Introduction  简介

Post-traumatic stress disorder (PTSD) is a condition that can develop following exposure to extremely traumatic events such as interpersonal violence, combat, life-threatening accidents or natural disasters. Symptoms of PTSD include distressing and intrusive memories and nightmares of the trauma, irritability, hypervigilance (enhanced state of threat sensitivity or preoccupation with the potential for danger), difficulty sleeping, poor concentration and emotional withdrawal. Individuals with PTSD frequently avoid places, activities or things that could remind them of the trauma1. PTSD severity is worsened by co-occurring conditions that also arise concomitantly with PTSD, as a result of the trauma exposure, of shared causal determinants or of PTSD itself, and disproportionally affect disadvantaged populations1 (Box 1). Co-occurring conditions can include substance abuse, mood and anxiety disorders, impulsive or dangerous behaviour or self-harm2. PTSD is also associated with considerable medical comorbidities, including chronic pain and inflammation, cardiometabolic disorders and heightened risk of dementia35. Thus, the total disease burden (disability plus premature mortality) that is attributable to PTSD is extremely high6.
创伤后应激障碍(PTSD)是一种在遭受极度创伤性事件(如人际暴力、战斗、危及生命的意外事故或自然灾害)后可能出现的状况。PTSD 的症状包括令人痛苦的侵入性记忆和创伤噩梦、易怒、过度警觉(增强的威胁敏感性或对潜在危险的专注)、睡眠困难、注意力不集中和情感退缩。PTSD 患者常常避免可能让他们想起创伤的地方、活动或事物 1 。PTSD 的严重程度因与 PTSD 同时发生的共病而加剧,这些共病可能是由于创伤暴露、共同的病因决定因素或 PTSD 本身,并且不成比例地影响弱势群体 1 (图 1)。共病可能包括物质滥用、情绪和焦虑障碍、冲动或危险行为或自伤 2 。PTSD 还与相当多的医学共病相关,包括慢性疼痛和炎症、心代谢障碍和痴呆风险增加 35 。 因此,归因于创伤后应激障碍(PTSD)的总疾病负担(残疾加过早死亡)极高。

Table 1 describes current diagnostic criteria for PTSD according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) and highlights areas of change from DSM-IV. These include several criteria and symptoms that must be fulfilled. Alongside these changes in diagnostic criteria, there has been a major shift in scientific research in PTSD. Initial studies aimed to examine processes associated with stress responses and fear memories, with the idea that trauma exposure was the proximal cause of PTSD79. The study of PTSD has a distinct scientific advantage compared with many other psychiatric disorders in that amygdala-based fear circuitry and hypothalamically regulated endocrine responses to stress are fairly conserved across species, which makes inferences from basic animal research translationally useful. However, traditional animal models lack neural areas that approximate a human prefrontal cortex and, accordingly, lack the ability to model human cognitive control of stress and conditioned fear. Limitations of exposure-based animal models also became apparent as epidemiological studies highlighted that the majority of trauma survivors do not develop PTSD. These considerations prompted an increased emphasis on individual differences in humans that contribute to symptom onset, progression and resilience following trauma exposure7. In this Primer, we discuss advances in understanding pathophysiology and treatment of PTSD.
表 1 描述了根据《精神疾病诊断与统计手册》(第五版,DSM-5)的当前诊断标准,PTSD 的诊断标准,并突出了与 DSM-IV 的变化领域。这些包括必须满足的几个标准和症状。在这些诊断标准的变化的同时,PTSD 的科学研究也发生了重大转变。最初的研究旨在检查与压力反应和恐惧记忆相关的过程,认为创伤暴露是 PTSD 的直接原因。与许多其他精神疾病相比,PTSD 的研究具有独特的科学优势,因为基于杏仁核的恐惧回路和下丘脑调节的应激内分泌反应在物种间相对保守,这使得从基础动物研究中得出的推论在转化应用中很有用。然而,传统的动物模型缺乏近似人类前额叶皮层的神经区域,因此缺乏模拟人类对压力和条件恐惧的认知控制的能力。 暴露基础动物模型的局限性也变得明显,因为流行病学研究表明,大多数创伤幸存者不会发展成创伤后应激障碍。这些考虑促使人们更加重视人类个体差异,这些差异有助于创伤暴露后的症状出现、进展和恢复力 7 。在本篇综述中,我们讨论了关于创伤后应激障碍的病理生理学和治疗的进展。

Table 1 DSM-5 criteria for PTSD
表 1 DSM-5 关于创伤后应激障碍的诊断标准

Epidemiology  流行病学

Military  军事

One of the first large epidemiological studies of PTSD was carried out soon after the establishment of the DSM-III diagnosis to ascertain the scope of the problem in a nationally representative sample of Vietnam War veterans in the United States10. Initial estimates suggested a lifetime PTSD prevalence of 30%, with 15% of veterans still experiencing symptoms of PTSD more than 10 years after the conclusion of the war. A reanalysis of these data to determine the proportion of PTSD directly attributable to war-zone trauma (verified with military records and adjusted for functional impairment) showed that 19% of veterans developed war-related PTSD during their lifetime and 9% continued to have PTSD at the time of the original assessment11. 10 years after the conclusion of the Vietnam War, the rates of current PTSD were as high as 28% in veterans who had experienced combat exposure. A recent follow-up study of the original cohort showed that, 40 years after the end of the war, 11% of Vietnam veterans are currently experiencing PTSD symptoms that impair functioning12.
创伤后应激障碍 | 自然综述疾病基础 美国对越战退伍军人进行的一项早期大型流行病学调查是在 DSM-III 诊断建立后不久进行的,以确定全国代表性样本中问题的范围。 10 初步估计显示,终身创伤后应激障碍的患病率为 30%,其中 15%的退伍军人战争结束后 10 多年仍在经历创伤后应激障碍的症状。对这些数据进行重新分析,以确定创伤后应激障碍中直接归因于战场创伤的比例(经军事记录验证并调整了功能障碍)显示,19%的退伍军人一生中发展了与战争相关的创伤后应激障碍,9%在原始评估时继续患有创伤后应激障碍。 11 越南战争结束后 10 年,经历过战斗暴露的退伍军人当前创伤后应激障碍的患病率高达 28%。一项对原始队列的最新随访研究显示,战争结束后 40 年,11%的越南退伍军人目前正经历影响功能的创伤后应激障碍症状。 12

More recent studies of war fighters from various countries who have served in Iraq or Afghanistan over the past 13 years show high variation in PTSD rates. However, analyses of combined data sets, as well as meta-analyses, have shown that differences in estimates are directly related to the level of combat exposure, with an overall average prevalence of 6% in population samples from all services and countries (including support personnel) and 13% in combat-exposed infantry units13,14. One study that merged data sets from UK and US military personnel who had served in Iraq showed that apparent national differences in PTSD prevalence were mostly owing to the differences in the level of exposure to combat14. Interestingly, the ‘dose–response’ curve associating PTSD with severity of combat trauma (measured as the number of direct and indirect combat events) tended to reach a plateau at approximately 25–30% developing the condition, which suggests that once a certain threshold of severe exposure was reached, the risk did not continue to increase. This may be an epidemiological indicator of resiliency11,15. Prospective longitudinal studies of military service members have greatly added to our knowledge by showing that the clinical course of combat-related PTSD is often chronic, but also includes spontaneous recovery, as well as late-onset or delayed PTSD16.
近年来对过去 13 年在伊拉克或阿富汗服役的各国战士的研究表明,创伤后应激障碍(PTSD)的患病率存在很大差异。然而,对合并数据集的分析以及荟萃分析表明,估计值之间的差异与战斗暴露程度直接相关,所有军种和国家的总体平均患病率为 6%(包括支援人员),而在战斗暴露的步兵单位中为 13% 13,14 。一项合并了曾在伊拉克服役的英国和美国军事人员数据集的研究表明,PTSD 患病率的国家差异主要归因于战斗暴露程度的差异 14 。有趣的是,将 PTSD 与战斗创伤严重程度(以直接和间接战斗事件的数量衡量)相关的“剂量-反应”曲线往往在约 25-30%的患病率时达到平台期,这表明一旦达到一定程度的严重暴露,风险就不会继续增加。这可能是弹性的流行病学指标 11,15 。 前瞻性纵向研究显示,军事服务人员的临床病程通常为慢性,但也包括自发恢复,以及晚发或延迟性创伤后应激障碍。

Civilian  平民

Epidemiological studies in the general population have evaluated the prevalence of both trauma exposure and PTSD17,18. An initially surprising observation was the high frequency of exposure to traumatic events in populations given that PTSD was first defined in the DSM-III as a response to events “outside the range of normal human experience” (Ref. 19). Studies revealed that approximately 70% of adult women in the United States had been exposed to a serious trauma18, and the majority of the population regardless of sex experienced exposure to at least one traumatic event in their lifetime17. Studies from multiple countries have reported similarly high estimates of trauma exposure2022.
流行病学研究表明,在普通人群中,创伤暴露和 PTSD 的患病率都得到了评估。一个最初令人惊讶的观察结果是,在 PTSD 首次在 DSM-III 中被定义为对“超出正常人类经验范围”的事件的反应(参考文献 19)的人群中,创伤事件的暴露频率很高。研究表明,美国约 70%的成年女性曾经历过严重的创伤(参考文献 1),无论性别,大多数人群在其一生中至少经历过一次创伤事件(参考文献 2)。来自多个国家的多项研究报道了类似的创伤暴露高估计值(参考文献 3)。

As in military samples, studies in the general population have consistently shown that the majority of trauma-exposed individuals do not develop PTSD17 (Fig. 1a). In 2014, the only large-scale study so far was reported, examining PTSD prevalence across representative international population samples using identical methodology. The study showed that current PTSD prevalence (that is, in the past 12 months) averaged 1.1% (with a range of 0.2–3.8%)23 (Fig. 1b). However, the lifetime burden is substantially higher; for example, for South Africa, the 12-month prevalence is 0.4% whereas the lifetime prevalence is 2.3%. PTSD prevalence, early age of PTSD onset and level of social or occupational impairment strongly correlated with the number of lifetime traumatic events: that is, the more exposures the more likely PTSD is to manifest early, persist and be severe. PTSD prevalence has also been shown to be directly related to the severity of traumatic events, with certain events, such as rape or direct combat trauma, conferring very high risk (≥25–50%).
如军事样本研究所示,在普通人群中,研究一致表明,大多数创伤暴露者不会发展为创伤后应激障碍(PTSD) 17 (图 1a)。2014 年,迄今为止唯一一项大规模研究报道了,使用相同的方法,对代表性国际人口样本中的 PTSD 患病率进行了调查。该研究显示,当前 PTSD 患病率(即在过去的 12 个月内)平均为 1.1%(范围为 0.2-3.8%) 23 (图 1b)。然而,终身负担要高得多;例如,对于南非,12 个月患病率为 0.4%,而终身患病率为 2.3%。PTSD 患病率、PTSD 发病的早期年龄以及社会或职业障碍程度与终身创伤事件的数量强烈相关:即暴露越多,PTSD 越有可能早期出现、持续存在并严重。PTSD 患病率也已被证明与创伤事件的严重程度直接相关,某些事件,如强奸或直接战斗创伤,会带来非常高的风险(≥25-50%)。

Figure 1: The prevalence of PTSD.
图 1:PTSD 的患病率。
figure 1

a | Most individuals exposed to trauma do not develop post-traumatic stress disorder (PTSD)17. Such low rates of PTSD after trauma suggest that PTSD is only one of many responses to trauma. Many individuals do not develop mental health symptoms following trauma exposure. b | The mean 12-month prevalence of PTSD in various countries around the world is shown23. *Witnessing a trauma can be deemed a trauma in and of itself. Childhood traumas are any traumatic exposures that occur in childhood and can include (but are not exclusively) child abuse.
a | 大多数遭受创伤的人不会发展成创伤后应激障碍(PTSD)。创伤后 PTSD 的低发生率表明,PTSD 只是对创伤的许多反应之一。许多人在遭受创伤后不会出现心理健康症状。 b | 下面显示了世界各地各种国家 PTSD 的 12 个月平均患病率。*目睹创伤本身就可以被视为一种创伤。儿童创伤是指在儿童时期发生的任何创伤性暴露,包括(但不限于)儿童虐待。

PowerPoint slide  幻灯片

Across different populations and countries, differences in PTSD prevalence can be to attributed to geographically specific distributions of trauma type and severity, or to other factors such as the resultant loss of personal, social and material resources, which are crucial predictors of the development and the persistence of PTSD17,18,24,25. However, cross-national differences might also be attributable to cultural differences in reporting or experiencing of PTSD symptoms. Similarly, the greater PTSD prevalence in women could result from greater exposure to experiences that are associated with the highest prevalence of PTSD17,18, but it might also associate with sex-specific risk factors26 (Box 2). Multiple studies have shown a strong association of PTSD with comorbid conditions, particularly depression and substance use disorders, and general physical health effects spanning all disease categories in both military personnel and civilians35,27,28. A range of brain, molecular, neuroendocrine and autonomic nervous system disturbances associated with PTSD are likely to influence these comorbid conditions and to provide challenges for treatment.
在不同人群和国家中,创伤后应激障碍(PTSD)的患病率差异可以归因于特定地理区域的创伤类型和严重程度分布,或者归因于其他因素,如个人、社会和物质资源的损失,这些因素是 PTSD 发展和持续的关键预测因素。然而,跨国家差异也可能归因于报告或经历 PTSD 症状的文化差异。同样,女性 PTSD 患病率较高可能源于她们更多地暴露于与 PTSD 最高患病率相关的生活经历,但也可能与性别特定的风险因素有关(图 2)。多项研究表明,PTSD 与共病状况有强烈的关联,尤其是抑郁症和物质使用障碍,以及军事人员和平民中所有疾病类别的一般身体健康影响。与 PTSD 相关的各种大脑、分子、神经内分泌和自主神经系统紊乱可能会影响这些共病状况,并为治疗带来挑战。

Box 2: PTSD in women
第 2 个方框:女性创伤后应激障碍

Current research offers competing explanations for the observation that the lifetime risk for post-traumatic stress disorder (PTSD) in women is twice that in men17. One theory explains the greater prevalence in women as a function of greater exposure to events that are highly causally linked with PTSD, such as sexual abuse and rape238. Indeed, the female sex effect on PTSD symptoms became nonsignificant after accounting for patient sexual victimization history239. Women are also more likely to be revictimized or exposed to multiple forms of violence in their lifetime than men, which can be difficult to capture in prevalence studies. Of note, a meta-analysis of sex differences in PTSD prevalence did not report a difference in lifetime risk of PTSD among survivors of rape, childhood sexual abuse or nonsexual child abuse or neglect240.
当前研究对观察到的女性创伤后应激障碍(PTSD)终身风险是男性的两倍这一现象提出了相互竞争的解释。一种理论认为,女性中 PTSD 的更高发病率是她们更多地暴露于与 PTSD 高度因果相关的事件,如性虐待和强奸的结果。事实上,在考虑了患者的性受害者历史后,女性性别对 PTSD 症状的影响变得不再显著。女性在其一生中比男性更有可能再次受害或暴露于多种形式的暴力中,这在流行病学研究可能难以捕捉。值得注意的是,一项关于 PTSD 发病率性别差异的荟萃分析没有报告强奸、儿童性虐待或非性虐待儿童虐待或忽视的幸存者中 PTSD 终身风险存在差异。

