How Well Do We Understand the Long-Term Health Implications of Childhood Bullying?

Zarate-Garza, Pablo Patricio MD; Biggs, Bridget K. PhD; Croarkin, Paul DO; Morath, Brooke BSc; Leffler, Jarrod PhD; Cuellar-Barboza, Alfredo MD; Tye, Susannah J. PhD

doi: 10.1097/HRP.0000000000000137
Psychopathology

Abstract: Once dismissed as an innocuous experience of childhood, bullying is now recognized as having significant psychological effects, particularly with chronic exposure. Victims of bullying are at risk for a number of psychiatric disturbances, and growing evidence suggests that the pathophysiological effects of bullying, as with other forms of trauma and chronic stress, create additional health risks. We review the literature on the known sequelae of bullying, including psychiatric and physiological health effects, with a focus on implications for the victim. In addition, since it is now well established that early and chronic exposure to stress has a significant negative impact on health outcomes, we explore the implications of this research in relation to bullying and victimization in childhood. In particular, we examine how aspects of the stress response, via epigenetic, inflammatory, and metabolic mediators, have the capacity to compromise mental and physical health, and to increase the risk of disease. Research on the relevant mechanisms associated with bullying and on potential interventions to decrease morbidity is urgently needed.

From the Department of Psychiatry, Autonomous University of Nuevo Leon (Mexico) (Drs. Zarate-Garza and Cuellar-Barboza); Departments of Psychiatry and Psychology (Drs. Zarate-Garza, Biggs, Croarkin, Leffler, and Tye, and Ms. Morath), and of Molecular Pharmacology and Experimental Therapeutics (Dr. Tye), Mayo Clinic, Rochester, MN; Department of Psychiatry, University of Minnesota (Dr. Tye).

Supported by National Institute of Mental Health K23 grant no. MH100266 (Dr. Croarkin) and State of Minnesota Mayo-Minnesota Partnership Award (Dr. Tye).

Correspondence: Susannah J. Tye, Department of Psychiatry & Psychology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Email: tye.susannah@mayo.edu

Article Outline

Bullying victimization is a significant predictor of future psychological health problems,1 yet we have limited understanding of how it affects acute and long-term physical health. The field of stress neuroendocrinology has established a wealth of data, however, demonstrating that early and chronic stress can profoundly and negatively affect neuroendocrine, inflammatory, and metabolic processes via epigenetic programming to increase the risk for obesity, cardiovascular disease, cognitive impairment, and accelerated cellular aging.2–7 Exposure to the stress of bullying thus has significant potential to harm both the psychological and physical health of the individual. Moreover, it is becoming increasingly apparent that the physiological mechanisms through which early-life stress affects endocrine and inflammatory processes may be the very same mechanisms that contribute to the poor psychological health outcomes associated with bullying. Given the inherent vulnerability of the developing child and adolescent to the stress-related insults imposed by bullying victimization, it is imperative that basic research findings be rapidly translated to clinical practice. Early intervention is essential to bolster both physiological and psychological resilience and to minimize negative long-term health implications.8

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BULLYING AS A FORM OF CHRONIC STRESS

Stress can be divided into acute and chronic forms, as well as being both positive and negative in valence (eustress and distress, respectively).9 The acute stage is one of protection and facilitates the body’s capacity to respond to the demands of the environment. The immediate reaction of “flight or fight” is activated in order to cope with the situation, and once the stress has subsided, homeostasis returns.10 Under chronic stress, however, homeostatic mechanisms fail, and the individual can experience a state of allostatic overload.10 This chronic stress can eventually induce significant and deleterious health consequences that stem from associated elevations of inflammatory mediators, from deficits in neurotrophic factors, and from metabolic adaptations that facilitate insulin desensitization, lipid storage, and other metabolic syndrome–like outcomes, all working together to alter stress reactivity.8–11 Herein we review the harmful psychological and physiological effects of chronic exposure to bullying stress. Our review of the bullying literature focuses primarily on peer-to-peer bullying in childhood and adolescence; much of the research on bullying has been conducted during these developmental periods and focused on the health implications of peer victimization. This period is also one of developmental vulnerability in which the experience of bully victimization can become biologically embedded to modify the individual’s long-term health trajectory.12 Although beyond the scope of the current review, it is important to acknowledge that parents, teachers, and other adults can also bully children and that, in such instances, the health implications are likewise significant.

