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There’s a new cure for postpartum depression; but don’t celebrate just yet. It’s far from a panacea, and it’s not for everyone. The devil is in the details.

Post-partum depression (PPD) affects about 15% of women. It can have serious consequences for both mother and child, ranging from bonding issues to suicidal or infanticidal thoughts. Treatment with counselling, medication, and social support is not always successful. Antidepressants are often used, but it’s not clear which ones are likely to be effective or when they are preferable to non-drug options; and they may take several weeks to work. A more drastic remedy, electroconvulsive therapy (ECT), has helped some women who failed to respond to medication and counselling. Researchers have been looking for better options, and Sage Therapeutics thinks they have found one. In March, 2019, their new drug Zulresso (brexanolone) was approved by the FDA, the first drug to be specifically approved for PPD. It has a big advantage over antidepressants in that it works quickly, in just a couple of days.

It’s not available to just anybody. It carries a boxed warning. Because of concerns of serious risk, Zulresso was approved with a Risk Evaluation and Mitigation Strategy (REMS), which restricts its use to certified health care facilities and requires formal enrollment in a program. The drug is administered as a continuous IV infusion over 60 hours (2.5 days). Patients must be admitted to the hospital and monitored carefully for excessive sedation or sudden loss of consciousness. They must have continuous pulse oximetry monitoring. They can’t breastfeed, because there is no data on the drug’s safety during breastfeeding. They are not allowed to be alone with their children. Hospitalization is inconvenient and expensive. It means patients will be away from home and will have to disrupt family life and arrange childcare. And the cost is estimated to be $34,000 for the drug alone, a barrier to many new mothers who might benefit from the infusion.

What is it?

Brexanolone is not a typical antidepressant. It is a synthetic source of the neurosteroid allopregnanolone. It modulates the receptors for GABA, the primary inhibitory transmitter in the brain. Allopregnanolone is produced in the body from progesterone; levels rise during pregnancy and drop post-partum. There is some evidence that PPD patients may have lower levels than non-depressed women, and brexanolone is hypothesized to relieve depression by raising allopregnanolone levels. But it’s all speculation: we really don’t know how it works, and we don’t know what causes PPD.

The research

It’s not clear to me why they first decided to evaluate brexanolone for PPD or how they decided on the 60-hour infusion protocol. I will have to give them the benefit of the doubt and assume they had good reasons. There is evidence of effectiveness from blinded, placebo-controlled studies, but some may question the results because the studies were all funded by the manufacturer, and we know manufacturer-funded studies are more likely to be positive than independent studies.

Open-label, proof-of-concept study: four women with severe PPD received brexanolone titrated to a dose reflecting third-trimester allopregnanolone levels; all had remission of symptoms. With such small numbers and no controls, it’s uncertain what the results mean.

A phase 2 double-blind, randomized, placebo-controlled trial of patients with severe PPD measured an average decrease in the Hamilton Rating Scale for Depression of 21 points for 10 women who got a brexanolone infusion and a decrease of 8.8 points for 11 women who got a placebo infusion.

Two randomized double-blind, placebo-controlled phase 3 trials were reported in a single article in Lancet.

The first compared two different doses of brexanolone to placebo in patients with severe PPD and measured changes in the Hamilton Rating Scale for Depression.

Dose Number of subjects Decrease in depression scale
90 μg/kg per h 45 17.7
60 μg/kg per h 47 19.5
Placebo 46 14.0

 

The second compared the higher dose to placebo in patients with moderate PPD.

Dose Number of subjects Decrease in depression scale
90 μg/kg per h 54 14.6
Placebo 54 12.1

 

The authors said these were significant and clinically meaningful results. Yes, the drug consistently performed better than placebo, but it struck me as odd that the lower dose got a better response than the higher dose in the first trial and that the results for the 90 μg/kg per h dose in the second trial were worse than in the first trial and were essentially the same as the placebo results in the first trial. Why did they choose the higher dose for the second study? And in an appendix they reported the results of another, possibly more relevant tool, the EPDS, which showed significant results at 30 days only for the 60 μg/kg per h dose. And the results of the phase 3 study were less impressive than the phase 2 results. Something doesn’t add up; further trials are needed for clarification. Keep in mind that studies of antidepressants tend to have large placebo responses.

The reduction in the Hamilton scores was reported as clinically significant, but one of the researchers said that less than half (“nearly half”) of the brexanolone recipients were in remission and were no longer considered to be clinically depressed.

Preclinical testing in a mouse model was consistent with human studies, but that’s not entirely reassuring, since the model may not be valid and mice are different from humans.

There are some unanswered questions. Would it be safe to breastfeed? In the human studies, patients were only followed for 30 days; long-term results are not known. Did anyone relapse later? Could a second infusion be given for a relapse? How many patients were also taking antidepressant medication and how did that affect results?

Conclusion: Apparently effective, but problematic

Zulresso will probably not be used as a first-line treatment. The cost and the need for hospitalization will discourage many potential users. If it is used for patients who were treated first with antidepressants, counselling, and social support and failed to improve, that will mean a delay that will negate the advantage of a quick response.

The same company that sells Zulresso, Sage Therapeutics, is working on another drug for PPD, a pill that can be taken once daily. I’m going to go out on a limb here and predict that Zulresso will not last and will be supplanted by other drugs that are more user-friendly (and hopefully less expensive). Fingers crossed.

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Posted by Harriet Hall

Harriet Hall, MD also known as The SkepDoc, is a retired family physician who writes about pseudoscience and questionable medical practices. She received her BA and MD from the University of Washington, did her internship in the Air Force (the second female ever to do so),  and was the first female graduate of the Air Force family practice residency at Eglin Air Force Base. During a long career as an Air Force physician, she held various positions from flight surgeon to DBMS (Director of Base Medical Services) and did everything from delivering babies to taking the controls of a B-52. She retired with the rank of Colonel.  In 2008 she published her memoirs, Women Aren't Supposed to Fly.