By contrast, some epidemiological surveys involving a broad range of traumatic exposures have shown that the twofold greater risk for PTSD in women cannot be accounted for by greater exposure to trauma, even when accounting for prior history of victimization or abuse. This finding suggests that women are more vulnerable to PTSD than men241,242. The sex difference seems to be consistent across many trauma types240. Genetic studies have suggested higher heritability risk in women77, and molecular genetic studies confirmed allelic variation in the adenylate cyclase activating polypeptide 1 (pituitary) receptor type I (ADCYAP1R1) gene in relation to PTSD risk in women26.
与相比,一些涉及广泛创伤暴露的流行病学调查表明,即使在考虑了先前受害或虐待的历史后,女性患 PTSD 的风险增加两倍也无法归因于对创伤的更大暴露。这一发现表明,女性比男性更容易患 PTSD。这种性别差异似乎在许多创伤类型中是一致的。遗传学研究表明,女性有更高的遗传风险,分子遗传学研究证实了与女性 PTSD 风险相关的腺苷酸环化酶激活多肽 1(垂体)受体 I 型(ADCYAP1R1)基因中的等位基因变异。

In reality, the greater prevalence of PTSD in women might reflect a combination of greater exposure and vulnerability. A prospective epidemiological study of PTSD risk in abused and neglected children showed that the higher level of revictimization in female victims than in male victims explained a substantial proportion (39%) of the sex differences in PTSD risk. However, a significant sex difference remained after adjusting for greater exposure in women. More research is clearly needed.
实际上,女性 PTSD(创伤后应激障碍)的更高发病率可能反映了更大的暴露和易感性。一项针对受虐待和忽视的儿童 PTSD 风险的纵向流行病学研究显示,女性受害者比男性受害者有更高的再次受害水平,这解释了 PTSD 风险性别差异的相当一部分(39%)。然而,在调整女性更大的暴露后,仍然存在显著的性别差异。显然需要更多的研究。

Mechanisms/pathophysiology
机制/病理生理学

Molecular and neurochemical factors
分子和神经化学因素

Early studies in patients with PTSD showed autonomic reactivity, indicated by increased heart rate and skin conductance in response to trauma-related cues, and exaggerated startle responses. These findings recapitulated symptoms of general hyperarousal and distress following traumatic reminders in PTSD29,30. Indeed, several pharmacological challenge studies with yohimbine (an α2-adrenergic receptor antagonist) showed exaggerated neurochemical and behavioural responses consistent with central noradrenergic hyper-reactivity in PTSD9,30,31.
早期对创伤后应激障碍(PTSD)患者的研究表明,他们在面对与创伤相关的提示时,会出现自主神经反应,表现为心率加快和皮肤电导率增加,以及夸张的惊跳反应。这些发现与 PTSD 患者在创伤提醒后出现的普遍过度警觉和痛苦症状相吻合。事实上,多项使用育亨宾(一种α2-肾上腺素受体拮抗剂)进行的药理学挑战研究显示,PTSD 患者表现出与中枢去甲肾上腺素过度反应一致的超量神经化学和行为反应。

The hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system constitute the body's fundamental stress response; however, contrary to initial predictions of elevated stress hormones in PTSD, an unusual pattern of low basal (unstimulated) cortisol levels and raised catecholamine levels is evident and has been widely replicated in trauma survivors with PTSD31,32. Epigenetic, molecular and endocrine studies of glucocorticoid signalling and glucocorticoid receptor sensitivity later confirmed a distinct set of HPA axis alterations that reflect exaggerated negative feedback sensitivity in PTSD (Fig. 2), with some evidence for the role of genetic variants in HPA axis-related genes, including nuclear receptor subfamily 3 group C member 1 (NR3C1; encoding the glucocorticoid receptor) and FKBP5 (encoding FK506-binding protein 5)33,34. The glucocorticoid receptor functions as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid-responsive genes and activates their transcription; the receptor also regulates other transcription factors. FKBP5 has a role in immunoregulation but also has important functions in regulating the amount of glucocorticoids that are available to the glucocorticoid receptor. Prospective longitudinal studies have shown that markers, such as increased startle reactivity, were not observed in those at risk for PTSD but were observed weeks following exposure in those with PTSD30. By contrast, reduced glucocorticoid signalling was observed before, and shortly after, trauma exposure in those who developed PTSD35,36, which confirms an early hypothesis that insufficient glucocorticoid signalling at the time of trauma results in unopposed sympathetic nervous system activation that enhances the consolidation (Box 3) of the traumatic memory32. Converging data support the idea that frequent voluntary or involuntary retrieval of traumatic memories promotes a traumatic memory that is highly distressing and, therefore, difficult to extinguish37,38. The formation of strong emotional memories is adaptive because remembering danger when appropriately signalled might enhance survival. However, in the absence of sufficient glucocorticoid signalling, the distress that occurs once reminded, and the generalization of triggers, could result in a cascade of maladaptive symptoms. Psychophysiological data from multiple centres also showed deficits in fear conditioning and extinction learning (Box 3) in PTSD30,39, which have been supplemented by neuroimaging and genetic data in animal models and patients with PTSD40.
下丘脑-垂体-肾上腺(HPA)轴和交感神经系统构成了身体的根本应激反应;然而,与创伤后应激障碍(PTSD)中应激激素升高的初始预测相反,一种异常的低基础(未刺激)皮质醇水平和升高的儿茶酚胺水平模式明显,并在 PTSD 创伤幸存者中得到广泛复制。关于糖皮质激素信号传导和糖皮质激素受体敏感性的表观遗传学、分子和内分泌学研究后来证实了一组独特的 HPA 轴改变,这些改变反映了 PTSD 中负反馈敏感性的过度夸张(图 2),并有一些证据表明遗传变异在 HPA 轴相关基因中的作用,包括核受体亚家族 3 组 C 成员 1(NR3C1;编码糖皮质激素受体)和 FKBP5(编码 FK506 结合蛋白 5)。糖皮质激素受体作为转录因子,与糖皮质激素反应元件结合,激活糖皮质激素反应基因的转录;受体还调节其他转录因子。 FKBP5 在免疫调节中发挥作用,同时在调节可用的糖皮质激素量方面也具有重要作用。前瞻性纵向研究表明,在 PTSD 风险人群中未观察到如增加的惊跳反应等标志物,但在 PTSD 患者暴露后几周观察到这些标志物。相比之下,在发展为 PTSD 的人中,在创伤暴露前和暴露后不久观察到糖皮质激素信号减弱,这证实了一个早期假设,即在创伤时糖皮质激素信号不足会导致不受抑制的交感神经系统激活,从而增强创伤记忆的巩固(框 3)。汇聚的数据支持这样一个观点,即频繁的自愿或非自愿回忆创伤记忆会促进一种高度令人痛苦的创伤记忆,因此难以消除。强烈的情绪记忆的形成是适应性的,因为当适当信号时,记住危险可能会增强生存。 然而,在缺乏足够的糖皮质激素信号的情况下,一旦被提醒,就会发生痛苦,触发因素的泛化可能导致一系列不适应症状的级联反应。来自多个中心的生理心理数据也显示了 PTSD 中恐惧条件反射和灭绝学习的缺陷(图 3),这些缺陷已被动物模型和 PTSD 患者的神经影像学和遗传学数据所补充。

Figure 2: The function of the HPA axis in PTSD and controls.
图 2:创伤后应激障碍(PTSD)和对照组中下丘脑-垂体-肾上腺(HPA)轴的功能。
figure 2

a | Network-level differences in hypothalamic–pituitary–adrenal (HPA) responses to stress are evident in post-traumatic stress disorder (PTSD). The increased secretion of corticotropin-releasing hormone from the hypothalamus in PTSD is represented by a thick black line. The decreased adrenal release of cortisol in PTSD is represented by the thin black line. The increased negative feedback inhibition of the HPA axis by cortisol in PTSD is represented by thick red lines. b | Key molecular factors affecting genomic sensitivity to glucocorticoid signalling are shown. Cortisol binds to the glucocorticoid receptor (GR) in the cytoplasm, which is coded by nuclear receptor subfamily 3 group C member 1 (NR3C1). The glucocorticoid–GR complex is further bound by chaperone proteins that include FK506-binding protein 5 (FKBP5). Genetic variation of NR3C1 and FKBP5 are implicated in functional differences in glucocorticoid signalling in PTSD. The chaperone-bound glucocorticoid–GR complex is translocated into the nucleus and binds to glucocorticoid response elements (GRE), which ultimately affects transcription of a large number of genes. c | Several systems are affected by differential glucocorticoid signalling, including the brain, cardiometabolic sites, reproductive organs and the immune system. HSP90, heat shock protein 90. Part a adapted with permission from Ref. 32, Massachusetts Medical Society.
创伤后应激障碍(PTSD)中下丘脑-垂体-肾上腺(HPA)对压力的反应在网络上存在差异。PTSD 中下丘脑释放的促肾上腺皮质激素释放激素(CRH)增加由粗黑色线表示。PTSD 中肾上腺皮质醇释放减少由细黑色线表示。PTSD 中皮质醇对 HPA 轴的负反馈抑制增加由粗红色线表示。b | 影响基因组对糖皮质激素信号传导敏感性的关键分子因素显示。皮质醇与细胞质中的糖皮质激素受体(GR)结合,该受体由核受体亚家族 3 组 C 成员 1(NR3C1)编码。糖皮质激素-GR 复合物进一步与包括 FK506 结合蛋白 5(FKBP5)在内的伴侣蛋白结合。NR3C1 和 FKBP5 的遗传变异与 PTSD 中糖皮质激素信号传导的功能差异有关。伴侣蛋白结合的糖皮质激素-GR 复合物被转运到细胞核并绑定到糖皮质激素反应元件(GRE),最终影响大量基因的转录。 c | 多个系统受不同的糖皮质激素信号传导影响,包括大脑、心代谢部位、生殖器官和免疫系统。HSP90,热休克蛋白 90。部分 a 经授权改编自参考文献 32,马萨诸塞州医学协会。

PowerPoint slide  幻灯片

Pro-inflammatory cytokines, endocannabinoids and neurosteroids are of interest as mediators of the stress response9,4143, particularly in the setting of low glucocorticoid signalling in PTSD44,45. Multiple studies have shown immune activation in PTSD that is consistent with inflammation4347. Immune-related genes and pathways have also been identified in genome-wide gene expression and methylation studies in peripheral blood46,48. In addition, endocannabinoids are functionally associated with glucocorticoid regulation and are involved in both the initiation and the termination of the acute stress response49. Glucocorticoid action to facilitate the consolidation of aversive memories is mediated by cannabinoid type 1 (CB1) receptors. Altered blood levels of 2-arachidonoylglycerol and anandamide in patients with PTSD have been shown in three studies of civilian trauma41,50,51. Neurosteroids such as allopregnanolone have been investigated in several studies because of their inhibitory effects on glucocorticoid and noradrenaline signalling30,31. Finally, sleep physiology studies from multiple centres have indicated rapid eye movement sleep fragmentation and decreased slow wave sleep in those with PTSD52; alterations in circadian rhythmicity of cortisol and other HPA axis changes have been linked with sleep disturbances in PTSD53,54.
促炎细胞因子、内源性大麻素和神经甾体作为压力反应的介质引起关注,尤其是在创伤后应激障碍(PTSD)中低糖皮质激素信号传导的背景下。多项研究表明,PTSD 中存在与炎症一致的免疫激活。在周围血的全基因组基因表达和甲基化研究中也确定了与免疫相关的基因和通路。此外,内源性大麻素与糖皮质激素调节功能相关,并参与急性压力反应的启动和终止。糖皮质激素通过促进厌恶记忆的巩固发挥作用,这一作用是通过大麻素类型 1(CB1)受体介导的。在三项关于平民创伤的研究中,已经发现创伤后应激障碍(PTSD)患者的 2-花生四烯酰甘油和安那度胺的血液水平发生改变。由于它们对糖皮质激素和去甲肾上腺素信号传导的抑制作用,研究了几种神经甾体,如阿洛孕诺酮。 最后,来自多个中心的睡眠生理学研究表明,创伤后应激障碍(PTSD)患者存在快速眼动睡眠片段化和慢波睡眠减少;皮质醇和其他 HPA 轴变化的昼夜节律性改变与 PTSD 中的睡眠障碍有关。

Interest in the neurobiology of resilience and in endogenous substances that might promote resilience such as neuropeptide Y (NPY), dehydroepiandrosterone (DHEA) and brain-derived neurotrophic factor (BDNF)9,31 has grown. Indeed, many of these factors have been considered as potential treatment targets55,56. However, more research is needed to replicate preliminary findings in adequately powered studies and to determine whether the markers that are thought to be important to PTSD pathophysiology can be identified in large longitudinal genome-wide epigenetic or transcriptomic studies57. Any mechanistic relevance that these ‘resilience’ factors have remains to be determined.
对弹力神经生物学和可能促进弹力的内源性物质(如神经肽 Y(NPY)、脱氢表雄酮(DHEA)和脑源性神经营养因子(BDNF))的兴趣有所增加。事实上,许多这些因素已被视为潜在的治疗靶点。然而,需要更多研究来复制初步发现,并在足够样本量的研究中确定是否可以在大型纵向全基因组表观遗传学或转录组学研究中识别出被认为对 PTSD 病理生理学重要性的标记。这些“弹力”因素所具有的任何机制相关性仍有待确定。

Longitudinal studies have highlighted the importance of cumulative traumatic exposures and the progressive dysregulation of biological systems in the development of PTSD36,58,59. Thus, it is important to identify biological alterations associated with pre-traumatic and peri-traumatic risk factors for PTSD and to determine how these ‘set the stage’ for processes that sustain symptoms60. For example, although glucocorticoid signalling alterations have been associated with both PTSD risk and early peri-traumatic responses, some evidence suggests that these alterations change in association with symptom severity6167. That is, a patient can experience a worsening of symptoms related to the acquisition of other alterations to these pathways. Similarly, inflammatory processes can be predictors of PTSD but have been shown (in one prospective study) to change over time and to be linked with the development of comorbid medical illness68. Emergent studies are highlighting that ameliorative experiences, such as successful psychotherapy, can reverse some markers associated with PTSD64,6971, and such studies will greatly supplement knowledge about the biological mechanisms associated with recovery.
纵向研究突出了累积性创伤暴露和生物系统渐进性失调在 PTSD 发展中的重要性。因此,识别与 PTSD 前创伤和围创伤风险因素相关的生物改变,以及确定这些改变如何“为维持症状的过程奠定基础”至关重要。例如,尽管糖皮质激素信号改变与 PTSD 风险和早期围创伤反应相关,但一些证据表明,这些改变与症状严重程度相关。也就是说,患者可能会因为其他途径的改变而经历症状的恶化。同样,炎症过程可以是 PTSD 的预测因素,但(在一项前瞻性研究中)已被证明会随时间变化,并与合并医疗疾病的发展相关。 新研究突显,改善性体验,如成功的心理治疗,可以逆转与 PTSD 相关的一些标志物,此类研究将极大地补充关于恢复相关生物学机制的知识。

