Diagnosis and classification of disorders specifically associated with stress: proposals for ICD‐11

The diagnostic concepts of post‐traumatic stress disorder (PTSD) and other disorders specifically associated with stress have been intensively discussed among neuro‐ and social scientists, clinicians, epidemiologists, public health planners and humanitarian aid workers around the world. PTSD and adjustment disorder are among the most widely used diagnoses in mental health care worldwide. This paper describes proposals that aim to maximize clinical utility for the classification and grouping of disorders specifically associated with stress in the forthcoming 11th revision of the International Classification of Diseases (ICD‐11). Proposals include a narrower concept for PTSD that does not allow the diagnosis to be made based entirely on non‐specific symptoms; a new complex PTSD category that comprises three clusters of intra‐ and interpersonal symptoms in addition to core PTSD symptoms; a new diagnosis of prolonged grief disorder, used to describe patients that undergo an intensely painful, disabling, and abnormally persistent response to bereavement; a major revision of “adjustment disorder” involving increased specification of symptoms; and a conceptualization of “acute stress reaction” as a normal phenomenon that still may require clinical intervention. These proposals were developed with specific considerations given to clinical utility and global applicability in both low‐ and high‐income countries.     

5‐HTTLPR genotype potentiates the effects of war zone stressors on the emergence of PTSD,depressive and anxiety symptoms in soldiers deployed to iraq

Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5‐HTTLPR) genotype in predicting the emergence of post‐traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5‐HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5‐HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or L_G) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (L_A). These data suggest that 5‐HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress.     

Childhood adversity during the post-apartheid transition and COVID-19 stress independently predict adult PTSD risk in urban South Africa: A biocultural analysis of the stress sensitization hypothesis

Objectives

The COVID-19 pandemic in South Africa introduced new societal adversities and mental health threats in a country where one in three individuals are expected to develop a psychiatric condition sometime in their life. Scientists have suggested that psychosocial stress and trauma during childhood may increase one's vulnerability to the mental health consequences of future stressors—a process known as stress sensitization. This prospective analysis assessed whether childhood adversity experienced among South African children across the first 18 years of life, coinciding with the post-apartheid transition, exacerbates the mental health impacts of psychosocial stress experienced during the 2019 coronavirus (COVID-19) pandemic (ca. 2020–2021).

Materials and Methods

Data came from 88 adults who participated in a follow-up study of a longitudinal birth cohort study in Soweto, South Africa. Childhood adversity and COVID-19 psychosocial stress were assessed as primary predictors of adult PTSD risk, and an interaction term between childhood adversity and COVID-19 stress was calculated to evaluate the potential effect of stress sensitization.

Results

Fifty-six percent of adults exhibited moderate-to-severe PTSD symptoms. Greater childhood adversity and higher COVID-19 psychosocial stress independently predicted worse post-traumatic stress disorder symptoms in adults. Adults who reported greater childhood adversity exhibited non-significantly worse PTSD symptoms from COVID-19 psychosocial stress.

Discussion

These results highlight the deleterious mental health effects of both childhood trauma and COVID-19 psychosocial stress in our sample and emphasize the need for greater and more accessible mental health support as the pandemic progresses in South Africa.     

Post‐traumatic stress disorder: a state‐of‐the‐art review of evidence and challenges

Post‐traumatic stress disorder (PTSD) is arguably the most common psychiatric disorder to arise after exposure to a traumatic event. Since its formal introduction in the DSM‐III in 1980, knowledge has grown significantly regarding its causes, maintaining mechanisms and treatments. Despite this increased understanding, however, the actual definition of the disorder remains controversial. The DSM‐5 and ICD‐11 define the disorder differently, reflecting disagreements in the field about whether the construct of PTSD should encompass a broad array of psychological manifestations that arise after trauma or should be focused more specifically on trauma memory phenomena. This controversy over clarifying the phenotype of PTSD has limited the capacity to identify biomarkers and specific mechanisms of traumatic stress. This review provides an up‐to‐date outline of the current definitions of PTSD, its known prevalence and risk factors, the main models to explain the disorder, and evidence‐supported treatments. A major conclusion is that, although trauma‐focused cognitive behavior therapy is the best‐validated treatment for PTSD, it has stagnated over recent decades, and only two‐thirds of PTSD patients respond adequately to this intervention. Moreover, most people with PTSD do not access evidence‐based treatment, and this situation is much worse in low‐ and middle‐income countries. Identifying processes that can overcome these major barriers to better management of people with PTSD remains an outstanding challenge.     

