shelves in a few months, and we have answers to your questions.

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.

CHRIS AIKEN: Last week the FDA approved Zuranolone, brand Zurzuvae zur-ZOO-vay, for postpartum depression. The approval was a Pyrrhic victory for Sage Therapeutics, the company that developed the drug to replace its predecessor, Brexanolone, the cumbersome IV drug that was approved for postpartum depression in 2019 as Zulresso.

Brexanolone was a scientific breakthrough, but not a financial success; Sage had to lay off half its workforce shortly after the drug’s release. The drug worked well, but was hard to deliver, requiring overnight delivery by IV infusion, including oxygen checks because brexanolone is so sedating it can knock people unconscious. Think back to 2020 when brexanolone was first hitting the shelves and COVID precautions were in full swing. Were you in any position to open an overnight IV clinic? Probably not. Even hospitals did not rise to the occasion. Most of us were trying to figure out how to deliver care with as little contact as possible.

Only about 1,000 women have received brexanolone, and the miniscule market has not helped its pricing. A single treatment costs $34,000 for the drug alone, and more for the overnight monitoring. Sage was hoping to break out of this morass with an oral version that women could take at home, and that’s where zuranolone comes in.

 Zuranolone is sedating, but no one has lost consciousness on it, so it comes with a simple warning not to drive for 12 hours after taking it, so dose it at night. And it has the bioavailbility that brexanolone lacked, so it can be taken orally, although it needs a fatty meal to grease the wheels of absorption in the gut. 

Last week, I posted the FDA’s announcement on the DailyPsych, my feed on LinkedIn, Twitter, and Threads. If you want to follow the conversation, join in @ChrisAikenMD. We got a lot of thoughtful questions in the comments on that post, and we’re going to answer as many as we can here. But first a preview of the CME quiz for this podcast.

Earn CME credits through the link in the show notes

1. Zuranolone is a synthetic analogue of which hormone?

A. Pregnenolone

B. Prednisone

C. Estrogen

D. Allopregnanolone

Question one, does zuranolone treat major depressive disorder, the non-postpartum type?

That’s a big maybe. Sage originally developed zuranolone for treatment resistant depression, but it failed there so they moved on to try it in a more responsive group of regular major depression. The first two trials were encouraging, but as the trials got larger, the benefits got smaller, and in the latest trials zuranolone’s antidepressant effects were nothing more than a flash in the pan, fizzling out within a week and leaving no trace of the initial separation from placebo.

After reviewing those 5 trials, the FDA passed, telling Sage they needed more data before they would consider it in major depression. But on the same day the FDA approved zuranolone in post-partum depression, and here’s where they story gets interesting, because its mechanism may explain why.

 And that brings us to question 2, how does it work?

Zuranolone and brexanolone have the same mechanism. These are not really drugs in the traditional sense. They are synthetic analogues of a naturally occurring hormone – allopregnanolone – that rises during pregnancy and takes a sharp fall after delivery. 

Allopregnanolone modulates the GABA-a receptor that is involved in anxiety, mood, and cognition – the same one that benzodiazepines attach to – so you can imagine the postpartum period is almost like a massive benzodiazepine withdrawal. Well, not exactly – we’ll get to that – but what’s interesting here is this treatment was designed to fit the pathophysiology of postpartum depression, and it works. Mood improves as the falling levels of allopregnanolone are replaced with its synthetic analogue.

Question 3: With its GABA-ergic mechanism, is zuranolone just a benzodiazepine masquerading as a neurosteroid?

No – it works on the same receptor as the benzodiazepines, GABA-A, benzos bind to a different part of that receptor. Zuranolone’s binding allows it to have broader effects across the GABA-ergic circuits, that compose about 30% of brain circuits. The details get a little complex, but for our neuropharmacology diehards, zuranolone affects both phasic (synaptic) and tonic (extrasynaptic) GABA currents, while benzos affect only the phasic (synaptic) ones. For the rest of us, a more meaningful difference is this one. Over the long-term, benzodiazepines downregulate GABA-A receptors, while zuranolone upregulates them. At least, that’s what we read in an industry-sponsored poster (Stahl S et al, Zuranolone, a Positive Allosteric Modulator of the GABAA Receptor: Hypothesized Mechanism of Action in Major Depressive Disorder), and we expect to hear this fact repeated as it implies that zuranolone does not cause tolerance or addiction like the benzos do. But think twice if you hear that. Benzos do not downregulate the GABA-A receptor except at super-high doses you’d never see in practice, and downregulation is not thought to be the pathway through which they cause tolerance. 

