患者说酮有助于治疗他们的精神疾病。 科学家正在竞相理解其中的原因

当伊恩·坎贝尔（Iain Campbell）在上班的路上凝视着车窗外时，他第一次感觉到某种非同小可的东西正在重塑他体验世界的方式。

这种感觉是从一次极其平常的观察中浮现出来的：当看着路边的树木在眼前掠过时，他感到平静，甚至可能是快乐。

“我已经很长一段时间没有经历过这种感觉了，可能是从我小时候起（就失去了这种感觉），”住在苏格兰爱丁堡的坎贝尔说。

“我当时不知道发生了什么，但我想这可能就是正常（人）的感觉。”

坎贝尔一生的大部分时间都患有双相情感障碍。 他的家族患有精神疾病，他的亲人有的自杀了。 多年来，他尝试了不同的治疗方法，但“越来越难以忍受”（这些治疗方法）。

到底发生了什么变化？ 几周前，他开始了新的饮食习惯。

坎贝尔面临着（新的）体重增加和代谢问题，这是精神科药物的常见副作用。

为了减肥，他大幅减少碳水化合物的摄入，转而专注于蛋白质和脂肪。 事实证明，他在不知不觉中进入了酮症：一种代谢状态，身体从（利用）葡萄糖作为主要能量来源，转变为利用来自脂肪的酮（作为主要能量来源）。

他开始通过播客和 YouTube 视频了解生酮饮食，即高脂肪和极低碳水化合物。 很快，他就通过家庭验血来追踪自己的酮水平。

“我意识到实际上是酮水平使我的症状发生了这种转变，这是其他任何方法都没有的，”他说。 “这对我来说非常重要，就像改变了生活一样。”

职业生涯的起步时刻

饮食到底是如何发挥这种魔力的呢？ 坎贝尔决定在爱丁堡大学攻读心理健康博士学位，希望自己进行研究并了解是否可以帮助他人。

在在线论坛上，双相情感障碍患者分享了类似的轶事——他们发现自己的情绪有所改善，思路更加清晰，抑郁发作次数也减少了。

但当坎贝尔寻找方法启动适当的临床试验来测试饮食的有效性时，他变得灰心了。

“这真的就像你被认为是古怪的，”他说，“有一次，我竟然认为没有人会为这项研究付科研经费。”

他制作了一段 45 分钟的视频，总结了使用生酮饮食治疗双相情感障碍的生物学原理，并将其发布在社交媒体上，之后并没有抱太大期望。

但一些医生在看到生酮饮食的实践潜力后，已经开始研究，其中包括哈佛医学院和麦克莱恩医院的精神病学家克里斯·帕尔默。

几年前，帕尔默对这种饮食有自己的启示，他在 2017 年的一份病例报告中详细介绍了这一点。 他说，两名精神分裂情感障碍患者“其精神病症状得到了真正戏剧性的、改变生活的改善”。

2021 年初，他开始与 Jan 和 David Baszucki（一位富有的科技企业家）的长子合作。Baszucki的儿子Matt 患有双相情感障碍，近年来一直在服用多种药物。

当Jan Baszucki的儿子尝试生酮饮食时，Jan向帕尔默寻求帮助。

“几个月内，我们看到了巨大的变化，”Jan说。

受到启发，Jan开始联系临床医生和研究人员，希望为这种治疗带来更多的知名度和资金。 由于仍然缺乏关于饮食的严格数据，她希望看到研究人员进行大型临床试验来支持像她儿子康复这样的轶事。

很快，一位大慈善家与坎贝尔取得了联系，准备支付他的躁郁症研究以及其他研究的费用。

现在，大约有十几项临床试验正在进行中，测试饮食对精神疾病的影响，尤其是双相情感障碍、精神分裂症和抑郁症，还有厌食症、酗酒和创伤后应激障碍等疾病。

“研究和临床兴趣突然增多了，”马萨诸塞州精神病学家乔治亚·埃德博士说，她大约十年前开始在自己的实践中使用生酮饮食。

从癫痫护理到主流

经典的生酮饮食含有大量的脂肪，大约 90% 的卡路里都来自脂肪。 其他版本也出现了，可以降低脂肪含量，为蛋白质和碳水化合物提供更多空间。

认真的生酮饮食追随者可能会购买一种设备来测量血液中的酮水平，以追踪他们是否进入了意味着他们正在经历所谓的营养性酮症的范围。

这种饮食进入主流引发了关于其优点的大量争论，一些医学团体提出了担忧。 然而，人们也越来越关注它的潜力，并且临床试验正在进行中，不仅针对肥胖，而且针对各种其他疾病。