Neurobiology of comorbid post‐traumatic stress disorder and alcohol‐use disorder

Post‐traumatic stress disorder (PTSD) and alcohol‐use disorder (AUD) are highly comorbid in humans. Although we have some understanding of the structural and functional brain changes that define each of these disorders, and how those changes contribute to the behavioral symptoms that define them, little is known about the neurobiology of comorbid PTSD and AUD, which may be due in part to a scarcity of adequate animal models for examining this research question. The goal of this review is to summarize the current state‐of‐the‐science on comorbid PTSD and AUD. We summarize epidemiological data documenting the prevalence of this comorbidity, review what is known about the potential neurobiological basis for the frequent co‐occurrence of PTSD and AUD and discuss successes and failures of past and current treatment strategies. We also review animal models that aim to examine comorbid PTSD and AUD, highlighting where the models parallel the human condition, and we discuss the strengths and weaknesses of each model. We conclude by discussing key gaps in our knowledge and strategies for addressing them: in particular, we (1) highlight the need for better animal models of the comorbid condition and better clinical trial design, (2) emphasize the need for examination of subpopulation effects and individual differences and (3) urge cross‐talk between basic and clinical researchers that is reflected in collaborative work with forward and reverse translational impact.     

Cells, biomarkers, and post-traumatic stress disorder: evidence for peripheral involvement in a central disease

Post-traumatic stress disorder (PTSD) is a complicated CNS syndrome. Looking beyond the CNS, recent studies suggest that peripheral blood mononuclear cells could cause and/or exacerbate PTSD. This review summarizes the literature, describes associations between circulating peripheral blood cells and PTSD, proposes a novel mechanism, and analyzes several biomarkers that appear to associate with PTSD symptoms. Several experimental animal models have shown that peripheral blood mononuclear cell activity can cause hippocampal volume loss and PTSD-like symptoms. Data from these models suggest that a traumatic event and/or traumatic events can trigger peripheral cells to migrate, mediate inflammation, and decrease neurogenesis, potentially leading to CNS volume loss. Biomarkers that associate with PTSD symptoms have the potential to differentiate PTSD from traumatic brain injury, but more work needs to be done. Research examining the mechanism of how traumatic events are linked to peripheral blood mononuclear cell functions and biomarkers may offer improved diagnoses and treatments for PTSD patients.     

Oleuropein reduces anxiety-like responses by activating of serotonergic and neuropeptide Y (NPY)-ergic systems in a rat model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experiences. This psychopathological response to traumatic stressors induces anxiety in rats. Oleuropein (OLE), a major compound in olive leaves, reportedly possesses several pharmacological properties, including anti-cancer, anti-diabetic, and anti-atherosclerotic and neuropsychiatric activities. However, the anxiolytic-like effects of OLE and its mechanism of action in PTSD are unclear. The present study used several behavioral tests to examine the effects of OLE on symptoms of anxiety in rats after a single prolonged stress (SPS) exposure by inhibiting the hypothalamic-pituitary-adrenal axis. Male Sprague Dawley rats received OLE (10, 50 and 70?mg/kg, i.p., once daily) for 14 days after SPS exposure. Daily OLE (70?mg/kg) administration significantly increased the number and duration of open arm visits in the elevated plus maze (EPM) test, reduced the anxiety index and grooming behavior in the EPM test, and increased the time spent and number of central zone crossings in the open field test. OLE also blocked the SPS-induced decrease in hippocampal serotonin and neuropeptide Y expression in hippocampus. These findings suggest that OLE has anxiolytic-like effects on behavioral and biochemical symptoms similar to those observed in patients with PTSD.     

创伤后应激障碍（PTSD）的生物学研究概述

创伤后应激障碍（posttraumatic stress disorder,PTSD）是灾害后精神及行为障碍的一种重要表现形式,具有发病率及患病率高、病程长、疗效差等特点,严重影响了临床救治。对于创伤后应激障碍发病机制及其防治的研究日益受到关注。致力于PTSD研究的研究者,从行为学、神经内分泌等宏观研究,到形态学、细胞分子生物学等功能研究,再到临床实验研究,做了大量的工作,得到了许多具有实际指导意义的结果。本文针对国内外研究者近年来在这方面的研究现状进行综述,从宏观上为PTSD后续的研究提供一些循证的证据。     

Genetic factors and epigenetic factors for autism: Endoplasmic reticulum stress and impaired synaptic function

