剥夺睡眠可以治疗抑郁症吗？
琳达·格兹 （Linda Geddes）2018年 2月 17日
http://www.bbc.com/future/story/20170720-when-you-cant-remember-where-you-are-or-how-you-got-there
首先让人感到安吉丽娜（Angelina）发生变化的是她的手。她一边用意大利语和护士聊天，一边开始打手势，指指戳戳，比划形状，用手指在空中画圈。过了一会儿，安吉丽娜变得越来越活跃。我发现她说的话带上了旋律，我确定之前不是这样的。然后，她额头的皱纹开始松弛，嘴唇撅起又伸展，眼睛皱起来。无需翻译，我都能知道她的精神状态。
安吉丽娜醒过来的时候，刚好是我要入睡的时候。凌晨两点，我们坐在米兰精神病房灯光明亮的厨房里，吃意大利面。我的眼睛后面隐隐作痛，注意力很难集中，但是安吉丽娜至少要再等17个小时才会睡觉。所以我也决心度过一个漫长的夜。为了让我相信她的决心，安吉丽娜摘下了眼镜，直视着我，用拇指和食指撑开眼睛周围有皱纹的灰色皮肤。她说了一句意大利语："Occhiaperti。"意为，睁开眼睛。
这是安吉丽娜刻意坚持不睡觉三天中的第二天。她患有躁郁症，两年来一直在严重的抑郁中度过。这种做法看似非常不适合她，但是安吉丽娜和她的医生都希望这种疗法能够拯救她。过去二十年，米兰的圣拉法尔医院（San Raffaele Hospital）的精神科和临床生物心理科主管弗朗西斯科·贝内德蒂（Francesco Benedetti）一直在研究所谓的清醒疗法，依靠明亮的光照和锂盐治疗药物无法治疗的抑郁症。美国、英国以及其他欧洲国家的医院也开始留意并尝试类似疗法。这种"生物钟疗法"的工作原理是促进懒惰的生物钟恢复正常。他们认为这会让我们对抑郁症的潜在病理学原理和睡眠的功能产生新的认识。
"睡眠剥夺对健康者和抑郁症患者有相反的作用，"贝内德蒂说。如果你身体健康，但是不睡觉，你的心情就会变差。但如果你感到抑郁，它能够促进你的心情和认知能力立刻改善。贝内德蒂补充说，不过有一个陷阱：一旦你睡觉，补上几个小时睡眠，复发率高达95%。
1959年德国发表的一份报告首次提到睡眠剥夺的抗抑郁效果。德国图宾根（Tubingen）的年轻学者伯克哈德·普夫卢格（Burkhard Pflug）对此产生兴趣。他的博士论文对此展开研究。在20世纪70年代，他还开展后续研究。通过系统研究睡眠剥夺者，他确定一个晚上保持清醒有可能让患者脱离抑郁困扰。
20世纪90年代初，年轻的心理医生贝内德蒂开始对这个想法产生兴趣。在那之前几年，百忧解（Prozac）的问世为抑郁症的治疗带来了一场革命。但是这类药品很少在躁郁症患者身上试用。后来糟糕的经历也让内德蒂认识到抗抑郁药物对躁郁症患者基本没有作用。
贝内德蒂的患者亟需替代药物，而他的指导医师恩里科·斯梅拉尔迪（Enrico Smeraldi）想出了新的办法。贝内德蒂在阅读了清醒疗法的相关早期论文以后，对他自己的患者进行了测试，结果是积极的。贝内德蒂说："我们知道这个办法有用，带有严重病史的患者立刻就好转了。我的任务就是寻找方法让他们维持健康的状态。"
于是，他和同事转向科技文献以寻找办法。一些美国的研究表明锂盐可能会延长睡眠剥夺的效果。于是他们对此展开研究，发现65%服用锂盐的患者在三个月后对睡眠剥夺有持续的反应，而没有服用锂盐的只有10%有这种反应。
由于打瞌睡也会影响到疗效，他们就开始寻找新的方法让患者在晚上保持清醒状态，并从航空医学汲取灵感。飞机上会用明亮的灯光让飞行员保持警觉状态。它和锂盐一样，可以延长睡眠剥夺的效果。
"我们决定对他们使用一整套疗法，效果非常好，"贝内德蒂说。在20世纪90年代末之前，他们通常的治疗方法就是三合一生物钟疗法：睡眠剥夺、锂盐还有灯光。在一周之内，每隔一天剥夺睡眠一次。在接下来的两周，每天早晨用明亮的灯光照射30分钟。时至今日，他们仍在坚持这一方案。"我们并不认为这是剥夺人的睡眠，而是修改作息周期，从24小时延长到48小时，"贝内德蒂说，"接受治疗者每两天睡一次觉，想睡多久睡多久。"
1996年，圣拉法尔医院首次引入三合一生物钟疗法。自此以后，这种疗法帮助近千名躁郁症患者康复——他们中的很多人此前使用抗抑郁药物，但是没有效果。结果说明了一切：根据最近的数据，70%有抗药性的躁郁症患者在第一周就对三合一生物钟疗法有反应。55%在一个月后病情有了持续的改善。
假如抗抑郁药物能够奏效，也需要一个月以上的时间才能奏效，而且它可能会增加自杀的风险。与此同时，生物钟疗法能够立刻并持续减少自杀的念头，甚至在剥夺睡眠一晚后就能起效。