“这不是一种时尚饮食，”谢巴尼·塞西博士说，他在斯坦福大学领导了这种饮食对心理健康潜力的研究。 “这是一种医疗干预。”

生酮饮食是一百多年前针对小儿癫痫而开发的，并且在过去三十年中在该领域重新兴起。

“这是癫痫治疗的一般标准，”约翰·霍普金斯大学的儿科神经学家埃里克·科索夫博士说。

人们认为，癫痫病的这一记录为其在精神病学中的应用铺平了道路。 条件之间存在联系。 为癫痫发作开发的药物通常用于治疗双相情感障碍等一系列精神疾病。

帕尔默说：“即使我们没有研究表明或证明它们对精神疾病患者有帮助，我们也会在标签外使用它们，因此，从很多方面来说，这并不是什么新鲜事。”

代谢联系

各种精神疾病和代谢问题（例如高血糖和胰岛素抵抗、2 型糖尿病、肥胖和高血压）之间也存在着密切的关联。

患有精神疾病的人面临更高的风险。 不仅仅是精神药物会导致体重增加和其他问题。 研究表明，甚至在患有严重精神疾病的人服用药物或被诊断之前，这些问题就可能出现。

“我们很早就知道，患有严重精神疾病的人的大脑新陈代谢发生了一些不太正常的事情，”麦克莱恩医院精神障碍科主任、一名 哈佛医学院教授。

几十年来，精神病学领域积累了大脑和身体其他部位能量问题的证据——与生酮饮食无关。

“我们不能说其中存在因果关系，但有很多联系值得进一步探索，”翁格尔说，他的工作重点是双相情感障碍和精神分裂症的这一主题。

所有这些数据都足以让人怀疑“代谢问题可能不仅仅是无辜的旁观者”，事实上，它们可能在精神疾病的发展、严重程度或病程中发挥直接作用，”埃德说。

酮的力量背后的理论

那么，阻止癫痫发作的饮食到底是如何对难以治疗的精神疾病发挥强大作用的呢？

即使几十年后，研究癫痫的科学家仍然不能确切地确定为什么它对这种疾病有效。

“它影响着许多不同的机制，”南佛罗里达大学研究生酮饮食的分子药理学和生理学教授多米尼克·达戈斯蒂诺（Dominic D'Agostino）说。

这就是为什么他喜欢将饮食描述为更像是“霰弹枪”而不是“子弹”。（as being more like a "shotgun" than a "bullet."）

在酮症期间，身体本质上改变了代谢齿轮。 它越来越多地利用酮（由肝脏中脂肪分解产生）而不是葡萄糖。

“我们知道这种情况发生在生酮饮食中，”科索夫说，“酮可以用作能量，但如何帮助癫痫发作是下一个棘手的问题。”

由于饮食消除了碳水化合物，血糖会下降，胰岛素敏感性会提高。

“你可以减轻你真正脆弱的胰岛素信号系统的压力，”埃德说，同时为细胞提供另一种燃料，可以使“可能一直口吃的大脑部分恢复正常”。

帕尔默和其他科学家认为，线粒体（细胞产生能量的动力源）的问题是精神疾病的核心。

多伦多大学药理学和精神病学教授安娜·安德里亚扎（Ana Andreazza）说：“这可能是由于线粒体在维持关键大脑功能中发挥着重要作用。”

在她的实验室中，安德里亚扎研究了哪些生物途径使精神疾病患者更容易遭受线粒体功能障碍的影响。

对这些重要发电厂的累积损害最终会导致“代谢转变”，从而以多种方式造成严重破坏——从乳酸产量的增加中可以明显看出这一点。

“这些发现对于许多精神疾病来说是令人信服的，”她说。

她说，酮可能通过缓解氧化应激（一种自由基的有害积累）来帮助线粒体，并提供一种能源来规避线粒体中功能失调的机制。

达戈斯蒂诺说：“一旦线粒体功能和代谢健康趋于正常，神经递质系统就会恢复，甚至大脑的血流也会恢复。”