Genetic factors  遗传因素

As has been amply shown across many fields of medicine, discovery of risk-associated alleles can provide initial clues to pathogenesis, which might lead to novel therapeutics or tools for stratifying patients for basic and clinical research. The rationale for examining genetic factors in PTSD has come from twin studies that suggest that PTSD risk is moderately heritable72. However, the genetic contribution to PTSD is complex, as genetic factors can also influence exposure to potentially traumatic events such as combat or assaultive violence73,74. Even after accounting for genetic effects on risk of exposure, a substantial proportion of vulnerability to PTSD is heritable73,7577. Twin studies might highlight the importance of heritable temperamental factors, such as novelty-seeking behaviour and neuroticism in PTSD, or they might identify biological markers that associate with PTSD risk78. For some, trauma exposure functions as a catalyst to augment the effect of hereditary and other environmental contributions to PTSD, such that individuals with the greatest exposure to combat trauma were at increased risk for PTSD as a function of both genetic and environmental factors79. Furthermore, a specific functional polymorphism of FKBP5 has been shown to be associated with increased risk of developing PTSD and other stress-related disorders in response to childhood trauma80. Specifically, DNA demethylation occurs in the functional glucocorticoid response elements of FKBP5 and regulates its function, providing an initial observation of a molecular mechanism of genotype-directed epigenetic change in response to environmental stressors81. Interestingly, a large proportion of the genetic liability for PTSD is shared with other psychiatric disorders that can be comorbid with PTSD, such as anxiety and panic disorder, major depression and substance use; genes that confer risk for PTSD might also influence risk for other psychiatric disorders and vice versa82.
如许多医学领域所充分展示的那样,发现与风险相关的等位基因可以提供对发病机制的初步线索,这可能导致新的治疗方法或用于对基本和临床研究进行患者分层的工具。检查 PTSD 中遗传因素的合理性来源于双生子研究,这些研究表明 PTSD 风险中等程度地具有遗传性。然而,PTSD 的遗传贡献是复杂的,因为遗传因素也可以影响暴露于潜在的创伤事件,如战斗或攻击性暴力。即使在考虑了遗传效应对暴露风险的影响之后,PTSD 易感性的很大一部分仍然是可遗传的。双生子研究可能强调可遗传的性情因素的重要性,例如在 PTSD 中的新奇寻求行为和神经质,或者它们可能识别与 PTSD 风险相关的生物标志物。对于一些人来说,创伤暴露充当催化剂,增强遗传和其他环境因素对 PTSD 的影响,使得暴露于战斗创伤最大的人由于遗传和环境因素的双重作用而增加了 PTSD 的风险。 此外,FKBP5 的特定功能多态性已被证明与儿童创伤后发展 PTSD 和其他与压力相关的疾病风险增加有关 80 。具体来说,FKBP5 的功能性糖皮质激素反应元件发生 DNA 去甲基化,调节其功能,为环境应激源引起的基因型导向表观遗传变化的分子机制提供了初步观察 81 。有趣的是,PTSD 的遗传易感性很大一部分与其他可以与 PTSD 共病的心理疾病(如焦虑症和惊恐障碍、重度抑郁症和物质使用)共享;赋予 PTSD 风险的基因也可能影响其他心理疾病的风险,反之亦然 82

As the data from large-scale genetic studies emerge, it will be important to re-evaluate conclusions drawn from twin studies. Indeed, to the same extent that parental PTSD is a risk factor on the basis of non-genetic mechanisms of transmission, a twin could have shared genetic risk factors as well as shared developmental experiences. For example, maternal PTSD is a risk factor for PTSD83 and could contribute risk through epigenetic changes61 independent of allelic variation81. For this reason, it is important to carry out large-scale genome-wide association studies (GWAS), perform adequately powered large epigenomic studies46,84 and replicate findings in independent studies85. Unlike in GWAS, considerable conceptual and technical problems must be resolved to address epigenetic influences on PTSD risk86. In particular, our knowledge about the epigenome is still fairly limited, making it difficult to interpret epigenetic variations as relating to stable disease processes. Furthermore, in PTSD, studies of epigenetic regulation have had to focus on peripheral cells such as leukocytes. Such cells inhabit different regulatory environments from critical brain circuits and, therefore, these studies have limitations. Studies of gene expression in critical neural circuits are similarly limited. Nonetheless, studies examining genetic, epigenetic and gene expression markers from blood can be compared with neuroendocrine information from blood, providing some validation of functional relevance87,88. The fact that neuroendocrine biomarkers change over time in association with symptom severity provides additional validation87,89. As these methodologies are embraced, methods that provide durable insights will be required. For example, validation of candidate markers through unbiased genome-wide sampling will be required; this has been achieved with respect to the identification of variation in levels of glucocorticoid receptor co-chaperones in those with PTSD, such as FKBP5 (Refs 84,88). Furthermore, as methylation is only one of several mechanisms for gene regulation, other mechanisms of epigenetic regulation must be examined90,91.
随着大规模遗传研究数据的出现,重新评估双生子研究得出的结论将变得重要。事实上,与父母 PTSD 基于非遗传的传播机制是一个风险因素一样,双生子可能既有共同的遗传风险因素,也有共同的发展经历。例如,母体 PTSD 是 PTSD 的风险因素,并且可以通过表观遗传变化独立于等位基因变异来增加风险。因此,进行大规模的全基因组关联研究(GWAS)、充分有力的大规模表观基因组研究,并在独立研究中复制发现,这一点很重要。与 GWAS 不同,为了解决表观遗传对 PTSD 风险的影响,必须解决相当多的概念和技术问题。特别是,我们对表观基因组的知识仍然相当有限,这使得很难将表观遗传变异解释为与稳定的疾病过程相关。此外,在 PTSD 中,表观遗传调控的研究不得不集中在如白细胞等外周细胞上。 这些细胞居住在不同的调节环境中,与关键大脑回路不同,因此,这些研究存在局限性。对关键神经网络中基因表达的类似研究也受到限制。尽管如此,从血液中检查遗传、表观遗传和基因表达标记的研究可以与血液中的神经内分泌信息进行比较,从而为功能相关性提供一些验证 87,88 。神经内分泌生物标志物随时间变化并与症状严重程度相关联的事实提供了额外的验证 87,89 。随着这些方法的采用,需要提供持久见解的方法。例如,需要通过无偏见的全基因组采样来验证候选标记;这已经在识别 PTSD 患者中糖皮质激素受体共伴侣水平变化方面实现,例如 FKBP5(参考文献 84,88)。此外,由于甲基化只是基因调节的几种机制之一,因此必须检查其他表观遗传调节机制 90,91

Only five GWAS in patients with PTSD have so far been published. These encompass diverse settings including all-male or all-female cohorts, subjects of European or African ancestry (that is, African Americans) in the United States and exposure to military, civilian and childhood trauma. The hypothesis-free GWAS approach has already identified several novel potential PTSD-associated loci, including those containing the gene encoding nuclear receptor RORα (RORA)92, the gene encoding Tolloid-like protein 1 (TLL1)93, a novel RNA gene long intergenic non-coding RNA (lincRNA) AC068718.1 (Ref. 94), the gene encoding phosphoribosyl transferase domain-containing protein 1 (PRTFDC1)95 and the single-nucleotide polymorphism rs717947 at chromosome 4p15 (Ref. 85). Although promising, these first studies were fairly small and underpowered96, and most did not meet the conventional criteria of genome-wide significance (set at P < 5 × 10−8), did not replicate the same single-nucleotide polymorphisms or have an effect in the same direction in an independent sample.
目前仅发表了五篇关于创伤后应激障碍(PTSD)患者的全基因组关联研究(GWAS)。这些研究涵盖了多种环境,包括全部由男性或女性组成的队列,美国欧洲或非洲血统(即非裔美国人)的受试者以及军事、平民和童年创伤的暴露。无假设的 GWAS 方法已经确定了几个新的潜在 PTSD 相关位点,包括编码核受体 RORα(RORA)的基因 92 ,编码 Tolloid 样蛋白 1(TLL1)的基因 93 ,一种新的 RNA 基因长间基因非编码 RNA(lincRNA)AC068718.1(参考文献 94),编码磷酸核糖转移酶结构域蛋白 1(PRTFDC1)的基因 95 以及位于 4p15 染色体上的单核苷酸多态性 rs717947(参考文献 85)。尽管前景看好,但这些初步研究规模较小,效力不足 96 ,并且大多数研究没有达到全基因组显著性的传统标准(设定为 P < 5 × 10^-4#),在独立样本中没有重复相同的单核苷酸多态性或产生相同方向的影响。

Pending progress in GWAS, genetic variants confidently associated with PTSD have yet to be identified. However, some genes have been identified in small candidate gene association studies97,98, including those related to the HPA axis, the noradrenergic system and the limbic amygdala frontal pathway that mediates fear processing. In one study, polymorphisms in FKBP5 were shown to have a significant association with severity of child abuse in the prediction of adult PTSD symptoms80, and the gene was subsequently shown to be demethylated in another intron after trauma81. These findings require follow-up because the expression of FKBP5 has been identified as altered in a genome-wide gene expression study of PTSD88 and was found to associate with the disorder in cross-sectional and longitudinal studies as described above.
在 GWAS 方面,尚未确定与 PTSD 有显著关联的遗传变异。然而,在小规模的候选基因关联研究中已经确定了某些基因,包括与 HPA 轴、去甲肾上腺素系统和介导恐惧处理的边缘系统杏仁核前额叶通路相关的基因。在一项研究中,FKBP5 基因的多态性与儿童虐待的严重程度与成人 PTSD 症状的预测有显著关联,该基因随后在创伤后的另一个内含子中被发现去甲基化。这些发现需要进一步研究,因为 FKBP5 的表达已被在 PTSD 的全基因组基因表达研究中确定发生改变,并在上述横断面和纵向研究中被发现与该疾病相关。

Finally, a current effort is underway to evaluate data obtained from very large sample sizes (>10,000 participants)98. The Psychiatric Genomics Consortium (PGC) has a PTSD working group that aims to carry out field-wide meta-analyses of genetic data obtained from patients with PTSD to identify new samples on which to perform additional GWAS98. Thus, there is every reason to believe that the identification and validation of relevant PTSD risk genes are imminent.
最后,一项当前的工作正在进行中,旨在评估从非常大的样本量(>10,000 名参与者)中获得的数据。精神病学基因组学联盟(PGC)有一个 PTSD 工作组,旨在对来自 PTSD 患者的遗传数据进行广泛的荟萃分析,以确定进行额外 GWAS 的新样本。因此,有充分的理由相信,相关 PTSD 风险基因的鉴定和验证即将到来。

Cognitive factors and neurocircuitry
认知因素和神经回路

The earliest neuroimaging and neurochemistry studies in PTSD focused on hippocampal dysregulation because deficits in memory performance and information processing were observed in patients with PTSD. Hippocampal functioning in PTSD was also of interest because of the role of the hippocampus in fear extinction and facilitation of the neuroendocrine response to stress, and because stress exposure and concomitant increases in brain glucocorticoid activity were found to damage hippocampal neurons in animal models and studies of human ageing99. Great interest was generated by an initial report of smaller hippocampal volume in those with PTSD100. However, a subsequent study of identical twins suggested that smaller hippocampal volumes reflected risk for PTSD rather than stress-induced glucocorticoid toxicity, which has not been shown in PTSD78. Smaller hippocampal volume has been shown to be a vulnerability factor in the persistence of PTSD101.
创伤后应激障碍 | 自然综述疾病基础 早期关于创伤后应激障碍的神经影像学和神经化学研究集中在海马体失调,因为在创伤后应激障碍患者中观察到记忆表现和信息处理能力下降。由于海马体在恐惧消退和促进神经内分泌对压力的反应中的作用,以及动物模型和人类衰老研究中发现压力暴露和大脑糖皮质激素活动的同时增加会损害海马体神经元,因此创伤后应激障碍中的海马体功能也引起了人们的兴趣。关于创伤后应激障碍患者海马体体积较小的初步报告引起了极大的兴趣。然而,一项对同卵双胞胎的研究表明,较小的海马体体积反映了创伤后应激障碍的风险,而不是应激诱导的糖皮质激素毒性,这在创伤后应激障碍中尚未得到证实。较小的海马体体积已被证明是创伤后应激障碍持续存在的易感因素。

Subsequent research expanded the focus from the hippocampus and identified circuits associated with the amygdala, medial prefrontal cortex, cingulate gyrus and insula as abnormal in patients with PTSD102. These studies were influenced by animal and human studies of fear conditioning and extinction7. A large number of studies showed decreased ventromedial prefrontal cortex and rostral anterior cingulate activation in response to both trauma-related and non-trauma-related stimuli in individuals with PTSD30,103106. Consistent with diminished prefrontal inhibition of fear circuitry, increased amygdala activation in those with the disorder was also shown in response to both trauma and non-trauma-related emotional stimuli in some30,106109 but not all studies. Meta-analyses of functional neuroimaging studies in PTSD suggested the amygdala can show hyperactivity and hypoactivity within the ventral anterior and dorsal posterior regions, respectively, which is consistent with the functional specificity of amygdala sub-nuclei106. Patients with PTSD who show symptoms of emotional detachment (such as depersonalization, derealization and emotional numbing) have increased activation of medial prefrontal cortex and rostral anterior cingulate regions110, which is consistent with inhibition of limbic regions111. These findings suggest that there are distinct patterns of amygdala activity and connectivity in different PTSD phenotypes and indicate the importance of considering the heterogeneous nature of this disorder when designing PTSD studies.
后续研究将焦点从海马体扩展到杏仁核、内侧前额叶皮层、扣带回和岛叶,发现这些回路在 PTSD 患者中异常 102 。这些研究受到了恐惧条件反射和消退的动物和人类研究的影响 7 。大量研究表明,PTSD 个体对创伤相关和非创伤相关刺激的反应中,腹内侧前额叶皮层和前扣带回的激活减少 30,103106 。与恐惧回路前额叶抑制减弱一致,一些但并非所有研究表明,该疾病患者的杏仁核在创伤和非创伤相关情绪刺激下也会激活增加 30,106109 。对 PTSD 功能神经影像学研究的荟萃分析表明,杏仁核可以在腹侧前部和背侧后部区域分别表现出过度活跃和低度活跃,这与杏仁核亚核的功能特异性一致 106 。 PTSD 患者表现出情感疏离症状(如去人格化、去现实化和情感麻木)时,内侧前额叶皮层和前扣带回前部区域的激活增加,这与边缘系统的抑制一致。这些发现表明,不同 PTSD 表型中杏仁核活动和连接存在独特模式,并指出在设计 PTSD 研究时考虑这种疾病的异质性很重要。