Bullying, a classic form of chronic social stress, has been defined as a systematic abuse of power, with aggressive behavior or intentional harm-doing by peers that is carried out repeatedly.13 Bullying can take on different forms, including physical (e.g., hitting and pushing), verbal (e.g., insults and intimidation), indirect (e.g., social manipulation and systematic exclusion), and virtual (e.g., cyberbullying).14 More than 25% of children report being bullied or being on the receiving end of peer victimization, and 10% to 14% of those suffered from chronic peer victimization, defined as frequent exposure during a period of six or more months. There is increasing evidence that chronicity of victimization and also severity15–17 are important mediators of long-term health and academic impact. Not surprisingly, children who experience chronic peer victimization suffer greater long-term psychological impact than those who experience briefer episodes of bullying.18,19 Peer victimization affects both genders, though the bullying methods may differ. For example, boys are, more often than girls, the recipients of direct physical and verbal aggression, whereas girls are, more often than boys, the recipients of more relational and social forms of bullying—although such differences are not always observed.20 In any event, a number of sex-specific psychiatric health outcomes have been reported.21

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BULLYING AND RISK FOR PSYCHIATRIC DISORDERS

Data regarding the impact of early risk factors for bullying exposure—be it as a bully, victim, or bully/victim—are rare.22 Evidence suggests, however, that the effects of being bullied are as severe as, or even more severe than, maltreatment in childhood.23 Longitudinal studies such as the recent Tracking Adolescents’ Individual Lives Survey (TRAILS)22 have shown that behavioral, emotional, and motor problems, socioeconomic status, and the experience of family breakup during preschool years are associated with involvement in bullying during late elementary and secondary school. Parenting behavior24 and factors in pregnancy have also been suggested to increase the risk of becoming a target of bullying,25 possibly through effects on stress responses at the physiological and behavioral levels. Vulnerability to bullying may thus arise from risk factors inherently associated with later development of psychiatric illness, and the presence of psychiatric illness is itself also associated with increased incidence of bully victimization in youth.26 It would be nevertheless be wrong to discount the harmful impact that the stress of bullying can have on individuals—which is to exacerbate the preexisting risk for, or early presentation of, a psychiatric illness. In this context, the Virginia Twin Study of Adolescent Behavioral Development, using data from 145 bully-discordant monozygotic juvenile twin pairs, found that bullying victimization was an environmental risk factor for psychiatric disturbance, including anxiety, depression, and suicidal ideation and behavior.27 Data from this prospective study demonstrated that being bullied had a significant environmental impact on childhood social anxiety (odds ratio [OR] = 1.7), separation anxiety (OR = 1.9), and young-adult suicidal ideation (OR = 1.3).27 A shared genetic influence on social anxiety and bullying victimization was also identified,27 which the authors noted was consistent with data suggesting that social anxiety could be both an antecedent to, and a consequence of, bullying. Prospective studies such as the above have been particularly valuable in establishing a clear role for exposure to bullying victimization in later development of mental illness. While retrospective and cross-sectional studies have helped to identify the presence of such a relationship, the directionality cannot be ascertained without longitudinal follow-up post-victimization. For example, retrospective and cross-sectional studies cannot determine whether individuals who develop depression or social anxiety were premorbidly more sensitive to criticism and rejection, and thus were more inclined to interpret earlier interpersonal experiences as bullying victimization.

Elucidating directionality within this relationship is important for understanding the health effects of stress related to bully victimization. Given the vulnerabilities associated with the risk for being affected by bullying behavior, be it as the victim or bully, compounded by the impact of stress in the development of psychopathology, it is not unexpected that depression, anxiety, and some abuse disorders are more common in the victims of chronic bullying. Of significant concern are reports from prospective studies that men who were victims of bullying are at 18 times more risk of suicidality than their non-bullied counterparts, while female victims have nearly 27 times more risk for panic disorders.21,28,29 Bullies, by contrast, have four times more risk for development of antisocial personality disorder.21,28,29 Taken together, such data suggest that significant negative psychiatric outcomes are associated with bullying behavior for both the victims and perpetuators. Factors increasing the risk for experiencing either (or both) can be identified early in life and have serious long-term consequences—ones that may be compounded by the social stress of the bullying process. The implication is that bullying is not only a sociological or biological process but something more complex: a biopsychosocial problem that requires an integrated, longitudinal research approach to identify risk factors and long-term health effects.