科学家寻找更多线索

酮症对线粒体的影响是酮类饮食有效的一种假设，但这可能不是全部。

关于饮食如何影响大脑的大部分数据来自对癫痫和其他神经系统疾病（如阿尔茨海默病和帕金森病）的研究。

科学家发现，精神分裂症、重度抑郁症和双相情感障碍等严重精神疾病与这些疾病有显着的相似之处：大脑炎症、氧化应激、线粒体功能障碍、以及葡萄糖和胰岛素问题。

研究表明，酮症在这些方面可能是有益的，尽管人类研究有限。 目前正在进行的一些针对生酮饮食的大型临床试验将试图查明到底发生了什么。

例如，迪安娜·凯利博士正试图确定饮食的潜在益处是否来自肠道微生物组。

“你可能会改变细菌的运作方式，这可能会影响你的行为和大脑，”马里兰大学精神病学教授凯利说，他正在领导一项针对精神分裂症的生酮饮食住院试验。

玛丽·菲利普斯博士研究了多巴胺如何影响双相情感障碍的奖赏回路，她认为这可能有助于解释其治疗效果。

她希望最近启动的双相情感障碍和酮饮食临床试验也能解决一个非常实际的问题：

“你怎么知道生酮饮食对哪些人有效？” 匹兹堡大学精神病学教授菲利普斯说，“这不是世界上最容易开始的饮食方法。”

早期结果显示出希望

目前关于其对心理健康潜力的大部分证据来自病例报告、观察数据和公开试验，这些为更严格的研究奠定了基础。

现有研究表明心理和代谢健康均有所改善。

Iain Campbell 的小型试点研究旨在测试随机对照试验的可行性，结果发现患者平均减重约 10 磅，血压“显着降低”。

“随着酮水平的上升，我们看到他们的情绪得到改善，他们的精力得到改善，他们的焦虑减少，他们的冲动减少，”坎贝尔说，他现在是爱丁堡大学代谢精神病学巴斯祖基研究员。

他们的血乳酸水平（线粒体功能障碍的标志）下降，大脑中的谷氨酸水平也下降，抗癫痫药物也有这种效果。

法国图卢兹最近进行的一项研究是针对患有严重精神疾病的住院患者进行的最大规模的研究。

该研究的合著者 Ede 表示，虽然有 3 名患者无法坚持下去，但到了第三周，28 名患者的抑郁和精神病症状有了显着改善。

最终，43% 的患者获得了临床缓解。

虽然没有对照组，但她指出，这些患者之前曾在同一位精神科医生的护理下住院——这次治疗唯一明显的区别是生酮饮食。

“所以我们相信饮食可能与结果有关，”埃德说。

在斯坦福大学，塞西的试点研究发现，大多数精神分裂症或双相情感障碍患者的饮食得到了“临床上有意义的改善”，并且接近一半的患者“实现了康复”。

参与研究的人中有四分之一患有代谢综合征（一系列危险因素，如胰岛素抵抗和高血压），但到最后，病情得到了逆转。

没有参与这项研究的阿尼萨·阿比-达加姆博士称，当与癫痫和精神疾病代谢功能障碍的现有证据一起考虑时，最初的数据“很有趣”。

石溪大学精神病学和行为健康系主任阿比-达加姆说：“所有这些都让我相信，有一个信号值得以严格的方式追求。”

但在可靠的临床数据出现之前，人们的大量关注引起了一些精神科医生的关注。

德鲁·拉姆齐博士担心，这种炒作已经造成了人们对生酮饮食在心理健康方面的不切实际的看法。 目前，他仍然持怀疑态度。

“它有效吗？它对某些人有效，这很棒，但大多数东西对某些心理健康的人有效，”营养精神病学家拉姆齐说。

支持者承认该领域仍处于早期阶段。

“对此你必须保持谦虚，”翁格尔说，“生酮饮食确实是一个测试案例，但它不是灵丹妙药。”

帕尔默说，饮食是一种强有力的干预措施，但“它并不能治愈每个患有精神疾病的人，甚至不一定能帮助每个人。”