The molecular pathogenesis of ASD (autism spectrum disorder), one of the heritable neurodevelopmental disorders, is not well understood, although over 15 autistic‐susceptible gene loci have been extensively studied. A major issue is whether the proteins that these candidate genes encode are involved in general function and signal transduction. Several mutations in genes encoding synaptic adhesion molecules such as neuroligin, neurexin, CNTNAP (contactin‐associated protein) and CADM1 (cell‐adhesion molecule 1) found in ASD suggest that impaired synaptic function is the underlying pathogenesis. However, knockout mouse models of these mutations do not show all of the autism‐related symptoms, suggesting that gain‐of‐function in addition to loss‐of‐function arising from these mutations may be associated with ASD pathogenesis. Another finding is that family members with a given mutation frequently do not manifest autistic symptoms, which possibly may be because of gender effects, dominance theory and environmental factors, including hormones and stress. Thus epigenetic factors complicate our understanding of the relationship between these mutated genes and ASD pathogenesis. We focus in the present review on findings that ER (endoplasmic reticulum) stress arising from these mutations causes a trafficking disorder of synaptic receptors, such as GABA (γ‐aminobutyric acid) B‐receptors, and leads to their impaired synaptic function and signal transduction. In the present review we propose a hypothesis that ASD pathogenesis is linked not only to loss‐of‐function but also to gain‐of‐function, with an ER stress response to unfolded proteins under the influence of epigenetic factors.     

The long-term costs of traumatic stress: intertwined physical and psychological consequences

The gradual emergence of symptoms following exposure to traumatic events has presented a major conceptual challenge to psychiatry. The mechanism that causes the progressive escalation of symptoms with the passage of time leading to delayed onset post-traumatic stress disorder (PTSD) involves the process of sensitization and kindling. The development of traumatic memories at the time of stress exposure represents a major vulnerability through repeated environmental triggering of the increasing dysregulation of an individual’s neurobiology. An increasing body of evidence demonstrates how the increased allostatic load associated with PTSD is associated with a significant body of physical morbidity in the form of chronic musculoskeletal pain, hypertension, hyperlipidaemia, obesity and cardiovascular disease. This increasing body of literature suggests that the effects of traumatic stress need to be considered as a major environmental challenge that places individual’s physical and psychological health equally at risk. This broader perspective has important implications for developing treatments that address the underlying dysregulation of cortical arousal and neurohormonal abnormalities following exposure to traumatic stress.     

Social rhythm regularity moderates the relationship between sleep disruption and depressive symptoms in veterans with post-traumatic stress disorder and major depressive disorder

ABSTRACT

Approximately 50% to 80% of individuals with posttraumatic stress disorder (PTSD) also meet criteria for major depressive disorder (MDD). Sleep disturbance is a major concern in both PTSD and MDD, and is associated with poor treatment response, poor functional outcome and increased suicide risk. Social rhythm regularity, or the consistency of daily habitual behaviors, is theoretically linked to circadian rhythms and may be disturbed in both PTSD and MDD. The present study examined the relationship between social rhythm regularity, sleep disruption and MDD and PTSD symptoms in a sample of veterans with comorbid PTSD and MDD. Baseline data were obtained from 56 male veterans who met DSM-IV criteria for PTSD and MDD. Veterans completed the Social Rhythm Metric (SRM), a self-report questionnaire that assesses the regularity of routines by determining how regularly individuals completed 17 different types of activities. In a linear regression model, increased minutes awake after sleep onset (WASO) was a significant predictor of increased depression scores on the Hamilton Rating Scale for Depression (p < .05). SRM scores did not significantly predict depressive symptoms, however the interaction of WASO and SRM significantly predicted depressive symptoms (p = <.05), with significant relationships found at SRM scores less than 3.62. Neither minutes awake after sleep onset, SRM scores, nor their interaction was associated with PTSD symptom severity. Social and possibly circadian rhythm regularity may represent a risk or resilience factor for individuals with comorbid PTSD and MDD. Findings highlight the importance of exploring the interactions of sleep and social/circadian rhythms in depression in order to inform continued treatment development.     