Indeed, PTSD can be characterized by two extremes of emotional dysregulation112 (Fig. 3). Emotional undermodulation involves diminished prefrontal inhibition of circuits involved in emotion processing and increased autonomic responsivity as shown during re-experiencing, fear, anger, guilt and shame. However, there is also evidence that patients experience emotional overmodulation, which reflects an exaggerated dampening of emotional expression and related emotional detachment, such as states of depersonalization and derealization, numbing and diminished somatic sensations. Such overmodulation is reflected by a heightened inhibition of limbic regions112. These contrasting states associate with distinct patterns of fronto-limbic activity and recapitulate the fundamental dynamic of PTSD as a condition in which individuals struggle to modulate distress associated with extreme arousal with avoidance and disengagement.
创伤后应激障碍(PTSD)可以表现为情绪调节的两极化 112 (图 3)。情绪低调节涉及情绪处理相关回路的前额叶抑制减弱和自主反应性增加,如重现、恐惧、愤怒、内疚和羞愧时的表现所示。然而,也有证据表明患者会经历情绪高调节,这反映了情绪表达和相关情感疏离的过度抑制,如去人格化和脱现实状态、麻木和躯体感觉减弱。这种过度调节体现在边缘系统的抑制增强 112 。这些对立状态与不同的前额叶-边缘活动模式相关,并概括了 PTSD 作为一种条件的根本动态,即个体在与极度唤醒相关的痛苦中努力通过回避和脱离来调节。

Figure 3: Emotional undermodulation and overmodulation in PTSD.
图 3:创伤后应激障碍(PTSD)中的情绪低调节和过度调节。
figure 3

Emotional undermodulation refers to diminished control or heightened emotional and autonomic responding as shown during reexperiencing, fear, anger, guilt and shame responses. Emotional overmodulation encompasses increased control of emotional states and related emotional detachment, such as states of depersonalization and derealization, emotional numbing and analgesia. These contrasting forms of emotion dysregulation suggest that post-traumatic stress disorder (PTSD) is a dynamic disorder that involves fluctuations between states of heightened emotional and autonomic experience and states of diminished emotional experience and autonomic blunting. This symptom complexity also seems to be represented in the neural circuitry that underlies PTSD. Consistent with diminished prefrontal inhibition of limbic regions during emotional undermodulation, studies have indicated decreased ventromedial prefrontal cortex and rostral anterior cingulate activation and increased amygdala activation in response to trauma and non-trauma-related emotional stimuli in those with PTSD30,104,105,106,107,109. By contrast, patients who have emotional overmodulation have shown increased activation of medial prefrontal cortex and rostral anterior cingulate regions, which have been suggested to lead to decreased amygdala activation112. Figure adapted with permission from Ref. 243, Wiley.
情绪低调节指在重演、恐惧、愤怒、内疚和羞愧反应期间表现出的情绪和自主神经反应的控制减弱或增强。情绪高调节包括对情绪状态和相关情绪分离的增加控制,如去人格化和脱现实状态、情绪麻木和镇痛。这些对比的情绪调节障碍形式表明,创伤后应激障碍(PTSD)是一种动态障碍,涉及高度情绪和自主神经体验状态与情绪体验减弱和自主神经钝化状态之间的波动。这种症状复杂性似乎也反映在 PTSD 的神经回路中。与情绪低调节期间前额叶对边缘区域的抑制减弱一致,研究表明,在 PTSD 患者中,对创伤和非创伤相关情绪刺激的反应中,腹内侧前额叶和前扣带回的激活减少,杏仁核的激活增加。 与情绪过度调节的患者相比,这些患者内侧前额叶皮层和前扣带回区域的激活增加,这已被提出可能导致杏仁核激活减少 112 。图经 Ref. 243,Wiley 许可改编。

PowerPoint slide  幻灯片

A more-comprehensive model of PTSD neurocircuitry has been suggested to acknowledge the interaction of three systems other than the fronto-limbic circuits. These systems are the default mode network, the salience network and the central executive network113115 (Fig. 4). Fluctuations in the activity of these circuits can explain how a patient with PTSD shifts into dramatically different states in an attempt to regulate their extreme emotional responses to cues or trains of thought116,117.
创伤后应激障碍(PTSD)神经回路的一个更全面的模型已被提出,以承认除了前额叶-边缘回路之外三个系统的相互作用。这些系统是默认模式网络、显著性网络和中央执行网络 113115 (图 4)。这些回路活动的波动可以解释为什么 PTSD 患者会进入截然不同的状态,试图调节他们对线索或思维序列的极端情绪反应 116,117

Figure 4: The default mode, salience and central executive networks in PTSD.
图 4:创伤后应激障碍(PTSD)中的默认模式、显著性网络和中央执行网络。
figure 4

Three intrinsic connectivity networks in the human brain have been identified as central to the understanding of higher cognitive function113: the central executive, salience and default mode networks. The responses of these networks generally increase and decrease proportionally and antagonistically during cognitive tasks. The central executive network is a frontoparietal network that is crucial to working memory and cognitive control of thought, emotion and behaviour. The salience network consists of the dorsal anterior cingulate cortex and the frontoinsular cortex and is involved in the detection of personally salient internal and external stimuli to direct behaviour with the goal of maintaining homeostasis. The default mode network, which consists of cortical midline structures and lateral parietal lobes, plays an important part in self-related processes, emotion regulation, social cognition, autobiographical memory and future-oriented thinking. Crucially, the anterior insula is thought to mediate the dynamic interface between externally oriented attention and internal self-reflective functioning, mediating switching between engagement of the central executive network and disengagement of the default mode network and facilitating engagement of brain areas mediating attention, working memory and higher-order cognitive processes. These three intrinsic networks might be associated with specific clinical symptoms observed in post-traumatic stress disorder (PTSD), including cognitive dysfunction (in the case of the central executive network), altered arousal and interoception (in the case of the salience network) and altered self-referential processing (in the case of the default mode network). Figure adapted from Ref. 188.
人脑中已识别出三个内在连接网络对于理解高级认知功能至关重要:中央执行网络、显著性网络和默认模式网络。这些网络在认知任务中的反应通常呈比例增加和减少,具有拮抗性。中央执行网络是一个额顶叶网络,对于工作记忆和思维、情感和行为认知控制至关重要。显著性网络由背侧前扣带回皮层和前岛叶皮层组成,涉及检测个人显著的内、外部刺激,以指导行为,目标是维持稳态。默认模式网络由皮质中线结构和侧顶叶组成,在自我相关过程、情绪调节、社会认知、自传体记忆和面向未来的思考中发挥着重要作用。 关键在于,前岛叶被认为在面向外部的注意力和内部自我反思功能之间起到动态接口的作用,调节中央执行网络参与和默认模式网络脱离之间的切换,并促进调节注意、工作记忆和高级认知过程的大脑区域的参与。这三个内在网络可能与创伤后应激障碍(PTSD)中观察到的特定临床症状相关,包括认知功能障碍(中央执行网络的情况)、唤醒和内省的改变(显著性网络的情况)以及自我参照处理的改变(默认模式网络的情况)。图来自参考文献 188。

PowerPoint slide  幻灯片

An important area of neuroimaging research has involved delineating brain neurochemistry using PET imaging. However, such studies have been limited by the lack of relevant PET tracers, for example, for glucocorticoid receptors or receptors for neuropeptides (such as corticotropin-releasing hormone and NPY). A single-photon emission computed tomography study has revealed lower GABA-A (γ-aminobutyric acid A) receptor binding in combat veterans with PTSD than in those without PTSD118. Other promising findings include differences in endocannabinoid receptor sensitivity, assessed using a selective cannabinoid-type receptor radioligand, between those with and those without the disorder51. Receptor number in tandem with blood anandamide (an endocannabinoid neurotransmitter) and cortisol concentrations could correctly classify 85% of patients with PTSD51. In another study, the distribution of selective dynorphin (an opioid peptide) and κ-type opioid receptor in the amygdala–anterior cingulate cortex–ventral striatal circuit was associated with the trauma of loss, a relationship that was influenced by glucocorticoid levels41. Reduced binding to the serotonin transporter in the amygdala has also been noted119, as have regionally specific, differential responses in glucose use following glucocorticoid injection in those with PTSD compared with unaffected individuals120.
神经影像学研究的一个重要领域涉及使用正电子发射断层扫描(PET)描绘大脑神经化学。然而,这些研究受到相关 PET 示踪剂缺乏的限制,例如糖皮质激素受体或神经肽受体(如促肾上腺皮质激素释放激素和 NPY)。一项单光子发射计算机断层扫描研究表明,与无 PTSD 的退伍军人相比,PTSD 退伍军人中 GABA-A(γ-氨基丁酸 A)受体结合降低 118 。其他有希望的发现包括使用选择性大麻素型受体放射性配体评估的,有和没有该疾病的人之间内源性大麻素受体敏感性的差异 51 。受体数量与血液中的大麻素神经递质(一种内源性神经递质)和皮质醇浓度相结合,可以正确分类 85%的 PTSD 患者 51 。在另一项研究中,选择性强啡肽(一种阿片肽)和κ型阿片受体在杏仁核-前扣带回皮层-腹侧纹状体回路中的分布与丧失的创伤相关,这种关系受糖皮质激素水平的影响 41 。 杏仁核中 5-羟色胺转运蛋白的减少也被观察到 119 ,与未受影响的个体相比,在 PTSD 患者中,糖皮质激素注射后葡萄糖使用的区域特异性差异反应也被观察到 120

It will be crucial to examine brain networks and neurochemistry in a longitudinal manner. In addition, the effects of pre-trauma risk factors, exposure to stressors, protective factors and the age of trauma onset on the development of PTSD will require focused investigation. It has yet to be established whether fear or chronic repeated re-experiencing of the traumatic event leads to sensitization and augmentation of emotional reactivity to promote the emergence and maintenance of brain changes or whether these changes result from genetic or early childhood factors that alter the circuitry, making recovery difficult.
将大脑网络和神经化学进行纵向研究至关重要。此外,需要重点研究创伤前风险因素、应激源暴露、保护因素和创伤发生年龄对创伤后应激障碍(PTSD)发展的影响。尚未确定是恐惧或对创伤事件的慢性重复重现导致了对情绪反应的敏感化和增强,从而促进了大脑变化的产生和维护,还是这些变化源于改变电路的遗传或早期童年因素,使得康复困难。

Diagnosis, screening and prevention
诊断、筛查和预防

Classification  分类

The original PTSD conceptualization emphasized the re-experiencing of phenomena, such as intrusive traumatic memories, nightmares and dissociation by patients as hallmark symptoms121. PTSD was first introduced into DSM-III in 1980 (Ref. 19) partly owing to emerging concerns about long-term stress responses in Vietnam War veterans. Psychiatry had previously recognized that longstanding traumatic neuroses could occur following combat exposure, but it was becoming apparent that similar symptoms were present in those who experienced interpersonal violence such as rape or assault, survived ethnic cleansing or genocide, or experienced serious accidents or natural disasters122. Given that the prevailing theory at that time was that stress effects would remit with removal of the stressor, the PTSD diagnosis was revolutionary in asserting long-term and transformative effects of trauma. When first conceptualized, no epidemiological studies of trauma exposure and its aftermath had been carried out that could inform the diagnosis122. Instead, PTSD was thought to be a reflection of a natural response to an unnatural circumstance. However, subsequent studies documented that, although trauma exposure was common, PTSD occurred in only a minority of survivors.
创伤后应激障碍(PTSD)的原有概念强调患者将现象重新经历,如侵入性创伤记忆、噩梦和解离,作为标志性症状 121 。PTSD 首次于 1980 年(参考文献 19)被纳入 DSM-III,部分原因是人们对越南战争老兵长期应激反应的担忧日益增加。精神病学先前已认识到,在战斗暴露后可能会发生长期的创伤性神经症,但越来越明显的是,那些经历过人际暴力(如强奸或攻击)、幸存种族清洗或种族灭绝或经历过严重事故或自然灾害的人也出现了类似的症状 122 。鉴于当时占主导地位的理论是压力效应会在去除压力源后缓解,PTSD 的诊断在断言创伤的长期和转化性影响方面具有革命性。在首次提出概念时,尚未进行过关于创伤暴露及其后果的流行病学研究,这些研究可以指导诊断 122 。相反,人们认为 PTSD 是自然对非自然情况的自然反应的反映。 然而,后续研究记录表明,尽管创伤暴露很常见,但创伤后应激障碍(PTSD)仅发生在少数幸存者中。

The DSM-III definition included 12 symptoms and highlighted the importance of re-experiencing the trauma. Numbing and constricted affect was a second symptom cluster. A variety of symptoms — such as hyperarousal, sleep disturbance, guilt, memory impairment and avoidance of traumatic triggers — were described in a third nonspecific cluster. The revised DSM-III (DSM-IIIR (1988)) and the DSM-IV (1994) definitions both included 17 symptoms and were based on observations that avoidance, numbing and interpersonal estrangement represented a dynamic adaptation that was thought to lessen the distress of traumatic memories; other symptoms were thought to represent physiological expressions of arousal or hyperviligence123.
DSM-III 的定义包括 12 个症状,并强调了重新经历创伤的重要性。麻木和情感受限是第二个症状群。第三组非特异性症状中描述了各种症状,如过度警觉、睡眠障碍、内疚、记忆障碍和避免创伤触发因素。修订后的 DSM-III(DSM-IIIR(1988))和 DSM-IV(1994)的定义都包括 17 个症状,并基于观察,认为回避、麻木和人际疏远代表了一种动态适应,被认为可以减轻创伤记忆的痛苦;其他症状被认为代表了觉醒或过度警觉的生理表达。

The first major revision to the definition since 1988 occurred in 2013 in DSM-5. Among the changes in diagnostic criteria for PTSD in DSM-5 (Ref. 1), which now includes 20 symptoms, was a modification of the avoidance and the interpersonal estrangement criterion C. The DSM-IV criteria are now separated into two subcategories: avoidance, and negative cognitions and mood symptoms, partly on the basis of factor analytical studies124. These changes have led to considerable diagnostic discordance between DSM-IV and DSM-5 PTSD in up to 30% of patients, which raises questions about the clinical use and implications of the recent changes125,126. Both diagnostic formulations are currently in use clinically and in the research setting. As negative cognitions are the focus of cognitive behavioural therapy (CBT) for PTSD, including them as a separate cluster could inadvertently increase the proportion of patients who respond to treatments designed to affect cognitions compared with treatments that preferentially target other PTSD symptoms or related dysfunctions. Moreover, negative cognitions might reflect second-order characteristics that are not directly tied to the underlying neurobiology of PTSD126. These controversies about DSM-5 and the need for continuity in the literature have meant that DSM-5 criteria have not been automatically embraced in international academic, clinical or legal circles.
自 1988 年以来,对创伤后应激障碍定义的第一次重大修订发生在 2013 年的 DSM-5 中。在 DSM-5 中对 PTSD 诊断标准的变化(参考文献 1),现在包括 20 个症状,其中对避免和人际疏远标准 C 进行了修改。DSM-IV 标准现在被分为两个子类别:避免和负面认知及情绪症状,部分基于因素分析研究。这些变化导致了 DSM-IV 和 DSM-5 PTSD 诊断在高达 30%的患者中存在相当大的差异,这引发了关于最近变化在临床应用和影响方面的问题。目前,这两种诊断方案在临床和研究环境中都在使用。由于负面认知是 PTSD 认知行为疗法(CBT)的重点,将其作为单独的一组可能会无意中增加对旨在影响认知的治疗反应的患者比例,与优先针对其他 PTSD 症状或相关功能障碍的治疗相比。 此外,消极的认知可能反映了与 PTSD 潜在神经生物学不直接相关的二级特征 126 。关于 DSM-5 的争议以及文献中需要连续性的需求意味着 DSM-5 标准并未在国际学术界、临床或法律界自动被接受。