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BULLYING AND SOMATIC SYMPTOMS

Gini and Pozzoli’s recent meta-analysis30 of the association between bullying and psychosomatic problems found that bullied children and adolescents have a significantly higher risk for psychosomatic problems than non-bullied peers. Commonly reported physical health problems associated with bullying include poor subjective health status, poor appetite, sleep disturbances, headaches, abdominal pain, breathing problems, and fatigue.31–33 This association between bullying, victimization, and somatic symptoms is observed in children as early as four years old (preschool age)34 and has led some researchers in the field to suggest that any recurrent and unexplained somatic symptom may be a warning sign of bullying victimization.35 While many children have somatic symptoms during times of emotional distress or trauma, these data underscore the importance of considering bullying as a differential among potential causes of somatic symptoms in children and adolescents. Together, this now well-established relation between psychological and somatic symptoms may serve to alert mental health and primary care providers to the potential experience of bullying and may help to facilitate the eradication of such harmful treatment in child and adolescent patient populations.36 It is important to note, though, that personal resources, ranging from self-efficacy to the availability of social support, can mitigate the impact of bullying on the development of psychological and somatic complaints,33 indicating that the deleterious effects of bullying do not affect all individuals equally. This finding is consistent with the potential for protective psychological constructs to buffer the physiological impact of stress on the body. Indeed, peer victimization in late childhood or early adolescence has been shown to impair adaptive stress responses,37 which itself may be represent a key, critical mechanism through which the psychological and physiological symptoms develop.

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STRESS RESPONSES AND ALLOSTATIC LOAD

Stress, both psychological and physiological, elicits a biological response that, if continued unabated, contributes to allostatic load on the brain and body.38 Allostatic load provides an index of biological “wear and tear” from cumulative exposure to stress.38 Over time, this increasing allostatic load accelerates the wear and tear on the body as a result of chronic exposure to fluctuating or heightened neural or neuroendocrine responses to stress.39 Through the process of increasing allostatic load, the accumulation of health-related risk factors increases an individual’s chances of developing disease.39 This increasing load, along with eventual allostatic overload, is now well established to be implicated in the development of a variety of diseases, including depression, diabetes, and heart disease.9,38,40–45 Allostatic load is also implicated in the acceleration of psychiatric illness progression and poor treatment outcomes.46–56 Research over the last two decades has illuminated the mechanisms through which continued physiological stress burden and accruing allostatic load can accelerate aging and neurodegenerative and disease processes.

The process of increasing allostatic load is one in which the body accrues damage over time, impairing its capacity to maintain and restore homeostasis in the face of future challenges. It is through this process, mediated in part by epigenetic modifications that alter system-wide responses (discussed below), that early adverse experiences, such as chaotic family environments, low socioeconomic status, and experiences of abuse and other forms of interpersonal aggression, have been associated with a variety of poor health outcomes in adolescence and adulthood, including higher rates of chronic illness and death from disease.57–65 Markers for disease risk, such as inflammation and increased blood pressure, are also associated, in adulthood, with the experience of adverse, stressful experiences in childhood.66–74 The impact of early-life stress on long-term health is likely to be further mediated by the potential for early adversity to impair children’s development of skills that foster resilience. Specifically, early-life stressors increase the likelihood that individuals will develop cognitive and interpersonal styles,75,76 as well as coping behaviors,77 that reduce their capacity to cope with stress in the future. These negative effects are further likely to influence the types of environments in which affected children reside later in life, and to increase the probability that individuals will perceive and react to stress in ways that escalate exposure to stressful circumstances.78 The cumulative direct and indirect effects of early-life stress can therefore work together, over time, to enhance the negative health impacts through increased biological vulnerability together with increased rates of sequential exposures to perceived stressors.79–81