安吉丽娜初次诊断出躁郁症是30年前，当时她年近40岁。在诊断之前，她度过了极度压抑的一段时间：他的丈夫面临与工作相关的诉讼，他们担心家中的经济不够维持自己和孩子的生活。安吉丽娜得了三年抑郁症，此后她的情绪起伏不定，经常低落。她服用大量药物，包括抗抑郁药、情绪稳定剂、抗焦虑药和安眠药。她讨厌吃药，因为这会让她感觉自己是一个病人，尽管她也承认这是事实。
她说，如果我三天前见到她，我可能会认不出来她。她百事无心，不洗头，不化妆，身上还发臭。她对未来也非常悲观。她第一天剥夺睡眠之后，感觉更有精力了，但是在恢复睡眠后，精力又出现衰退。即便如此，现在她会为了与我见面提前去理发。我夸赞了她的容貌。她一边轻拍着自己染成金色的波浪卷发，一边感谢我注意到了她。
到3点整，我们来到灯光室，一进门感觉好像是时光穿梭到中午。明亮的日光从头顶的天窗倾泻下来，洒落在靠墙的一排五把扶手椅上。当然，这只是幻觉——蓝天和阳光不过是彩色的塑料和非常明亮的灯产生的效果——但是效果仍然非常让人兴奋。我就好像中午坐在阳光下的躺椅上，唯一缺少的就是温度。
七个小时前，当我在翻译帮助下采访安吉丽娜的时候，她回答时脸上面无表情。现在是凌晨3点20分，她开始微笑，甚至开始用英语和我对话。她此前声称自己不说英语。到傍晚的时候，她和我讲述了她之前开始写作的家族史。现在她想重拾写作，并邀请我去西西里她的家里住。
为何通宵这样简单的事情能给他们带来如此巨大的变化？要分析这其中的原理并不简单：我们仍未充分了解抑郁的本质和睡眠的功能，两者都涉及大脑的多个区域。但是，最近的一些研究开始提供一些看法。
抑郁症患者在睡眠和清醒时的大脑活动与健康者不同。白天的时候，昼夜节律系统——人体内部24小时运转的生物钟——发出的起床信号被认为能帮助我们抵御睡意。到晚上，身体又会用促进睡眠的信号取而代之。我们的脑细胞也按照这样的周期工作，在清醒状态下对刺激感到兴奋，在睡眠时兴奋度会消失。但是对抑郁症患者和躁郁症患者来说，这些波动似乎会减弱或者不存在。
抑郁症还与每天荷尔蒙分泌和体温节奏的变化有关。疾病越是严重，节奏越是紊乱。就像睡眠信号一样，这些节律是由身体的昼夜节律系统驱动。而该系统本身的动力来自一组互动蛋白质，它们被赋予"时钟基因"的代码，通过一整天的节律表达出来。它们驱动数百个不同的细胞过程，按照节奏逐一开始和结束。生物钟在身体的每个细胞里运转，包括脑细胞在内。它由大脑名为视交叉上核的感光区域协调。
"当人处于严重抑郁状态时，他们的昼夜节律会变得非常平缓，他们的褪黑素不会像平常人那样到晚上就增加分泌。他们的皮质醇一般都会在晚上处于较高水平，而非下降，"瑞典哥德堡萨赫尔格雷斯卡大学医院（Sahlgrenska University Hospitalin Gothenburg）的心理科医生斯坦·斯泰因格里姆松（SteinnSteingrimsson）说。他目前正在测试清醒疗法。
抑郁症的康复与这些周期的正常化有关。"我认为抑郁症是昼夜节律以及大脑稳态变平缓的后果之一，"贝内德蒂说，"当我们剥夺患者的睡眠时，这一周期过程会得到恢复。"
但是这种恢复是如何实现的？一种可能是抑郁症患者只需要增加睡眠压力，强制启动懒惰的系统。有人认为，睡眠压力之所以会增加，是因为大脑中腺苷的逐渐释放。它会在白天逐渐积累起来，然后与神经元上的腺苷受体相连，让我们感到困倦。触发这些受体的药物也有相同的效果。而阻碍这一过程的药物——比如咖啡因——会让我们感到清醒。
为了调查清醒状态的抗抑郁效果是否以这一过程为基础，马萨诸塞州的塔夫茲大学（Tufts University）的研究人员把高剂量的刺激腺苷受体的混合物投喂给有抑郁症类似症状的老鼠，以模仿睡眠剥夺时发生的情况。在12个小时后，老鼠的健康有所改善，测量标准是当被迫游泳或尾巴被悬吊时它们尝试逃跑所用的时间。
我们还知道睡眠剥夺对抑郁症患者的大脑有其他影响。它会改变大脑调节心情的区域里神经递质的平衡，让大脑处理情绪部位恢复正常活动，并加强它们之间的联系。
正如贝内德蒂团队发现的那样，如果清醒疗法促进懒惰的昼夜节律系统启动，锂盐和光照疗法似乎有助于维持其疗效。锂盐多年来被用作情绪稳定剂，但是没人真的了解它的工作原理。但是，据我们所知，它能增强Per2蛋白的表达，驱动细胞内的分子钟。
同时，明亮的灯光能够改变视交叉上核的节律，并更为直接的增强大脑内情绪处理区域的活动。的确，美国精神医学学会（American Psychiatric Association）表示，在治疗非季节性抑郁症时，光照疗法和大多数抗抑郁药物同样有效。