Zuranolone is likely to be restricted as a controlled substance, but exactly how is under review. The FDA cites a study where it had similar rewarding qualities as alprazolam (Xanax) and was more rewarding than a placebo.

Zuranolone works, but does it keep working?

Zuranolone’s main advantage is its rapid-onset. Patients felt better within 3 days of taking it, and the drug is meant to be taken short-term, as a 2-week course, but what happens after those 2 weeks? The longest they’ve measured is 4 weeks after the last dose. At that time, there was a mild decline in its benefits, but it still surpassed placebo. Specifically, the effect size dropped from 0.5 to 0.3 a month after it was stopped – to put that in perspective, at the end of the 2 week treatment it was as powerful as a benzodiazepine in anxiety. A month later, it was as powerful as an SSRI is in anxiety.

But the picture was different in the major depression trials, and that’s a big reason it failed to gain approval there. In major depression, the effects were only notable for a few days. After that it fizzled out.

This is important, because most patients with postpartum depression have chronic mood disorders. Zuranolone will help them get back on their feet, but they’ll need something else – maybe psychotherapy – maybe exercise – maybe antidepressants or lithium – to keep depression at bay. And a lot of postpartum episodes are due to bipolar disorder, the link is strong enough that postpartum depression is considered a sign of bipolar. That brings us to the next question….

How will this affect bipolar patients?

There are no studies of zuranolone or brexanolone in bipolar disorder, and no studies in depression with mixed features either. We just don’t know, but we can say there was no sign of manic-induction in the trials. And while we have no reason to think that its gaba-ergic mechanism will trigger mania, this is new territory, so keep an open mind and stay tuned.

If this med has GABA-ergic effects, why is it being used for depression instead of anxiety?

The simple answer is that postpartum anxiety is not a disorder they can get approval for. Anxiety is a big part of the picture for a lot of women who go through this, and anxiety levels did improve with zuranolone – as did sleep – in the postpartum trials. We don’t think this is simply an antianxiety effect that is making people less depressed, however. The GABA system is linked to depression, but the link is poorly understood – one theory is that it involves GABA’s regulatory effects on the hypothalamic–pituitary– adrenal axis.

Question 7: What else does zuranolone treat?

So far we’ve seen positive trials in Parkinson’s tremor and primary insomnia. In animal models, it has anticonvulsant effects which may make it helpful in epilepsy. It is also under investigation for bipolar depression, and we’ve heard talk about studies in post-traumatic stress disorder and premenstrual dysphoric disorder – neurosteroids like allopregnanolone are involved in the pathophysiology of those conditions – but nothing published yet.

Question 8: When is this drug going to be available?

The FDA has some details to finish up over the next 3 months, including what level of control to restrict it as, so the earliest we expect to see it on the pharmacy shelves late 2023.

Can you breastfeed on zuranolone?

This is an unknown, so the FDA is recommending against breastfeeding while taking the drug – which is how the studies were done. Zuranolone caused sedation for 1 in 4 women who took it, so it may not be safe in breastfeeding. On the other hand, Dr. Deligiannidis, who lead the clinical trials, told Time magazine that the levels that pass into breast milk are very low – we couldn’t find that data though so assume it is unpublished.

For women who are breastfeeding, we recommend continuing to pump during the 2 week treatment so they don’t lose their lactation ability.

For the mother, zuranolone was well tolerated – the main side effects were"drowsiness, dizziness, diarrhea," and no one lost consciousness as they did in the brexanolone trials.

Question 10: Can you give zuranolone with other psych drugs?