Although limited data are available on the impact of bullying on health over the lifespan, the health effects of stress associated with bullying and victimization would presumably follow the same pattern. That is, drawing from the literature on other types of chronic stress in childhood, on allostatic load, and on associated risks for health and mental health problems, it is reasonable to consider chronic peer victimization as capable of generating negative outcomes through similar cascading processes. We posit that the psychological experience of chronic peer victimization activates biological responses and also serves to interfere with health-related behaviors (e.g., sleep, diet, and exercise) that further perturb basic homeostatic mechanisms and compromise long-term psychological and physiological health. This suggestion is in line with studies showing that the long-term psychological impact of peer victimization is mediated by activation of the physiological stress response (i.e., hypothalamic-pituitary-adrenal axis and autonomic nervous system) in response to the anticipation of victimization.82

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EPIGENETICS: ENCODING LONG-TERM HEALTH EFFECTS

An individual’s behavioral, physiological, and social conditions collectively influence, and are influenced by, the epigenome.83 Epigenetic marks are sculpted by environmental interactions during development. Functionally, these marks modify the activation of certain genes to shape cellular and system-wide responses upon reexposure to similar stimuli. The most important influences on epigenetic programming include stress, inflammation, and the individual’s metabolic status (integrated metabolic function across multiple bodily systems), and these integrated systems, in turn, functionally co-regulate each other.84 These processes enable early stress exposure to leave a lasting imprint on stress responsivity, associated immune activations, and metabolic efficiency.83 Epigenetics thus represents an important biological mechanism through which social stressors such as bullying can directly and physiologically contribute to the development of disease.85 The number of human studies that have directly assessed the impact of early-life peer bullying on epigenetic profiles is limited,86 though the impact of early-life stress on the epigenome, along with the associated health effects, is well established.87,88 Inherent in this conceptualization is that the disease process involves the integration of social, behavioral, and biological factors—all of which are mediated by, and mediate, epigenetic marks. More research is needed.

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BULLYING, INFLAMMATION, AND METABOLIC DYSFUNCTION

Preclinical and clinical evidence demonstrates a link between early-life stress and inflammation.89 While acute inflammatory responses are important for fighting infection and healing processes, chronic inflammation is a significant contributing factor to the development and progression of various serious diseases, including cardiovascular disease.90 Chronic inflammatory states are activated and maintained by environmental stressors as well as by a range of health-risk behaviors, including poor diet, lack of exercise, and sleep disturbance.91,92 One marker of inflammation, C-reactive protein (CRP), has been extensively researched because of its association with cardiovascular risk93,94 and metabolic syndrome.95,96 In line with the stressful nature of peer victimization and the association between early-life stress and chronic inflammation in later life, a growing evidence base indicates that childhood bullying predicts low-grade systemic inflammation into adulthood.29,97 Recent work in this area has shown that involvement in childhood bullying, either as a bully or bully/victim, can predict changes in CRP levels well into adulthood.29 The directional impact, however—relative to those uninvolved in bullying—was different for those two groups. Victimization was associated with greater increases in CRP levels, and bullying was associated with lower increases. These long-term effects held even following adjustment for other related and potentially confounding factors, including body mass index, substance use, childhood physical and mental health status, and exposure to other early-life psychosocial adversities, suggesting that the bullying experience itself was a significant contributor to inflammatory status.29

The link between bullying, stress, and inflammation is supported by data from another recent study demonstrating that childhood bully victims had increased levels of CRP at midlife and higher risk for clinically relevant inflammation (CRP > 3 mg/l).97 Again, these findings remained significant when controlling for potentially confounding variables such as body mass index and psychopathology in childhood, and smoking, diet, and exercise in adulthood. An interesting finding from the same study was that central distribution of fat was more prevalent in individuals who had been bullied.97 Given that central adiposity contributes to an overall inflammatory state,98 it is important to keep in mind the potential link between bullying and metabolic dysfunction. Studies focusing on early-life stress, though not specifically on bullying, suggest that the interaction among stress, inflammation, and metabolic dysfunction are more interdependent than previously appreciated. For example, a longitudinal study demonstrated that early adversity was predictive of higher body mass index, which, in turn, was predictive of higher levels of inflammatory mediators, including CRP.89 While the studies specific to bullying suggest that it has a direct and deleterious physiological impact, it is likely that ongoing stress and maladaptive health behaviors can further compound the negative health consequences of that altered physiology. Given that maladaptive health behaviors alone foreshadow chronic inflammation in young adulthood, they serve as promising target for intervention to reduce long-term health consequences.