创伤后应激障碍机制的研究进展

创伤后应激障碍(Post-traumatic stress disorder;PTSD)是一种由严重强烈的伤害事件造成的精神障碍,随着近年来社会应激事件的增多和自然灾害的发生,创伤应激障碍的发病率逐渐增高。同时为了研究对应的治疗方法,人们对创伤应激障碍的机制进行了更深入的探索,也有了新的进展。本文着重从激素、神经营养因子、免疫系统等方面来总结创伤后应激障碍发生的生物学机制。激素方面,PTSD主要与交感肾上腺髓质系统(Sympatho-adrenomedullarysystem,SAS)和下丘脑-垂体-肾上腺轴(Hypothalamicpituitary-adrenal axis,HPA)的功能异常有关;神经营养因子方面,其产生与分泌的异常增加或减少可能是PTSD产生的重要机制;免疫系统方面,PTSD可能与免疫系统相关的蛋白质、细胞的数量和功能变化有关。整合神经生物学与分子生物学、表观遗传学、蛋白质组学及分子影像学的成果将对PTSD的研究产生推动作用。     

Sex differences in salivary cortisol in response to acute stressors among healthy participants, in recreational or pathological gamblers, and in those with posttraumatic stress disorder

Sex differences in incidence and severity of some stress-related, neuropsychiatric disorders are often reported to favor men, suggesting that women may be more vulnerable to aberrant hypothalamic-pituitary-adrenal (HPA) axis responses to stress. In this review, we discuss several investigations that we, and others, have conducted assessing salivary cortisol as a measure of HPA function. We have examined basal cortisol among healthy men and women and also following acute exposure to stressors. Among healthy participants, men had higher basal cortisol levels than did women. In response to acute stressors, such as carbon dioxide or noise, respectively, cortisol levels were comparable between men and women or higher among women. We have also examined cortisol levels among those with problem eating, gambling, or posttraumatic stress disorder (PTSD). Women with restrained eating habits have higher basal cortisol levels than do women without restrained eating habits. Pathological gamblers have more aberrant stress response to gambling stimuli than do recreational gamblers, and these effects are more prominent among men than women. Men who have motor vehicle accident related PTSD, demonstrate more aberrant cortisol function, than do their female counterparts. Although these sex differences in cortisol seem to vary with type of stress exposure and/or pathophysiological status of the individual, other hormones may influence cortisol response. To address this, cortisol levels among boys and girls with different stress-related experiences, will be the subject of future investigation.     

Use of a Portable Biofeedback Device to Improve Insomnia in a Combat Zone,a Case Report

Insomnia is a common problem in situations of stress. Some forms of stress, however, may contraindicate the use of traditional, pharmacological interventions. Working in a combat zone is such a situation. Alternative means of improving sleep are clearly needed for Service Members. We report a case involving a medical provider who was serving in a military, emergency-services facility in Iraq, and who presented with anxiety, depressed mood, and insomnia. Symptoms were sub-threshold for major depressive disorder or acute stress disorder. Mood and anxiety symptoms responded to traditional therapy techniques, but problems with insomnia remained. The patient was given a portable biofeedback device that employs an infrared sensor photoplethysmograph to measure heart rate variability (HRV) from peripheral finger pulse. One week later, sleep was significantly improved. Symptom improvement lasted to at least 6 weeks while in theater. One year later, a check-in with the patient revealed that after returning home, he had been diagnosed with post traumatic stress disorder (PTSD). PTSD symptoms had resolved after 6 months of psychopharmacology and cognitive behavioral therapy. These results indicate that biofeedback may be a useful means of improving sleep in a combat zone, but that such improvements may not necessarily prevent the development of more serious symptoms later. No clear causality can be inferred from a single case, and further study is needed to determine if this finding have wider applicability.     

Symbiont community diversity is more variable in corals that respond poorly to stress

Coral reefs are declining globally as climate change and local water quality press environmental conditions beyond the physiological tolerances of holobionts—the collective of the host and its microbial symbionts. To assess the relationship between symbiont composition and holobiont stress tolerance, community diversity metrics were quantified for dinoflagellate endosymbionts (Family: Symbiodiniaceae) from eight Acropora millepora genets that thrived under or responded poorly to various stressors. These eight selected genets represent the upper and lower tails of the response distribution of 40 coral genets that were exposed to four stress treatments (and control conditions) in a 10‐day experiment. Specifically, four ‘best performer’ coral genets were analyzed at the end of the experiment because they survived high temperature, high pCO₂, bacterial exposure, or combined stressors, whereas four ‘worst performer’ genets were characterized because they experienced substantial mortality under these stressors. At the end of the experiment, seven of eight coral genets mainly hosted Cladocopium symbionts, whereas the eighth genet was dominated by both Cladocopium and Durusdinium symbionts. Symbiodiniaceae alpha and beta diversity were higher in worst performing genets than in best performing genets. Symbiont communities in worst performers also differed more after stress exposure relative to their controls (based on normalized proportional differences in beta diversity), than did best performers. A generalized joint attribute model estimated the influence of host genet and treatment on Symbiodiniaceae community composition and identified strong associations among particular symbionts and host genet performance, as well as weaker associations with treatment. Although dominant symbiont physiology and function contribute to host performance, these findings emphasize the importance of symbiont community diversity and stochasticity as components of host performance. Our findings also suggest that symbiont community diversity metrics may function as indicators of resilience and have potential applications in diverse disciplines from climate change adaptation to agriculture and medicine.     