尽管清醒疗法针对躁郁症呈现出富有希望的结果，它在其他国家发展缓慢。"你可以愤世嫉俗的说，原因是没有专利，" 南伦敦和莫兹利NHS信托基金会（South London and Maudsley NHS Foundation Trust）心理咨询师大卫·韦尔（David Veale）说。
当然，医药业并没有为贝内德蒂提供资金以进行生物钟疗法试验。相反，直到目前为止，他一直依靠通常捉襟见肘的政府资助。他目前的研究是欧盟资助的。他讽刺的说，如果他按照传统路线，接受行业资助，对病人进行药物试验，他很可能就不会像现在这样住在两居室公寓，开着一辆1998年的本田思域。
对医药业解决方案的偏见导致很多心理医师不知道生物钟疗法。"很多人对此完全不知道，"韦尔说。
另外，睡眠剥夺或灯光照射尚未找到合适的安慰剂，这就意味着无法进行大范围的随机安慰剂控制试验。因此，有人怀疑它的实际效果。"尽管越来越多的人对它产生兴趣，但是我觉得很少人会将此类疗法作为惯例——证据还有待加强。在实施睡眠剥夺等治疗时，还有一些实践上的困难，"牛津大学流行性心理疾病学教授约翰·格迪斯（John Geddes）说。
即便如此，以这些过程为基础的生物钟疗法已经开始引起广泛的注意。"对睡眠和昼夜节律系统的生物学认知正在为疗法的研究提供前景良好的目标，"格迪斯说，"它超越了医药学——针对睡眠的心理学疗法有可能遏制甚或预防心理障碍。"
英国、美国、丹麦和瑞典的心理医师正在调查能否把生物钟疗法作为普通抑郁症的一种疗法。"到目前为止，大多数研究的范围都非常小，"目前在伦敦莫兹利医院（Maudsley Hospital）规划一项可行性研究的韦尔说，"我们需要证明这是可行的，而且人们能够坚持做到。"
到目前为止的研究得出的结论并不一致。丹麦哥本哈根大学抑郁症非药物疗法研究者克劳斯·马天尼（Klaus Martiny）发表了两项实验结果，研究睡眠剥夺、每天早晨明亮光照以及规律睡觉对普通抑郁症的效果。在第一个研究中，75名患者服用抗抑郁药度洛西汀，并结合生物钟疗法或日常锻炼。在一周以后，生物钟疗法组41%的被试者感受到症状减半，而与之相比锻炼组的比例是13%。在29周以后，62%接受清醒疗法的患者症状消除，与之相比锻炼组的比例是38%。
马天尼的第二个研究里，服用抗抑郁药没有效果的严重抑郁的住院患者接受了相同的生物钟疗法组合，作为他们正在进行的药物和心理疗法的补充。在一周后，生物钟疗法组的病情改善程度大幅超过标准疗法组，不过在随后的数周，控制组又追赶上来。
现在还没有研究直接对比清醒疗法和抗抑郁药物。也没有研究单独对比光照疗法和锂盐。即便这只对少数人有效，很多抑郁症患者——以及心理医师——有可能觉得无需药物的疗法很有吸引力。
"我依靠推销药品为生，但我依然认为不需要药物的疗法对我很有吸引力，"纽约哥伦比亚大学（Columbia University）临床精神病学教授乔纳森·斯图尔特（Jonathan Stewart）说。他正在纽约州精神病研究所（New York State Psychiatric Institute）开展一项清醒疗法实验。
与贝内德蒂不同，斯图尔特只让患者坚持不睡一个晚上："我觉得很多人不会同意在医院住三天，而且这也需要照料等很多资源，"他说。相反，他的方法是"睡眠时段提前"，即在睡眠剥夺一晚后的数天，患者睡觉和起床的时间会系统性的提前。到目前为止，斯图尔特已经用这一方法为20名患者提供治疗，其中12名对该疗法有反应——大多数都发生在第一周。
它还可以作为预防性措施：最近的研究表明，十几岁的少年，如果家长设定并且成功执行较早的睡觉时间，他们出现抑郁和产生自杀想法的风险较低。就像光照疗法和睡眠剥夺一样，我们不清楚其准确的原理，但是研究者猜测重点在于睡眠时间与自然的白天黑夜周期靠拢。
但是到目前为止，睡眠时段提前的研究并未进入主流。斯图尔特也接受它并不是适合所有人。"对于那些被治好的人来说，这是奇迹。但是就像百忧解并不能让所有人好转一样，这种疗法也做不到。我的问题是，我无法提前知道它对谁会有帮助。"
抑郁症可能发生在任何一个人身上，但是越来越多的证据表明基因变异有可能破坏昼夜节律系统，让某些人变得较为脆弱。一些生物钟基因的变异与情绪障碍风险有关。
压力还会让问题变得更为复杂。我们对压力的反应主要是通过荷尔蒙皮质醇的中介。而皮质醇受到昼夜节律系统牢牢的控制，但是皮质醇本身也会对昼夜节律系统中的生物钟计时有直接影响。所以，如果你的生物钟不强，压力增加可能会足以颠覆你的昼夜节律系统。
