产后抑郁新解
新生命的诞生往往伴随着各种积极的情绪：敬畏、喜悦、释然……然而，对于许多新手父母而言，这段产后时光也可能被持续数月甚至数年的严重抑郁笼罩。舍曲林（Zoloft，又名“左洛复”）和氟西汀（Prozac，又名“百忧解”）等经典抗抑郁药固然能为部分患者提供慰藉，但对更多产后抑郁症患者而言，这些药无效，他们却几乎没有其他选择。如今，随着一款更具针对性的新药问世，这种困局正有所改变。
产后抑郁症（Postpartum Depression，PPD）指分娩后出现的抑郁发作。在这一关键时期，女性罹患抑郁症的风险高达生命中其他时期的两倍，且病程可能持续很长时间。常见症状包括持续的绝望与悲伤、恶心、睡眠与饮食习惯改变、性欲减退、阵发性哭泣、焦虑、易怒、强烈的孤立感和情绪不稳，部分患者甚至会产生伤害自己或婴儿的念头。这是一种非常普遍的情绪障碍。研究发现，全球约17.22%的人患有产后抑郁症。然而，这些症状常常被忽视，无法得到及时干预与治疗，最终会对伴侣造成严重困扰，甚至严重损害婴儿的长期情绪与认知发展。
在很长一段时间里，产后抑郁症都被归为普通抑郁症中的一类。究其本质，它确实是一种情绪失调。但近年来的研究日益明确，产后抑郁是一个独立的疾病实体。其独特性在于，它与怀孕和产后剧烈的激素波动，以及大脑为应对这些波动所产生的、可能增加个体情绪障碍易感性的特殊反应模式密切相关。
有些患者会将产后抑郁症形容为一团笼罩周身、挥之不去的沉重乌云，让她们感到自己与挚爱的家人之间存在深厚的隔阂，还常常会被一些不切实际的念头困扰，例如认为自己是家庭的负担。
即便能够识别出症状，在积极求医、尝试多种抗抑郁药物的情况下，病情依旧可能反复发作。当常规治疗方案已山穷水尽，留给她们的通常只有三种选择：氯胺酮、电休克疗法，或入院接受精神科治疗。但现在，她们即将迎来“第四种希望”：舒拉诺龙（Zuranolone）。
人们常将女性健康问题简单归咎于“激素”，但激素的作用远比想象中复杂和强大。妊娠晚期，为了维持孕妇的情绪稳定，两种关键激素——孕酮（progesterone）及一种名为别孕烷醇酮（allopregnanolone）的神经类固醇——的水平会飙升至正常月经周期时的100多倍。大脑由此被“重塑”，为女性履行母职做好准备。然而，这些激素水平会在分娩后断崖式下跌。对于部分女性而言，她们的大脑无法有效补偿这种剧变，因此极易诱发情绪障碍。
产后抑郁症与普通抑郁症的一个关键区别正在于此：普通抑郁症更像是一种大脑固有的状态；而产后抑郁症则是由怀孕引发的大脑系统性改变。因此，治疗的关键就在于对其进行“重置”。
舒拉诺龙是美国生物制药公司Sage Therapeutics和渤健公司（Biogen）联合研发的一种神经活性类固醇抗抑郁药。其与前文提到的几种经典抗抑郁药的作用机制截然不同。此前的抗抑郁药物通常是各类选择性5-羟色胺再摄取抑制剂（SSRI），可暂时阻断神经细胞回收“快乐信使”的通路，提升大脑中让你感到“快乐”、“平静”、“愉悦”的化学物质水平。但这一过程需要数周甚至更长时间才能在体内建立起稳定效果，且并非对所有患者有效。
相比之下，舒拉诺龙的靶点直达产后抑郁症的核心生理机制。其化学结构和作用与大脑在孕期大量产生的别孕烷醇酮高度相似，可直接作用于大脑中负责在感受到压力时镇静下来的关键神经回路——GABA系统。患者服下药物后，它会迅速进入大脑，附着在因激素水平骤降而变得不敏感的GABA-A受体上，重新恢复它们的灵敏度。一项双盲、Ⅲ期临床试验证实，口服舒拉诺龙药物能在3日内起效，且在每日口服一次、为期两周的疗程结束后，大多数患者的症状不会复发。
早在2019年，Sage Therapeutics开发的注射版本药物布瑞诺龙（Brexanolone）就得到了美国食品药品监督管理局的批准，是全球首款专用于治疗成人产后抑郁症的药物。舒拉诺龙则进一步优化了该神经活性类固醇针对突触和突触外GABA受体的选择性，改为口服版本，克服了别孕烯醇酮需要住院静脉注射给药长达60小时的重大缺陷。
2023年8月，舒拉诺龙作为全球首个用于治疗成人产后抑郁症的口服新药，被美国食品与药品监督管理局（FDA）批准上市，商品名为Zurzuvae。2025年9月，该药物也得到了欧盟卫生与食品安全总署的上市批准。截至目前，尚未得到此药在中国市场获批的消息。
舒拉诺龙的研发突破源于科学史上一次偶然的意外发现。2008年，研究员杰米·马圭尔（Jamie Maguire）在博士后阶段研究了一种名为月经性癫痫（catamenial epilepsy，月经周期特定时期癫痫加重）的疾病，重点关注脑部神经类固醇的保护作用，并为此通过基因工程改造了一批小鼠，干扰和改变小鼠大脑中的神经类固醇信号。