代谢精神病学起飞

人们对高脂肪、最低碳水化合物饮食的热潮反映了一场更广泛的运动，以更好地认识代谢健康与精神疾病之间的联系。

生酮饮食研究只是现在被称为代谢精神病学的一个不断发展的研究领域的一个分支。

Sethi 在 2015 年启动斯坦福大学项目时创造了这个术语，她说这个想法是研究如何治疗代谢健康——解决高血糖、胰岛素抵抗和肥胖等疾病——也可以改善精神问题。

虽然酮是最突出的例子，但她说药物也在研究中，包括使身体对胰岛素更敏感的药物——胰岛素是帮助将葡萄糖引入细胞的激素。

对于接受过肥胖医学和精神病学培训的塞西来说，这种方法很直观。 在医学院时，她第一次目睹了酮对精神病患者的潜力。

一位患有难治性精神分裂症的女性曾尝试通过饮食来减肥和控制糖尿病。 令塞西当时惊讶的是，它还帮助患者消除了幻觉。

最近的一项临床试验强调了解决代谢问题的前景，而不仅仅是生酮饮食。

患有难治性双相抑郁症和胰岛素抵抗（但不包括 2 型糖尿病）的患者服用了糖尿病药物二甲双胍。

研究结束时，一半服用该药物的人逆转了胰岛素抵抗，并且发现他们的精神症状显着改善，尽管大多数人已经病了 25 年而没有任何缓解。

“我有点震惊，”领导这项研究的加拿大达尔豪斯大学精神病学家辛西娅·卡尔金博士说。 “二甲双胍并不是一种抗抑郁药，而是它可以逆转胰岛素抵抗并改善结果。”

健康的“顺风”

患者和临床医生都不会等待更大规模试验的结果来尝试生酮。

在网上，患者分享他们尝试饮食的经验和挑战。 像塞西和埃德这样培训其他临床医生的医生经常用它来治疗患者。

大约四年前，洛里·卡茨 (Lori Katz) 在尝试了多种双相情感障碍的治疗方法后，最终来到了塞西 (Sethi) 的斯坦福诊所，她在 18 岁时就得到了双相情感障碍的诊断结果。

她还与慢性疼痛、暴饮暴食和情绪化饮食以及不必要的体重增加作斗争。 她的抑郁症让她考虑接受电休克治疗 (ECT)。

生酮饮食是一种很好的调整，但卡茨在塞西的监督下尝试了一下。

“突然之间，我的体重下降得非常快，而且对自己吃的东西非常满意，”住在加利福尼亚州圣克鲁斯的训狗师卡茨说。

她说她周围的人很快就注意到她情绪的变化。

“这不仅仅是抑郁症状，而且是缺乏控制的感觉，”她说。 她说，生酮饮食“就像一股顺风——把我吹向更美好的未来。”

最终，她开始去健身房并进行更长时间的散步。 在多年没有浪漫的“动力”之后，一个女朋友进入了她的生活。

卡茨说，她不能总是完美地遵循饮食，并注意到当她不那么严格时情绪的变化。 它并没有消除患有精神疾病的现实。

“我会接受这个，但问题是我是否更有弹性？是的。我更乐观吗？是的。我感觉我拥有这个工具吗？是的，当我进入那里并得到支持时。我需要保持酮症状态。”

能做到吗？

事实上，任何一种饮食方式都很难坚持——而一种需要很大程度上放弃面包和糖果等常见舒适食物的饮食方式——可能更具挑战性。

坎贝尔的研究中约有四分之一的人退出了，他指出这与其他生酮饮食的试点试验类似。

路易斯维尔大学的精神病学家里夫·埃尔-马拉赫 (Rif El-Mallakh) 博士二十多年前就对这种饮食产生了兴趣，并相信它有效。

他说，他在一些患者身上取得了早期成功，但多年来运气不佳：“我无法让人们坚持下去，所以我根本不像其他人那样兴奋。 ”

然而，已经在实践中使用它的医生表示，只要有足够的教育和支持，患者就可以取得成功。

马特·伯恩斯坦博士在他的一些患者身上发现了惊人的结果。

有些人选择最严格的饮食形式，特别是在症状严重的情况下，但他强调，这种饮食是可以定制的，甚至“适度的版本”也对一些患者产生了“令人难以置信的改变”。

他会让他们慢慢适应，逐渐减少碳水化合物的摄入量。

“有些人喜欢突然这样做，但对很多人来说，这并不是最好的事情，”波士顿精神病康复项目 Ellenhorn 的首席医疗官伯恩斯坦说。

“我们的想法是，这将是可持续的，而不仅仅是你做几个月然后停止的事情。”