确实，如果老鼠被反复暴露在电击等有害刺激之下且无法躲避，就可能触发抑郁症状——这种现象被称为习得无助感。在面对持续的压力时，动物最终会放弃并表现出类似抑郁症的行为。圣迭戈加利福尼亚大学（University of California, San Diego）的心理医师大卫·威尔士（David Welsh）分析了带有抑郁症状的老鼠的大脑，发现它们的大脑奖励回路中的两个关键区域存在昼夜节律紊乱——该系统与抑郁症存在很重要的关系。
但是威尔士也展示了昼夜节律系统紊乱本身可能带来类似抑郁的症状。他把健康老鼠大脑中的主时钟的关键基因去除后，老鼠看起来就像之前研究中存在抑郁症状的老鼠。"他们不需要习得无助感，他们已经很无助了，"威尔士说。
那么，如果昼夜节律系统紊乱有可能是抑郁症的一个原因，那么应该做些什么来预防而非治疗？是否有可能加强你的生物钟以增强心理恢复力，而不是通过放弃睡眠来治疗抑郁症？
马天尼就是这样认为。他现在正在测试保持规律的日常作息能否防止已经康复出院的抑郁症住院患者旧病复发。他说："问题常常出在那里。在出院后，他们的抑郁症又恶化了。"
来自哥本哈根的45岁护工彼得（Peter）从十几岁时就开始与抑郁症作斗争。就像安吉丽娜等许多抑郁症患者一样，病症初次发作之前，他面临巨大的压力和变化。在他13岁那年，照顾他长大的姐姐离开了家，他的母亲对他漠不关心，他的父亲也是严重的抑郁症患者。不久以后，他的父亲因癌症过世——这对他来说也是一次冲击，因为父亲直到过世前一周才把医生对他的生存期预测说出来。
彼得因抑郁症住院六次，去年四月住院一个月。"从某些方面来看，住院是一种压力的缓解，"他说。不过，他觉得愧对自己七岁和九岁的两个儿子。"我的小儿子说，我在医院的每个晚上，他都会哭，因为我没法抱他。"
所以，当马天尼告诉彼得他正在寻找研究的被试者，彼得就欣然同意参加。名为"昼夜节律加强疗法"的研究理念是希望通过睡觉、起床、三餐和锻炼的规律化，加强人的昼夜节律，督促人们更多的参加户外活动，接触日光。
彼得五月出院，在随后的四个星期内，他佩戴了一个记录自己活动和睡眠的设备，并定期回答情绪有关的问卷。如果他的日常惯例中出现了偏移，他就会接到电话询问他发生了什么事。
当我见到彼得的时候，我开玩笑说到他的黑眼圈。显然，他对待这些建议非常认真。他笑着说："是的，我会出门去公园，如果天气好，我还会带孩子去海滩散步，或者去游乐场，因为这样我就能接受光照，这会改善我的情绪。"
他作出的改变不止这些。现在，他每天六点起床，帮助他的妻子照顾孩子。即使不饿，他也会吃早餐：通常是酸奶和木斯里（瑞士什锦麦片）。他白天不睡觉，努力在晚上十点前上床睡觉。如果他晚上醒过来，他会练习医院里学到的正念。
马天尼在电脑上提取彼得的数据，确定睡眠和起床时间开始提早，这说明他的睡眠质量有提高，这也反映在他的情绪分数上。刚出院时，他的情绪分数为6分（满分10分）。但是在两周保持八九点钟起床之后，有一天他的情绪分数甚至达到10分。在六月初，他返回养老院工作，一周工作35个小时。"生活规律确实给了我很大的帮助，"他说。
到目前为止，马天尼的研究招募了20名患者，他的目标是120人。所以，要想知道有多少人会作出像彼得一样的反应以及他的心理健康能否保持下去，还为时过早。即便如此，有越来越多的证据表明，良好的睡眠习惯有助于人们的心理健康。根据2017年9月发表在《柳叶刀精神病学》（Lancet Psychiatry）上的一项研究——到目前为止最大的心理干预随机试验——在经历为期10天的认知行为疗法后，失眠症患者的偏执心理以及幻想都持续下降。他们的抑郁和焦虑症状也减少了，噩梦少了，心理健康和日常生活有了改善。在试验过程中，他们进入抑郁期或出现焦虑症的可能性下降。
睡眠，日常活动和光照。这是一个简单的公式，很容易被想当然。但是，想象一下，这有可能真的能够减少抑郁症，并帮助患者更快的康复。这不仅能改善无数人的生活质量，还能为医疗系统节省开支。
在与安吉丽娜通宵过后一周，我打电话给贝内德蒂，询问安吉丽娜的情况。他告诉我，在第三次睡眠剥夺之后，她感到自己的症状得到了充分的缓解，并和她的丈夫回西西里去了。那一周，他们要过50年结婚纪念。此前，我问过安吉丽娜，她觉得自己的丈夫会不会注意到她的症状发生了变化，她说希望丈夫注意到她身体外形的变化。
希望如此。她的前半生一直缺少希望，我觉得对希望的回归是给他们最珍贵的金婚礼物。
Can staying awake beat depression?
Making people stay awake for hours in a hospital may seem an odd way to battle depression – but for some people it is proving a promising therapy. Linda Geddes reports.
