Harold J. Bursztajn, MD

As the most recent wave of COVID-19 recedes, we can begin to learn from the example of vaccine avoidance how to help frightened, grieving, and misinformed patients who are vulnerable to hyperfocus on rare risks as a form of helplessness avoidance. Integrating specialty expertise via conversation—for example, between infectious disease specialists and psychodynamically informed psychiatrists—can help vulnerable patients become immunized against vaccine avoidance driven by fear and helplessness. Integrating expertise across specialties can also help us communicate effectively when participating in media-enabled public health education.

For example, the widespread alarm over news about the occurrence of blood clots in a tiny percentage of individuals who have received the Johnson & Johnson COVID-19 vaccine

 provides a useful, if troubling, lesson about how wishful thinking undermines rational choice. Wishful thinking, including magical thinking such as perfectionism compounded by hindsight and our understandable wish for certainty to avoid mortal danger at any cost, has created unintended mortal risks of its own.

It is wishful thinking to insist that any medical remedy be free of side effects or a “magic bullet” with 100% effectiveness. In clinical practice, we regularly inform patients of substantial side effects, the benefit/risk ratios, and available alternative treatments. When new data emerge, the benefit/risk ratio may change, and patients should be so informed. That is very different from the government’s pause of the use of the Johnson & Johnson vaccine for patients of all ages, irrespective of their vulnerability to side effects, the potential benefits, and what alternatives were practically available. This blanket measure, intended to reassure the public, had the opposite effect. A “where there is smoke, there is fire” response cascaded through the Internet and clouded both the benefit/risk ratio for the Johnson & Johnson vaccine and its efficacy relative to the other available vaccines in preventing COVID-19 morbidity and mortality. This is in the United States, where approximately a million people have died of COVID-19 in a population of 330 million,

 a death rate of about 1 in 330 (the risk for any individual varies by age and other factors).

Rationally, we should welcome any vaccine that dramatically reduces this risk. Yet in fast-moving cyberspace, our tunnel-vision focus on a newly reported, frightening yet isolated cluster of cases is likely to outrun daily reports of the all too familiar, and thus normalized, larger number of no less tragic deaths from COVID-19. Contrast this reaction with risk levels that individuals ordinarily accept, such as having children in the face of the—alas—still present risk of maternal mortality.

This situation has many other analogues in medicine. For instance, some of us, when we are patients, worry about Guillain-Barré syndrome after influenza immunization, even though the risk of Guillain-Barré is much higher after infection with influenza than after immunization.

 Ideally, such comparisons of risks and benefits should be simple and straightforward to make. Why, then, when it comes to threats to our health, are they not? When we are frightened that our survival is somehow at stake, powerful feelings distort our reasoning to avoid feeling helpless.

When we feel in danger, we simplify. We tend to pay more attention to information that is recent or more readily available. The newly reported risk of a tragic yet rare side effect potentially related to vaccination all too often obscures the greater risks, both long- and short-term, of the ravages of the COVID-19 pandemic. Once we fixate on what is new and potentially dangerous, it tends to remain on our mental radar screen, regardless of data to the contrary. Moreover, individuals can all too easily avoid potential risks of vaccination by not being vaccinated, whereas even with masks and other precautions, we feel far greater helplessness relative to avoiding the risks of COVID-19. To avoid feeling helpless, it is easier and thus all too convenient to focus on easily avoidable yet low vaccination risks than on the far less easily avoidable yet high COVID-19 risks. In addition, we tend to feel greater shame when we do something that turns out badly than when we do 

 do something and it turns out badly. Thus, deaths due to inaction (not getting vaccinated) seem less frightening than deaths due to action (getting vaccinated).

Especially in the midst of fear and tragedy, we want to avoid helplessness at any cost, which makes us susceptible to wishful thinking and fantasies of omnipotence and the perfection of 20-20 hindsight. That susceptibility is compounded by internet transmission of misinformation and fear-mongering. It is no news that bad news beats good news in the marketplace of attention. Moreover, misleading reductionism typically carries the day (the curse of the sound bite). Now, on the small screens of mobile phones, we too often read the screaming headlines without getting to potentially reassuring qualifiers in the body of an article. Asking avoidant patients what information they have, where they get their information, and what it means to them is vital. In the same vein, asking about any individual or family history of adverse interactions with medications or the medical system may be helpful.

