'If you could have the next Prozac, that’s in­tox­i­cat­ing': Sage’s post­par­tum de­pres­sion tri­umph and the fail­ure that fol­lowed

In 2015, psy­chi­a­trist Saman­tha Meltzer-Brody saw an un­be­liev­able trans­for­ma­tion in a new moth­er who had been ad­mit­ted to her psy­chi­a­try clin­ic. With­drawn and hav­ing sui­ci­dal thoughts, the woman was in­fused with an ex­per­i­men­tal drug. With­in 24 hours, she bright­ened and was eat­ing, talk­ing and smil­ing.

“It was like when you come home from your sum­mer va­ca­tion, and your flow­ers are all dried up and wilt­ed,” said Meltzer-Brody, a re­searcher and chair of psy­chi­a­try at the Uni­ver­si­ty of North Car­oli­na at Chapel Hill. “Then they get a great soak­ing of wa­ter, and every­body perks up.”

Post­par­tum de­pres­sion af­fects a shock­ing 1 in 8 new moth­ers — rough­ly 500,000 women in the US each year. But like much of women’s health, it’s been un­der­stud­ied and over­looked.

Last month, af­ter years of de­vel­op­ment and false starts, Sage Ther­a­peu­tics launched zu­ra­nolone, the pill-form fol­low-up to the drug that Meltzer-Brody’s pa­tient re­ceived. The drug mim­ics a hor­mone that nat­u­ral­ly ris­es dur­ing preg­nan­cy and plum­mets af­ter de­liv­ery, and it is by all mea­sures a break­through that will help thou­sands of women.

But the sci­en­tif­ic and med­ical jour­ney the drug rep­re­sents has been matched by tu­mult at the biotech. With suc­cess at hand in post­par­tum de­pres­sion, Sage made a fate­ful de­ci­sion. Based on a par­al­lel, though less cer­tain, the­o­ry of how the brain and the drug might work on brain cir­cuits in men and women, it went af­ter ma­jor de­pres­sion, a far larg­er and more lu­cra­tive in­di­ca­tion af­fect­ing not just half a mil­lion peo­ple but a pop­u­la­tion more than 40 times that size.

“There’s a big leap from post­par­tum women to now let’s give it to every­body,” Meltzer-Brody said. “But how would you not try it? If you could have the next Prozac, that’s in­tox­i­cat­ing.”

Sage is still reel­ing from that de­ci­sion to­day. Blind­sided by the FDA’s re­jec­tion in ma­jor de­pres­sion, the com­pa­ny was met with one of the year’s harsh­est biotech crash­es, cut­ting Sage’s shares in half and valu­ing the com­pa­ny just above the cash in its ac­counts.

To un­der­stand how it got to this point — and what comes next — End­points News in­ter­viewed more than 20 cur­rent and for­mer em­ploy­ees, ad­vi­sors, and in­de­pen­dent sci­en­tists and psy­chi­a­trists. Zu­ra­nolone’s sto­ry high­lights the non­lin­ear process of drug dis­cov­ery, the ever-frus­trat­ing mys­tery that is de­pres­sion, and an ac­knowl­edg­ment that it’s time to stop treat­ing the men­tal ill­ness as one ho­moge­nous con­di­tion.

***

‘It re­al­ly was the nat­ur­al, no-lose, study to do.’

***

Pre­ci­sion med­i­cine has yet to sig­nif­i­cant­ly im­pact the field of psy­chi­a­try. Over the past decades, as drug de­vel­op­ers sliced dis­eases like can­cer in­to small­er and small­er in­di­ca­tions based on ge­net­ics, com­pa­nies work­ing on men­tal dis­or­ders stuck to the stan­dard play­book of us­ing the same drugs to treat mul­ti­ple con­di­tions and big­ger pop­u­la­tions.