尽管数量在不断增加，但接受过提供这种饮食疗法培训的精神科医生并不多。

伯恩斯坦和其他医生表示，那些有严重精神疾病史的人应该接受医疗监督。 可能需要调整实验室工作和药物。

尽管乐观，但仍有许多悬而未决的问题。

在他的初步研究中，伊恩坎贝尔已经听到了他梦想的一些真实结果，以帮助其他人找到这种治疗方法

“他们会向我描述，‘这完全改变了我的生活，我与家人重新建立了联系。我第一次可以再次工作，’”他说。

编辑和视觉设计由 Carmel Wroth 负责。 视觉制作由Katie Hayes Luke)制作。

Patients say keto helps with their mental illness. Science is racing to understand why

https://www.npr.org/sections/health-shots/2024/01/27/1227062470/keto-ketogenic-diet-mental-illness-bipolar-depression

Iain Campbell was gazing out the bus window on his way to work when he first sensed something radical was reshaping how he experienced the world. 

The inkling emerged from an altogether ordinary observation: He felt peaceful, maybe even happy as he watched the trees along the road pass by. 

"I hadn't experienced that in a really long time, probably since I was a kid," says Campbell, who lives in Edinburgh, Scotland. 

"I didn't know what was going on at the time, but I thought this might be what it feels like to be normal."

Campbell had lived with bipolar disorder for much of his life. Mental illness runs in his family, and he'd lost loved ones to suicide. Over the years, he tried different treatments, but it had become "increasingly difficult to live with."

What had changed? A few weeks earlier, he'd started a new diet. 

Campbell dealt with unwanted weight gain and metabolic troubles, a common side effect of psychiatric medications. 

In an effort to lose weight, he drastically cut back on carbs and instead focused on protein and fat. It turns out he'd unknowingly entered ketosis: A metabolic state where the body switches from glucose as its primary energy source to ketones, which come from fat. 

He started learning about the ketogenic diet, which is high fat and very low carb, on podcasts and YouTube videos. Soon, he was tracking his ketone levels, courtesy of an at-home blood test. 

"I realized it was actually the ketone level that was making this shift in my symptoms in a way that nothing else ever had," he says. "It struck me as really significant, like life-changing." 

How exactly was a diet performing this alchemy? Campbell decided to pursue a PhD in mental health at the University of Edinburgh, hoping to do his own research and learn if it could help others.

In online forums, people with bipolar disorder were sharing similar anecdotes— they were finding improvements in their mood, increased clarity and fewer episodes of depression. 

But as Campbell searched for ways to launch a proper clinical trial to test the diet's effectiveness, he became discouraged. 

"It was really like you were considered wacky," he says, "At one point, I thought nobody's going to pay for this research." 

He put together a 45-minute video summing up the biological rationale for using the ketogenic diet in bipolar disorder and posted it on social media, not expecting much after that.

But some doctors had already started researching it after seeing the potential in their practice, among them Chris Palmer, a psychiatrist at Harvard Medical School and McLean Hospital. 

Palmer had his own revelation about the diet a few years earlier, which he detailed in a 2017 case report. Two patients with schizo-affective disorder had "truly dramatic, life-changing improvement in their psychotic symptoms," he says. 

In early 2021, he started working with the eldest son of Jan and David Baszucki, a wealthy tech entrepreneur. Their son Matt had bipolar disorder and had been on many medications in recent years. 

Jan Baszucki enlisted Palmer's help as her son gave the ketogenic diet a try. 

"Within a couple of months, we saw a dramatic change," she says.

Inspired, she started contacting clinicians and researchers, looking to bring more visibility — and funding — to the treatment. Since rigorous data on the diet is still lacking, she wants to see researchers conduct large clinical trials to back up anecdotes like her son's recovery. 

Soon a big-time philanthropist was in touch with Campbell, ready to pay for his bipolar study – and others.

Now, around a dozen clinical trials are in the works, testing the diet's effect on mental illness, most notably for bipolar disorder, schizophrenia and depression, but also for conditions like anorexia, alcoholism and PTSD.

"The research and the clinical interest is suddenly exploding," says Dr. Georgia Ede, a psychiatrist in Massachusetts, who began using the ketogenic diet in her own practice about a decade ago. 