An examination of data from the World Mental Health Survey comparing the DSM-IV, DSM-5, International System of Classification (ICD-10) and proposed ICD-11 criteria showed that only one-third of patients met PTSD criteria across all four diagnostic schemes127. Accordingly, adopting the DSM-5 classification to epidemiological, biological and treatment research will probably yield results different from those that have previously been obtained. Furthermore, definitions of what constitutes a traumatic event in the DSM and ICD classification systems are different (Table 2). If studies are to remain comparable over time, evaluation of biological markers and treatment response on the basis of specific, well-described symptom clusters, rather than relying on DSM-5 criteria alone, will be of importance. However, against this background, an important development in DSM-5 has been the inclusion of a more developmentally sensitive phenotypic characterization of the disorder in young children.
世界精神卫生调查数据比较了 DSM-IV、DSM-5、国际疾病分类(ICD-10)和拟议的 ICD-11 标准,结果显示,在所有四种诊断方案中,只有三分之一的患者符合 PTSD 标准。因此,采用 DSM-5 分类进行流行病学、生物学和治疗研究可能会得到与之前获得的结果不同的结果。此外,DSM 和 ICD 分类系统中关于构成创伤事件的定义不同(表 2)。为了使研究在时间上保持可比性,基于具体、详细描述的症状群评估生物标志物和治疗反应,而不是仅依赖 DSM-5 标准,将具有重要意义。然而,在这种背景下,DSM-5 的一个重要发展是在幼儿中纳入了对该疾病更敏感的表型特征描述。

Table 2 Definition of a traumatic event in DSM and ICD classification systems
表 2 DSM 和 ICD 分类系统中创伤事件的定义

A major advance in understanding PTSD signs and symptoms has come from longitudinal studies. These studies have confirmed that PTSD can emerge many years after the traumatic exposure. In the initial years after the diagnosis was first codified in 1980, the concept of delayed PTSD was controversial because it challenged the idea that PTSD is caused by the acute stress response or by its failure to resolve16,128. Indeed, symptomatic distress can increase with the passage of time rather than reflect delayed presentation for treatment129. This temporal increase can be partly attributed to further stresses in the aftermath of the initiating traumatic exposure or the erosion of previously effective self-regulation or extinction learning128. Increased distress may also be explained by biological phenomena such as kindling and sensitization130. Kindling refers to the process through which patterns of negative information processing become easier to activate even with increasingly minimal cues131. Sensitization refers to the progressively greater responses that develop over time in those who are repeatedly exposed to environmental risk factors that magnify the intensity of the response to a single new perturbation132. Delayed-onset PTSD is often preceded by subsyndromal symptoms, which impart morbidity in their own right, as well being predictors of ‘full’ PTSD130.
创伤后应激障碍(PTSD)的征兆和症状的理解取得了重大进展,这得益于纵向研究。这些研究证实,PTSD 可能在创伤暴露多年后出现。在 1980 年首次将诊断编码后的最初几年,延迟性 PTSD 的概念颇具争议,因为它挑战了 PTSD 是由急性应激反应或其未能解决的观点。事实上,症状性痛苦可能会随着时间的推移而增加,而不是反映治疗延迟的出现。这种时间上的增加可以部分归因于初始创伤暴露后的进一步压力,或先前有效的自我调节或灭绝学习的侵蚀。增加的痛苦也可能由诸如点燃和敏感化等生物学现象来解释。点燃是指负性信息处理模式在越来越微小的提示下变得更容易激活的过程。 敏化是指那些反复接触环境风险因素以放大对单个新干扰反应强度的人随着时间的推移而逐渐增强的反应。延迟性创伤后应激障碍通常先出现亚综合征症状,这些症状本身就有病理性,同时也是“完全”创伤后应激障碍的预测因素。

Another classification issue has concerned the definition of trauma exposure, including which events should be used in the stressor criterion1. This matter has relevance for establishing causation in litigation, disability assessment and compensation. For example, the effect of bullying, the sudden death of one's child as a result of illness, or situations involving interpersonal stress stemming from electronic or social media would not be considered to meet the definition under DSM-5 unless an assault is threatened or occurs, the trauma was accidental or violent, or if the patient is repeatedly exposed to images of traumatic events (for example, as in the case of emergency first responders)1. DSM-5 also recognizes that subjective responses such as fear, helplessness or horror might not be immediate responses to trauma. Indeed, military and emergency service personnel learn to override their avoidance and fear reactivity to carry out their duties and do not regularly report these reactions133.
创伤暴露的定义问题引起了另一个分类问题,包括哪些事件应被用于应激标准。这个问题与诉讼中的因果关系确定、残疾评估和赔偿有关。例如,欺凌、因疾病导致的孩子突然死亡或涉及电子或社交媒体引起的人际压力的情况,除非有袭击威胁或发生,创伤是意外或暴力的,或者患者反复接触创伤事件的图像(例如,在紧急情况下的第一响应人员),否则不会被视为符合 DSM-5 的定义。DSM-5 还认识到,恐惧、无助或恐怖等主观反应可能不是对创伤的直接反应。事实上,军事和紧急服务人员学会克服他们的回避和恐惧反应以履行职责,并且不会定期报告这些反应。

Finally, DSM-5 also removed PTSD from the anxiety disorder section and created a new category of trauma-related disorder1. However, other diagnoses, including depression and panic disorder, frequently emerge following trauma exposure in the absence of PTSD128. Accordingly, the question arises as to whether the traumatic stress response contributing to these disorders differentiates them from the same diagnoses emerging in the absence of a traumatic stressor. The issue of shared causal mechanisms106 is also relevant to the investigation of comorbid disorders that are also present in the majority of patients with PTSD134136.
最后,DSM-5 也将 PTSD 从焦虑障碍部分移除,并创建了一个新的创伤相关障碍类别 1 。然而,包括抑郁症和惊恐障碍在内的其他诊断,在没有 PTSD 的情况下,经常在创伤暴露后出现 128 。因此,问题随之而来,即导致这些障碍的创伤应激反应是否将它们与在没有创伤应激源的情况下出现的相同诊断区分开来。共享因果机制 106 的问题也与调查共病障碍相关,这些障碍也存在于大多数 PTSD 患者的多数中 134136

Diagnosis  诊断

In principle, it is straightforward to diagnose PTSD in circumstances in which the clinician knows or suspects the patient has been exposed to an extremely traumatic event or critical incident. A series of questions can be asked to determine the presence, frequency and intensity of the symptoms of PTSD. However, diagnosing PTSD when symptoms are present but when the patient does not volunteer information is difficult, particularly if the clinician does not ask (or does not know to ask) about potential exposures.
原则上,在临床医生知道或怀疑患者经历过极其创伤性事件或关键事件的情况下,诊断创伤后应激障碍(PTSD)是 straightforward 的。可以通过一系列问题来确定 PTSD 症状的存在、频率和强度。然而,当症状存在但患者没有提供信息时,诊断 PTSD 是困难的,尤其是如果临床医生没有询问(或不知道如何询问)潜在的暴露情况。

Furthermore, cross-cultural validity of the diagnosis is an important consideration because of the relevance of the disorder in refugee populations and in global humanitarian and disaster settings. Specifically, studies have confirmed the symptom clusters across cultures but practitioners in these settings should have an awareness of specific culture-bound trauma constructs137. The diagnosis is also difficult to make when the patient does not wish to be identified as someone who has PTSD, such as military personnel or emergency first responders. Moreover, many of the symptoms of PTSD are not apparent and rely on disclosures of traumatic nightmares, numbing, avoidance or impaired concentration, of which patients might have limited awareness. In addition, patients might believe that disclosing these symptoms will result in occupational or other restrictions. Alternatively, some might wish to exaggerate their symptoms for secondary gain.
此外,由于该疾病在难民群体和全球人道主义和灾难环境中的相关性,诊断的文化适用性是一个重要考虑因素。具体而言,研究已确认症状群在不同文化中的存在,但在此类环境中的从业者应了解特定的文化相关创伤结构。当患者不愿被识别为患有 PTSD(如军事人员或紧急救援人员)时,诊断也变得困难。此外,许多 PTSD 的症状并不明显,依赖于患者对创伤性噩梦、麻木、回避或注意力受损的披露,患者可能对这些症状的认识有限。此外,患者可能认为披露这些症状会导致职业或其他限制。或者,有些人可能希望夸大他们的症状以获得间接利益。

Even among those who do not have a specific reason to conceal or to amplify symptoms, the diagnosis of PTSD can be difficult to make because of the propensity to colloquially normalize distress after traumatic events138, compounded with a tendency to avoid speaking of distressing memories. Often, patients with PTSD focus on their co-occurring somatic complaints such as musculoskeletal pain or gastrointestinal or neurocognitive symptoms28,139. As a consequence, PTSD can present a diagnostic challenge in non-mental health settings. A study in a primary care setting identified that only 11% of patients with PTSD detected by structured interview were listed as such in clinical files140. To complicate matters, somatic symptoms, which can relate to neuroendocrine and autonomic dysregulation in PTSD, might also be attributed to illness caused by toxic environmental exposures, especially in combat environments, and have led to controversies about the existence of distinct illnesses, such as Gulf War Syndrome141. Thus, self-reporting instruments and structured diagnostic interviews are recommended in clinical practice to improve the reliability of diagnosis.
即使在那些没有特定原因隐藏或放大症状的人中,由于在创伤事件后习惯性地将痛苦正常化,加上避免谈论痛苦记忆的倾向,PTSD 的诊断也可能很困难。通常,PTSD 患者会关注他们共存的躯体症状,如肌肉骨骼疼痛或胃肠道或神经认知症状。因此,在非心理健康环境中,PTSD 的诊断可能是一个挑战。一项在初级保健环境中的研究发现,通过结构化访谈检测到的 PTSD 患者中,只有 11%在病历中被列为 PTSD。为了使问题更加复杂,与 PTSD 中神经内分泌和自主神经失调相关的躯体症状也可能归因于有毒环境暴露引起的疾病,特别是在战斗环境中,这导致了关于是否存在特定疾病(如海湾战争综合症)的争议。因此,建议在临床实践中使用自我报告工具和结构化诊断访谈,以提高诊断的可靠性。

No objective laboratory tests can so far confirm the presence of trauma exposure or PTSD, although there is great interest in the development of these tools. Indeed, biological assessments might identify a range of physiological and neurobiological signs and symptoms that might facilitate diagnostic assessment and the prediction of treatment response30,142.
目前尚无客观的实验室检测可以确认创伤暴露或创伤后应激障碍的存在,尽管对这些工具的开发有很大兴趣。事实上,生物评估可能识别一系列生理和神经生物学症状,这可能有助于诊断评估和预测治疗效果。

Screening  筛查

The prevalence and the burden of diseases associated with PTSD highlight the importance of screening in clinical settings, including primary care, and in populations at risk for trauma exposure. Any health professional involved in the follow-up care of those with physical injuries of accidents or assault should be able to detect PTSD symptoms32. Many screening measures are available that can detect cumulative exposure to trauma and resultant symptoms143145. A positive finding should be followed up by a comprehensive mental health evaluation. Ideally, screening will also assess other comorbid disorders.
疾病与创伤后应激障碍(PTSD)的患病率和负担突出了在临床环境中,包括初级保健和易受创伤暴露风险的人群中进行筛查的重要性。任何参与那些因事故或攻击而遭受身体伤害的人的后续护理的健康专业人员都应能够检测到 PTSD 症状 32 。有许多筛查措施可以检测到创伤的累积暴露和由此产生的症状 143145 。阳性结果应随后进行全面的心理健康评估。理想情况下,筛查还应评估其他共病障碍。

In populations at risk of delayed-onset PTSD, continued assessment is recommended128. In some settings, such as primary care, annual screening is a reasonable minimum recommended standard but should be implemented more frequently in settings in which trauma exposures are common146. For military populations, there is greater acceptance of the benefits of screening at post-deployment than at pre-deployment146. The challenges of screening for PTSD include the inability to determine the cause of symptoms, the high false-positive rate and low predictive value in settings in which prevalence is expected to be fairly low145. Screening in primary care settings and screening that is combined with care coordination seem to be more effective than population screening147, particularly in high-risk populations.
在存在延迟发病 PTSD 风险的人群中,建议持续评估。在一些环境中,如初级保健,年度筛查是一个合理的最低推荐标准,但在创伤暴露普遍的环境中应更频繁地实施。对于军事人群,对部署后筛查益处的接受程度高于部署前。筛查 PTSD 的挑战包括无法确定症状的原因,以及在预期患病率相对较低的环境中,高假阳性率和低预测价值。在初级保健环境中进行的筛查以及与护理协调相结合的筛查似乎比人群筛查更有效,尤其是在高风险人群中。

Prevention  预防

Opportunities for PTSD prevention are considerable for military personnel, emergency first responders and, increasingly, journalistic war correspondents. Prevention programmes aim to promote good psychological health and adaptive methods for coping in the face of adversity146. Several approaches — such as resilience training, prevention interventions and reintegration interventions — have been implemented on the basis of theoretical frameworks in military settings148. Although data are lacking regarding the success of such programmes, rehearsal and preparation for trauma are thought to remove some of the elements of shock and to permit adaptive responding during a threat. In civilians, preparedness for trauma might also enhance resilience149.
预防创伤后应激障碍(PTSD)的机会对于军事人员、紧急救援人员以及越来越多的战地记者来说是相当大的。预防项目旨在促进良好的心理健康和应对逆境的适应方法 146 。在军事环境中,基于理论框架已实施了多种方法——如韧性训练、预防干预和复员干预——。尽管缺乏关于此类项目成功的数据,但人们认为,对创伤的排练和准备可以消除一些震惊的元素,并允许在威胁期间进行适应性反应。在平民中,对创伤的准备也可能增强韧性 149

Preventing PTSD is difficult among persons already exposed to mass communal violence and major disasters. However, relevant information about what to do in the aftermath of trauma is scant, and concerns have been raised that scientific research or programme evaluation in emergency settings might interfere with the provision of care. The sense of urgency to help after major events such as disasters makes research very difficult to carry out in these circumstances and is often perceived as showing intellectual indifference rather than a desire to assist150. Furthermore, experience with critical incident stress debriefing — which aims to enhance individuals' natural resilience and coping capacity following adversity — highlights that not all attempts guarantee effectiveness; no benefit was shown in intervention trials146. In addition, reviews of clinical trials do not support this approach in civilians151; however, such interventions might have a role in occupational groups, such as emergency first responders, though data are lacking. The current standard is to offer psychological ‘first aid’, but little systematic evidence is available to support this approach146.
预防创伤后应激障碍对于已经遭受大规模群体暴力和重大灾难的人来说很困难。然而,关于创伤后应采取何种措施的相关信息很少,人们也提出了担忧,认为在紧急情况下进行的科学研究或项目评估可能会干扰护理的提供。在重大事件(如灾害)之后帮助人们的紧迫感使得在这些情况下进行研究非常困难,并且常常被视为表现出知识冷漠而非援助的愿望。此外,对关键事件压力缓解的经验——旨在提高个人在逆境后的自然弹性和应对能力——表明并非所有尝试都能保证有效性;干预试验中未显示出任何益处。此外,临床试验的回顾不支持这种在平民中的方法;然而,这种干预在职业群体(如紧急救援人员)中可能发挥作用,尽管数据不足。当前的标准是提供心理“急救”,但很少有系统证据支持这种方法。

