Brexanolone

[Evidence Based]

Anyone know anything about the new postpartum depression drug approved by the FDA today? Seems to be super cumbersome to administer (60 hour IV infusion) and comes with a crazy price tag ($34,000 plus inpatient hospital stay), which seems like it will limit its utilization. A (very cursory) look at the RCT data in The Lancet showed a 2 point HAM-D benefit compared to placebo, which seems.... underwhelming.
But I'm just a PGY-1 and know very little about perinatal psychiatry, so would be interested in hearing folks' thoughts!

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[wolfvgang22]

A very expensive GABA agonist, it appears.

 

[TexasPhysician]

I’m not impressed by the benefits, and it has almost no utility. Fairly shocked any company spent the money on this.

 

[clausewitz2]

A very expensive GABA agonist, it appears.

It's subunit specific and there is a lot of interesting molecular work suggesting that hormonal changes in pregnancy significantly alter GABA function, for example antagonism of some specific GABA subunits is actually anxiolytic in pregnancy but not in non-pregnant people. Which is to say I can wave my hands in a very interesting pattern around this medication without having strong intuitions about it or much in the way of expectations.

I can see it getting used sometimes at a center like ours but I am guessing it is going to be a strictly tertiary center type of deal.

 

[tr]

I'm quite excited about this. It works within 24-48 h, which is a huge advantage over existing treatments. The IV infusion is definitely limiting and will restrict its use to the most severely affected patients. I understand the company is working on an orally bioavailable form of brexanolone that may have wider utility.

Characterizing it as an expensive GABA agonist is oversimplified. GABA acts at two different types of receptors with multiple isoforms, and the neurotransmission is affected in complex ways by various allosteric modulators, of which allopregnanolone is one. Allo also exerts negative modulation on nAchR and 5HT3R mediated neurotransmission.

It's true that while the pilot data were smashing, the larger RCT did not do as well because of unexpectedly good response in the placebo group. (17-19 points on the HAMD in 2 days is tremendous; 14 points for placebo was definitely not predicted.)

It's possible that this speaks to the utility of an inpatient stay where the patient is removed from the environmental stressors that are contributing to the PPD. The pilot data showed sustained benefit from brexanolone at 1 and 6 months. I will be quite surprised if the RCT placebo group shows the same.

 

[WisNeuro]

Is there any other long-term data on this, because the difference in 60-day from Tx and placebo looks clinically the same?

 

[tr]

Is there any other long-term data on this, because the difference in 60-day from Tx and placebo looks clinically the same?

I saw the 6 month data in a presentation. Poking around it looks like journal articles on that cohort are only reporting to 30 days. I will dig around more later when I can get on a computer.

 

[Sushirolls]

Doubt this will have a significant future as its currently presented.

 

[QofQuimica]

I saw the 6 month data in a presentation. Poking around it looks like journal articles on that cohort are only reporting to 30 days. I will dig around more later when I can get on a computer.

@tr is there anything known about the mechanism for the LOC that can occur with this drug?

 

[Merely]

Damn I’m a ms4 doin psych and I don’t know **** when you guys talk...it’s like I’m from mars

 

[Evidence Based]

It's true that while the pilot data were smashing, the larger RCT did not do as well because of unexpectedly good response in the placebo group. (17-19 points on the HAMD in 2 days is tremendous; 14 points for placebo was definitely not predicted.)

It's possible that this speaks to the utility of an inpatient stay where the patient is removed from the environmental stressors that are contributing to the PPD. The pilot data showed sustained benefit from brexanolone at 1 and 6 months. I will be quite surprised if the RCT placebo group shows the same.

Thanks for the input that's interesting to hear! Agree that this is a huge placebo response, so not sure how excited it merits getting if most of the effect is just 2/2 having a couple days in a hospital without a newborn to take care of. Would be interested to see how the data on the oral formulation stacks up.

Definitely let us know if you dig up any of the longer term data! I've been casually googling and haven't seen much.

 

[tr]

@tr is there anything known about the mechanism for the LOC that can occur with this drug?

I dunno, I didn't participate in running these trials so I didn't see any of the participants myself (at least not while they were in the trial). It seemed like sedation was the main adverse effect and I wonder whether the couple of cases of LOC might just have been extreme sedation. The authors did say they did not record any respiratory or hemodynamic compromise. This has been a concern for a lot of us from a clinical perspective though, since even if the oral formulation comes through we definitely wouldn't want to send anyone caring for a newborn home with something that could sedate them to the point of LOC.

Agree that this is a huge placebo response, so not sure how excited it merits getting if most of the effect is just 2/2 having a couple days in a hospital without a newborn to take care of.

So these are the figures from the Lancet article. Placebo effect was large like I said but this does not look to me like the effect is all ascribable to placebo, although in Study 2 the difference is not sustained. Kinda seems like 60 works better than 90 though.

