In their landmark paper on the current state of knowledge in the field of preventive psychiatry, Fusar‐Poli et al¹ state that “robust genetic and environmental epidemiological knowledge is required to inform evidence‐based preventive approaches”. Indeed, in order to most effectively tailor selective and indicated preventive interventions to an individual's needs, a valid biological and biographical marker panel predictive of future disease risk is essential.

The classical vulnerability‐stress model and the extended vulnerability‐stress‐coping model assume an intricate interplay of biological, particularly genetic, factors with both negative and positive environmental influences in shaping the spectrum of risk and resilience towards mental disorders². However, as rightfully stated by the authors¹, there is currently a “lack of valid biomarkers of risk”, and “the variance explained [by polygenic risk scores] is still too small for implementation in selective prevention and does not provide singular neurobiological targets”. In other words, to date the field of genetic research, including gene‐environment interaction studies and genome‐wide approaches, has not fulfilled its initial promise to unambiguously unravel the pathogenetic mechanisms of mental disorders. Consequently, at the present stage, genetic markers are indeed not suitable as valid biomarkers that could inform targeted preventive interventions.

In recent years, however, increasing evidence has accumulated for epigenetic mechanisms such as DNA methylation and histone modifications to crucially govern gene function beyond variation of the DNA itself, and to dynamically respond to environmental influences³. Along these lines, epigenetic markers have been suggested to represent an adaptive (or maladaptive) mechanism in the face of environmental challenge, a “molecular embodiment of biography”, a “biological archiving” of trauma, adversity, lifestyle and sociocultural context at the crossroads between biology and environment.

Thus, beyond the static genetic level, plastic epigenetic mechanisms seem to be of particular relevance in the conferral of risk or resilience towards mental disorders. Accordingly, epigenetic signatures such as alterations in DNA methylation in blood or saliva have been associated with a number of mental disorder phenotypes^{4, 5}. Furthermore, there is initial evidence for peripheral epigenetic markers to be modifiable by psychotherapeutic interventions such as cognitive‐behavioral therapy, in that disease‐associated DNA methylation pat­terns have been shown to “normalize” along with treatment response⁵. Overall, these findings suggest a great potential for epigenetic signatures to represent: a) predictive disorder risk markers reflecting both biological and biographical vulnerability, and b) malleable targets for preventive interventions.

Indeed, in plants there is ample evidence for an epigenetic memory of resistance towards environmental pathogens, which has been proposed as a potential new direction in preventing disease in crops⁶. Also, oncological research has identified numerous epigenetic targets in cancer treatment, such as histone deacetylases (HDACs) or DNA methyltransferases (DNMTs), which could further inform preventive strategies for various diseases⁷.

With respect to mental disorders, a study probing the effects of a randomized controlled family‐centered prevention training program (Strong African American Families, SAAF) discerned parental depressive symptoms to be predictive of accelerated epigenetic aging in the offspring and, reciprocally, the preventive intervention to confer a protective effect regarding epigenetic aging⁸.

Additionally, a lifestyle intervention such as physical activity, which is consid­ered to contribute to the promotion of mental health, has been shown to impact the epigenetic machinery. Finally, the field of “nutritional psychiatry” has recently been refueled by evidence for folic acid and vitamin B12 to influence DNA methylation status. In turn, nutritional supplements or epigenetic mod­ifiers such as the natural methyl‐group do­nor S‐adenosyl methionine have been suggested as promising adjuncts in the prevention of mental disorders⁵.

Given this burgeoning evidence for a possible role of epigenetic processes as target­able risk markers in selective and indicated prevention of mental disorders, further research – ideally expanding to an epigenome‐wide and environment‐wide level as well as applying a longitudinal study design covering the critical time windows of mental disorder manifestation – is needed to validate and confirm the potential of epigenetic signatures to integratively reflect both a genetic and environmental risk, and thereby confer vulnerability to mental disorder onset.

Additionally, future studies are warranted to explore the malleability of epigenetic markers by preventive interventions. These might comprise classical preventive measures derived from cognitive‐behavioral therapy, as well as explore psycho­pharmacological options, given that several psychoactive substances – such as selective serotonin reuptake inhibitors, antipsychotics, lithium and valproate – have already been reported to impact the epigenetic machinery. Along those lines, “epigenetic drugs” such as HDAC or DNMT inhibitors, if designed specifically enough, might catalyze preventive effects by enhancing learning and neuronal plasticity.

However, some caveats have to be considered when pursuing this line of research. While there is some evidence from studies in rodents and rhesus monkeys, or human positron emission tomography (PET) studies, for a certain comparability of peripheral and central epigenetic processes, some epigenetic signatures seem to be tissue‐ or even cell‐specific, which might limit their use as reliable peripheral biomarkers of mental disorder risk. Also, a number of factors impacting epigenetic mechanisms – such as smoking, exercise, nutrition, body weight, alcohol and drug consumption, or physical diseases – might confound the validity of epigenetic processes as risk markers of mental disorders. Finally, as a general proviso in biomarker research, ethical guidelines and social as well as legal policies for clinical and scientific use of epigenetic information should be implemented alongside such research efforts.

In sum, epigenetics is to be considered a promising field in mental disorder prevention research. First, epigenetic markers – as accessible, integrated and dynamic biosensors of biological as well as biographical risk of mental disorders – might be particularly suited as both indicators and targets of preventive interventions. Second, epigenetic processes – if modifiable by selective or indicated preventive measures – could biologically and thus mechanistically confer resilience towards mental disorders. Finally, as epigenetically imprinted trauma has been reported to potentially be transmissible to future generations via the germ­line⁹, successful preventive interventions embodied in epigenetic signatures might even promote a “transgenerational prevention” of mental disorders, by providing an epigenetic memory of the ability to adapt to a changing environment to future generations.