Another area of great interest is the development of PTSD prophylaxis through the administration of medication in the emergency room or in intensive care units152,153. These studies are based on evidence that reactivated memory traces are vulnerable to disruption in the peri-traumatic phase, offering a potential ‘time window’ to enhance cognition by affecting reconsolidation of trauma memories154,155. Naturalistic studies have shown that people who take large doses of opiates during or immediately after trauma exposure are less likely to develop PTSD than those who do not take such medications156,157; propranolol was the first of these treatments to be proposed for this use as it has the potential to interfere with the role of noradrenaline in the consolidation of traumatic memories158. However, the results so far in clinical trials have shown no benefit159. The role of cortisol in preventing PTSD has also been considered given that low levels of cortisol in the immediate aftermath of traumatic events has been found to predict later PTSD diagnosis160,161. In this example, naturalistic studies have shown that, in patients with septic shock, prednisone administration was associated with the development of fewer traumatic memories than placebo treatment162. In the case of cortisol prophylaxis, several early studies have yielded promising results, particularly when a high dose is administered once during the ‘golden hours’ following trauma exposure159,163. Given that a prevailing model of PTSD development involves a failure to mount neural defensive responses to sympathetic nervous system activation (leading to the development of a stronger and a more emotional memory), cortisol treatment during a critical post-traumatic window might facilitate such responses163 (Fig. 5). Cortisol not only reduces sympathetic nervous system activation but also facilitates fear extinction. One small randomized trial found that hydrocortisone administration within 12 hours of trauma also decreased the risk of PTSD164. Two studies showed that the dose of narcotic analgesic administered during admission to hospital after traumatic injury decreased the risk of PTSD independently of the severity of injury; however, the role of narcotic analgesics in preventing PTSD has not been tested in a clinical trial157,165.
另一个备受关注的研究领域是通过在急诊室或重症监护室给药来开发 PTSD 的预防措施。这些研究基于证据,即在创伤期,重新激活的记忆痕迹容易受到干扰,这为通过影响创伤记忆的重新巩固来增强认知提供了一个潜在的“时间窗口”。自然 istic 研究表明,在创伤暴露期间或之后立即服用大剂量阿片类药物的人比那些没有服用此类药物的人不太可能发展为 PTSD;普萘洛尔是第一种被提议用于这种用途的治疗方法,因为它有可能干扰去甲肾上腺素在创伤记忆巩固中的作用。然而,迄今为止的临床试验结果尚未显示出任何益处。鉴于在创伤事件发生后立即发现皮质醇水平低可以预测后来的 PTSD 诊断,因此也考虑了皮质醇在预防 PTSD 中的作用。 在这个例子中,自然主义研究表明,在患有脓毒症的患者中,与安慰剂治疗相比,泼尼松的使用与创伤记忆的发展减少有关 162 。在皮质醇预防的情况下,几项早期研究已经产生了有希望的结果,尤其是在创伤暴露后的“黄金时段”一次性给予高剂量时 159,163 。鉴于 PTSD 发生的一个主要模型涉及未能对交感神经系统激活产生神经防御反应(导致更强烈和更具情感的记忆发展),在关键创伤后窗口期给予皮质醇治疗可能有助于产生这种反应 163 (图 5)。皮质醇不仅减少交感神经系统激活,还促进恐惧消退。一项小型随机试验发现,在创伤后 12 小时内给予氢化可的松也降低了 PTSD 的风险 164 。 两项研究表明,在创伤性损伤后入院期间使用的阿片类镇痛药剂量可以降低 PTSD 的风险,而不论损伤的严重程度;然而,阿片类镇痛药在预防 PTSD 中的作用尚未在临床试验中得到检验。

Figure 5: Consequences of reduced cortisol signalling in acute aftermath of trauma.
图 5:创伤急性期皮质醇信号减少的后果。
figure 5

In response to trauma, catecholamines (such as adrenaline (epinephrine) and noradrenaline (norepinephrine)) are produced, which mediate the sympathetic nervous system response to stress and have a role in memory formation. In patients who develop post-traumatic stress disorder (PTSD), the role of cortisol to counteract these stress hormones is thought to be reduced. Some evidence suggests that administration of cortisol in the aftermath of trauma might prevent the eventual development of PTSD.
创伤反应时,会产生儿茶酚胺(如肾上腺素(肾上腺素)和去甲肾上腺素(去甲肾上腺素)),这些物质介导交感神经系统对压力的反应,并在记忆形成中发挥作用。在患有创伤后应激障碍(PTSD)的患者中,认为皮质醇对抗这些压力激素的作用减弱。一些证据表明,在创伤后给予皮质醇可能预防最终发展为 PTSD。

PowerPoint slide  幻灯片

Management  管理

Psychotherapy  心理治疗

Despite the emerging understanding of PTSD as a disorder involving substantial brain, molecular and neurochemical change, pharmacotherapy treatments have not conclusively shown efficacy that is equivalent to psychotherapy, which is generally recommended as a first-line treatment (Table 3). A range of trauma-focused as well as non-trauma-focused psychotherapies, including CBT, supportive therapy, non-directive counselling, present-centred therapy and interpersonal therapy (Box 3) have shown clinical benefits in the treatment of PTSD166,167. Some treatment approaches favour targeting specific trauma-related symptoms, behaviours, thoughts or perceptions, whereas others have a wider focus on meaning making or addressing current life stressors and goals. Both trauma-focused CBT and non-trauma-focused therapy have consistently been shown to be superior to wait-list conditions (Box 3) in reducing PTSD symptoms; trauma-focused treatments are generally accepted as the most efficacious. Of course, comparison of no treatment to active treatment can fail to account for nonspecific effects of therapy and can lead to overstated conclusions about the superiority of an identified treatment168.
尽管人们对创伤后应激障碍(PTSD)作为一种涉及大脑、分子和神经化学变化的疾病的认识正在不断加深,但药物治疗尚未显示出与心理治疗相当的有效性,而心理治疗通常被推荐作为一线治疗方法(表 3)。包括认知行为疗法(CBT)、支持性治疗、非指导性咨询、以现在为中心的治疗和人际治疗(框 3)在内的各种创伤焦点和非创伤焦点心理治疗在治疗 PTSD 方面已显示出临床益处。一些治疗方法倾向于针对特定的创伤相关症状、行为、想法或感知,而其他治疗方法则更广泛地关注意义构建或应对当前的生活压力和目标。创伤焦点 CBT 和非创伤焦点治疗均一致显示出优于等待名单条件(框 3)在减少 PTSD 症状方面的优势;创伤焦点治疗方法通常被认为是最有效的。当然,将无治疗与积极治疗进行比较可能无法解释治疗的非特异性效应,可能导致对特定治疗方法优越性的过度评价 168

Table 3 Overview of interventions for PTSD
表 3 PTSD 干预措施概述

A typical psychotherapeutic treatment for PTSD is delivered through weekly sessions, generally over 6–16 weeks as the global standard. However, patients might require several more sessions over months or years. The discrepancy between treatment recommendations in the literature and those used in clinical practice has not been sufficiently addressed. Indeed, although these treatments are often provided in healthcare systems such as the Veterans Administration in the United States, most patients with PTSD remain with a considerable symptom burden over prolonged periods of time.
创伤后应激障碍的典型心理治疗方法是通过每周一次的会话进行,通常为 6-16 周,这是全球标准。然而,患者可能需要几个月或几年内进行更多次会话。文献中治疗建议与临床实践中使用的治疗建议之间的差异尚未得到充分解决。事实上,尽管这些治疗通常在美国退伍军人管理局等医疗体系中提供,但大多数患有创伤后应激障碍的患者在长时间内仍承受相当大的症状负担。

Trauma-focused CBTs, such as prolonged exposure therapy and cognitive processing therapy, for symptoms of PTSD have been the most thoroughly studied and have shown equivalent effectiveness in head-to-head comparisons169. These therapies are based on the idea that promoting emotion regulation and extinction learning will neutralize the distress of trauma-related thoughts and images and obviate the need for avoidance behaviours170,171. Prolonged exposure therapy facilitates habituation using principles of extinction learning, habituation and desensitization through progressive exposure to the trauma narrative and triggering settings (Fig. 6). Cognitive processing therapy addresses shame, guilt or feelings of mistrust. More recently, narrative exposure therapy has been described, which focuses on life histories through narration and has been successfully used in complex forms of PTSD. This therapy is particularly helpful with refugees and asylum seekers and has been successfully provided by lay counsellors who have no formal clinical education172.
创伤聚焦的认知行为疗法,如暴露疗法和认知加工疗法,对于 PTSD 症状的研究最为深入,并在直接比较中显示出等效的有效性。这些疗法基于促进情绪调节和消除学习的理念,以中和与创伤相关的想法和图像的痛苦,并消除回避行为的需求。暴露疗法通过渐进式暴露于创伤叙述和触发环境,利用消除学习的原则促进习惯化、习惯化和脱敏(图 6)。认知加工疗法针对羞愧、内疚或信任感缺失。最近,还描述了叙事暴露疗法,它通过叙述聚焦于生活史,并在复杂的 PTSD 形式中成功应用。这种疗法特别有助于难民和寻求庇护者,并由没有正式临床教育的非专业咨询师成功提供。

Figure 6: The timing of treatment of PTSD.
图 6:创伤后应激障碍(PTSD)的治疗时机。
figure 6

Psychotherapies aim to promote emotion regulation and extinction learning to neutralize the distress of trauma-related thoughts. Administration of drugs that have the capacity to manipulate the process of memory formation, consolidation, retrieval, reconsolidation or extinction can be used to prevent the onset of post-traumatic stress disorder (PTSD) or to treat the condition once it is apparent.
心理治疗旨在促进情绪调节和灭绝学习,以中和与创伤相关想法的痛苦。可以使用具有操纵记忆形成、巩固、检索、再巩固或灭绝过程能力的药物来预防创伤后应激障碍(PTSD)的发生,或一旦出现该状况就进行治疗。

PowerPoint slide  幻灯片

Eye movement desensitization and reprocessing (EMDR) is another trauma-focused therapy for which efficacy has been shown. Though its mechanism of action is a subject of debate, EMDR also incorporates elements of exposure, cognitive restructuring and relaxation. In EMDR, the therapist uses different forms of bilateral stimulation (most commonly lateral eye movements) to encourage a dual awareness while the patient recollects the trauma173,174. Once accessed, the memory is amenable to modification and positive cognitions can be introduced in the place of negative ones. In direct comparison studies, EMDR has been shown to be as efficacious as other trauma-focused CBTs175,168.
眼动脱敏与再加工(EMDR)是另一种已证明有效的创伤聚焦疗法。尽管其作用机制存在争议,EMDR 也结合了暴露、认知重构和放松的元素。在 EMDR 中,治疗师使用不同形式的双侧刺激(最常见的是侧向眼动)来鼓励患者在回忆创伤时产生双重意识。一旦访问到记忆,它就易于修改,可以在消极认知的地方引入积极的认知。在直接比较研究中,EMDR 已被证明与其他创伤聚焦认知行为疗法(CBT)一样有效。

Treatments that do not involve direct confrontation with traumatic material, such as present-centred or interpersonal therapy approaches, have been shown to be almost comparable to trauma-focused approaches in some studies, with the potential benefit of lower drop-out rates176178. However, almost all clinical guidelines and expert reviews have assigned higher evidence statements to trauma-focused approaches179184, probably because of how well studied these therapies have been in large-scale efficacy and effectiveness trials. Furthermore, trauma-focused therapies aim to target fear-based emotional reactions that are thought to underpin PTSD pathology, as described above.
治疗方法不涉及直接面对创伤材料,如以现在为中心或人际治疗方法的,一些研究表明,这些方法几乎与创伤聚焦方法相当,具有潜在的低脱落率优势。然而,几乎所有临床指南和专家评审都赋予了创伤聚焦方法更高的证据陈述,这可能是由于这些疗法在大规模疗效和有效性试验中得到了很好的研究。此外,创伤聚焦疗法旨在针对上述所述的基于恐惧的情感反应,这些反应被认为是 PTSD 病理的基础。

Patients with a history of interpersonal violence, early-life trauma or those with a complex presentation of PTSD that includes emotional detachment might be better treated with phase-oriented approaches185. Phase-oriented therapies involve skills training, mood regulation and grounding, identifying attachment schemas and developing competence in social interactions. Once these skills have been developed, the patient can then participate in modified exposure-based therapy focusing on emotional stability and negative personal schemas186,187. Other therapies of interest include self-regulation therapies (for example, biofeedback and neurofeedback) and behaviour-based self-regulation therapies (for example, yoga and mindfulness training). These treatments permit brain, central nervous system and behavioural regulation of stress, arousal and interoceptive awareness188,189.
患者如有人际暴力史、早年创伤或 PTSD 复杂表现(包括情感疏离)可能更适合采用阶段导向方法治疗。阶段导向疗法包括技能训练、情绪调节和扎根,识别依恋模式并发展社交互动能力。一旦这些技能得到发展,患者可以参与基于修改后的暴露疗法,重点关注情绪稳定和负面个人模式。其他感兴趣的疗法包括自我调节疗法(例如,生物反馈和神经反馈)和基于行为的自我调节疗法(例如,瑜伽和正念训练)。这些治疗允许对大脑、中枢神经系统和行为的压力、唤醒和内省意识进行调节。