 

[dl2dp2]

So these are the figures from the Lancet article. Placebo effect was large like I said but this does not look to me like the effect is all ascribable to placebo, although in Study 2 the difference is not sustained. Kinda seems like 60 works better than 90 though.

These curves look eerily like the curves from the ketamine trials. Midazolam cures treatment resistant depression!

Why does placebo (??when delivered IV) have such a rapid onset of antidepressant effect? Do people not find this curious?

 

[FlowRate]

"No, we won't approve Brexanolone or Ketamine until you've tried ECT."

Turns out it's secretly a ploy by the ECT lobby to get more people to try their product, which just so happens to work better despite the unappealing packaging.

 

[Salpingo]

I can think of many more creative ways of reducing HAM-D scores over 48 hours for MUCH less than $34,000.

 

[clausewitz2]

I can think of many more creative ways of reducing HAM-D scores over 48 hours for MUCH less than $34,000.

Giving someone $34,000 might also have a similar effect.

 

[WisNeuro]

Why does placebo (??when delivered IV) have such a rapid onset of antidepressant effect? Do people not find this curious?

There is a decent amount of research out there, with some sham surgery stuff too, that would suggest the more invasive (or perception of) the procedure, the more robust the placebo response.

 

[WisNeuro]

Also, I am curious as to what this looks like plotted against a TAU group.

 

[tr]

These curves look eerily like the curves from the ketamine trials. Midazolam cures treatment resistant depression!

Why does placebo (??when delivered IV) have such a rapid onset of antidepressant effect? Do people not find this curious?

I can't speak to the ketamine data but for brexanolone, many of these women may have gone from awakening every two hours all night long, weeks on end, to the screams of a tiny parasite who was gnawing for sustenance at their most sensitive body parts, to a quiet, controlled environment in which the entire purpose was for them to rest and recover their mental health. It's not... totally surprising that lots of them felt better even without the drug.

I don't even know if it's proper to call this placebo. It might have been instructive to plot the HAMD scores of their spouses at home and see if there was a complementary inverse curve.

 

[tr]

"No, we won't approve Brexanolone or Ketamine until you've tried ECT."

Turns out it's secretly a ploy by the ECT lobby to get more people to try their product, which just so happens to work better despite the unappealing packaging.

Works great, sorry about the memory loss. On the bright side, you won't even remember what you were depressed about!

 

[birchswing]

These curves look eerily like the curves from the ketamine trials. Midazolam cures treatment resistant depression!

Why does placebo (??when delivered IV) have such a rapid onset of antidepressant effect? Do people not find this curious?

This may sound a bit weird, but I really like getting plain isotonic IV fluids.

I associate it with feeling better quickly.

I also like the rapid rush of salt taste in the mouth when they start a line.

I have spells of tachycardia that are unexplained (I just mention that to give the context, not looking for opinion on it), and one time an ER doctor was nice enough to admit me overnight and even though I had no signs of dehydration gave me IV fluids and I just felt so much better. I have a touch of dysautonomia and POTS so it could have been the volume loading, but not sure.

Sidestepping my personal situation, maybe the hydration just feels good? I mean people go to oxygen bars I suppose because it feels good (or placebo good?) even though there's already sufficient oxygen in the air.

I once read something, perhaps here or perhaps on the the last psychiatrist, about the value of giving a patient a pill and the meaning of the pill. That it wasn't in this case the contents of the pill but what it represented—someone validating a concern and providing care.

When you get an IV, it's more than a pill. Maybe it really feels like someone cares. Maybe it means you can forget your cares and the running of your body because a machine is doing it now—you don't even have to remember to drink, and the machine is not unlike a mother carrying an infant in the womb who is attached to an umbilical cord.

 

[FlowRate]

There is a decent amount of research out there, with some sham surgery stuff too, that would suggest the more invasive (or perception of) the procedure, the more robust the placebo response.

See also: botox for migraines. The placebo had a very robust response but you can tell whether you had botox or placebo, so botox is likely even more reinforcing. (not only did I get my face poked, but now I can't move my eyebrows, this stuff must be working!)

 

[dl2dp2]

Giving someone $34,000 might also have a similar effect.

This is a testable hypotheses. I suspect that this won’t work. If you think back about your hospitalized severe depressed patients, the news of them newly getting 34k would really change their feelings? No it’s largely a biological thing. No psychotherapy that I know of works within 48 hours.

 

[WisNeuro]

This is a testable hypotheses. I suspect that this won’t work. If you think back about your hospitalized severe depressed patients, the news of them newly getting 34k would really change their feelings? No it’s largely a biological thing. No psychotherapy that I know of works within 48 hours.

In-vivo exposures for very circumscribed fears can have some pretty quick results after a intensive session. It still needs reinforcement with further sessions, but it is pretty common to have a big response at first.

 

[WisNeuro]

See also: botox for migraines. The placebo had a very robust response but you can tell whether you had botox or placebo, so botox is likely even more reinforcing. (not only did I get my face poked, but now I can't move my eyebrows, this stuff must be working!)