意外的是，这些转基因小鼠在繁殖时出现了严重问题。它们在分娩前一切正常，产后却表现出忽视幼崽、不筑巢等类似抑郁症的行为。但当杰米为这些母鼠注射了一种能恢复其神经类固醇信号反应能力的化合物后，它们的母性行为便恢复了正常。这项发表于《神经元》（Neuro）杂志的研究首次在实验中直接建立了大脑中神经类固醇与产后抑郁行为之间的因果联系，确定了孕期及产后的GABA-A受体调节功能障碍会导致动物出现产后抑郁，为后续药物研发奠定了关键基础。
舒拉诺龙的潜力巨大，但其推广使用仍面临诸多局限。
首先是副作用问题。在临床试验中，它的治疗效果卓越，且起效迅速，约60%的服用者抑郁症状得到了显著缓解。这个数字看似不高，但已优于传统抗抑郁药约50%的有效率。然而，其带来的头晕、嗜睡和恶心等副作用同样不容忽视，这导致约16%的患者需要减少剂量，4%的患者因无法耐受而停药。
除此之外，还有费用和获取方面的问题。一个疗程的预期花费接近1.6万美元（约合人民币11万元），为没有医疗保险和社会经济地位较低的女性带来了沉重的财务负担。在美国，尽管医疗补助计划和大多数健康保险公司会将该药纳入报销范围，但某些地区对患者提出了更苛刻的要求：要想在医保内获批用药，必须先提供使用其他抗抑郁药治疗失败的证明。
比新疗法开发更严峻的是诊断的困境。据估计，表现出产后抑郁症（PPD）症状的女性中，得到确诊的不到一半，其中获得有效治疗的患者更是少数。为何会出现如此大的落差？原因来自诸多方面。
首先是个人认知的障碍。“当局者迷，旁观者清”，从客观的第三视角看待产后抑郁和亲身经历可能是完全不同的体验。产后抑郁症的症状具有很强的迷惑性，尤其容易和“产后情绪低落”（baby blues）产生混淆。这常常导致它被低估和忽视，即使是专业医护人员，有时也很难第一时间意识到自己正身处其中。产后情绪低落是一种更常见、更轻微的短期情绪波动，通常会在几周内自行缓解；产后抑郁症则远比它深刻、黑暗、持久。
其次是来自社会期望的压力。新生命诞生后，人们普遍认为，这是一个女性生命中最美好的时光（之一），新妈妈应该感到快乐与幸福，而非悲伤。这与患者内心的痛苦形成了巨大的反差，导致许多人甚至羞于承认自己的困境，并将其归咎于个人意志的薄弱，陷入自责，进而加重病情。
最后是临床筛查不足与疾病的污名化。作为一类近年才独立出来的病种，临床上对产后抑郁症缺乏有效的常规筛查手段；而全社会对精神类疾病，尤其是女性患病存在深刻的偏见。
比如“歇斯底里”（hysteria）这一舶来的成语，其在英文中的词源是希腊语的“子宫”（hystera）。古希腊医学认为，女性的情绪波动、焦虑、抑郁、失眠等症状，源于“子宫在身体内游走”，压迫了其他器官。它被定义为只有拥有子宫的人（女性）才会得的病，认为女性天生就是非理性的。直到1980年，美国精神医学学会（APA）发布的《精神障碍诊断与统计手册》第三版（DSM-III）才正式将“歇斯底里”从医学诊断中删除。
从以上这些因素出发，你会发现，对女性产后抑郁症状的忽视来自一种自相矛盾的社会心态。一方面，社会对女性激素引起的情绪波动抱有负面的刻板印象；另一方面，对于怀孕这一更为剧烈且影响深远的生理事件，人们却普遍期望母亲能“迅速恢复”。
更深层的原因在于……[查看全文]
Is There New Hope for Treating Postpartum Depression?
Kendra Pierre-Louis: For Scientific American’s Science Quickly, I’m Kendra Pierre-Louis, in for Rachel Feltman.
The birth of a child comes with a swirl of positive emotions: awe, joy, relief.
And yet, for many birthing parents, this postpartum period can also be accompanied by months—or even years—of debilitating depression. For some of these parents, traditional antidepressant meds like sertraline, better known as Zoloft, and fluoxetine, aka Prozac, have provided some relief. But many with postpartum depression have had little recourse. That may be starting to change.
Science journalist Marla Broadfoot looked into a new drug that might better treat people for whom relief has remained elusive.
Marla joins us today to talk about her recent story in Scientific American. Welcome, Marla.