“It was all about clump­ing, not split­ting,” said Steve Kanes, Sage’s for­mer chief med­ical of­fi­cer. “There re­al­ly wasn’t a dri­ve to think about ei­ther phys­i­o­log­i­cal­ly or ge­net­i­cal­ly dis­sect­ing out the pa­tient pop­u­la­tion in­to groups that are sim­i­lar to each oth­er.”

At first, Sage seemed like the ex­cep­tion. The com­pa­ny was cen­tered around a neu­ro­trans­mit­ter known as GA­BA, which, along with its coun­ter­part glu­ta­mate, acts as the brakes and gas ped­als of the brain. Im­bal­ances in the com­mu­ni­ca­tions be­tween the cir­cuits of brain cells that re­ly on the two chem­i­cals are hy­poth­e­sized to play a role in most ma­jor psy­chi­atric dis­eases.

In 1986, while search­ing for nat­ur­al mol­e­cules that could fine-tune those com­mu­ni­ca­tions, Steve Paul — the sci­en­tif­ic di­rec­tor of the Na­tion­al In­sti­tute of Men­tal Health — made a sur­pris­ing dis­cov­ery. Al­lo­preg­nanolone, a metabo­lite of the hor­mone prog­es­terone, en­hanced the in­hibito­ry re­cep­tors that GA­BA nor­mal­ly binds to.

Al­lo­preg­nanolone was large­ly as­so­ci­at­ed with the men­stru­al cy­cle and preg­nan­cy. But an­i­mal test­ing found that lev­els of the mol­e­cule rose dur­ing stress, and a col­league dis­cov­ered that it could quell se­vere seizures in ro­dents.

“It was al­ways my be­lief that we could po­ten­tial­ly make drugs out of this,” Paul said.

Paul got his chance in 2010, af­ter an al­most two-decade stint at Eli Lil­ly that fol­lowed his gov­ern­ment ca­reer. Backed by $35 mil­lion from Third Rock Ven­tures, Paul found­ed Sage to test his neu­ros­teroid the­o­ry. The team im­me­di­ate­ly faced two big chal­lenges. Could the mol­e­cules be turned in­to con­ve­nient pills? And of the dizzy­ing list of con­di­tions neu­ros­teroids had been im­pli­cat­ed in since Paul’s time at NIMH, which would Sage pick? There would be false starts on both fronts.

Neu­ros­teroids are greasy, in­sol­u­ble, and no­to­ri­ous­ly hard to for­mu­late in ways that can be giv­en to pa­tients. Paul’s for­mer NIMH col­league Michael Ro­gaws­ki, who stud­ied epilep­sy and brain in­jury, had moved to acad­e­mia and was try­ing to start a clin­i­cal tri­al us­ing an in­fu­sion of al­lo­preg­nanolone. The study was put on hold be­cause the mol­e­cule leached in­to its plas­tic IV bag. But Sage’s chemists were able to solve the prob­lem (though it would lead to bit­ter dis­putes about who de­served cred­it for de­vel­op­ing the ther­a­py).

The first pa­tient to get the drug was a young man with dead­ly, repet­i­tive seizures. Doc­tors put him in­to a month­s­long co­ma to keep him alive, and were hop­ing that a five-day in­fu­sion of al­lo­preg­nanolone would keep his seizures at bay as they reawak­ened him.

It worked. The man’s seizures stopped, and he re­turned home and re­cov­ered. The stun­ning out­come led Sage to pri­or­i­tize the se­vere form of the epilep­sy — called su­per re­frac­to­ry sta­tus epilep­ti­cus — as its lead pro­gram and cen­tral sto­ry dur­ing its IPO in 2014.

The lengthy in­fu­sion made sense for pa­tients who were on death’s door, but Sage was al­ready work­ing on a fol­low-up that would be tak­en as a pill for milder dis­ease. While its sci­en­tists put the fin­ish­ing touch­es on that drug, Sage’s re­search lead­ers were tasked with iden­ti­fy­ing oth­er con­di­tions where an al­lo­preg­nanolone in­fu­sion could give a quick read on the drug’s po­ten­tial ef­fi­ca­cy.

