Prevention in psychiatry: a role for epigenetics?
Authors: Katharina Domschke
Journal: World Psychiatry (2021)

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 phenotypes4, 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.