Marla Broadfoot: Thanks for having me.
Pierre-Louis: At a very basic level can you explain what postpartum depression is?
Broadfoot: So at a basic level it is a mood disturbance. For a long time it was lumped in with all kinds of depression, like garden-variety depression, but only recently have people begun to realize—and researchers in particular—realize that [it] is its own entity.
Pierre-Louis: Mm-hmm.
Broadfoot: And part of that has to do with hormones and the big fluctuations in hormones during pregnancy and in the postpartum period and how the brain responds to that and how the brain responds in ways that maybe make you more vulnerable to mood disorders.
Pierre-Louis: And developing a mood disorder or some sort of a mental health issue post-pregnancy’s extremely common, correct?
Broadfoot: Yes, it’s very common. I mean, I think it’s 500,000 people in the U.S. develop postpartum [depression] every year, so that’s very common.
Pierre-Louis: And I know in the article you begin by talking about this woman named Kristina Leos. Can you tell me about her?
Broadfoot: Yeah, so Kristina is a 40-year-old nurse and mother of three, lives in Midlothian, Texas. And she told me that postpartum depression felt like a heavy cloud hanging over her. She felt like she was separated from her family and everything she loved. And it made her believe things that weren’t real. She thought that she was a burden to her family, that she was unfit to be a mother. At one point she actually [messaged] a friend and said, “Please come take my baby. I, I can’t take care of her. You could take care of her.” And she was, yeah, not afraid to die at one point. She even envisioned just driving off a bridge and thinking that would probably be the be—best outcome.
Pierre-Louis: Oh, wow.
Broadfoot: And because she was a nurse she kind of recognized the signs. And so she tried just about everything—she tried a bunch of different antidepressants and doses, and she would get better a little bit, and then she’d get worse again.
Pierre-Louis: Mm-hmm.