Pharmacological treatment
药物治疗

Only two medications, which are both selective serotonin reuptake inhibitors (sertraline and paroxetine), have received an indication from the FDA for use in PTSD, but many medications are used off label on the basis of existent and emerging studies of PTSD biology (Table 3). Several national societies have adopted recommendations from international consensus guidelines (Table 4), which have varied widely in the past 10 years, and tailored these to their current systems of care. The initial interest in using selective serotonin reuptake inhibitors in PTSD was based on the high comorbidity of PTSD with mood and anxiety disorders for which antidepressants are effective. This rationale also prompted extensive studies of tricyclic antidepressants and monoamine oxidase inhibitors, but these drugs were associated with considerable adverse effects and higher drop-out rates than selective serotonin reuptake inhibitors190,191. As shown in Table 4, considerable variation is evident in the recommendations that have been made over the past decade. There are good grounds for caution against the widespread use of atypical antipsychotic medications given the risks that were initially not well appreciated, especially cardiovascular and metabolic risks192. Current evidence favours selective serotonin reuptake inhibitors as the class with the most evidence supporting their use as first-line psychopharmacological treatment options for patients requiring medications190,191,193. There is also much attention on addressing specific symptoms, such as sleep disturbance or nightmares.
仅有两种药物,即选择性 5-羟色胺再摄取抑制剂(舍曲林和帕罗西汀),获得了 FDA 在 PTSD 治疗中的使用批准,但许多药物基于现有的和新兴的 PTSD 生物学研究(表 3)被非正式使用。几个国家学会采纳了国际共识指南的建议(表 4),这些建议在过去 10 年中差异很大,并根据自己的当前护理体系进行了调整。最初对在 PTSD 中使用选择性 5-羟色胺再摄取抑制剂的兴趣是基于 PTSD 与情绪和焦虑障碍的高共病率,这些障碍对抗抑郁药有效。这一理由也促使对三环类抗抑郁药和单胺氧化酶抑制剂的广泛研究,但这些药物与选择性 5-羟色胺再摄取抑制剂相比,副作用更大,脱落率更高。如表 4 所示,过去十年中提出的建议存在相当大的差异。 有充分的理由对广泛使用非典型抗精神病药物保持谨慎,因为最初并未充分认识到其风险,尤其是心血管和代谢风险。现有证据支持选择性 5-羟色胺再摄取抑制剂作为具有最多证据支持其作为一线精神药理学治疗选择的药物类别。同时,也有许多关注点在于解决特定症状,如睡眠障碍或噩梦。

Table 4 Key recommendations from several clinical practice guidelines for PTSD
表 4:来自多个临床实践指南针对 PTSD 的关键建议

It has been tempting to make inferences about PTSD neurobiology on the basis of the presumed mechanisms of drugs used to treat PTSD and, conversely, to use evidence obtained in animal and human studies of PTSD to explain why antidepressants are effective. However, such research suffers from post hoc fallacy: even in trials in which selective serotonin reuptake inhibitors show efficacy in PTSD, this does not necessarily indicate that the condition has anything to do with dysregulation or deficiency in serotonin systems.
它一直很有诱惑力,根据用于治疗 PTSD 的药物假定的机制来推断 PTSD 的神经生物学,反之,利用在动物和人类研究中获得的 PTSD 证据来解释为什么抗抑郁药有效。然而,此类研究存在事后归因谬误:即使在选择性 5-羟色胺再摄取抑制剂在 PTSD 试验中显示出疗效的试验中,这也并不一定意味着该疾病与 5-羟色胺系统的失调或缺乏有任何关系。

Conversely, attempts to identify pharmacological agents for PTSD on the basis of PTSD pathophysiology have also presented some challenges. These efforts have been constrained by the lack of both appropriate tools for the study of structure and function of the living human brain and data from unbiased large-scale molecular and genomic studies. In the absence of these, the PTSD field has developed and tested pharmacological strategies on the basis of emergent findings of biological alterations in PTSD, with limited success. For example, following observations of hippocampal abnormalities in PTSD, there was interest in phenytoin and tianeptine194 for their potential to reverse stress-induced hippocampal atrophy. Later studies, including the above-mentioned twin studies69 called into question that glucococorticoid-induced apoptosis was the cause of the neuroimaging findings of smaller hippocampal volumes in patients with PTSD195197.
相反,基于 PTSD 病理生理学来识别用于治疗 PTSD 的药物的努力也面临了一些挑战。这些努力受到缺乏研究活人脑结构和功能适当工具以及来自无偏见的大规模分子和基因组研究数据的限制。在没有这些的情况下,PTSD 领域基于 PTSD 中生物改变的突发发现,开发和测试了药物策略,但效果有限。例如,在观察到 PTSD 患者海马体异常后,人们对苯妥英和替扎尼定 194 表现出兴趣,因为它们有可能逆转由压力引起的海马体萎缩。后来的研究,包括上述提到的双胞胎研究 69 ,质疑了糖皮质激素诱导的细胞凋亡是 PTSD 患者神经影像学发现海马体体积较小的原因 195197

Similarly, anti-adrenergic drugs (such as α2-adrenergic agonists or β-adrenergic antagonists) have received attention on the basis of evidence for noradrenergic dysregulation in PTSD. However, experiences with clonidine or propranolol in PTSD were disappointing. There has been interest in the α1-adrenergic blocker prazosin for the treatment of PTSD-related nightmares198, but results from a large multicentre Veterans Affairs trial in the United States seemed to show limited or no efficacy compared with placebo (preliminary results)199. The development of glucocorticoid-based treatments for PTSD has also been an important emerging area of research given the substantial evidence for HPA axis alteration in PTSD200. A small trial with the glucocorticoid receptor antagonist mifepristone yielded modest results201, and several small trials using cortisol treatment have reported significant efficacy202,203. However, these data await confirmation from larger trials, which are currently ongoing.
同样,基于对创伤后应激障碍(PTSD)中去甲肾上腺素失调的证据,抗肾上腺素药物(如α2-肾上腺素能激动剂或β-肾上腺素能拮抗剂)也引起了关注。然而,在 PTSD 中使用可乐定或普萘洛尔的经历令人失望。对于治疗 PTSD 相关的噩梦,α1-肾上腺素能阻滞剂哌唑嗪引起了兴趣,但美国一项大型多中心退伍军人事务部试验的结果似乎表明,与安慰剂相比,其疗效有限或没有(初步结果)。鉴于 PTSD 中 HPA 轴改变的大量证据,基于糖皮质激素的治疗 PTSD 也是一个重要的新兴研究领域。一项使用糖皮质激素受体拮抗剂米非司酮的小型试验产生了适度结果,而使用皮质醇治疗的一些小型试验报告了显著的疗效。然而,这些数据需要更大规模试验的确认,这些试验目前正在进行中。

Some definitive conclusions can be drawn regarding the use of medications in PTSD treatment. What is clear from meta-analyses of randomized clinical trials is that certain drug treatments, particularly selective serotonin reuptake inhibitors, are superior to placebo in reducing PTSD severity204. Effect sizes in medication studies are also lower than those observed in psychotherapy trials, and medication effects are less enduring than those of psychotherapy. The lower effect sizes might partly result from higher but considerable placebo effects in medication trials that are more difficult to control for than in psychotherapy trials (which compare active treatment to wait-listed controls), and this might be a source of confounding variables. It is also clear that some medications, such as the benzodiazepines, should not be used in the treatment of PTSD205. Benzodiazepines are problematic because of the development of dependence and the possibility of withdrawal symptoms, which can exacerbate PTSD symptoms190,191. Similar caution is warranted for hypnotics even though they are highly prescribed in clinical practice. An important area requiring clarification is whether medications should be used in addition to, or instead of, psychotherapeutic approaches. In the absence of studies that directly compare these two modalities, most published guidelines include separate recommendations for medications and psychotherapy.
一些关于在创伤后应激障碍(PTSD)治疗中使用药物的确切结论可以得出。从随机临床试验的荟萃分析中可以清楚地看出,某些药物治疗,尤其是选择性 5-羟色胺再摄取抑制剂,在减轻 PTSD 严重程度方面优于安慰剂。药物研究中的效应量也低于心理治疗试验中观察到的效应量,并且药物的效果不如心理治疗持久。较低的效应量可能部分源于药物试验中较高的但相当大的安慰剂效应,这在心理治疗试验中更难控制(心理治疗试验比较的是活跃治疗与等待名单上的对照组),这可能是混杂变量的来源。很明显,一些药物,如苯二氮䓬类药物,不应用于 PTSD 的治疗。苯二氮䓬类药物存在问题,因为它们会导致依赖性和可能出现停药症状,这些症状可能会加剧 PTSD 的症状。尽管在临床实践中催眠剂被大量使用,但对此也应保持谨慎。 一个需要明确的重要领域是,是否应将药物治疗与心理治疗方法同时使用,还是替代使用。由于缺乏直接比较这两种方法的临床研究,大多数已发表的指南包括对药物和心理治疗的单独建议。

New developments  新发展

Some promising pharmacological treatments for PTSD are being developed on the basis of emerging information about PTSD pathophysiology. In addition to the glucocorticoid-based therapies described above, other novel compounds that require further research include corticotropin-releasing hormone antagonists206 and drugs that affect the endocannabinoid system. CB1 receptor-mediated endocannabinoid signalling has also been implicated in the extinction of adverse memories in animal studies. Augmenting levels of anandamide (an endogenous cannabinoid) in the amygdala modulates short-term fear extinction207,208. Elevated CB1 receptor availability in those with PTSD was shown using a selective PET ligand, with correspondingly lower circulating levels of anandamide in blood. These findings might also have implications for the use of cannabinoids, including tetrahydrocannabinol, in PTSD treatment.
一些针对 PTSD 的具有潜力的药物治疗正在基于对 PTSD 病理生理学的新信息开发。除了上述基于糖皮质激素的治疗方法外,还需要进一步研究的其他新型化合物包括促肾上腺皮质激素释放激素拮抗剂和影响内源性大麻素系统的药物。动物研究表明,CB1 受体介导的内源性大麻素信号传导也与不良记忆的消除有关。通过增加杏仁核中大麻素(一种内源性大麻素)的水平,可以调节短期恐惧消除。使用选择性 PET 配体已显示,PTSD 患者 CB1 受体可用性升高,血液中相应的大麻素循环水平降低。这些发现也可能对包括四氢大麻酚在内的在大麻素在 PTSD 治疗中的应用有影响。

Another compound of interest is ketamine. Ketamine is a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors that affects learning and memory. A rapid reduction in PTSD symptoms has been shown following the intravenous administration of ketamine209. Drugs such as 3,4-methylenedioxy-methamphetamine (MDMA), which blocks dopamine reuptake and has been linked with NMDA receptor action, has also garnered interest. Given that these compounds have the potential for abuse, determining whether their use in PTSD treatment outweighs the potential risks is important210,211. Finally, drugs that might enhance resilience — such as NPY agonists — are also an important development for the field of PTSD treatment55. The use of transcranial magnetic stimulation, deep brain stimulation and new neurofeedback techniques is another potential frontier in PTSD212,213.
另一种感兴趣的化合物是氯胺酮。氯胺酮是影响学习和记忆的 N-甲基-d-天冬氨酸 (NMDA) 受体的非竞争性拮抗剂。静脉注射氯胺酮 209 后,PTSD 症状迅速减轻。3,4-亚甲二氧基甲基苯丙胺 (MDMA) 等药物可阻断多巴胺再摄取并与 NMDA 受体作用有关,也引起了人们的兴趣。鉴于这些化合物具有滥用的可能性,确定它们在 PTSD 治疗中的使用是否超过潜在风险很重要 210,211 。最后,可能增强恢复力的药物——如 NPY 激动剂——也是 PTSD 治疗领域的重要发展 55 。经颅磁刺激、深部脑刺激和新的神经反馈技术的使用是 PTSD 212,213 的另一个潜在前沿。

The use of pharmacotherapy as adjunctive treatment with established trauma-focused psychological therapies is another intense focus of research214. The most well studied of these has been the use of d-cycloserine in conjunction with prolonged exposure psychotherapy to accelerate extinction of fear conditioning215. D-Cycloserine is a glycine receptor agonist with demonstrated effects on extinction learning in animals215. This treatment has not yet proven to be successful in augmenting or accelerating efficacy of exposure-based therapy, but several trials are currently underway with the anticipation that a subgroup of patients showing fear-based symptoms may benefit. An initial trial with hydrocortisone augmentation suggested that this adjunctive treatment might prevent drop-outs216. This study was also noteworthy in suggesting that specific subgroups with glucocorticoid dysregulation may be more responsive to this augmentation strategy.
药物治疗作为已建立的创伤焦点心理治疗的辅助治疗,是研究的热点之一。其中研究最深入的是将 d-环丝氨酸与长期暴露心理治疗联合使用,以加速恐惧条件反射的消退。D-环丝氨酸是一种甘氨酸受体激动剂,在动物实验中已显示出对消退学习的影响。这种治疗方法尚未证明能够增强或加速基于暴露的疗法的疗效,但目前正在进行的几项试验预计,表现出基于恐惧症状的患者群体可能会从中受益。一项初步的氢化可的松增强试验表明,这种辅助治疗可能有助于预防脱落。这项研究还值得注意的是,它提出了具有糖皮质激素失调的特定亚组可能对这种增强策略更敏感。

Quality of life  生活质量

PTSD by definition can only be diagnosed if it appreciably affects occupational, interpersonal or social quality of life domains1,217. More severe PTSD symptoms are associated with poorer quality of life218, an association that has been shown across cultures219. Figure 7 outlines the timing of quality of life issues in association with PTSD.
创伤后应激障碍(PTSD)的定义是只有在它显著影响职业、人际或社会生活质量领域时才能被诊断。更严重的 PTSD 症状与生活质量较差相关,这种关联已在不同文化中得到证实。图 7 概述了与 PTSD 相关的质量问题的时间线。

Figure 7: Timing of quality of life issues with PTSD.
图 7:创伤后应激障碍(PTSD)生活质量问题的时间线。
figure 7

Several domains of quality of life are affected in patients with post-traumatic stress disorder (PTSD) at different times.
创伤后应激障碍(PTSD)患者的多个生活质量领域在不同时间受到影响。

PowerPoint slide  幻灯片

Symptoms such as poor sleep quality as a result of nightmares or hyperarousal can lead to poor concentration and irritability, affecting work performance and professional relationships. For deployment-related PTSD, interaction with authority figures can be a reminder of the environment in which the exposure occurred, leading the survivor to avoid the workplace or result in altercations with workplace superiors220. Victims of interpersonal assault might overgeneralize contact with individuals reminiscent of their attacker and the survivor might feel uncomfortable in close physical proximity to co-workers. Sexual assault victims can also experience chronic pelvic pain and other somatic complaints221. These problems can also occur in social settings. Avoidance symptoms and phobic behaviours are common, extending to reluctance or refusal to take public transportation to and from work or other activities, which further exacerbates social isolation.
症状如因噩梦或过度警觉导致的睡眠质量差,可能导致注意力不集中和易怒,影响工作表现和职业关系。对于与部署相关的创伤后应激障碍,与权威人物的互动可能成为提醒暴露发生环境的因素,导致幸存者避免工作场所或与工作场所上级发生冲突 220 。人际攻击的受害者可能会过度概括与攻击者相似的人的接触,幸存者可能在与同事的近距离身体接触中感到不适。性侵犯受害者也可能经历慢性盆腔痛和其他躯体症状 221 。这些问题也可能发生在社交场合。回避症状和恐惧行为很常见,甚至扩展到不愿意或拒绝乘坐公共交通工具上下班或其他活动,这进一步加剧了社会隔离。

Individuals who have poor social support are less likely to recover from the effects of PTSD222. However, having PTSD directly undermines social support networks, placing a substantial burden on personal and familial relationships. Many individuals with PTSD have difficulties with intimacy at all levels, ranging from physical contact to engaging in personal dialogue requiring empathy and an implicit assumption of safety223. The generalized emotional numbing makes it difficult for patients to receive and to give affection and increases isolation. Indeed, PTSD is associated with disruption of familial ties and poor parenting behaviour, leading to separation, divorce and disruption of the family, even further undermining the most salient social supports that can promote resilience220,224.
个体如果缺乏社会支持,则不太可能从创伤后应激障碍(PTSD)的影响中恢复过来。然而,PTSD 会直接破坏社会支持网络,给个人和家庭关系带来沉重负担。许多患有 PTSD 的人在与亲密关系方面存在困难,从身体接触到需要同理心和隐含安全感的个人对话,范围广泛。普遍的情感麻木使患者难以接受和给予关爱,并加剧了孤立感。事实上,PTSD 与家庭关系的破裂和不良的育儿行为有关,导致分离、离婚和家庭破裂,进一步削弱了可以促进韧性的最显著的社会支持。

