剝奪睡眠可以治療抑鬱症嗎？
琳達·格茲 （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
首先讓人感到安吉麗娜（Angelina）發生變化的是她的手。她一邊用意大利語和護士聊天，一邊開始打手勢，指指戳戳，比劃形狀，用手指在空中畫圈。過了一會兒，安吉麗娜變得越來越活躍。我發現她說的話帶上了旋律，我確定之前不是這樣的。然後，她額頭的皺紋開始鬆弛，嘴唇撅起又伸展，眼睛皺起來。無需翻譯，我都能知道她的精神狀態。
安吉麗娜醒過來的時候，剛好是我要入睡的時候。淩晨兩點，我們坐在米蘭精神病房燈光明亮的廚房裏，吃意大利麵。我的眼睛後麵隱隱作痛，注意力很難集中，但是安吉麗娜至少要再等17個小時才會睡覺。所以我也決心度過一個漫長的夜。為了讓我相信她的決心，安吉麗娜摘下了眼鏡，直視著我，用拇指和食指撐開眼睛周圍有皺紋的灰色皮膚。她說了一句意大利語："Occhiaperti。"意為，睜開眼睛。
這是安吉麗娜刻意堅持不睡覺三天中的第二天。她患有躁鬱症，兩年來一直在嚴重的抑鬱中度過。這種做法看似非常不適合她，但是安吉麗娜和她的醫生都希望這種療法能夠拯救她。過去二十年，米蘭的聖拉法爾醫院（San Raffaele Hospital）的精神科和臨床生物心理科主管弗朗西斯科·貝內德蒂（Francesco Benedetti）一直在研究所謂的清醒療法，依靠明亮的光照和鋰鹽治療藥物無法治療的抑鬱症。美國、英國以及其他歐洲國家的醫院也開始留意並嚐試類似療法。這種"生物鍾療法"的工作原理是促進懶惰的生物鍾恢複正常。他們認為這會讓我們對抑鬱症的潛在病理學原理和睡眠的功能產生新的認識。
"睡眠剝奪對健康者和抑鬱症患者有相反的作用，"貝內德蒂說。如果你身體健康，但是不睡覺，你的心情就會變差。但如果你感到抑鬱，它能夠促進你的心情和認知能力立刻改善。貝內德蒂補充說，不過有一個陷阱：一旦你睡覺，補上幾個小時睡眠，複發率高達95%。
1959年德國發表的一份報告首次提到睡眠剝奪的抗抑鬱效果。德國圖賓根（Tubingen）的年輕學者伯克哈德·普夫盧格（Burkhard Pflug）對此產生興趣。他的博士論文對此展開研究。在20世紀70年代，他還開展後續研究。通過係統研究睡眠剝奪者，他確定一個晚上保持清醒有可能讓患者脫離抑鬱困擾。
20世紀90年代初，年輕的心理醫生貝內德蒂開始對這個想法產生興趣。在那之前幾年，百憂解（Prozac）的問世為抑鬱症的治療帶來了一場革命。但是這類藥品很少在躁鬱症患者身上試用。後來糟糕的經曆也讓內德蒂認識到抗抑鬱藥物對躁鬱症患者基本沒有作用。
貝內德蒂的患者亟需替代藥物，而他的指導醫師恩裏科·斯梅拉爾迪（Enrico Smeraldi）想出了新的辦法。貝內德蒂在閱讀了清醒療法的相關早期論文以後，對他自己的患者進行了測試，結果是積極的。貝內德蒂說："我們知道這個辦法有用，帶有嚴重病史的患者立刻就好轉了。我的任務就是尋找方法讓他們維持健康的狀態。"
於是，他和同事轉向科技文獻以尋找辦法。一些美國的研究表明鋰鹽可能會延長睡眠剝奪的效果。於是他們對此展開研究，發現65%服用鋰鹽的患者在三個月後對睡眠剝奪有持續的反應，而沒有服用鋰鹽的隻有10%有這種反應。
由於打瞌睡也會影響到療效，他們就開始尋找新的方法讓患者在晚上保持清醒狀態，並從航空醫學汲取靈感。飛機上會用明亮的燈光讓飛行員保持警覺狀態。它和鋰鹽一樣，可以延長睡眠剝奪的效果。
"我們決定對他們使用一整套療法，效果非常好，"貝內德蒂說。在20世紀90年代末之前，他們通常的治療方法就是三合一生物鍾療法：睡眠剝奪、鋰鹽還有燈光。在一周之內，每隔一天剝奪睡眠一次。在接下來的兩周，每天早晨用明亮的燈光照射30分鍾。時至今日，他們仍在堅持這一方案。"我們並不認為這是剝奪人的睡眠，而是修改作息周期，從24小時延長到48小時，"貝內德蒂說，"接受治療者每兩天睡一次覺，想睡多久睡多久。"