By Linda Geddes From Mosaic 23 January 2018
The first sign that something is happening is Angelina’s hands. As she chats to the nurse in Italian, she begins to gesticulate, jabbing, moulding and circling the air with her fingers. As the minutes pass and Angelina becomes increasingly animated, I notice a musicality to her voice that I’m sure wasn’t there earlier. The lines in her forehead seem to be softening, and the pursing and stretching of her lips and the crinkling of her eyes tell me as much about her mental state as any interpreter could.
Angelina is coming to life, precisely as my body is beginning to shut down. It’s 2am, and we’re sat in the brightly lit kitchen of a Milanese psychiatric ward, eating spaghetti. There’s a dull ache behind my eyes, and I keep on zoning out, but Angelina won’t be going to bed for at least another 17 hours, so I’m steeling myself for a long night. In case I doubted her resolve, Angelina removes her glasses, looks directly at me, and uses her thumbs and forefingers to pull open the wrinkled, grey-tinged skin around her eyes. “Occhi aperti,” she says. Eyes open.
This is the second night in three that Angelina has been deliberately deprived of sleep. For a person with bipolar disorder who has spent the past two years in a deep and crippling depression, it may sound like the last thing she needs, but Angelina – and the doctors treating her – hope it will be her salvation. For two decades, Francesco Benedetti, who heads the psychiatry and clinical psychobiology unit at San Raffaele Hospital in Milan, has been investigating so-called wake therapy, in combination with bright light exposure and lithium, as a means of treating depression where drugs have often failed. As a result, psychiatrists in the USA, the UK and other European countries are starting to take notice, launching variations of it in their own clinics. These ‘chronotherapies’ seem to work by kick-starting a sluggish biological clock; in doing so, they’re also shedding new light on the underlying pathology of depression, and on the function of sleep more generally.
“Sleep deprivation really has opposite effects in healthy people and those with depression,” says Benedetti. If you’re healthy and you don’t sleep, you’ll feel in a bad mood. But if you’re depressed, it can prompt an immediate improvement in mood, and in cognitive abilities. But, Benedetti adds, there’s a catch: once you go to sleep and catch up on those missed hours of sleep, you’ll have a 95% chance of relapse.
The antidepressant effect of sleep deprivation was first published in a report in Germany in 1959. This captured the imagination of a young researcher from Tubingen in Germany, Burkhard Pflug, who investigated the effect in his doctoral thesis and in subsequent studies during the 1970s. By systematically depriving depressed people of sleep, he confirmed that spending a single night awake could jolt them out of depression.
Benedetti became interested in this idea as a young psychiatrist in the early 1990s. Prozac had been launched just a few years earlier, hailing a revolution in the treatment of depression. But such drugs were rarely tested on people with bipolar disorder. Bitter experience has since taught Benedetti that antidepressants are largely ineffective for people with bipolar depression anyway.
We decided to give them the whole package, and the effect was brilliant – Francesco Benedetti, psychologist
His patients were in desperate need of an alternative, and his supervisor, Enrico Smeraldi, had an idea up his sleeve. Having read some of the early papers on wake therapy, he tested their theories on his own patients, with positive results. “We knew it worked,” says Benedetti. “Patients with these terrible histories were getting well immediately. My task was finding a way of making them stay well.”
So he and his colleagues turned to the scientific literature for ideas. A handful of American studies had suggested that lithium might prolong the effect of sleep deprivation, so they investigated that. They found that 65% of patients taking lithium showed a sustained response to sleep deprivation when assessed after three months, compared to just 10% of those not taking the drug.
Since even a short nap could undermine the efficacy of the treatment, they also started searching for new ways of keeping patients awake at night, and drew inspiration from aviation medicine, where bright light was being used to keep pilots alert. This too extended the effects of sleep deprivation, to a similar extent as lithium.
“We decided to give them the whole package, and the effect was brilliant,” says Benedetti. By the late 1990s, they were routinely treating patients with triple chronotherapy: sleep deprivation, lithium and light. The sleep deprivations would occur every other night for a week, and bright light exposure for 30 minutes each morning would be continued for a further two weeks – a protocol they continue to use to this day. “We can think of it not as sleep-depriving people, but as modifying or enlarging the period of the sleep–wake cycle from 24 to 48 hours,” says Benedetti. “People go to bed every two nights, but when they go to bed, they can sleep for as long as they want.”
San Raffaele Hospital first introduced triple chronotherapy in 1996. Since then, it has treated close to a thousand patients with bipolar depression – many of whom had failed to respond to antidepressant drugs. The results speak for themselves: according to the most recent data, 70% of people with drug-resistant bipolar depression responded to triple chronotherapy within the first week, and 55% had a sustained improvement in their depression one month later.
And whereas antidepressants – if they work – can take over a month to have an effect, and can increase the risk of suicide in the meantime, chronotherapy usually produces an immediate and persistent decrease in suicidal thoughts, even after just one night of sleep deprivation.
***
Angelina was first diagnosed with bipolar disorder 30 years ago, when she was in her late 30s. The diagnosis followed a period of intense stress: her husband was facing a tribunal at work, and they were worried about having enough money to support themselves and the kids. Angelina fell into a depression that lasted nearly three years. Since then, her mood has oscillated, but she’s down more often than not. She takes an arsenal of drugs – antidepressants, mood stabilisers, anti-anxiety drugs and sleeping tablets – which she dislikes because they make her feel like a patient, even though she acknowledges this is what she is.