The classic ketogenic diet contains an eye-popping amount of fat, roughly 90% of calories coming from that alone. Other versions have come along that dial down the fat and allow more room for protein and slightly more carbohydrates.

Serious followers may buy a device to measure ketone levels in their blood, to track whether they've entered a range that means they're experiencing what's called nutritional ketosis. 

The diet's entrance into the mainstream has fed plenty of debate about its merits, with some medical groups raising concerns. Yet, there's also growing attention — and clinical trials underway — on its potential, not only for obesity but a variety of other conditions. 

"It's not a fad diet," says Dr. Shebani Sethi, who's leading research into the diet's potential for mental health at Stanford University. "It's a medical intervention."

The ketogenic diet was developed over a hundred years ago for pediatric epilepsy and has seen a resurgence in that field over the last three decades.

"It's a general standard of care for epilepsy," says Dr. Eric Kossoff, a pediatric neurologist at Johns Hopkins University. 

This track record in epilepsy, the thinking goes, paves the way for its adoption in psychiatry. There are links between the conditions. Medications developed for seizures are regularly prescribed for a range of psychiatric conditions such as bipolar disorder. 

"We use them off label, even when we don't have studies to suggest or prove that they are helpful for people with mental illness," says Palmer, "So, in many ways, this is nothing new." 

There's also a well-documented association between a variety of psychiatric conditions and metabolic problems like high blood sugar and insulin resistance, Type 2 diabetes, obesity and hypertension.

People with psychiatric disorders are at an increased risk. And it's not just that psychiatric meds can cause weight gain and other issuses. Research shows these problems can arise even before someone with serious mental illness takes medication or is diagnosed. 

"We've known for a long time that there's something going on in the metabolism of the brain that's not quite right in people with severe mental illness," says Dr. Dost Öngür, chief of the division of Psychotic Disorders at McLean Hospital and a professor at Harvard Medical School. 

This evidence of energy problems in the brain and elsewhere in the body has accumulated over the decades in psychiatry — unrelated to the ketogenic diet. 

"We can't say that there's a causal relationship, but there are a lot of connections that should be explored further," says Öngür whose work has focused on this theme in bipolar and schizophrenia. 

All of this data is strong enough to suspect that "metabolic problems may be more than just innocent bystanders," that they may, in fact, play a direct role in the development, severity or course of psychiatric conditions," says Ede.

So, how exactly could a diet that stops seizures also exert powerful effects on tough-to-treat psychiatric illness? 

Even after decades, scientists who study epilepsy aren't exactly sure why it works for that illness.

"It's impacting so many different mechanisms," says Dominic D'Agostino, a professor of molecular pharmacology and physiology at South Florida University who studies the ketogenic diet. 

That's why he likes to characterize the diet as being more like a "shotgun" than a "bullet." 

During ketosis, the body essentially changes metabolic gears. It increasingly draws on ketones — made from the breakdown of fat in the liver – instead of glucose. 

"We know this happens on a ketogenic diet," says Kossoff, "Ketones can be used for energy, but how that helps seizures is the next tricky question."

Because the diet eliminates carbohydrates, blood sugar comes down and insulin sensitivity improves.

"You take pressure off of your really delicate insulin signaling system," says Ede, while offering cells another fuel that could bring parts of the "brain back online that may have been stuttering."

Palmer and other scientists believe problems with mitochondria — the powerhouses of the cells that produce energy — are central to mental illness. 

"This is likely due to mitochondria's essential role in maintaining key brain function," says Ana Andreazza, a professor of pharmacology and psychiatry at the University of Toronto. 

In her lab, Andreazza studies what biological pathways make people with psychiatric illness more vulnerable to mitochondrial dysfunction. 

Cumulative damage to these vital power houses ultimately leads to a "metabolic shift" that wreaks havoc in myriad ways — what's apparent in their increased production of lactate. 

"The findings are compelling for many psychiatric disorders," she says. 

It's possible the ketones help the mitochondria by relieving oxidative stress — a harmful build up of free radicals, she says, and by providing an energy source that circumvents the dysfunctional machinery in the mitochondria.

"Once you trend towards more normal mitochondrial function and metabolic health, that's restoring neurotransmitter systems, it's even restoring blood flow to the brain," says D'Agostino.