1996年，聖拉法爾醫院首次引入三合一生物鍾療法。自此以後，這種療法幫助近千名躁鬱症患者康複——他們中的很多人此前使用抗抑鬱藥物，但是沒有效果。結果說明了一切：根據最近的數據，70%有抗藥性的躁鬱症患者在第一周就對三合一生物鍾療法有反應。55%在一個月後病情有了持續的改善。
假如抗抑鬱藥物能夠奏效，也需要一個月以上的時間才能奏效，而且它可能會增加自殺的風險。與此同時，生物鍾療法能夠立刻並持續減少自殺的念頭，甚至在剝奪睡眠一晚後就能起效。
安吉麗娜初次診斷出躁鬱症是30年前，當時她年近40歲。在診斷之前，她度過了極度壓抑的一段時間：他的丈夫麵臨與工作相關的訴訟，他們擔心家中的經濟不夠維持自己和孩子的生活。安吉麗娜得了三年抑鬱症，此後她的情緒起伏不定，經常低落。她服用大量藥物，包括抗抑鬱藥、情緒穩定劑、抗焦慮藥和安眠藥。她討厭吃藥，因為這會讓她感覺自己是一個病人，盡管她也承認這是事實。
她說，如果我三天前見到她，我可能會認不出來她。她百事無心，不洗頭，不化妝，身上還發臭。她對未來也非常悲觀。她第一天剝奪睡眠之後，感覺更有精力了，但是在恢複睡眠後，精力又出現衰退。即便如此，現在她會為了與我見麵提前去理發。我誇讚了她的容貌。她一邊輕拍著自己染成金色的波浪卷發，一邊感謝我注意到了她。
到3點整，我們來到燈光室，一進門感覺好像是時光穿梭到中午。明亮的日光從頭頂的天窗傾瀉下來，灑落在靠牆的一排五把扶手椅上。當然，這隻是幻覺——藍天和陽光不過是彩色的塑料和非常明亮的燈產生的效果——但是效果仍然非常讓人興奮。我就好像中午坐在陽光下的躺椅上，唯一缺少的就是溫度。
七個小時前，當我在翻譯幫助下采訪安吉麗娜的時候，她回答時臉上麵無表情。現在是淩晨3點20分，她開始微笑，甚至開始用英語和我對話。她此前聲稱自己不說英語。到傍晚的時候，她和我講述了她之前開始寫作的家族史。現在她想重拾寫作，並邀請我去西西裏她的家裏住。
為何通宵這樣簡單的事情能給他們帶來如此巨大的變化？要分析這其中的原理並不簡單：我們仍未充分了解抑鬱的本質和睡眠的功能，兩者都涉及大腦的多個區域。但是，最近的一些研究開始提供一些看法。
抑鬱症患者在睡眠和清醒時的大腦活動與健康者不同。白天的時候，晝夜節律係統——人體內部24小時運轉的生物鍾——發出的起床信號被認為能幫助我們抵禦睡意。到晚上，身體又會用促進睡眠的信號取而代之。我們的腦細胞也按照這樣的周期工作，在清醒狀態下對刺激感到興奮，在睡眠時興奮度會消失。但是對抑鬱症患者和躁鬱症患者來說，這些波動似乎會減弱或者不存在。
抑鬱症還與每天荷爾蒙分泌和體溫節奏的變化有關。疾病越是嚴重，節奏越是紊亂。就像睡眠信號一樣，這些節律是由身體的晝夜節律係統驅動。而該係統本身的動力來自一組互動蛋白質，它們被賦予"時鍾基因"的代碼，通過一整天的節律表達出來。它們驅動數百個不同的細胞過程，按照節奏逐一開始和結束。生物鍾在身體的每個細胞裏運轉，包括腦細胞在內。它由大腦名為視交叉上核的感光區域協調。
"當人處於嚴重抑鬱狀態時，他們的晝夜節律會變得非常平緩，他們的褪黑素不會像平常人那樣到晚上就增加分泌。他們的皮質醇一般都會在晚上處於較高水平，而非下降，"瑞典哥德堡薩赫爾格雷斯卡大學醫院（Sahlgrenska University Hospitalin Gothenburg）的心理科醫生斯坦·斯泰因格裏姆鬆（SteinnSteingrimsson）說。他目前正在測試清醒療法。