To be effective, public education about risk assessment must recognize this emotional component of our mental functioning. For the informed consent process of vaccination to be meaningful and effective, it helps to recognize the way fear in the midst of a pandemic intoxicates sober cognition with perfectionism and magical thinking. Therefore, when we communicate about newly emergent questions as to vaccination-related side effects, it will also help to keep in mind that our own public and social media communication may have side effects far greater than the vaccine side effects we seek to reduce.

 is a faculty member at Creighton University School of Medicine, and an infectious diseases physician who practices in Omaha, Nebraska, locale of one of the first cases of the suspected Johnson & Johnson COVID-19 vaccine-related blood clots. 

 is a faculty member at Harvard Medical School, and a practicing psychiatrist in Cambridge, Massachusetts, with a longstanding interest in decision-making under conditions of trauma and uncertainty.

Use of the Janssen (Johnson & Johnson) COVID-19 vaccine: updated interim recommendations from the Advisory Committee on Immunization Practices - United States, December 2021.

2. Bursztajn HJ, Feinbloom RI, Hamm RM, Brodsky A. 

Medical Choices, Medical Chances: How Patients, Families, and Physicians Can Cope With Uncertainty

Coronavirus in the U.S.: Latest map and case count

Maternal mortality rates in the United States, 2020

. NCHS Health E-Stats. 2022. Accessed March 4, 2022.

Guillain-Barre syndrome, influenza, and influenza vaccination: the epidemiologic evidence.

Articles

We seek to reduce vaccine side effects—but what about the social media-compounded fears of anti-COVID vaccination?

Vaccination Avoidance as Risk Avoidance Driven by Fear and Helplessness

Harold J. Bursztajn, MD, shares his love of art and family history, and how it inspires him daily. 

s associate professor of psychiatry at Harvard Medical School and practices clinical and forensic psychiatry in Cambridge, Massachusetts.

Videos

One doctor shares how family history and art have inspired him. 

Inspirational Musings: Art and Family History 

Since its birth in the early 19th century, psychiatry has sought to ground its diagnoses in the same mechanistic explanatory models that were emerging as hallmarks of the other branches of modern medicine.

 Drawing on the nascent fields of genetics and Darwinian evolution, psychiatry entered a debate over the origins of human behavior: nature vs nurture? As the debate raged on, studies of human traits and behavior were co-opted by promoters of nefarious political agendas, with scientists at the center of numerous atrocities throughout the 20th century.

 For all their harms, genetic determinist models, which explained human variation purely in terms of nature (ie, genetics), bore disappointingly little fruit.

Social reductionist models, which explained human variation purely in terms of environmental factors, fared no better. Neither model could account for the pronounced changes in behavior and gene expression in response to events experienced over the course of an individual’s lifetime. Nor could they explain how such changes, conferring either vulnerability or resilience in the face of trauma, could be passed between generations.

By the mid-20th century, the burgeoning field of 

 had begun to bridge the divide between genetics and developmental biology,

 and, by the start of the 21st century, scientists increasingly turned to epigenetic approaches to disentangle the molecular mechanisms by which genes give rise to specific phenotypes; determine how the expression of genes could be modulated by stochastic factors; and establish how such modulations can be passed to offspring. Across fields of medicine, researchers today strive to elucidate the mechanisms by which adverse life experiences shape the development of disease and devise novel therapeutic interventions to supplant currently inadequate treatment and prevention paradigms. Nowhere is this work more necessary than in psychiatry, where diagnoses continue to elude biological definition and where remedies are frequently inadequate to address widespread suffering.

Because the models employed by researchers and clinicians in the study and treatment of disease shape patients’ understanding of their own suffering, the dominance of reductionist models can leave both patients and clinicians feeling powerless in the fight against fate, whether inscribed by circumstance or biology. The emergence of epigenetic models has generated a surge of optimism, opening new possibilities for psychiatric intervention.

The term epigenetics was coined in 1942 (prior to the discovery of the molecular basis of heredity) by developmental biologist 

, as a neologism combining epigenesis (embryonic development) and genetics.

 Waddington described epigenetics as “the branch of biology which studies the causal interaction between genes and their products [that] brings the phenotype into being”; this definition is broader than the one in use today.