Quality of life is also affected by lack of resources222,225. When trauma exposure results in devastating loss of home and material possessions, such as in response to natural disaster or displacement, or when trauma occurs in an impoverished environment, the considerable life disruption further decreases quality of life. Finally, PTSD itself often results in the loss of personal, social and material resources, leading to a pattern of declining quality of life over time222,226. Psychotherapy can be successful in improving PTSD and quality of life227,228. However, the longer the duration of PTSD illness, the more these secondary losses in quality of life will remain even if symptoms themselves improve with treatment229.
生活质量也受到资源缺乏的影响。当创伤暴露导致家庭和物质财产的巨大损失,如自然灾害或流离失所的应对,或者当创伤发生在贫困环境中时,这种重大的生活破坏进一步降低了生活质量。最后,创伤后应激障碍本身往往会导致个人、社会和物质资源的丧失,导致生活质量随时间下降的模式。心理治疗可以成功地改善创伤后应激障碍和生活质量。然而,创伤后应激障碍的病程越长,即使症状本身随着治疗而改善,这些生活质量方面的次级损失也会持续存在。

Outlook  展望

Biological studies have largely supported the idea that PTSD is a multisystem disorder that affects stress-activated central and peripheral processes. These studies have also highlighted the heterogeneity of PTSD among individuals. This heterogeneity probably represents the complexity of genetic, developmental and cognitive risk factors, psychiatric comorbidity, the age at which trauma exposure occurs, and the trauma ‘dose’ and repetition. The course of the disorder is dynamic and fluctuates in its presentation over time. Similarly to most psychiatric disorders, it is not yet clear whether PTSD can be distinguished into categorical subtypes or whether the diversity of presentations will be better captured dimensionally.
生物研究在很大程度上支持了 PTSD 是一种影响应激激活的中央和周围过程的全身性疾病这一观点。这些研究还突出了 PTSD 在个体之间的异质性。这种异质性可能代表了遗传、发育和认知风险因素、精神共病、创伤暴露的年龄以及创伤“剂量”和重复的复杂性。该疾病的病程是动态的,其表现随时间波动。与大多数精神疾病类似,目前尚不清楚是否可以将 PTSD 区分成分类亚型,或者是否需要以维度方式更好地捕捉其表现形式的多样性。

Appropriate stratification of patients by genetic risk factors, when possible, will permit a clearer understanding of the specific vulnerabilities to biological or psychosocial factors. Although PTSD is clearly precipitated by circumstances, stratification by genetics offers the potential for advancement in this field. Such stratification might ‘liberate’ investigators from reliance on putative subtypes on the basis of signs and symptoms and might help in the interpretation of developmental risk factors. Furthermore, current efforts to identify risk-associated alleles for PTSD through large-scale GWAS are prompting alignment of phenotypic assessments (including symptoms, trauma exposure measures and intermediate phenotypes), which should facilitate our ability to evaluate and to synthesize information from smaller studies.
患者根据遗传风险因素进行适当的分层,在可能的情况下,将有助于更清晰地理解对生物或心理社会因素的特定易感性。尽管 PTSD 明显是由环境因素引起的,但按遗传因素进行分层为该领域的发展提供了潜力。这种分层可能“解放”研究人员,使他们不再依赖于基于症状和体征的假设亚型,并有助于解释发育风险因素。此外,通过大规模 GWAS 识别与 PTSD 相关的风险等位基因的努力,正在推动表型评估(包括症状、创伤暴露措施和中间表型)的统一,这应该有助于我们评估和综合来自较小研究的资料。

Given human genetic and cultural diversity and the complexity of social and other environmental risk factors, approaches must be developed that extend collection of samples from patients with diverse ancestral backgrounds. Indeed, from a scientific point of view and from a global health equity perspective, it is important to determine the degree to which treatment response depends on individual genetics, local environmental factors and sociocultural factors. It will also be important to use genetic information to better understand the neurobiology of PTSD. Parallel efforts in understanding genome-wide epigenetics and differential expression of genes might yield advance development of novel treatment and prevention strategies (Fig. 8).
考虑到人类遗传和文化多样性以及社会和其他环境风险因素的复杂性,必须开发出能够从具有不同祖先背景的患者中收集样本的方法。事实上,从科学观点和全球卫生公平的角度来看,确定治疗反应在多大程度上取决于个体遗传、当地环境因素和社会文化因素是很重要的。利用遗传信息更好地理解 PTSD 的神经生物学也将很重要。在理解全基因组表观遗传学和基因差异表达方面的平行努力可能会促进新型治疗和预防策略的先进发展(图 8)。

Figure 8: Systems biology approach to biomarker discovery and validation.
图 8:生物标志物发现和验证的系统生物学方法。
figure 8

Bioinformatic techniques applied to multidimensional data — including developmental events, culture, gender, genetic variants, epigenetic modifications, brain structural and functional measures, gene transcripts, proteins and metabolites — are used to detect molecular networks and signalling pathways that are key drivers in biologically valid subtypes of post-traumatic stress disorder (PTSD). Validation of identified networks requires multiple approaches that include large-scale longitudinal cohort studies in humans and relevant animal models of specific relevant behaviours. The animal models enable validation of measurement of identified networks in brain regions with proxy markers in peripheral tissues, such as circulating mononuclear cells. The identification of key driver molecular networks linked to PTSD can be interrogated in vitro with neurons derived from reprogrammed skin fibroblasts. These in vitro-derived cells can be used for a variety of discovery purposes, including the study of cell–cell signalling and high-throughput screening to test if existing and novel drugs target the key driver molecular networks identified in PTSD. GWAS, genome-wide association studies; iPSCs, induced pluripotent stem cells; PBMCs, peripheral blood mononuclear cells.
生物信息学技术应用于多维数据——包括发育事件、文化、性别、遗传变异、表观遗传修饰、大脑结构和功能测量、基因转录、蛋白质和代谢物——用于检测在生物有效亚型创伤后应激障碍(PTSD)中的关键驱动分子网络和信号通路。验证所识别的网络需要多种方法,包括在人类中进行的大规模纵向队列研究和相关特定行为动物模型。动物模型使大脑区域中具有外周组织中代理标记的识别网络测量得到验证,如循环单核细胞。与 PTSD 相关的关键驱动分子网络的识别可以通过体外培养的由重编程皮肤成纤维细胞获得的神经元进行探究。这些体外获得的细胞可用于各种发现目的,包括研究细胞间信号传导和高通量筛选,以测试现有和新型药物是否针对 PTSD 中识别的关键驱动分子网络。 GWAS,全基因组关联研究;iPSCs,诱导多能干细胞;PBMCs,外周血单个核细胞。

PowerPoint slide  幻灯片

Indeed, although genes contribute to risk of PTSD, twin studies show that nongenetic factors also considerably contribute to the risk of developing PTSD following trauma. The major candidate mechanisms by which developmental experience is thought to modulate PTSD risk include epigenetic regulation of gene expression and both implicit and explicit forms of long-term memory. These mechanisms probably come into play both during development and following trauma. The epigenetic contributions to risk are of interest, not only in PTSD but also in many mental disorders. Regulation of gene expression, including epigenetic regulation, is exquisitely cell type-specific and is indeed central to the definition of cell types. Gene regulation in response to environmental stimuli — whether normal sensory or physiological stimuli or extreme stimuli (such as trauma) — depend on the specific receptors, signal transduction machinery and enzymes that modify transcription factors, histones or DNA in the cell. As a result, as described in earlier sections, barriers to epigenetic research in mental illness stem from the difficulty in obtaining relevant brain tissue from patients and in obtaining adequate samples post mortem. In post-mortem tissue, the effects of traumatic events might prove difficult to disentangle from other causes of epigenetic regulation that might represent responses to other experiential stimuli, physiological changes, drugs or illness. While studies of epigenetic regulation in peripheral tissues may not reflect neural underpinnings of PTSD, they may be relevant since PTSD is a multisystem disease involving peripheral neural and hormonal responses. Another concern in the interpretation of epigenetic studies is the independent effect size of regulating any particular gene. The combination of inherited allelic variants and the regulation of many genes in relevant cells and circuits probably contribute to PTSD. Future research has the opportunity to pursue correlative studies of central and peripheral components of gene regulation in translational models. Human studies of PTSD should similarly examine correlations among blood, cerebrospinal fluid, fresh human brain tissue when available and post-mortem brain samples to validate informative methodologies.
确实,尽管基因对 PTSD 的风险有贡献,但双生子研究表明,非遗传因素也对创伤后发展 PTSD 的风险有相当大的贡献。被认为可以调节 PTSD 风险的主要候选机制包括基因表达的表观遗传调控以及长期记忆的隐性和显性形式。这些机制可能在发育期间以及创伤后发挥作用。表观遗传对风险的影响不仅对 PTSD,而且对许多精神疾病都很有兴趣。基因表达的调控,包括表观遗传调控,具有高度细胞类型特异性,确实是细胞类型定义的核心。对环境刺激(无论是正常的感觉或生理刺激还是极端刺激,如创伤)的基因调控取决于特定的受体、信号转导机制和修饰转录因子、组蛋白或细胞 DNA 的酶。 因此,如前几节所述,精神疾病表观遗传学研究障碍源于难以从患者获得相关脑组织以及在死后获得足够的样本。在死后组织中,创伤事件的影响可能难以与其他可能代表对其他经验性刺激、生理变化、药物或疾病的反应的表观遗传调控原因区分开来。虽然外周组织中的表观遗传调控研究可能不反映 PTSD 的神经基础,但它们可能相关,因为 PTSD 是一种多系统疾病,涉及外周神经和激素反应。在解释表观遗传学研究时,另一个担忧是调节任何特定基因的独立效应量。遗传等位基因变异的组合以及相关细胞和回路中许多基因的调控可能有助于 PTSD。未来的研究有机会在转化模型中追求基因调控中枢和外围成分的相关性研究。 人类对 PTSD 的研究应类似地检查血液、脑脊液、新鲜的人脑组织(如有)以及死后脑样本之间的相关性,以验证信息性方法的有效性。

Animal studies can also continue to provide important information regarding the relationship between blood and brain pathways, provided that the question of evolutionary conservation from the chosen animal model to the human is kept in mind. An example of this integrative approach recently showed that glucocorticoid receptor signalling was the only convergent pathway identified by gene expression analysis from blood, the hippocampus and the amygdala in both male and female rats that showed vulnerability to prior exposure to predator-scent stress230. This approach provides a basis for comparative gene network analyses from stress-exposed vulnerable and resilient animals and trauma-exposed people who do or do not have PTSD. Such data will facilitate further developments in molecular studies of PTSD in blood.
动物研究也可以继续提供关于血液和脑通路之间关系的重要信息,前提是考虑到从所选动物模型到人类的进化保守性问题。这种综合方法的一个例子最近表明,糖皮质激素受体信号传导是唯一通过从血液、海马体和杏仁核的基因表达分析在男性和雌性大鼠中识别出的趋同途径,这些大鼠先前对捕食者气味压力表现出易感性。这种方法为从易受压力暴露的脆弱和适应性强的动物以及创伤暴露的人(无论是否患有创伤后应激障碍)的比较基因网络分析提供了基础。这些数据将促进对血液中创伤后应激障碍的分子研究的进一步发展。

The field of PTSD has begun to consider multi-omic technology and the promise of systems biology, which have showed value in other medical areas such as cancer231,232. This approach remains aspirational for understanding PTSD pathophysiology but could ultimately yield clinically useful diagnostic biomarkers and molecular targets for drug discovery. With the increasing ability to obtain high-dimensional data — including genome-scale genetic and epigenetic data, as well as transcriptomic, proteomic and metabolomic data — there will be opportunities to develop and to test computational strategies for identifying molecular networks that are relevant to PTSD in peripheral tissues and probably in post-mortem brain and in patient-derived cells that have been reprogrammed into neurons. Indeed, the value of high-dimensional data will be greatly increased as the field of PTSD explores the application of new technologies including reprogramming of isogenic stem cell lines and patient fibroblasts or lymphocytes into neurons and brain organoids, which can be compared with post-mortem brain samples from patients. Such technologies, although still in their early stages, are exciting because they provide access to human cells to study the effects of molecular risk factors for a human condition. Integration of information about the cellular effects of genetic risk, and of transcriptomic and proteomic data sets from isogenic and patient-derived cells reprogrammed into neurons, with data sets derived from studies of patients with PTSD should lead to a deeper understanding of the molecules and the pathways underlying PTSD risk and resilience.
创伤后应激障碍(PTSD)领域已经开始考虑多组学技术和系统生物学的承诺,这些技术在其他医学领域(如癌症)中已显示出价值。这种方法对于理解 PTSD 的病理生理学仍然具有抱负性,但最终可能产生临床上有用的诊断生物标志物和药物发现的分子靶点。随着获取高维数据能力的不断提高——包括基因组规模的遗传和表观遗传数据,以及转录组、蛋白质组和代谢组数据——将有机会开发并测试计算策略,以识别与 PTSD 相关的分子网络,这些网络可能存在于外周组织中,也可能存在于死后脑组织和患者来源的细胞中,这些细胞已被重新编程为神经元。事实上,随着 PTSD 领域探索新技术的应用,包括同源干细胞系和患者成纤维细胞或淋巴细胞的重编程为神经元和脑类器官,这些可以与患者的死后脑样本进行比较,高维数据的价值将大大增加。 这些技术虽然仍处于早期阶段,但令人兴奋,因为它们提供了研究人类条件分子风险因素对人类细胞影响的机会。整合关于遗传风险细胞效应的信息,以及同源和患者来源的细胞重编程为神经元后的转录组和蛋白质组数据集,与来自研究 PTSD 患者的数据集相结合,应有助于更深入地了解 PTSD 风险和恢复力的分子和途径。

The path is long but the identification of genetic and other contributors to risk and the study of their functions in appropriate cell types should facilitate the identification of new drug targets. Such advances should make cell-based screens of chemical libraries and existing drugs possible, with a view to using existing drugs for a different purpose, as has been the practice in cancer, autoimmunity and many other fields of medicine. With a great deal of hard work, drug discovery for PTSD can move from the limited number of hypotheses available today to a vast number of new possibilities.
路径漫长,但识别遗传和其他风险因素以及研究它们在适当细胞类型中的功能应有助于识别新的药物靶点。这些进展应使基于细胞的化学库和现有药物的筛选成为可能,目的是将现有药物用于不同的用途,正如在癌症、自身免疫和许多其他医学领域所做的那样。通过大量的辛勤工作,PTSD 的药物发现可以从今天有限的假设数量转移到大量新的可能性。