抑鬱症的康複與這些周期的正常化有關。"我認為抑鬱症是晝夜節律以及大腦穩態變平緩的後果之一，"貝內德蒂說，"當我們剝奪患者的睡眠時，這一周期過程會得到恢複。"
但是這種恢複是如何實現的？一種可能是抑鬱症患者隻需要增加睡眠壓力，強製啟動懶惰的係統。有人認為，睡眠壓力之所以會增加，是因為大腦中腺苷的逐漸釋放。它會在白天逐漸積累起來，然後與神經元上的腺苷受體相連，讓我們感到困倦。觸發這些受體的藥物也有相同的效果。而阻礙這一過程的藥物——比如咖啡因——會讓我們感到清醒。
為了調查清醒狀態的抗抑鬱效果是否以這一過程為基礎，馬薩諸塞州的塔夫茲大學（Tufts University）的研究人員把高劑量的刺激腺苷受體的混合物投喂給有抑鬱症類似症狀的老鼠，以模仿睡眠剝奪時發生的情況。在12個小時後，老鼠的健康有所改善，測量標準是當被迫遊泳或尾巴被懸吊時它們嚐試逃跑所用的時間。
我們還知道睡眠剝奪對抑鬱症患者的大腦有其他影響。它會改變大腦調節心情的區域裏神經遞質的平衡，讓大腦處理情緒部位恢複正常活動，並加強它們之間的聯係。
正如貝內德蒂團隊發現的那樣，如果清醒療法促進懶惰的晝夜節律係統啟動，鋰鹽和光照療法似乎有助於維持其療效。鋰鹽多年來被用作情緒穩定劑，但是沒人真的了解它的工作原理。但是，據我們所知，它能增強Per2蛋白的表達，驅動細胞內的分子鍾。
同時，明亮的燈光能夠改變視交叉上核的節律，並更為直接的增強大腦內情緒處理區域的活動。的確，美國精神醫學學會（American Psychiatric Association）表示，在治療非季節性抑鬱症時，光照療法和大多數抗抑鬱藥物同樣有效。
盡管清醒療法針對躁鬱症呈現出富有希望的結果，它在其他國家發展緩慢。"你可以憤世嫉俗的說，原因是沒有專利，" 南倫敦和莫茲利NHS信托基金會（South London and Maudsley NHS Foundation Trust）心理谘詢師大衛·韋爾（David Veale）說。
當然，醫藥業並沒有為貝內德蒂提供資金以進行生物鍾療法試驗。相反，直到目前為止，他一直依靠通常捉襟見肘的政府資助。他目前的研究是歐盟資助的。他諷刺的說，如果他按照傳統路線，接受行業資助，對病人進行藥物試驗，他很可能就不會像現在這樣住在兩居室公寓，開著一輛1998年的本田思域。
對醫藥業解決方案的偏見導致很多心理醫師不知道生物鍾療法。"很多人對此完全不知道，"韋爾說。
另外，睡眠剝奪或燈光照射尚未找到合適的安慰劑，這就意味著無法進行大範圍的隨機安慰劑控製試驗。因此，有人懷疑它的實際效果。"盡管越來越多的人對它產生興趣，但是我覺得很少人會將此類療法作為慣例——證據還有待加強。在實施睡眠剝奪等治療時，還有一些實踐上的困難，"牛津大學流行性心理疾病學教授約翰·格迪斯（John Geddes）說。
即便如此，以這些過程為基礎的生物鍾療法已經開始引起廣泛的注意。"對睡眠和晝夜節律係統的生物學認知正在為療法的研究提供前景良好的目標，"格迪斯說，"它超越了醫藥學——針對睡眠的心理學療法有可能遏製甚或預防心理障礙。"
英國、美國、丹麥和瑞典的心理醫師正在調查能否把生物鍾療法作為普通抑鬱症的一種療法。"到目前為止，大多數研究的範圍都非常小，"目前在倫敦莫茲利醫院（Maudsley Hospital）規劃一項可行性研究的韋爾說，"我們需要證明這是可行的，而且人們能夠堅持做到。"
到目前為止的研究得出的結論並不一致。丹麥哥本哈根大學抑鬱症非藥物療法研究者克勞斯·馬天尼（Klaus Martiny）發表了兩項實驗結果，研究睡眠剝奪、每天早晨明亮光照以及規律睡覺對普通抑鬱症的效果。在第一個研究中，75名患者服用抗抑鬱藥度洛西汀，並結合生物鍾療法或日常鍛煉。在一周以後，生物鍾療法組41%的被試者感受到症狀減半，而與之相比鍛煉組的比例是13%。在29周以後，62%接受清醒療法的患者症狀消除，與之相比鍛煉組的比例是38%。