Outcomes and moderators of a preventive school-based mental health intervention for children affected by war in Sri Lanka: a cluster randomized trial

We aimed to examine outcomes, moderators and mediators of a preventive school-based mental health intervention implemented by paraprofessionals in a war-affected setting in northern Sri Lanka. A cluster randomized trial was employed. Subsequent to screening 1,370 children in randomly selected schools, 399 children were assigned to an intervention (n=199) or waitlist control condition (n=200). The intervention consisted of 15 manualized sessions over 5 weeks of cognitive behavioral techniques and creative expressive elements. Assessments took place before, 1 week after, and 3 months after the intervention. Primary outcomes included post-traumatic stress disorder (PTSD), depressive, and anxiety symptoms. No main effects on primary outcomes were identified. A main effect in favor of intervention for conduct problems was observed. This effect was stronger for younger children. Furthermore, we found intervention benefits for specific subgroups. Stronger effects were found for boys with regard to PTSD and anxiety symptoms, and for younger children on pro-social behavior. Moreover, we found stronger intervention effects on PTSD, anxiety, and function impairment for children experiencing lower levels of current war-related stressors. Girls in the intervention condition showed smaller reductions on PTSD symptoms than waitlisted girls. We conclude that preventive school-based psychosocial interventions in volatile areas characterized by ongoing war-related stressors may effectively improve indicators of psychological wellbeing and posttraumatic stress-related symptoms in some children. However, they may undermine natural recovery for others. Further research is necessary to examine how gender, age and current war-related experiences contribute to differential intervention effects.     

Genotype‐dependent consequences of traumatic stress in four inbred mouse strains

Post‐traumatic stress disorder (PTSD) is an anxiety disorder that develops in predisposed individuals following a terrifying event. Studies on isogenic animal populations might explain susceptibility to PTSD by revealing associations between the molecular and behavioural consequences of traumatic stress. Our study employed four inbred mouse strains to search for differences in post‐stress response to a 1.5‐mA electric foot shock. One day to 6 weeks after the foot shock anxiety, depression and addiction‐like phenotypes were assessed. In addition, expression levels of selected stress‐related genes were analysed in hippocampus and amygdala. C57BL/6J mice exhibited up‐regulation in the expression of Tsc22d3, Nfkbia, Plat and Crhr1 genes in both brain regions. These alterations were associated with an increase of sensitized fear and depressive‐like behaviour over time. Traumatic stress induced expression of Tsc22d3, Nfkbia, Plat and Fkbp5 genes and developed social withdrawal in DBA/2J mice. In 129P3/J strain, exposure to stress produced the up‐regulation of Tsc22d3 and Nfkbia genes and enhanced sensitivity to the rewarding properties of morphine. Whereas, SWR/J mice displayed increase only in Pdyn expression in the amygdala and had the lowest conditioned fear. Our results reveal a complex genetic background of phenotypic variation in response to stress and indicate the SWR/J strain as a valuable model of stress resistance. We found potential links between the alterations in expression of Tsc22d3, Nfkbia and Pdyn, and different aspects of susceptibility to stress.     

Progress in understanding mood disorders: optogenetic dissection of neural circuits

Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression‐like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit‐targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depression‐related behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders .     

创伤后应激障碍（PTSD）的生物学研究概述

创伤后应激障碍(posttraumatic stress disorder,PTSD)是灾害后精神及行为障碍的一种重要表现形式,具有发病率及患病率高、病程长、疗效差等特点,严重影响了临床救治。对于创伤后应激障碍发病机制及其防治的研究日益受到关注。致力于PTSD研究的研究者,从行为学、神经内分泌等宏观研究,到形态学、细胞分子生物学等功能研究,再到临床实验研究,做了大量的工作,得到了许多具有实际指导意义的结果。本文针对国内外研究者近年来在这方面的研究现状进行综述,从宏观上为PTSD后续的研究提供一些循证的证据。     

Epigenetics and memory: causes,consequences and treatments for post‐traumatic stress disorder and addiction

Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress‐related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug‐seeking responses. This may, in part, account for the fact that individuals with post‐traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug‐seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress‐induced relapse.