 In the time since the identification of DNA as carrier of the genetic code, the definition of epigenetics has narrowed to refer specifically to heritable alterations in gene expression that do not involve direct changes in DNA sequence.

In the mid-1970s, investigators identified the first molecular mechanisms that might explain how patterns of gene expression could vary so dramatically among an individual’s different cell types, all of which contain the same set of chromosomes.

 and John E. Pugh proposed a molecular mechanism for this differential gene expression: Covalent addition of methyl groups at specific DNA sites sterically inhibit the docking of transcriptional machinery at those sites.

 DNA methylation was thus deemed an epigenetic marker of gene inactivation.

, demonstrated that the covalent modification of histone proteins was also a critical mechanism of gene regulation. Adding chemical groups (eg, methyl, acetyl) to histones adjusts how tightly DNA wraps around them to form chromatin, which thereby changes the accessibility of that DNA to transcriptional machinery.

 Subsequent work demonstrated additional epigenetic regulatory mechanisms of chromatin remodeling (eg, nucleosome sliding). Notably, epigenetic markers and mechanisms were shown to be heritable, not only clonally (ie, between generations of mature cell populations within an individual), but also between generations of individuals, passed from parent to offspring.

Although epigenetics would eventually be applied to study psychiatric illnesses in the search for so-called missing heritability, the observation that chronic mental states and/or behaviors can be passed down through generations had occurred decades earlier. Among the first to consider epigenetics in the context of psychiatry was psychoanalyst and developmental psychologist

 In his 1950 book Childhood and Society, Erikson articulated his theory of “ego epigenesis.” Borrowing the term epigenesis from the field of developmental biology, he described a staged model of individual identity (ego) formation analogous to that of embryonic development in utero. Erikson wrote that identity arose through an individual’s resolution of a predetermined series of conflicts and asserted that an individual’s specific resolution to these conflicts was shaped by both innate biological factors and environmental inputs. His version of epigenetics focused on psychosocial processes rather than biological mechanisms, and it suggested psychoanalysis as a primary intervention.

Epigenetics was first introduced into the field of psychiatric genetics by 

 Gottesman and Shields argued that the development of schizophrenia depended upon both genes and the environment. Thus, the task at hand was to elucidate the mechanisms through which environmental and genetic factors interact to produce psychosis. Despite the immediate popularity of the book, the application of epigenetic approaches to psychiatry did not take off in earnest for another 2 decades.

 In the June 2000 edition of Nature, Gottesman and colleagues penned an editorial bemoaning their field’s failure to investigate “[t]he roles for epigenetic factors in psychiatric disorders...in a systematic way” and imploring fellow researchers to consider an epigenetic basis for “nonorganic brain” disorders (ie, those for which no clear physiological or genetic lesion could be found).

 Subsequent commentators noted that epigenetic models could better account for the clinical presentation of psychiatric diagnoses than genetic models based solely on variation in nucleic acid sequence.8

Although studies in the 1990s revealed that the gene alterations in organic psychiatric disorders, such as Rett and 

, produced those conditions via epigenetic mechanisms, researchers began to investigate epigenetic mechanisms in nonorganic disorders only in the first decade of the new millennium.

 Since then, epigenetic mechanisms have been uncovered in many psychiatric illnesses (Table).

 However, it currently remains unclear whether these changes are causes or effects of the disorders in which they arise.

Current Findings in Various Psychiatric Disorders

To separate cause from effect, researchers are developing animal models of epigenetic alterations. 

et al laid the foundation with their establishment of a rodent model of epigenetic transmission.

 Building upon studies in the late 1960s, Meaney demonstrated that variations in maternal care in rats could elicit specific behavioral and endocrine responses to stress in offspring, and that those responses could be passed from one generation to the next via nongenomic mechanisms.

Ongoing efforts are aimed at linking findings in animal stress response models to the changes observed in patients in response to adverse events.

Given the proliferation of studies, there could be pressure on this emerging science to identify a single physiological cause of challenging psychiatric disorders and to produce a biologic cure for them. However, we caution against this line of thinking. Without careful consideration, applications of epigenetic research are liable to fall prey to reductionism, thereby replicating the mistakes of previous models. Nonetheless, the evidence that our behavioral responses to trauma can be understood in part through epigenetics has the potential to cause a conceptual shift in the treatment of psychiatric disorders.