Post­par­tum de­pres­sion emerged as a top pick.

***

‘We’ve got to have more in­no­va­tion in de­pres­sion …
this can’t be seen as a cau­tion­ary tale.’

***

The ra­tio­nale was sim­ple. Dur­ing preg­nan­cy, the ovaries and pla­cen­ta pump out prog­es­terone, caus­ing lev­els of its metabo­lite al­lo­preg­nanolone to rise. The mol­e­cules plum­met af­ter the ba­by and pla­cen­ta are de­liv­ered. Some stud­ies sug­gest­ed al­lo­preg­nanolone lev­els were low­er in women with de­pres­sion right be­fore or af­ter giv­ing birth.

“That was in­ter­pret­ed as the re­moval of an an­ti­de­pres­sant sub­stance,” Ro­gaws­ki said. “So the con­cept was, could you mit­i­gate this by re­plac­ing al­lo­preg­nanolone?”

Kanes, the for­mer chief med­ical of­fi­cer who joined Sage in 2013, won­dered why the idea hadn’t been test­ed soon­er. “It seems so el­e­gant and straight­for­ward,” he said.

One scape­goat is the Di­ag­nos­tic and Sta­tis­ti­cal Man­u­al of Men­tal Dis­or­ders, the guide­book for men­tal health work­ers, which still lumps post­par­tum and ma­jor de­pres­sion to­geth­er. An­oth­er rea­son was the in­dus­try’s hes­i­tan­cy to test drugs in preg­nant or breast­feed­ing women. “So it’s been avoid­ed like the plague,” Meltzer-Brody said.

When Sage ex­ec­u­tives first start­ed kick­ing the idea around, they doubt­ed that a mul­ti­day in­fu­sion would ap­peal to new moth­ers. But then they met Meltzer-Brody, who was run­ning an in­pa­tient psych clin­ic at UNC specif­i­cal­ly for preg­nant and post­par­tum women. “That’s when the light bulb went on,” said Ki­ran Red­dy, a for­mer Third Rock Ven­tures em­ploy­ee who helped launch Sage.

Meltzer-Brody and her de­part­ment chair David Ru­bi­now, who had pre­vi­ous­ly worked with Paul as a clin­i­cal di­rec­tor at NIMH, flew up to Cam­bridge to pitch Sage on us­ing al­lo­preg­nanolone in post­par­tum women. The group agreed to test 60-hour in­fu­sions of the drug, a some­what ar­bi­trary time­frame deemed long enough to wean a pa­tient on and off over the course of a week­end. The first pa­tient’s 24-hour turn­around in Meltzer-Brody’s clin­ic would be­come leg­endary in the field.

“Ei­ther this was one heck of a place­bo re­sponse, or there was some­thing there,” she said of the 2015 test.

When three more moth­ers with post­par­tum de­pres­sion got the drug, it was like a switch flipped in each of them. The rapid and sus­tained re­sponse stunned Sage, and the com­pa­ny quick­ly moved to test the in­fu­sion, which it re­named brex­anolone, against a place­bo lat­er that year.

The fol­low­ing sum­mer, Sage an­nounced a re­sound­ing suc­cess. Sev­en of the 10 pa­tients who got the drug im­proved sig­nif­i­cant­ly and stayed well for 30 days, com­pared to just 2 of 11 place­bo pa­tients.

Three years lat­er, the FDA would ap­prove the in­fu­sion for post­par­tum de­pres­sion, and Sage brought it to mar­ket as Zul­res­so. It was a com­mer­cial flop. In­sur­ers balked at its $34,000 price tag and the lengthy hos­pi­tal stay, which most doc­tors and pa­tients weren’t pre­pared for ei­ther. Ear­li­er this year, CEO Bar­ry Greene said that on­ly “hun­dreds” of pa­tients had got it, “not the thou­sands of moms we hoped to help.”