The effect of ketosis on the mitochondria is one hypothesis for why keto diets could work, but it may not be the whole story.

Much of the data on how the diet affects the brain come from research into epilepsy and other neurological diseases like Alzheimer's and Parkinson's. 

Scientists find serious mental illnesses like schizophrenia, major depression and bipolar disorder share notable similarities with these conditions: Inflammation in the brain, oxidative stress, mitochondrial dysfunction, and issues with glucose and insulin. 

Research suggests ketosis can be beneficial on these fronts, although human studies are limited. Some of the larger clinical trials now underway for keto diets will seek to pin down what's going on.

For example, Dr. Deanna Kelly is trying to determine if the diet's potential benefits emerge from the microbiome in the gut. 

"You're potentially changing the way bacteria are functioning and that could affect your behavior and your brain," says Kelly, a professor of psychiatry at the University of Maryland, who's leading an inpatient trial on the ketogenic diet for schizophrenia.

Other scientists are studying the diet's effect on neurotransmitters like GABA — which acts as a kind of brake in the brain. 

Dr. Mary Phillips, who has studied how dopamine affects the reward circuit in bipolar disorder, thinks that may help explain its therapeutic effects. 

She hopes her clinical trial of bipolar and the keto diet, which launched recently, also gets at a very practical question: 

"How do you know which people the ketogenic diet is going to work for?" says Phillips, a professor of psychiatry at the University of Pittsburgh, "It's not the easiest diet in the world to get started on." 

Much of the current evidence on its potential for mental health comes from case reports, observational data and open trials that have laid the groundwork for more rigorous studies. 

The research that exists shows improvements in both mental and metabolic health. 

Iain Campbell's small pilot study, designed to test the feasibility of a randomized controlled trial, found patients lost an average of about 10 pounds and had "significant reductions" in blood pressure. 

"As the ketone level went up, we saw their mood improved, their energy improved, their anxiety decreased and their impulsivity decreased," says Campbell who's now a Baszucki research fellow in metabolic psychiatry at the University of Edinburgh. 

Their blood lactate levels, a sign of mitochondrial dysfunction, dropped as did glutamate in the brain, an effect also seen with anti-seizure medications. 

A recent study from Toulouse, France, is the largest to look at hospitalized patients with severe mental illness.

Though three patients couldn't stick with it, the 28 who did had substantial improvements in their symptoms of depression and psychosis by the third week, says Ede, a co-author of the study. 

Ultimately, 43% achieved clinical remission.

There was no control group, but she points out these patients had been hospitalized before under the care of the same psychiatrist — with the only clear difference in treatment this time being the ketogenic diet. 

"So we believe the diet probably had something to do with the outcome," says Ede.

At Stanford, Sethi's pilot study found the majority of patients with schizophrenia or bipolar disorder had "clinically meaningful improvement" on the diet and close to half "achieved recovery." 

A quarter of those who entered the study had metabolic syndrome — a cluster of risk factors like insulin resistance and high blood pressure — and by the end, had reversed the condition 

Dr. Anissa Abi-Dargham, who isn't involved in the research, calls the initial data "intriguing," when considered alongside the existing evidence on epilepsy, and metabolic dysfunction in psychiatric illness. 

"All this together convinces me there is a signal that is worth pursuing in a rigorous way," says Abi-Dargham, chair of the department of psychiatry and behavioral health at Stony Brook University. 

But the rush of attention ahead of solid clinical data has raised eyebrows among some psychiatrists. 

Dr. Drew Ramsey worries the hype has created an unrealistic perception about the ketogenic diet in mental health. For now, he remains skeptical. 

"Does it work? It works for some people, which is awesome, but most things work for some people in mental health," says Ramsey, a nutritional psychiatrist. 

Proponents readily acknowledge the field is still in the early stages.

"You have to be modest about this," says Öngür, "The ketogenic diet is really a test case, but it's not the silver bullet."

Palmer says the diet is a powerful intervention, but "it's not going to cure everybody with mental illness, or even necessarily help everybody." 

The groundswell of excitement around a high-fat, minimal carb diet reflects a broader movement to better recognize the link between metabolic health and mental illness. 

Ketogenic diet research is just one branch of a growing area of research now being called metabolic psychiatry.

Sethi, who coined the term when she launched Stanford's program in 2015, says the idea is to study how treating metabolic health – tackling conditions like high blood sugar, insulin resistance and obesity – may also improve psychiatric problems. 