Even if interventions based on epigenetic research are not imminent, we assert that epigenetics currently constitutes an invaluable clinical tool for improving care. In a historical moment in which physicochemical explanatory models enjoy unprecedented cultural cachet, epigenetics can empower patients through biomedical recognition of the importance of their lived experiences, and the role they have in shaping the course of illness. Epigenetics might allow patients to shed the stigma and internalized shame of psychiatric illness and thereby better engage with existent therapeutic paradigms.

Patients are often blamed, and blame themselves, not only for the onset of mental illness, but also for their apparent inability to overcome it.

 Possible epigenetic factors might explain why traditional treatment strategies are not working (eg, why a patient may still be depressed even though they are on an antidepressant; why a patient’s delusional beliefs persist despite antipsychotic medication). A more complicated picture of the factors contributing to the development and perpetuation of a disorder may alleviate some of the guilt patients frequently describe about being unable to improve.

Furthermore, epigenetic models illustrate how psychiatric illnesses emerge as the result of many cumulative processes. Such nuanced understanding may allow for greater patience and more realistic expectations on the part of patients, their family members, and clinicians about the expediency and results of treatment. Treatment can be understood as a process that takes time, as one would not expect gene expression to be modified in a day. Epigenetics may also allow clinicians to recognize and operationalize a more holistic view of patients, considering both their deficits and their unique strengths in managing their struggles. Accounting for patients’ family histories of risk and resilience, and their environment and environmental responses, could widen the discussion and reveal new opportunities for intervention.

We see the field of epigenetics as an opportunity to harness both nature and nurture to improve mental health care. However, we argue that this knowledge, including the possibility of modifying gene expression, should not lead to the expectation or goal of eliminating suffering, nor to perfecting or standardizing our response to it. Our hope is that knowledge and application of the science of epigenetics can result in an increased understanding and compassion for the complexity of what it means to be human.

s associate professor of psychiatry at Harvard Medical School and practices clinical and forensic psychiatry in Cambridge, Massachusetts. 

is a current research fellow of the American Unit of the UNESCO Bioethics Chair. 

is a community psychiatrist with VinFen, affiliated with the Massachusetts Mental Health Center, and is a current research fellow of the American Unit of the UNESCO Bioethics Chair. 

is the cofounder and executive director of the Harvard Law School Project on Disability and is a visiting professor at Harvard Law School. All report no conflicts of interest.

1. Bursztajn HJ, Feinbloom RI, Hamm RM, Brodsky A. 

Psychiatric genetics and prejudice: can the science be separated from the scientist? 

3. Zuk O, Hechter E, Sunyaev SR, Lander ES. 

The mystery of missing heritability: genetic interactions create phantom heritability

 Canalization of development and the inheritance of acquired characters

8. Trerotola M, Relli V, Simeone P, Alberti S. 

Epigenetic inheritance and the missing heritability

9. Peedicayil J. A brief history of epigenetics in psychiatry. In: Peedicayil J, Grayson DR, Avramopoulos D, eds. 

10. Petronis A, Gottesman II, Crow TJ, et al. 

Psychiatric epigenetics: a new focus for the new century. 

11. Czarny P, Białek K, Ziółkowska S, et al. 

The importance of epigenetics in diagnostics and treatment of major depressive disorder

12. Smigielski L, Jagannath V, Rössler W, et al. 

Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings. 

13. Bellia F, Vismara M, Annunzi E, et al. 

Genetic and epigenetic architecture of obsessive-compulsive disorder: in search of possible diagnostic and prognostic biomarkers

14. Blacker CJ, Frye MA, Morava E, et al. 

A review of epigenetics of PTSD in comorbid psychiatric conditions

15. Hübel C, Marzi SJ, Breen G, Bulik CM. 

Epigenetics in eating disorders: a systematic review

16. Kuehner JN, Bruggeman EC, Wen Z, Yao B. 

Epigenetic regulations in neuropsychiatric disorders

18. Francis D, Diorio J, Liu D, Meaney MJ. 

Nongenomic transmission across generations of maternal behavior and stress responses in the rat

Assessing mental illness stigma: a complex issue

The emergence of epigenetic models has generated a surge of optimism, opening new possibilities for psychiatric intervention.