If I’d met her three days ago, she says, it’s unlikely I would have recognised her. She didn’t want to do anything, she’d stopped washing her hair or wearing make-up, and she stank. She also felt very pessimistic about the future. After her first night of sleep deprivation, she’d felt more energetic, but this largely subsided after her recovery sleep. Even so, today she felt motivated enough to visit a hairdresser in anticipation of my visit. I compliment her appearance, and she pats her dyed, golden waves, thanking me for noticing.
At 03:00, we move to the light room, and entering is like being transported forward to midday. Bright sunlight streams in through the skylights overhead, falling on five armchairs, which are lined up against the wall. This is an illusion, of course – the blue sky and brilliant sun are nothing more than coloured plastic and a very bright light – but the effect is exhilarating nonetheless. I could be sitting on a sun lounger at midday; the only thing missing is the heat.
How could something as simple as staying awake overnight bring about such a transformation?
When I’d interviewed her seven hours earlier, with the help of an interpreter, Angelina’s face had remained expressionless as she’d replied. Now, at 03:20, she is smiling, and even beginning to initiate a conversation with me in English, which she’d claimed not to speak. By dawn, Angelina’s telling me about the family history she’s started writing, which she’d like to pick up again, and inviting me to stay with her in Sicily.
How could something as simple as staying awake overnight bring about such a transformation? Unpicking the mechanism isn’t straightforward: we still don’t fully understand the nature of depression or the function of sleep, both of which involve multiple areas of the brain. But recent studies have started to yield some insights.
The brain activity of people with depression looks different during sleep and wakefulness than that of healthy people. During the day, wake-promoting signals coming from the circadian system – our internal 24-hour biological clock – are thought to help us resist sleep, with these signals being replaced by sleep-promoting ones at night. Our brain cells work in cycles too, becoming increasingly excitable in response to stimuli during wakefulness, with this excitability dissipating when we sleep. But in people with depression and bipolar disorder, these fluctuations appear dampened or absent.
When people are seriously depressed, their circadian rhythms tend to be very flat – Steinn Steingrimsson, Sahlgrenska University Hospital
Depression is also associated with altered daily rhythms of hormone secretion and body temperature, and the more severe the illness, the greater the degree of disruption. Like the sleep signals, these rhythms are also driven by the body’s circadian system, which itself is driven by a set of interacting proteins, encoded by ‘clock genes’ that are expressed in a rhythmic pattern throughout the day. They drive hundreds of different cellular processes, enabling them to keep time with one another and turn on and off. A circadian clock ticks in every cell of your body, including your brain cells, and they are coordinated by an area of the brain called the suprachiasmatic nucleus, which responds to light.
“When people are seriously depressed, their circadian rhythms tend to be very flat; they don’t get the usual response of melatonin rising in the evening, and the cortisol levels are consistently high rather than falling in the evening and the night,” says Steinn Steingrimsson, a psychiatrist at Sahlgrenska University Hospital in Gothenburg, Sweden, who is currently running a trial of wake therapy.
Recovery from depression is associated with a normalisation of these cycles. “I think depression may be one of the consequences of this basic flattening of circadian rhythms and homeostasis in the brain,” says Benedetti. “When we sleep-deprive depressed people, we restore this cyclical process.”
But how does this restoration come about? One possibility is that depressed people simply need added sleep pressure to jump-start a sluggish system. Sleep pressure – our urge to sleep – is thought to arise because of the gradual release of adenosine in the brain. It builds up throughout the day and attaches to adenosine receptors on neurons, making us feel drowsy. Drugs that trigger these receptors have the same effect, whereas drugs that block them – such as caffeine – make us feel more awake.
To investigate whether this process might underpin the antidepressant effects of prolonged wakefulness, researchers at Tufts University in Massachusetts took mice with depression-like symptoms and administered high doses of a compound that triggers adenosine receptors, mimicking what happens during sleep deprivation. After 12 hours, the mice had improved, measured by how long they spent trying to escape when forced to swim or when suspended by their tails.
We also know sleep deprivation does other things to the depressed brain. It prompts changes in the balance of neurotransmitters in areas that help to regulate mood, and it restores normal activity in emotion-processing areas of the brain, strengthening connections between them.
And as Benedetti and his team discovered, if wake therapy kick-starts a sluggish circadian rhythm, lithium and light therapy seem to help maintain it. Lithium has been used as a mood stabiliser for years without anyone really understanding how it works, but we know it boosts the expression of a protein, called Per2, that drives the molecular clock in cells.
Bright light, meanwhile, is known to alter the rhythms of the suprachiasmatic nucleus, as well as boosting activity in emotion-processing areas of the brain more directly. Indeed, the American Psychiatric Association states that light therapy is as effective as most antidepressants in treating non-seasonal depression.
***
In spite of its promising results against bipolar disorder, wake therapy has been slow to catch on in other countries. “You could be cynical and say it’s because you can’t patent it,” says David Veale, a consultant psychiatrist at the South London and Maudsley NHS Foundation Trust.
Certainly, Benedetti has never been offered pharmaceutical funding to carry out his trials of chronotherapy. Instead, he has – until recently – been reliant on government funding, which is often in short supply. His current research is being funded by the EU. Had he followed the conventional route of accepting industry money to run drug trials with his patients, he quips, he probably wouldn’t be living in a two-bedroom apartment and driving a 1998 Honda Civic.