馬天尼的第二個研究裏，服用抗抑鬱藥沒有效果的嚴重抑鬱的住院患者接受了相同的生物鍾療法組合，作為他們正在進行的藥物和心理療法的補充。在一周後，生物鍾療法組的病情改善程度大幅超過標準療法組，不過在隨後的數周，控製組又追趕上來。
現在還沒有研究直接對比清醒療法和抗抑鬱藥物。也沒有研究單獨對比光照療法和鋰鹽。即便這隻對少數人有效，很多抑鬱症患者——以及心理醫師——有可能覺得無需藥物的療法很有吸引力。
"我依靠推銷藥品為生，但我依然認為不需要藥物的療法對我很有吸引力，"紐約哥倫比亞大學（Columbia University）臨床精神病學教授喬納森·斯圖爾特（Jonathan Stewart）說。他正在紐約州精神病研究所（New York State Psychiatric Institute）開展一項清醒療法實驗。
與貝內德蒂不同，斯圖爾特隻讓患者堅持不睡一個晚上："我覺得很多人不會同意在醫院住三天，而且這也需要照料等很多資源，"他說。相反，他的方法是"睡眠時段提前"，即在睡眠剝奪一晚後的數天，患者睡覺和起床的時間會係統性的提前。到目前為止，斯圖爾特已經用這一方法為20名患者提供治療，其中12名對該療法有反應——大多數都發生在第一周。
它還可以作為預防性措施：最近的研究表明，十幾歲的少年，如果家長設定並且成功執行較早的睡覺時間，他們出現抑鬱和產生自殺想法的風險較低。就像光照療法和睡眠剝奪一樣，我們不清楚其準確的原理，但是研究者猜測重點在於睡眠時間與自然的白天黑夜周期靠攏。
但是到目前為止，睡眠時段提前的研究並未進入主流。斯圖爾特也接受它並不是適合所有人。"對於那些被治好的人來說，這是奇跡。但是就像百憂解並不能讓所有人好轉一樣，這種療法也做不到。我的問題是，我無法提前知道它對誰會有幫助。"
抑鬱症可能發生在任何一個人身上，但是越來越多的證據表明基因變異有可能破壞晝夜節律係統，讓某些人變得較為脆弱。一些生物鍾基因的變異與情緒障礙風險有關。
壓力還會讓問題變得更為複雜。我們對壓力的反應主要是通過荷爾蒙皮質醇的中介。而皮質醇受到晝夜節律係統牢牢的控製，但是皮質醇本身也會對晝夜節律係統中的生物鍾計時有直接影響。所以，如果你的生物鍾不強，壓力增加可能會足以顛覆你的晝夜節律係統。
確實，如果老鼠被反複暴露在電擊等有害刺激之下且無法躲避，就可能觸發抑鬱症狀——這種現象被稱為習得無助感。在麵對持續的壓力時，動物最終會放棄並表現出類似抑鬱症的行為。聖迭戈加利福尼亞大學（University of California, San Diego）的心理醫師大衛·威爾士（David Welsh）分析了帶有抑鬱症狀的老鼠的大腦，發現它們的大腦獎勵回路中的兩個關鍵區域存在晝夜節律紊亂——該係統與抑鬱症存在很重要的關係。
但是威爾士也展示了晝夜節律係統紊亂本身可能帶來類似抑鬱的症狀。他把健康老鼠大腦中的主時鍾的關鍵基因去除後，老鼠看起來就像之前研究中存在抑鬱症狀的老鼠。"他們不需要習得無助感，他們已經很無助了，"威爾士說。
那麽，如果晝夜節律係統紊亂有可能是抑鬱症的一個原因，那麽應該做些什麽來預防而非治療？是否有可能加強你的生物鍾以增強心理恢複力，而不是通過放棄睡眠來治療抑鬱症？
馬天尼就是這樣認為。他現在正在測試保持規律的日常作息能否防止已經康複出院的抑鬱症住院患者舊病複發。他說："問題常常出在那裏。在出院後，他們的抑鬱症又惡化了。"