Yeah, part of the issue with many treatment trials, very hard to blind. Also, most trials do a poor job of tracking loss of blind in subjects and treaters in the study. Best practices would have both rate which condition they believed that they were in to see if there was a difference. I see that reported <5% of the time in RCT studies.

 

[dl2dp2]

In-vivo exposures for very circumscribed fears can have some pretty quick results after a intensive session. It still needs reinforcement with further sessions, but it is pretty common to have a big response at first.

Eh, even that for specific phobia it’s generally a course of exposure, and intensive exposure isn’t introduced in the first session. For PTSD def NOT effective in the first session. There are other brief interventions proposed ie SBIRT etc for addiction, but they just don’t work.

 

[WisNeuro]

Eh, even that for specific phobia it’s generally a course of exposure, and intensive exposure isn’t introduced in the first session. For PTSD def NOT effective in the first session. There are other brief interventions proposed ie SBIRT etc for addiction, but they just don’t work.

Assuming that we are measuring from the first exposure session. First session or two is usually evaluative/psychoeducational before the active treatment starts. But, we still commonly see a robust pop at the beginning, particularly for the specific phobias and panic with interoceptive issues. Not arguing against the point in general, but there are some instances where a quick improvement is seen, just in very circumscribed contexts.

 

[Salpingo]

This is a testable hypotheses. I suspect that this won’t work. If you think back about your hospitalized severe depressed patients, the news of them newly getting 34k would really change their feelings? No it’s largely a biological thing. No psychotherapy that I know of works within 48 hours.

Well, there was a roughly 50% drop in HAM-D of placebo group within 48 hours... so not sure it would be that big of a leap to say psychotherapy wouldn’t have a similar effect (for 34k, you could get it on a private plane on your way to Aruba).

 

[Armadillos]

Based on our other recent thread makes me wonder about ketamine for post-partum depression.

Given there is massive benefit to the patient and family if postpartum depression is rapidly improved, the durability concerns wouldn’t bother me as much. No idea if this has been studied at all and too lazy to look at the moment, but seems like the type of situation where rapid response is of the essence and I would be willing to sacrifice some durability.

 

[dl2dp2]

Well, there was a roughly 50% drop in HAM-D of placebo group within 48 hours... so not sure it would be that big of a leap to say psychotherapy wouldn’t have a similar effect (for 34k, you could get it on a private plane on your way to Aruba).

That's just it. My hypothesis is that the ritual of IV and infusion beats any 34k therapy by a mile. Feel free to write a grant to test your hypothesis if you don't believe me.

In my experience of outpatient practice, major depressive episodes are not usually rescued by a vacation--believe or not a commonly attempted coping strategy. In fact, very often vacations make these people feel worse after the fact because of isolation, guilt and rumination. Think about it, people have been trying to cure depression by sending people to faraway retreats since the Middle Ages. And the only retreats that actually worked were the ones where the water had lithium in it. If depression is this easy none of us would have a job.

 

[tr]

That's just it. My hypothesis is that the ritual of IV and infusion beats any 34k therapy by a mile.

Not disagreeing at all, but I thought the reason for the $34K price tag was actually the infusion (and hence required 3 day inpatient stay). I can't imagine that's the price for just the drug?

 

[WisNeuro]

Did you read the article in the op? It says "Sage will charge $34,000 for a single treatment course of Zulresso, before any discounts or rebates. There will also be the added expense of a short hospital stay."

For the low, low price of a second mortgage on your home, you too can have a treatment that is essentially the same as a saline drip!

 

[QofQuimica]

I dunno, I didn't participate in running these trials so I didn't see any of the participants myself (at least not while they were in the trial). It seemed like sedation was the main adverse effect and I wonder whether the couple of cases of LOC might just have been extreme sedation. The authors did say they did not record any respiratory or hemodynamic compromise. This has been a concern for a lot of us from a clinical perspective though, since even if the oral formulation comes through we definitely wouldn't want to send anyone caring for a newborn home with something that could sedate them to the point of LOC.

I wondered about that too. It's like when a consulting team tells me that the patient is "obtunded" or "lethargic." I suspect that word often means quite a different thing to me than it does to them! But from what I've read about brexanolone, they seem to be saying that it's causing actual syncope, not just sedation.

Not disagreeing at all, but I thought the reason for the $34K price tag was actually the infusion (and hence required 3 day inpatient stay). I can't imagine that's the price for just the drug?

Unfortunately, it's totally imaginable; there are plenty of examples, and a drug charge in the tens of thousands of dollars is the norm for biologically-derived antidotes like FAb fragments. This also gets back to the fact that whatever price the hospital puts on their chargemaster list may be very different than what ends up getting negotiated by the patient's insurance company if they have one. But still. I don't think anyone would argue that new drugs on patent (and especially those that are first in class like this) are insanely expensive.