The bias towards pharmaceutical solutions has kept chronotherapy below the radar for many psychiatrists. “A lot of people just don’t know about it,” says Veale.
It’s also difficult to find a suitable placebo for sleep deprivation or bright light exposure, which means that large, randomised placebo-controlled trials of chronotherapy haven’t been done. Because of this, there’s some scepticism about how well it really works. “While there is increasing interest, I don’t think many treatments based on this approach are yet routinely used – the evidence needs to be better and there are some practical difficulties in implementing things like sleep deprivation,” says John Geddes, a professor of epidemiological psychiatry at the University of Oxford.
Light therapy
Why not to try at home
In the case of wake therapy (see main story), Francesco Benedetti of the San Raffaele Hospital in Milan cautions that it isn’t something people should try to administer to themselves at home. Particularly for anyone who has bipolar disorder, there’s a risk of it triggering a switch into mania – although in his experience, the risk is smaller than that posed by taking antidepressants.
Keeping yourself awake overnight is also difficult, and some patients temporarily slip back into depression or enter a mixed mood state, which can be dangerous. “I want to be there to speak about it to them when it happens,” Benedetti says. Mixed states often precede suicide attempts.
All content within this story is provided for general information only, and should not be treated as a substitute for the medical advice of your own doctor or any other health care professional.
In the UK, the USA, Denmark and Sweden, psychiatrists are investigating chronotherapy as a treatment for general depression
Even so, interest in the processes underpinning chronotherapy is beginning to spread. “Insights into the biology of sleep and circadian systems are now providing promising targets for treatment development,” says Geddes. “It goes beyond pharmaceuticals – targeting sleep with psychological treatments might also help or even prevent mental disorders.”
In the UK, the USA, Denmark and Sweden, psychiatrists are investigating chronotherapy as a treatment for general depression. “A lot of the studies that have been done so far have been very small,” says Veale, who is currently planning a feasibility study at Maudsley Hospital in London. “We need to demonstrate that it is feasible and that people can adhere to it.”
So far, what studies there have been have produced mixed results. Klaus Martiny, who researches non-drug methods for treating depression at the University of Copenhagen in Denmark, has published two trials looking at the effects of sleep deprivation, together with daily morning bright light and regular bedtimes, on general depression. In the first study, 75 patients were given the antidepressant duloxetine, in combination with either chronotherapy or daily exercise. After the first week, 41% of the chronotherapy group had experienced a halving of their symptoms, compared to 13% of the exercise group. And at 29 weeks, 62% of the wake therapy patients were symptom-free, compared to 38% of those in the exercise group.
In Martiny’s second study, severely depressed hospital inpatients who had failed to respond to antidepressant drugs were offered the same chronotherapy package as an add-on to the drugs and psychotherapy they were undergoing. After one week, those in the chronotherapy group improved significantly more than the group receiving standard treatment, although in subsequent weeks the control group caught up.
No one has yet compared wake therapy head-to-head with antidepressants; neither has it been tested against bright light therapy and lithium alone. But even if it’s only effective for a minority, many people with depression – and indeed psychiatrists – may find the idea of a drug-free treatment attractive.
“I’m a pill pusher for a living, and it still appeals to me to do something that doesn’t involve pills,” says Jonathan Stewart, a professor of clinical psychiatry at Columbia University in New York, who is currently running a wake therapy trial at New York State Psychiatric Institute.
For those for whom it works, it’s a miracle cure… but it doesn’t help everybody – Jonathan Stewart, Columbia University
Unlike Benedetti, Stewart only keeps patients awake for one night: “I couldn’t see a lot of people agreeing to stay in hospital for three nights, and it also requires a lot of nursing and resources,” he says. Instead, he uses something called “sleep phase advance”, where on the days after a night of sleep deprivation, the time the patient goes to sleep and wakes up is systematically brought forward. So far, Stewart has treated around 20 patients with this protocol, and 12 have shown a response – most of them during the first week.
It may also work as a prophylactic: recent studies suggest that teenagers whose parents set – and manage to enforce – earlier bedtimes are less at risk of depression and suicidal thinking. Like light therapy and sleep deprivation, the precise mechanism is unclear, but researchers suspect a closer fit between sleep time and the natural light–dark cycle is important.
But sleep phase advance has so far failed to hit the mainstream. And, Stewart accepts, it’s not for everybody. “For those for whom it works, it’s a miracle cure. But just as Prozac doesn’t get everyone better who takes it, neither does this,” he says. “My problem is that I have no idea ahead of time who it’s going to help.”
***
Depression can strike anyone, but there’s mounting evidence that genetic variations can disrupt the circadian system to make certain people more vulnerable. Several clock gene variations have been associated with an elevated risk of developing mood disorders.
Stress can then compound the problem. Our response to it is largely mediated through the hormone cortisol, which is under strong circadian control, but cortisol itself also directly influences the timing of our circadian clocks. So if you have a weak clock, the added burden of stress could be enough to tip your system over the edge.