Can Epigenetics Promote Resilience Without Genetic Reductionism?

To recognize the role epigenetics in resilience after trauma, in both individuals who experience trauma and their descendants.

After participating in this activity, you should be better prepared to:

1. Understand how various mechanisms of epigenetics can potentially contribute to transgenerational transmission of resilience.

2. Discuss the various interpretations of the American Psychiatric Association’s definition of resilience.

3. Review the different treatment modalities that could prevent transmission of trauma.

4. Understand the potential variables that either strengthen or weaken an individual’s resilience and positive health outcomes.

This continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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 The fear, grief, social isolation, and loss associated with COVID-19 are all potentially traumatic. The ongoing pandemic makes the study of resilience mechanisms after catastrophic experience all the more timely, since what is true for the pandemic experience may be true for any traumatic experience that causes long-term isolation and helplessness. Based on the epigenetic mechanisms that promote transgenerational transmission of resilience, a growing body of research points the way to promising clinical and public health interventions. By applying what we are learning about the potential biopsychosocial mechanisms for transgenerational resilience, we can begin to design interventions to promote resilience, study their relative effectiveness, and implement them accordingly.

, approximately 70% of people worldwide will experience at least 1 traumatic event during their lifetimes, with 30.5% reporting more than 4 incidents.

 (PTSD) or other trauma- and stressor-related disorders.

 Traumatic events such as threats to one’s life, natural disasters (including the current pandemic), exposure to war and conflict, torture, discrimination, and decimation of communities serve as brutal reminders of our past. However, a clear resilience to such stressors enables the individual to thrive in spite of hardship and social isolation, as well as to endure the memories of these ordeals. The offspring of such survivors have been shown to thrive and they are often better adapted and more resilient than the previous generation.

 Awareness of potential epigenetic mechanisms may help to guide clinical and public mental health interventions to ensure that future generations are better equipped to avoid trauma- or stressor-related disorders.

Epigenetics is the study of heritable changes that occur without directly altering the nucleotide sequence of a genome. Various epigenetic processes function to determine an individual’s phenotype and control the expression of various proteins and their corresponding functional pathways. Epigenetic mechanisms of transmission include CpG islands (sites in the genome containing large numbers of CpG dinucleotide repeats), histones, and noncoding RNA. Methylation, the process of adding or removing a methyl group (–CH

), can occur at CpG islands and on histone proteins. In addition, histones can be altered in a variety of other ways, including acetylation, ubiquitination, phosphorylation, and the addition or removal of various sugars. These modifications alter the capacity for further transcription factors to express a gene.

Exposure to traumatic events can produce long-term epigenetic changes in consistent regions of the genome. 

 during episodes of trauma have long-term effects on glucocorticoid receptors, adipose tissue, the hypothalamic–pituitary–adrenal (HPA) axis, hippocampus, and amygdala.

 A combination of these factors may influence not only an individual’s own phenotype, but also how that individual and their offspring will respond to further stressors in life.

The ability to transmit epigenetic changes caused by trauma has been seen within both 

 Studies by Suter et al showed that plants such as 

 such as DNA methylation induced by life-threatening heat stress over 3 consecutive generations.

 Migicovsky et al found that when the first-generation (F

 were exposed to the same heat-induced stress as the parental generation, there was a significant decrease in the amount of global DNA methylation. The 

 developed larger leaves than the control group but became more resistant to further methylation, despite exposure to the same external stressor as the parental generation.

 Other studies have shown that various sites of 

Animal models using rodents have also shown consistent patterns of transmission across multiple generations. Dias and Ressler showed that rodents conditioned with a fear response to acetophenone gave birth to F

 (second-generation) offspring exhibiting similar fear behaviors. They determined that a persistent CpG hypomethylation of the 

 Exposure to social stressors has led to impaired rodent maternal behaviors across several generations, leading to offspring that consistently produce 

abnormal amounts of cortisone, oxytocin, and prolactin

 These findings are consistent with hormonal changes in human families who experienced similar 

Resilience is often cited as a key factor in preventing adverse changes in personality or affect in reaction to stressors experienced in one’s life.

 The American Psychiatric Association (APA) 

 as the ability to adapt in the face of adversity, trauma, tragedy, threats, or significant stress.