But Sage’s chemists had forged a back­up plan — a sim­i­lar but dis­tinct mol­e­cule that could be tak­en as a pill that would get the com­pa­ny ask­ing a fate­ful ques­tion.

***

‘It made all the sense in the world to ex­plore how far we could take this.’

***

Sage had al­ways been in­ter­est­ed in de­vel­op­ing new drugs for de­pres­sion writ large, even if the bi­o­log­i­cal ra­tio­nale for an al­lo­preg­nanolone ther­a­py wasn’t as clear-cut. Af­ter the promis­ing tri­al in post­par­tum women in 2016, the com­pa­ny be­gan chart­ing a course for tests in ma­jor de­pres­sion.

“You could not be sit­ting on a drug that hit a spe­cif­ic sub­type of ma­jor de­pres­sive dis­or­der with­out think­ing how and why might it work in a broad­er pop­u­la­tion,” Kanes said. “It made all the sense in the world to ex­plore how far we could take this.”

And while there was no way that mil­lions of peo­ple would sit for an in­fu­sion, a pill ver­sion of the ap­proach could have far more ap­peal. And the com­pa­ny had been work­ing on just that.

Since 2012, Sage’s for­mer di­rec­tor of chem­istry Gabriel Mar­tinez and chief sci­en­tif­ic of­fi­cer Al Ro­bichaud had been draft­ing struc­tures of hun­dreds of com­pounds that they hoped would tar­get GA­BA re­cep­tors just like al­lo­preg­nanolone.

Some of the most well-known psy­chi­atric drugs, in­clud­ing Xanax and Val­i­um, en­hance GA­BA re­cep­tors. The drugs, called ben­zo­di­azepines or ben­zos, are po­tent seda­tives that can re­duce anx­i­ety, in­som­nia, and seizures. But they have the po­ten­tial for abuse and ad­dic­tion, and they aren’t ef­fec­tive at treat­ing de­pres­sion.

Sage’s aim was to tar­get the re­cep­tors in a dif­fer­ent way. While ben­zos most­ly tar­get re­cep­tors in the synapse, al­lo­preg­nanolone al­so leaks out of that cleft to en­hance so-called ex­trasy­nap­tic re­cep­tors on the neu­ron, which ex­ert a damp­en­ing ef­fect that helps con­trol how numb or jumpy a brain cell is.

Work­ing with con­trac­tors in Chi­na and Eu­rope, Sage’s chemists searched their new­ly de­signed com­pounds for ones that mim­ic­ked al­lo­preg­nanolone’s ef­fects on ex­trasy­nap­tic re­cep­tors, Mar­tinez said. It would be­come the main ex­pla­na­tion, al­beit a cir­cu­lar one, for why Sage’s drug was dif­fer­ent from ben­zos and why it re­lieved de­pres­sion when the old­er GA­BA-en­hanc­ing drugs didn’t.

Sage al­so di­aled out the nat­ur­al mol­e­cule’s abil­i­ty to tar­get hor­mone re­cep­tors, which they thought would make it safer for long-term use and give the com­pa­ny a clean test of whether the drug’s ther­a­peu­tic ef­fects were re­al­ly work­ing through GA­BA, ac­cord­ing to Sage’s cur­rent chief sci­en­tif­ic of­fi­cer Mike Quirk.

At the be­hest of for­mer Sage CEO Jeff Jonas, who de­clined in­ter­view re­quests, the com­pa­ny’s sci­en­tists nom­i­nat­ed their fa­vorite mol­e­cule, which be­came zu­ra­nolone. Ini­tial­ly billed as a main­te­nance ther­a­py for sta­tus epilep­ti­cus, zu­ra­nolone would be­come the com­pa­ny’s north star af­ter its in­fu­sion ther­a­py for epilep­sy failed in 2017 and Jonas piv­ot­ed, go­ing all in on zu­ra­nolone’s an­ti­de­pres­sant po­ten­tial.