Indeed, you can trigger depressive symptoms in mice by repeatedly exposing them to a noxious stimulus, such as an electric shock, from which they can’t escape – a phenomenon called learned helplessness. In the face of this ongoing stress, the animals eventually just give up and exhibit depression-like behaviours. When David Welsh, a psychiatrist at the University of California, San Diego, analysed the brains of mice that had depressive symptoms, he found disrupted circadian rhythms in two critical areas of the brain’s reward circuit – a system that’s strongly implicated in depression.
But Welsh has also shown that a disturbed circadian system itself can cause depression-like symptoms. When he took healthy mice and knocked out a key clock gene in the brain’s master clock, they looked just like the depressed mice he’d been studying earlier. “They don’t need to learn to be helpless, they are already helpless,” Welsh says.
So if disrupted circadian rhythms are a likely cause of depression, what can be done to prevent rather than treat them? Is it possible to strengthen your circadian clock to increase psychological resilience, rather than remedy depressive symptoms by forgoing sleep?
Martiny thinks so. He is currently testing whether keeping a more regular daily schedule could prevent his depressed inpatients from relapsing once they’ve recovered and are released from the psychiatric ward. “That’s when the trouble usually comes,” he says. “Once they’re discharged their depression gets worse again.”
Peter is a 45-year-old care assistant from Copenhagen who has battled with depression since his early teens. Like Angelina and many others with depression, his first episode followed a period of intense stress and upheaval. His sister, who more or less brought him up, left home when he was 13, leaving him with an uninterested mother and a father who also suffered from severe depression. Soon after that, his father died of cancer – another shock, as he’d kept his prognosis hidden until the week before his death.
I take my children to the beach, for walks, or to the playground, because then I will get some light, and that improves my mood – Peter, patient
Peter’s depression has seen him hospitalised six times, including for a month last April. “In some ways being in hospital is a relief,” he says. However, he feels guilty about the effect it has on his sons, aged seven and nine. “My youngest boy said he cried every night I was in hospital, because I wasn’t there to hug him.”
So when Martiny told Peter about the study he had just started recruiting for, he readily agreed to participate. Dubbed ‘circadian-reinforcement therapy’, the idea is to strengthen people’s circadian rhythms by encouraging regularity in their sleep, wake, meal and exercise times, and pushing them to spend more time outdoors, exposed to daylight.
For four weeks after leaving the psychiatric ward in May, Peter wore a device that tracked his activity and sleep, and he completed regular mood questionnaires. If there was any deviation in his routine, he would receive a phone call to find out what had happened.
When I meet Peter, we joke about the tan lines around his eyes; obviously he’s been taking the advice seriously. He laughs: “Yes, I’m getting outdoors to the park, and if it’s nice weather, I take my children to the beach, for walks, or to the playground, because then I will get some light, and that improves my mood.”
Those aren’t the only changes he’s made. He now gets up at six every morning to help his wife with the children. Even if he’s not hungry he eats breakfast: typically, yoghurt with muesli. He doesn’t take naps and tries to be in bed by 22:00. If Peter does wake up at night, he practices mindfulness – a technique he picked up in hospital.
Martiny pulls up Peter’s data on his computer. It confirms the shift towards earlier sleep and wake times, and shows an improvement in the quality of his sleep, which is mirrored by his mood scores. Immediately after his release from hospital, these averaged around six out of 10. But after two weeks they’d risen to consistent eights or nines, and one day, he even managed a 10. At the beginning of June, he returned to his job at the care home, where he works 35 hours a week. “Having a routine has really helped me,” he says.
So far, Martiny has recruited 20 patients to his trial, but his target is 120; it’s therefore too soon to know how many will respond the same way as Peter, or indeed, if his psychological health will be maintained. Even so, there’s mounting evidence that good sleep routine can help our mental wellbeing. According to a study published in Lancet Psychiatry in September 2017 – the largest randomised trial of a psychological intervention to date – insomniacs who underwent a 10-week course of cognitive behavioural therapy to address their sleep problems showed sustained reductions in paranoia and hallucinatory experiences as a result. They also experienced improvements in symptoms of depression and anxiety, fewer nightmares, better psychological wellbeing and day-to-day functioning, and they were less likely to experience a depressive episode or anxiety disorder during the course of the trial.
Benedetti cautions that it isn’t something people should try to administer to themselves at home
Sleep, routine and daylight. It’s a simple formula, and easy to take for granted. But imagine if it really could reduce the incidence of depression and help people to recover from it more quickly. Not only would it improve the quality of countless lives, it would save health systems money.
A week after spending the night awake with Angelina, I call Benedetti to check her progress. He tells me that after the third sleep deprivation, she experienced a full remission in her symptoms and returned to Sicily with her husband. That week, they were due to be marking their 50th wedding anniversary. When I’d asked her if she thought her husband would notice any change in her symptoms, she’d said she hoped he’d notice the change in her physical appearance.
Hope. After she has spent more than half her life without it, I suspect its return is the most precious golden anniversary gift of all.
Disclaimer
All content within this story is provided for general information only, and should not be treated as a substitute for the medical advice of your own doctor or any other health care professional. The BBC is not responsible or liable for any diagnosis made by a user based on the content of this site. The BBC is not liable for the contents of any external internet sites listed, nor does it endorse any commercial product or service mentioned or advised on any of the sites. Always consult your own GP if you're in any way concerned about your health.
Patients’ names in this piece have been changed. The study published in Lancet Psychiatry was funded by Wellcome, which publishes Mosaic.