 Various interpretations of the APA’s definition have included an absence of psychopathology, an ability to return to homeostasis unimpaired by the traumatic event, or adaptive responses after exposure to adversity.

Some researchers have highlighted a combination of core, internal, and external resilience factors that can also contribute to how one succeeds in life.

 Core resilience is largely defined by one’s genome. Internal resilience, on the other hand, is distinguished by learned and shared behaviors that can be influenced by family, friends, and life experiences. These involve the development of healthy behaviors such as autonomy, self-control, hardiness, toughness, coping style, past experiences, resourcefulness, social competence, and grit. External resilience focuses primarily on socioecological factors, such as support from one’s community and access to social and health care services. Recognizing the different ways in which resilience can manifest and understanding these manifestations in multifactorial terms is the best method of combating and resisting traumatic adversity.

 Standardizing measures of resilience and change with respect to trauma has, however, proven to be difficult across disparate events, populations, and generations.

One measure of the impact of trauma on an individual is posttraumatic growth (PTG), which was defined in 1996 by Tedeschi and Calhoun to describe 

 Key components of affect were divided into 5 categories to measure and compare positive change due to trauma in various populations (

Table. Potential Positive Posttrauma Changes

 in a longitudinal study of 200 Israeli prisoners of war during the 1973 Yom Kippur War. Forty-three male Israeli combat veterans were second-generation survivors of the Holocaust. Dekel measured changes in PTG among both groups of veterans, with data sets collected at 30 and 35 years after the end of the war. The study found that veterans who were offspring of Holocaust survivors scored lower on PTG and had a lower likelihood of developing PTSD than veterans in the control group. A lower score on PTG as well as PTSD symptoms may indicate resilience to change as a result of trauma, whereas the effects of trauma may have been more pronounced in the control group (who were not offspring of Holocaust survivors). Whether a genetic component was responsible was not clear, but the authors proposed it as an area of further study.

Our genome and epigenetics may provide explanations of human resilience in the face of trauma. For example, the FK506-binding protein 51 (FKBP5) is a biomolecule that appears to modulate our reaction to stress and ability to exhibit resilience. The 

 for glucocorticoid receptors on chromosome 6 (6p21.31).

 Research has shown that behavioral responses to stress are 

—as is the HPA axis—and can be affected by factors such as exposure to trauma.

 In animal studies, mice with the gene for 

 removed show a stronger resilience to stressors by exhibiting a lowered fear response.

In another study of Holocaust survivors, 

 looked at the epigenetic mechanisms of transmission of the 

 gene, focusing primarily on DNA methylation of the CpG sites located in and proximal to intron 7 of 

 Methylation of bin 3/site 6 was found to be 10% higher in Holocaust survivors, but methylation of the same bin 3/site 6 was 7.7% lower in the offspring of Holocaust survivors than in the control groups. These findings were consistent when controlling for lifetime PTSD in the offspring and for possible childhood trauma. The 30-year age difference between the parents and their offspring could explain the differences in methylation; however, Yehuda et al noted that even a 1% to 2% difference in gene methylation can significantly alter gene expression.

 Furthermore, the study of Miller et al showed that methylation of specific CpG sites of 

 Greater methylation of the CpG site cg07485685 decreased PTSD symptom severity while increasing resiliency scores measured via the Brief Resilience Scale. A PTG inventory was also used to measure any positive changes as a result of trauma. Lower levels of PTG after trauma were associated with methylation of the same CpG site cg07485685 on

. These findings are consistent with the lower scores on PTG and lower levels of PTSD found in the study of Dekel et al in 2013.

Genes that are responsible for regulation of the HPA axis may also confer resilience to trauma. For example, multiple studies have found that childhood trauma and mistreatment are a risk factor for methylation of the human glucocorticoid receptor (NR3C1) gene and changes to the HPA axis.

 in newborn infants has been linked to prenatal exposure to stress.

 For instance, Perroud and colleagues examined the epigenetic changes in pregnant Tutsi survivors of the Rwandan genocide and their offspring. The mothers and their offspring were found to have 

Variations in single-nucleotide polymorphisms (SNPs), specifically rs10482672, were also found to increase the risk of psychopathology. 

 found that children who were identified as having this genotype were more vulnerable to developing substance abuse and antisocial behavior under adverse conditions, but at the same time were more likely to benefit from advantageous conditions.