Broadfoot: And so she got to the point, it was, I think, nine months after the birth of her third child, Victoria, that her doctor said they were running out of options.
Pierre-Louis: Mm-hmm.
Broadfoot: And she gave her three options, which were ketamine, electroshock therapy ...
Pierre-Louis: Mm-hmm.
Broadfoot: Or admission to a psychiatric hospital.
Pierre-Louis: Oh, wow.
Broadfoot: And at that point she already felt so much guilt from not really being there for her family that she couldn’t imagine—it was about Christmastime, too, and so she really didn’t wanna be away from them. And that’s where the story of zuranolone comes in.
Pierre-Louis: Yeah, what is zuranolone, and what makes it different from the antidepressants that she was taking?
Broadfoot: Yeah, so they act very differently on the brain, so there’s actually a lot that’s different about them. So the SSRIs are selective serotonin reuptake inhibitors, so essentially, they’re boosting kind of these feel-good brain chemicals.
Pierre-Louis: Mm-hmm.
Broadfoot: And that takes a while. It’s something that kinda has to build up in your system over time. So they typically take four to six weeks or longer, and maybe the first round won’t work, and so then you need to try a different one.
Pierre-Louis: Mm-hmm.
Broadfoot: Zuranolone is kind of a way of resetting your brain. So it is actually directly acting on the way that the brain circuitry works to help you calm down in times of stress. And so it—if you can target that, which zuranolone is targeting one—it’s called the GABA [gamma-aminobutyric acid] system.
Pierre-Louis: Mm-hmm.
Broadfoot: If it targets that, then you have a calming effect, and then it’s a more immediate effect. And they found that in clinical trials it worked within days. And the treatment typically takes a couple weeks to just fill the whole treatment, and then you typically don’t have symptoms come back after that.
Pierre-Louis: It seems like one of the differences between looking at postpartum depression versus sort of normal depression is normal depression is kind of, like, how your brain is, and postpartum is almost, like, pregnancy changes sort of the brain system and you’re trying to reset it.
Broadfoot: Yes.
Pierre-Louis: Is that ...
Broadfoot: I think that’s a really good point. I mean, it, it is obviously very complicated. [Laughs.]
Pierre-Louis: [Laughs.]
Broadfoot: But yes, your brain—you know, one thing that people often talk about is, “Oh, it’s just hormones.” Like, anything that’s women’s health is “just hormones.” But hormones are actually a really big deal. And so during pregnancy—I think it’s the third trimester of pregnancy—these hormones like progesterone and allopregnanolone, which is a related hormone, they increase [to as much as] 100 times what they normally are during a typical menstrual cycle.
Pierre-Louis: Mm-hmm.
Broadfoot: And that’s all just reprogramming your brain, kind of remodeling it to prepare you for motherhood. And then at childbirth it just drops off precipitously. And in some women that makes them very vulnerable to mood disorders because their brain hasn’t kind of compensated, and zuranolone is kind of designed to offset that drop-off.
Pierre-Louis: Kind of related to that can you tell me about the, like, melancholic mouse model, and why that was so important in helping research into postpartum depression?
Broadfoot: This is one of those interesting examples of serendipity in science. So there’s this researcher named Jamie Maguire, and about 17 years ago, when she was a postdoc training, she was interested in a different condition—it was a condition called catamenial epilepsy, where your seizures get worse during certain times of the month, during the menstrual cycle.
Pierre-Louis: Mm-hmm.
Broadfoot: And so she was interested in how neurosteroids, these brain steroids, might protect against these seizures. So she genetically engineered mice to kind of mess with and alter this neurosteroid signaling.
Pierre-Louis: Mm-hmm.
Broadfoot: And when she tried to breed these genetically engineered mice she found that they really weren’t breeding well, like, at all.So they seemed perfectly normal until they gave birth.
Pierre-Louis: Mm-hmm.
Broadfoot: And then they acted a lot like [they had] depression, so they had symptoms like they weren’t really taking care of their pups; they weren’t building the, like, the little nests that you need for them.