Yes. It can be taken with antidepressants – 15-20% of the women in the studies were taking them – but whether it will work with a GABA-ergic benzo or z-hypnotic on board is less clear; patients were not allowed to take those during the trials. It is metabolized by CYP3A4, and the dose needs to be approximately doubled if paired with a strong CYP3A4 inducer like carbamazepine or modafinil or cut in half with a strong CYP3A4 inhibitor like grapefruit juice or fluvoxamine.

Final bonus question #11: Why so many Z’s?

Medications with the letter Z are perceived as more potent and elicit a strong placebo effect, while those that start with the letter T or S are perceived as more tolerable.  

And now for the study of the day, A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression, by Sameer Jauhar and colleagues in Molecular Psychiatry.

Last year, Molecular Psychiatry published a review that garnered a lot of attention in the press and on social media because it concluded what many have suspected all along: There is no consistent evidence linking serotonin to depression.

This month, the same journal published a sharply worded rebuke of the earlier review, and while the new paper suggests the the issue is not as black-and-white as the old paper laid it out, but it doesn’t exactly connect the dots between SSRIs and depression, which is what the fuss was all about to begin with.

Written by 36 experts, it finds many flaws in the original review that fall into 3 categories. Here they are

1. Double counting data. The review lumped together single studies with meta-analyses that contained them.

2. Misinterpretations. The original review made a few leaps of logic that don’t hold true in the land of neurobiology. For example, when less serotonin is bound to the transporter, it does not mean there is more serotonin in the synapse. The original review claims that there is no evidence linking reduced binding at the serotonin transporter to depression, but there is good evidence for this link if we focus on specific brain regions. 

3. Tryptophan depletion. One of the core supports for the serotonin theory is a classic lab finding: that depression can be induced in the lab by depleting the diet of tryptophan, which is a precursor of serotonin. I say “in the lab” because you have to carefully create a meal plan to cut out all tryptophan; it doesn’t happen in everyday life. And the reverse is not true – adding tryptophan supplements to the diet does not improve mood. Rather, it just makes you tired, like you’d feel after a tryptophan-rich turkey dinner.

The original review attempted to debunk the tryptophan finding, but they missed a few papers that support it.

In the end, this was much ado about nothing. No self-respecting psychiatric textbook has suggested that depression is due to a chemical imbalance or a single neurotransmitter. But the media has, and that’s why the original review was so popular. The new review reminds us of where things stand

1. Tryptophan depletion does cause depression in some people, but we haven’t really figured out why since the first tryptophan depletion studies came out in 1977. 

2. Serotonin is involved in depression, but that’s about as meaningful as saying electricity is involved in your smartphone. There are 15 serotonin receptors in the brain. Some of them have pro-depressive properties; some have anti-depressive properties. Increasing serotonin just causes problems – like the kinds of side effects we see when people start an SSRI – much like turning up the electricity doesn’t make my phone work better. It just makes it heat up. 

Building on that analogy, if you deplete your phone of electricity, it will stop playing this podcast. But that doesn’t tell us how it started playing in the first place. 

We weren’t surprised by either of these papers, but the intensity of the public response did catch us off guard, and that the real take home point. Patients don’t like the black-box approach of evidence based medicine, where we put random drugs in the animal model slot machines, move the winners up to human trials, and bring the ones that bring down a symptom rating scale to market without ever understanding how they work. And that is why the zuranolone story is so compelling, because the drug was developed right out of the known pathophysiology of postpartum depression, or at least, a slither of what is known.

Falling allopregnanolone is not the only thing that depresses a new mother. Poverty, domestic abuse, isolation, sleep disruption, poor diet, lack of exercise, the gut microbiome, low vitamin B6, and complications of pregnancy are all implicated. 

Vitamin B6 converts to tryptophan, which is a precursor of serotonin, and here we come full circle. In 2021, researchers gave a daily dose of Vitamin B6 80mg late in the 3rd trimester of pregnancy – or a placebo – in women who had a high risk of developing postpartum depression. After delivery, the ones who got the vitamin B6 had significantly less depression.

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