 Children were placed in a fast-track program, which fostered the development of emotional regulation, self-control, and other treatments to minimize the effects of harsh parenting and violent environment. Those who received early intervention to reduce risks of developing psychopathology had a significantly decreased risk of external psychopathology via substance abuse or antisocial behavior later in life. Those in the control group, who had SNP rs10482672 but did not receive early treatment, had a higher likelihood of external psychopathology by the time they reached 25 years of age.

 In 2020, Miller et al also found methylation of 5 CpG sites in the 

 gene that were significantly linked with resilience.

 Three CpG sites were correlated with an increased score (indicating higher resilience) on the Brief Resilience Scale, whereas 2 CpG sites were correlated with decreased resilience. Authors in all studies noted the need for larger sample sizes as well as additional longitudinal studies.

What can be done to prevent transmission of past trauma to future generations? Studies have shown that nonpharmacological treatment of trauma- and stressor-related disorders can induce epigenetic changes in the genome responsible for the HPA axis.

 Roberts et al examined the methylation of 

 before and after exposure-based cognitive behavioral therapy (CBT) in patients previously diagnosed with agoraphobia. Those who reported benefits from CBT after completing treatment were found to have lower levels of methylation at a CpG island at intron 7 of 

. The severity of symptoms was reduced by an average of 69.5% in those who received exposure-based CBT, which correlated with the decrease in methylation. Individuals who reported little change from CBT were found to have either no significant changes or even increases in methylation of CpG islands at intron 7 of 

Bishop et al found similar results in patients with PTSD who received mindfulness-based stress reduction interventions. These patients showed levels of methylation of intron 7 of 

 significantly different after intervention compared with initial levels. Those who responded to treatment, as indicated by a 10-point drop in PTSD severity via a PTSD checklist, had 

significantly decreased levels of methylation

, whereas those who did not respond to treatment showed higher levels of methylation in a different site at bin 2 of 

 Mindfulness and techniques that encourage thought and understanding, such as CBT and storytelling, might 

Figure 1. Factors predictive of resilience from trauma and social isolation

Family and community play a strong role in enhancing an individual’s resilience. 

Fundamental building blocks for resilience

 include a secure foundation and promotion of self-esteem and self-efficacy.

 Strong bonds with caregivers and shared values and religious beliefs that find meaning in suffering are protective against adverse effects of trauma in children. Longitudinal studies of the effects of social relationships have found that support from family, friends, colleagues, and community leaders leads to a reduction in psychological distress, as well as a more rapid recovery from the effects of trauma.

Likewise, the World Health Organization has found that the arts have contributed to the improvement of public health. Music, art, dance, and communication through storytelling about past events at an early age not only reduce anxiety but also protect against cognitive decline later in life. Exposure to and involvement with the arts “trigger psychological, physiological, social, and behavioral responses” associated with positive health outcomes that may be linked to 

Exercise has long been associated with various health benefits and has been documented to be valuable for regulating reactions to stress, sleep, and resilience to mood disorders.

 In animal models, exercise serves a protective role in lowering the rates of 

 Mice who exercised via long-term wheel running had increased levels of galanin, a neuropeptide that has been 

 as well as the regulation of norepinephrine and other products of the HPA axis.

 in mice was also consistent with a significant increase in stress resilience, inducing methylation of 

 and downregulating noncoding RNA such as microRNA-124 in areas such as the hippocampus.

 Epigenetic changes as a result of exercise improved cognition in the mice of the parental generation as well as subsequent offspring.

 have correlated with findings in human studies, as mothers who exercised regularly before and during pregnancy had offspring who achieved higher levels of academic performance, excelling in language and math and having higher overall grade point averages.

 Other factors, such as shared environments and positive parental influences, may have played a part in the success, but they do not account for epigenetic differences in DNA seen at birth. Regular moderate exercise seems to confer a protective effect that enables future generations to adapt to and thrive in their new world.

Patients diagnosed with trauma- and stressor-related disorders show evidence of dysregulation of their HPA axis, resulting in persistent personality changes.

How can we begin to design interventions to promote resilience, study their relative effectiveness, and implement them accordingly?

Harold J. Bursztajn, MD

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Can Epigenetics Promote Resilience Without Genetic Reductionism?

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