***

‘A lot of clin­i­cians, in­clud­ing my­self, will use zu­ra­nolone if
it does get ap­proved, hop­ing that the re­sults will be dif­fer­ent.’

***

While await­ing re­sults of two larg­er al­lo­preg­nanolone in­fu­sion stud­ies in post­par­tum de­pres­sion, Sage plowed for­ward test­ing zu­ra­nolone in near­ly 90 men and women with ma­jor de­pres­sion in April 2017. The drug blew the com­pa­ny away with a whop­ping sev­en-point dif­fer­ence on a com­mon scale of de­pres­sion be­tween those who took the pill for two weeks and those who got a place­bo.

“It worked like gang­busters,” Kane said.

The treat­ment’s short course, far briefer than tra­di­tion­al an­ti­de­pres­sants, baf­fled and ex­cit­ed ex­perts. “It re­al­ly breaks the mold in terms of the way we’ve all been taught to think about ther­a­py for de­pres­sion,” said James Mur­rough, a psy­chi­a­trist at the Ic­ahn School of Med­i­cine at Mount Sinai.

But Sage’s first ma­jor de­pres­sion study would be its best. In a sec­ond study of 320 pa­tients from De­cem­ber 2019, zu­ra­nolone proved no bet­ter than place­bo. Even so, af­ter a meet­ing with the FDA ear­ly the next year, Sage as­suaged in­vestors that it on­ly need­ed one more suc­cess­ful tri­al in ma­jor de­pres­sion to sub­mit the drug for ap­proval.

The com­pa­ny slashed its work­force in half that spring to cut costs and struck a deal worth up to $3.1 bil­lion — rough­ly half up­front — with Bio­gen to joint­ly de­vel­op and com­mer­cial­ize zu­ra­nolone and an ear­li­er-stage drug for move­ment dis­or­ders. In a call with in­vestors in No­vem­ber 2020, Bio­gen’s CEO Michel Vounatsos said the drugs “po­ten­tial­ly rep­re­sent multi­bil­lion-dol­lar val­ue-cre­ation op­por­tu­ni­ties,” and an­oth­er ex­ec­u­tive called it a po­ten­tial “par­a­digm shift” in de­pres­sion treat­ment.

The fol­low­ing sum­mer, in Sage’s biggest ma­jor de­pres­sion study of 530 pa­tients, the drug re­duced de­pres­sion by rough­ly 1.7 points com­pared with place­bo af­ter two weeks. The dif­fer­ence was sta­tis­ti­cal­ly sig­nif­i­cant, but it failed to reach the two- or three-point bench­mark that many doc­tors con­sid­er mean­ing­ful.

Some psy­chi­a­trists ar­gued that the mag­ni­tude was sim­i­lar to what’s seen in stud­ies of stan­dard an­ti­de­pres­sants known as se­lec­tive sero­tonin re­up­take in­hibitors, or SS­RIs, and they were ea­ger to have a new tool for those who don’t re­spond to ex­ist­ing drugs.

“A lot of clin­i­cians, in­clud­ing my­self, will use zu­ra­nolone if it does get ap­proved, hop­ing that the re­sults will be dif­fer­ent,” Craig Chep­ke, a psy­chi­a­trist who runs a pri­vate prac­tice and has con­sult­ed for Sage, said be­fore the FDA de­ci­sion. “It’s not just a mi­nor vari­a­tion on a theme. This works on a com­plete­ly dif­fer­ent neu­ro­trans­mit­ter sys­tem.”

***

‘It’s a mir­a­cle that any of our drugs work in psy­chi­a­try be­cause, re­al­ly, we know so very lit­tle’

***

Sci­en­tists have long strug­gled to con­nect the dots be­tween what an­ti­de­pres­sants ac­tu­al­ly do in the brain and their mood-lift­ing ef­fects. The most com­mon de­pres­sion drugs — SS­RIs like Prozac — in­crease lev­els of sero­tonin in synaps­es. But what hap­pens over the four to six weeks be­fore re­lief sets in, and why they on­ly work for some peo­ple, is a mys­tery.