來自哥本哈根的45歲護工彼得（Peter）從十幾歲時就開始與抑鬱症作鬥爭。就像安吉麗娜等許多抑鬱症患者一樣，病症初次發作之前，他麵臨巨大的壓力和變化。在他13歲那年，照顧他長大的姐姐離開了家，他的母親對他漠不關心，他的父親也是嚴重的抑鬱症患者。不久以後，他的父親因癌症過世——這對他來說也是一次衝擊，因為父親直到過世前一周才把醫生對他的生存期預測說出來。
彼得因抑鬱症住院六次，去年四月住院一個月。"從某些方麵來看，住院是一種壓力的緩解，"他說。不過，他覺得愧對自己七歲和九歲的兩個兒子。"我的小兒子說，我在醫院的每個晚上，他都會哭，因為我沒法抱他。"
所以，當馬天尼告訴彼得他正在尋找研究的被試者，彼得就欣然同意參加。名為"晝夜節律加強療法"的研究理念是希望通過睡覺、起床、三餐和鍛煉的規律化，加強人的晝夜節律，督促人們更多的參加戶外活動，接觸日光。
彼得五月出院，在隨後的四個星期內，他佩戴了一個記錄自己活動和睡眠的設備，並定期回答情緒有關的問卷。如果他的日常慣例中出現了偏移，他就會接到電話詢問他發生了什麽事。
當我見到彼得的時候，我開玩笑說到他的黑眼圈。顯然，他對待這些建議非常認真。他笑著說："是的，我會出門去公園，如果天氣好，我還會帶孩子去海灘散步，或者去遊樂場，因為這樣我就能接受光照，這會改善我的情緒。"
他作出的改變不止這些。現在，他每天六點起床，幫助他的妻子照顧孩子。即使不餓，他也會吃早餐：通常是酸奶和木斯裏（瑞士什錦麥片）。他白天不睡覺，努力在晚上十點前上床睡覺。如果他晚上醒過來，他會練習醫院裏學到的正念。
馬天尼在電腦上提取彼得的數據，確定睡眠和起床時間開始提早，這說明他的睡眠質量有提高，這也反映在他的情緒分數上。剛出院時，他的情緒分數為6分（滿分10分）。但是在兩周保持八九點鍾起床之後，有一天他的情緒分數甚至達到10分。在六月初，他返回養老院工作，一周工作35個小時。"生活規律確實給了我很大的幫助，"他說。
到目前為止，馬天尼的研究招募了20名患者，他的目標是120人。所以，要想知道有多少人會作出像彼得一樣的反應以及他的心理健康能否保持下去，還為時過早。即便如此，有越來越多的證據表明，良好的睡眠習慣有助於人們的心理健康。根據2017年9月發表在《柳葉刀精神病學》（Lancet Psychiatry）上的一項研究——到目前為止最大的心理幹預隨機試驗——在經曆為期10天的認知行為療法後，失眠症患者的偏執心理以及幻想都持續下降。他們的抑鬱和焦慮症狀也減少了，噩夢少了，心理健康和日常生活有了改善。在試驗過程中，他們進入抑鬱期或出現焦慮症的可能性下降。
睡眠，日常活動和光照。這是一個簡單的公式，很容易被想當然。但是，想象一下，這有可能真的能夠減少抑鬱症，並幫助患者更快的康複。這不僅能改善無數人的生活質量，還能為醫療係統節省開支。
在與安吉麗娜通宵過後一周，我打電話給貝內德蒂，詢問安吉麗娜的情況。他告訴我，在第三次睡眠剝奪之後，她感到自己的症狀得到了充分的緩解，並和她的丈夫回西西裏去了。那一周，他們要過50年結婚紀念。此前，我問過安吉麗娜，她覺得自己的丈夫會不會注意到她的症狀發生了變化，她說希望丈夫注意到她身體外形的變化。
希望如此。她的前半生一直缺少希望，我覺得對希望的回歸是給他們最珍貴的金婚禮物。
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.
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Patients’ names in this piece have been changed. The study published in Lancet Psychiatry was funded by Wellcome, which publishes Mosaic.