Pierre-Louis: Mm-hmm.
Broadfoot: And so when, then, she gave them a compound that restored their ability to react to neurosteroid signals they behaved just as mouse mothers should. And that was the first time that there was really a kind of a direct connection between these brain steroids and postpartum depression.
Pierre-Louis: Zuranolone is potentially game-changing for many people, but there are some limitations around access, cost and, and effectiveness. Can you tell the listeners about it, about these caveats?
Broadfoot: Yeah, so it is—you know, like you said, it works remarkably well, and it’s fast-acting. So in clinical trials they found that about 60 percent of people who took it ...
Pierre-Louis: Mm-hmm.
Broadfoot: Had a meaningful reduction of depression. And 60 percent might not seem like a lot, but then when you compare that to traditional antidepressants, those only work about half the time.But the side effects are very real, so there’s dizziness, sleepiness, nausea.
Pierre-Louis: Mm-hmm.
Broadfoot: And because of that, you know, that’s prompted about 16 percent of women who take it to reduce the dose, and then about 4 percent just stop taking it altogether—the symptoms are just too much.
Pierre-Louis: Mm-hmm.
Broadfeet: And in addition to that there are issues with cost and access. So the drug costs nearly $16,000, and that’s for a two-week treatment. But then at the end of two weeks, as I said before, [for most people] the treatment is over, it’s done because it’s a reset.And it is covered by Medicaid and most health insurance companies, though some states require patients and providers to jump through a few hoops. Like my state of North Carolina, for instance, you have to show that you’ve tried and failed other antidepressants before you can try zuranolone.
Pierre-Louis: Mm-hmm.
Broadfoot: And then on top of that you’ve got all the other barriers that women, particularly women of color or people in rural areas, face as far as financial burdens or access to providers.
Pierre-Louis: I believe you mentioned in the piece that even getting diagnosed with postpartum depression can be really difficult.
Broadfoot: Yeah, I mean, I think it’s less than half of women who show symptoms of postpartum depression are actually diagnosed with the disease, and even less than them get effective treatment.
Pierre-Louis: Why is there such a big gap for something that is so debilitating?
Broadfoot: Yeah, I think that’s a really good question. I mean, I think—one thing that I found with Kristina is that even though she—she’s a neonatal intensive care nurse, so she sees women, many of whom are expressing symptoms, and when you’re in it as an individual it’s really hard to recognize it. And she is even having a hard time recognizing that she was depressed.
Pierre-Louis: Mm-hmm.
Broadfoot: And it also kind of conflicts with all these societal expectations about what it is to be a mother and how you need to be happy about it. It’s supposed to be the best time of your life, but yet you feel this way.
And I think it often gets conflated with “baby blues.”
Pierre-Louis: Mm-hmm.
Broadfoot: Which is hormonal, but it’s often crying spells and mood swings that typically resolve after a couple weeks. But with this it is much deeper and darker and longer-lasting. And I mean, some women have it—I, I mean, there are cases that have lasted for 11 years.
Pierre-Louis: Oh, wow.
Broadfoot: So I think that it’s just underrecognized and underappreciated. But I think it’s from both sides: it’s from the stigma of it and then also just a lack of ways to look for it in the clinic.
Pierre-Louis: It’s kind of funny, too, if you think about it because there are all of these sort of negative stereotypes associated with women and menstruation and, like, “her time of the month,” but then we treat something as big and significant and hormone-shifting, as you noted, as pregnancy, and we’re like, “Oh, you’ll just bounce back.”
Broadfoot: Mm-hmm. Well, I think it goes to the—also that, you know, you, you have pretty intense treatment until the baby’s born, and then all of a sudden the baby gets all the treatment, and the mother is kind of like, “Okay, you did your job.”And that’s where one of the clinicians I spoke to said that she really tries to start the conversation early, to make people aware that this is something that might happen and try to identify those that might be at higher risk and then be able to treat them after the fact. Because I do think the focus... [full transcript]