“It’s a mir­a­cle that any of our drugs work in psy­chi­a­try be­cause, re­al­ly, we know so very lit­tle,” Chep­ke said. “It’s a lot of con­jec­ture and ed­u­cat­ed guess­es.”

Stud­ies in post­par­tum ro­dents sug­gest that a mis­match be­tween fluc­tu­at­ing lev­els of both GA­BA re­cep­tors and al­lo­preg­nanolone, rather than the hor­mone it­self, could be to blame for de­pres­sion. Since re­searchers have long sus­pect­ed that GA­BA sig­nal­ing may be out-of-whack in ma­jor de­pres­sion, Kanes thinks it’s con­ceiv­able that some­thing sim­i­lar hap­pens in ma­jor de­pres­sion. In fact, Paul points to­ward small stud­ies show­ing that SS­RIs in­crease lev­els of al­lo­preg­nanolone.

But Sage’s strongest ra­tio­nale for test­ing its pill in the broad­er con­di­tion was that its in­fu­sion worked in post­par­tum women.

“It re­al­ly was the nat­ur­al, no-lose study to do,” Quirk said. “If you test­ed it in ma­jor de­pres­sion and it didn’t work, then you could say there is some­thing unique about post­par­tum de­pres­sion.”

Be­cause zu­ra­nolone works more quick­ly than SS­RIs, at least in post­par­tum de­pres­sion, Quirk and oth­er sci­en­tists are hope­ful that it will be eas­i­er to track the step-by-step changes it trig­gers in the brain. In fact, Tufts Uni­ver­si­ty neu­ro­sci­en­tist Paul Davies, work­ing with Sage, found that zu­ra­nolone not on­ly en­hances ex­ist­ing GA­BA re­cep­tors, but in­creas­es the num­ber of these re­cep­tors in neu­rons. Davies is cur­rent­ly try­ing to un­der­stand if this change ex­plains why the drug’s an­ti­de­pres­sant ef­fects linger af­ter pa­tients fin­ish their two-week course. “It’s a hy­poth­e­sis,” he said.

But even if it’s true, the idea doesn’t get to the crux of the is­sue. What is it about en­hanc­ing or boost­ing those re­cep­tors that al­le­vi­ate de­pres­sion?

Sage de­scribes de­pres­sion as a dis­ease of neur­al cir­cuits — where con­nec­tions and com­mu­ni­ca­tions be­tween brain re­gions re­ly­ing on GA­BA re­cep­tors get out of whack. Zu­ra­nolone es­sen­tial­ly ad­justs the ther­mo­stat back in­to its set­point, Quirk said. But ex­act­ly how that works, no­body knows.

“We still have a lot of learn­ing to do,” Quirk said. “In that sense, we’re not re­al­ly dif­fer­ent than the SS­RIs.”

***

‘The ma­jor de­pres­sion field has just been plagued with failed clin­i­cal tri­als’

***

While the FDA likes drug­mak­ers to know what their med­i­cines do, it doesn’t re­quire de­tailed ex­pla­na­tions of why ther­a­pies work. All that re­al­ly mat­ters is da­ta show­ing that a med­i­cine is safe and ef­fec­tive.

De­spite the murky re­sults in ma­jor de­pres­sion, the re­sults of two stud­ies of zu­ra­nolone in post­par­tum de­pres­sion were clear­er. But even there, the tri­al show­cased the two tru­isms of an­ti­de­pres­sants: the treat­ment doesn’t work for every­one, and many peo­ple feel bet­ter just by tak­ing a place­bo.

Bil­ly Dunn

Lead­ing up to the FDA’s de­ci­sion in Au­gust, there were signs that some­thing was amiss as Bio­gen and Sage went mum and stopped hyp­ing the drug’s block­buster po­ten­tial. For­mer em­ploy­ees told End­points that the com­pa­ny had worked “hand in glove” with the agency un­der its for­mer neu­ro­science leader Bil­ly Dunn and “were in dis­be­lief” by the re­jec­tion in ma­jor de­pres­sion.