Fusar-Poli等[ ^1]在其关于预防性精神病学领域当前知识状态的里程碑式论文中指出，“需要强大的遗传和环境流行病学知识来为基于证据的预防方法提供信息”。的确，为了最有效地根据个人需求定制选择性和有针对性的预防性干预措施，对未来疾病风险进行有效预测的有效生物学和传记标志物小组至关重要。

经典的脆弱性压力模型和扩展的脆弱性压力应对模型假定生物因素（尤其是遗传因素）之间的错综复杂的相互作用在形成对精神障碍的风险和适应力方面具有负面和正面的环境影响²。但是，正如作者正确地指出的¹，目前“缺乏有效的风险生物标志物”，并且“（通过多基因风险评分）解释的方差仍然太小，无法在选择性预防中实施，并且不提供单一的神经生物学目标”。换句话说，迄今为止，包括基因-环境相互作用研究和全基因组方法在内的遗传研究领域尚未实现其明确阐明精神障碍的发病机制的最初承诺。因此，在现阶段，遗传标记确实不适合作为可以为目标预防措施提供信息的有效生物标记。

但是，近年来，越来越多的证据为表观遗传机制（例如DNA甲基化和组蛋白修饰）提供了关键的控制基因功能的能力，超越了DNA本身的变异，并能够动态响应环境影响³。沿着这些思路，表观遗传标记已被提出来代表适应性（或适应不良）机制，以应对环境挑战，“传记的分子体现”，创伤，逆境，生活方式和社会文化背景下的“生物存档”在生物学和环境之间。

因此，除了静态遗传水平外，塑性表观遗传机制在赋予精神障碍风险或适应力方面似乎特别相关。因此，表观遗传学签名，如血液或唾液中DNA甲基化的改变，已经与许多精神障碍表型^4、5相关联。此外，有初步证据表明，外周表观遗传标记可通过心理干预（例如认知行为疗法）进行修改，因为与疾病相关的DNA甲基化模式已显示与治疗反应“正常化” ⁵。总体而言，这些发现表明表观遗传学特征具有很大的潜力来代表：a）反映生物学和传记脆弱性的预测性疾病风险标志物，以及b）预防性干预的可延展目标。

确实，在植物中，有足够的证据表明对环境病原体具有抗性的表观遗传记忆，这已被提议作为预防作物⁶疾病的潜在新方向。此外，肿瘤学研究已经确定了癌症治疗中的许多表观遗传学靶标，例如组蛋白脱乙酰基酶（HDACs）或DNA甲基转移酶（DNMTs），它们可以进一步为各种疾病的预防策略提供参考⁷。

关于精神障碍，一项针对以家庭为中心的随机对照预防培训计划（强壮的非洲裔美国家庭，SAAF）的效果进行研究的研究发现，父母的抑郁症状可以预测后代的表观遗传加速老化，并且相应地，可以采取预防性干预措施赋予表观遗传老化保护作用⁸。

此外，生活方式干预，例如体育锻炼，被认为有助于促进心理健康，已被证明会影响表观遗传机制。最后，叶酸和维生素B12影响DNA甲基化状态的证据为“营养精神病学”领域提供了新的动力。反过来，营养补充剂或表观遗传修饰剂（例如天然甲基供体S-腺苷甲硫氨酸）已被建议作为预防精神障碍的有前途的辅助手段⁵。

鉴于这些新兴的证据表明表观遗传过程可能在选择性和明确预防精神障碍中作为目标风险标志物可能发挥作用，因此需要进一步研究-理想地扩展到表观基因组范围和环境范围的水平，并应用涵盖关键因素的纵向研究设计精神障碍表现的时间窗口–需要验证和确认表观遗传学特征潜在地综合反映遗传和环境风险，从而赋予易患精神障碍的能力。

此外，有必要进行进一步的研究，以通过预防性干预来探索表观遗传标记的可塑性。鉴于已经报道了几种精神活性物质（例如选择性5-羟色胺再摄取抑制剂，抗精神病药，锂和丙戊酸盐）会影响表观遗传机制，因此，这些措施可能包括源自认知行为疗法的经典预防措施，以及探索心理药物选择。沿着这些思路，如果设计得足够专门，诸如HDAC或DNMT抑制剂之类的“表观遗传药物”可能会通过增强学习和神经元可塑性来催化预防作用。

但是，在进行这方面的研究时必须考虑一些注意事项。尽管有一些关于啮齿动物和恒河猴的研究或人类正电子发射断层扫描（PET）研究的证据，这些证据表明外围和中央表观遗传过程具有一定的可比性，但某些表观遗传特征似乎是组织或什至是细胞特异性的，可能限制其作为精神障碍风险的可靠外围生物标志物的使用。而且，许多影响表观遗传机制的因素，例如吸烟，运动，营养，体重，酒精和药物消耗或身体疾病，可能会使表观遗传过程作为精神障碍风险标志物的有效性混淆。最后，作为生物标志物研究的一般条件，

总之，表观遗传学被认为是预防精神障碍研究的一个有前途的领域。首先，表观遗传标记（作为可获取的，集成的，动态的生物传感器以及精神疾病的传记风险生物传感器）可能特别适合作为预防干预措施的指标和目标。第二，表观遗传过程-如果可以通过选择性或指定的预防措施改变-可以在生物学上并因此在机械上赋予对精神障碍的适应力。最后，如表观遗传学印迹创伤已经报道了潜在地经由种系是传染给后代⁹因此，表观遗传学特征中成功的预防干预措施甚至可能通过提供表观遗传学记忆来适应子孙后代不断变化的环境，甚至可以促进精神疾病的“跨代预防”。