While keto is the most prominent example she says medications are also under study, including drugs that make the body more sensitive to insulin — the hormone that helps usher glucose into cells. 

This approach is intuitive for Sethi, who trained in obesity medicine and psychiatry. It was in medical school when she first witnessed keto's potential for her psychiatric patients.

A woman with treatment-resistant schizophrenia had tried the diet to lose weight and manage her diabetes. To her surprise at the time, Sethi recalls it also helped the patient with hallucinations. 

A recent clinical trial underscores the promise of targeting metabolic problems, beyond just the ketogenic diet.

Patients with treatment resistant bipolar depression and insulin resistance, but not Type 2 diabetes, were prescribed the diabetes drug metformin. 

By the end of the study, half of those who took the medication had reversed their insulin resistance — and also found dramatic improvements in their psychiatric symptoms, even though most had been ill for 25 years without any remission. 

"I was kind of blown away," says Dr. Cynthia Calkin, a psychiatrist at Dalhousie University in Canada who led the study. "It's not that metformin is an antidepressant, it's that it can reverse insulin resistance and that improves outcomes."

Neither patients nor clinicians are waiting for the results of larger trials to try keto. 

Online, patients share their experiences with – and challenges – trying the diet. And doctors like Sethi and Ede, who trains other clinicians, regularly treat patients with it.

About four years ago, Lori Katz ended up at Sethi's Stanford clinic after trying many treatments for bipolar disorder — a diagnosis she received when she was 18 years old. 

She also struggled with chronic pain, binge eating and emotional eating, and unwanted weight gain. Her episodes of depression had led her to consider electroconvulsive therapy (ECT). 

The ketogenic diet was quite the adjustment, but Katz gave it a go, under Sethi's supervision. 

"Suddenly, I was losing weight really fast and was extremely satisfied with what I was eating," says Katz, a dog trainer who lives in Santa Cruz, Calif. 

She says those around her quickly noticed a change in her mood.

"It wasn't just the depressive symptoms, but it was the feeling of lack of control," she says. The keto diet, she says, "was like a tailwind — just blowing me into a better future."

Eventually, she started going to the gym and taking longer walks. And after years without a romantic drive, a girlfriend entered her life. 

Katz says she can't always follow the diet perfectly and notices the change in mood when she is less strict. It hasn't erased the reality of living with a mental illness. 

"I will live with this but it's a question of am I more resilient? Yes. Am I more optimistic? Yes. Am I feeling like I have this tool? Yes, when I get in there and I get the support. I need to stay in ketosis." 

Indeed any kind of diet can be hard to stick to – and one that involves largely giving up common comfort foods like bread and sweets – may be even more challenging.

About a quarter of those in Campbell's study withdrew, which he notes is similar to other pilot trials with the ketogenic diet. 

Dr. Rif El-Mallakh, a psychiatrist at the University of Louisville, became interested in the diet more than two decades ago and believes it works. 

He says he had early success with a few patients, but hasn't had much luck over the years: "I haven't been able to get people to stay on it, so I'm not at all as excited as maybe others."

However, doctors who already use it in their practice say with enough education and support patients can be successful.

Dr. Matt Bernstein has found striking results in some of his patients. 

Some opt for the most restrictive form of the diet, especially if they have severe symptoms, but he emphasizes it can be tailored and even a "modest version" has made an "incredible difference" for some patients. 

He'll ease them into it, lowering their carbohydrate intake gradually. 

"Some people like to do it cold turkey, but for a lot of people, that's not the best thing," says Bernstein, chief medical officer at Ellenhorn, a psychiatric recovery program in Boston. 

"The idea is that this is going to be sustainable and not just something you do for a few months and then stop." 

Not many psychiatrists are trained to offer the diet, although the numbers are growing. 

Bernstein and other doctors say those with a history of serious mental illness should have medical supervision. There can be lab work and medications that need to be adjusted. 

Despite the optimism, there are still many unanswered questions. 

In his initial research, Iain Campbell's already hearing some real results of his dream to help others find this treatment 

"They would describe it to me like, 'This changed my life completely, I'm reconnecting with my family. I can work again for the first time,'" he says. 

Editing and visual design by Carmel Wroth. Visual producing by Katie Hayes Luke.