Dunn de­part­ed the agency in ear­ly 2023 af­ter com­ing un­der fire for his role in the ap­proval of Aduhelm, the Alzheimer’s drug that many neu­rol­o­gists felt hadn’t been proven safe or ef­fec­tive. A for­mer leader at Sage, who was not au­tho­rized to speak pub­licly, said the FDA wasn’t con­vinced about the drug’s dura­bil­i­ty. And they felt like zu­ra­nolone’s re­jec­tion was a re­sult of the agency try­ing to be more con­ser­v­a­tive af­ter a string of con­tro­ver­sial ap­provals.

End­points was un­able to reach Dunn di­rect­ly, but a re­quest for com­ment was passed on through Prothena, a biotech com­pa­ny whose board he joined in May. Dunn didn’t re­spond. An FDA spokesper­son said the agency couldn’t com­ment.

With its big­ger com­mer­cial­iza­tion plans foiled, Sage an­nounced lay­offs, cut­ting 40% of its work­ers. The com­pa­ny de­clined to dis­cuss the FDA de­ci­sion and hasn’t said whether it will at­tempt new tests of zu­ra­nolone in ma­jor de­pres­sion. The stand­still is frus­trat­ing to for­mer Sage ex­ec­u­tives and ad­vi­sors, many of whom still be­lieve zu­ra­nolone works for ma­jor de­pres­sion.

“The ma­jor de­pres­sion field has just been plagued with failed clin­i­cal tri­als,” said Jamie Maguire, a neu­ro­sci­en­tist at Tufts and mem­ber of Sage’s sci­en­tif­ic ad­vi­so­ry board. “The is­sue has al­ways been and con­tin­ues to be, that we can’t iden­ti­fy and strat­i­fy pa­tients that would be amenable to this type of treat­ment. That’s go­ing to be a prob­lem for every new drug for ma­jor de­pres­sion, and un­til we ad­dress that, we will have an up­hill bat­tle.”

***

‘There’s not go­ing to be just one kind of de­pres­sion, just like there’s not one kind of breast can­cer’

***

While it’s tempt­ing to won­der if Sage’s mess is the re­sult of mov­ing be­yond a seem­ing­ly clean hy­poth­e­sis around neu­ros­teroid de­fi­cien­cy to a much murki­er but more com­mer­cial­ly tempt­ing one cen­tered on GA­BA, Quirk in­sists that this isn’t true.

“We want­ed to be fo­cused on a neur­al cir­cuit sto­ry,” he said. “Neu­ros­teroids are just a class of mol­e­cules that pro­vides a dif­fer­ent way of mod­u­lat­ing GA­BA re­cep­tors.”

The neu­ros­teroid and GA­BA mod­u­la­tion hy­pothe­ses for how al­lo­preg­nanolone and zu­ra­nolone work are not mu­tu­al­ly ex­clu­sive, and many re­searchers hope that zu­ra­nolone will spur more work in un­der­stand­ing GA­BA’s role in de­pres­sion.

“I think that there’s not go­ing to be just one kind of de­pres­sion, just like there’s not one kind of breast can­cer,” said Meltzer-Brody, the UNC re­searcher and clin­i­cian. “And that means you have to treat it dif­fer­ent­ly.”

Even so, the guide­book for men­tal health work­ers still lumps the two to­geth­er.

“It would be trag­ic if this is the end of the road, and the abrupt­ness of how this hap­pened scares off in­vest­ment in treat­ing de­pres­sion,” Meltzer-Brody said. “The men­tal health cri­sis is re­al. Sui­cide rates have nev­er been high­er.

“We’ve got to have more in­no­va­tion in de­pres­sion,” she added. “This can’t be seen as a cau­tion­ary tale.”