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COULD BULLYING INCREASE RISK FOR DISEASE?

Given the emerging evidence demonstrating a link between bullying, inflammation, and metabolic dysfunction, along with impact of early-life stress on health-risk behaviors, one might suspect that bullying could increase the risk for chronic lifestyle diseases in which these various processes are directly implicated. Although this association remains to be confirmed longitudinally, and many confounding factors limit retrospective confirmation, bullying by peers appears to have a direct and non-negligible effect on age-related disease risk, independent of other established risk factors.97,99 The biological mechanisms through which childhood bullying affects long-term health are likely mediated via its epigenetic imprint on stress, inflammation, and metabolic systems. More research in this area is urgently needed. Current data nevertheless underscore the importance of investigating bully victimization as a standard component of clinical practice today. Asking about bullying in child and adolescent psychiatry, family medicine, and primary care represents a practical first step toward intervening to prevent traumatic exposure and to reduce the risk for further psychiatric and other morbidities.100,101

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CONCLUSIONS

To date, the study of bullying has developed in parallel with the study of the physiology of stress, with limited convergence of these two fields. Currently, we do not possess sufficient data to definitively determine whether a direct cause-and-effect relationship exists between childhood bullying and poor long-term health outcomes. Synthesis of these two scientific literatures suggests, however, that chronic peer victimization could have significant physiological and mental health consequences and that cascading processes of the physiological stress response, including chronically elevated levels of inflammation, could play an important role. At this stage, however, our understanding of the relationship is primarily by extrapolating from one field to the other. Future collaboration between the two has the potential to produce findings with rich scientific and clinical implications.

Declaration of interest: Dr. Croarkin has received grant support from Pfizer Inc. and the Brain & Behavior Research Foundation, and in-kind support for equipment and supplies from Neuronetics and AssureRx Health. Dr Tye has received support from Teva Pharmaceuticals and the International Bipolar Foundation.

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REFERENCES

1. Kumpulainen K. Psychiatric conditions associated with bullying. Int J Adolesc Med Health 2008;20:121–32.
2. Zhang Y, Ren J. Epigenetics and obesity cardiomyopathy: from pathophysiology to prevention and management. Pharmacol Ther 2016.
3. Naninck EF, Hoeijmakers L, Kakava-Georgiadou N, et al. Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice. Hippocampus 2015;25:309–28.
4. Drury SS, Shirtcliff EA, Shachet A, et al. Growing up or growing old? Cellular aging linked with testosterone reactivity to stress in youth. Am J Med Sci 2014;348:92–100.
5. Zhang J, Abdallah CG, Chen Y, et al. Behavioral deficits, abnormal corticosterone, and reduced prefrontal metabolites of adolescent rats subject to early life stress. Neurosci Lett 2013;545:132–7.
6. Morris MJ, Beilharz JE, Maniam J, Reichelt AC, Westbrook RF. Why is obesity such a problem in the 21st century? The intersection of palatable food, cues and reward pathways, stress, and cognition. Neurosci Biobehav Rev 2015;58:36–45.
7. Dallman MF. Early life stress: nature and nurture. Endocrinology 2014;155:1569–72.
8. Walker AJ, Kim Y, Price JB, et al. Stress, inflammation, and cellular vulnerability during early stages of affective disorders: biomarker strategies and opportunities for prevention and intervention. Front Psychiatry 2014;5:34.
9. McEwen BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci 1998;840:33–44.
10. McEwen BS, Wingfield JC. What is in a name? Integrating homeostasis, allostasis and stress. Horm Behav 2010;57:105–11.
11. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med 1998;338:171–9.
12. Vaillancourt T, Hymel S, McDougall P. The biological underpinnings of peer victimization: understanding why and how the effects of bullying can last a lifetime. Theory Pract 2013;52:241–8.
13. Olweus D. Bullying at school. Basic facts and an effective intervention programme. Promot Educ 1994;1:27–31, 48.
14. Greif JL, Furlong MJ, Morrison G. Operationally defining “bullying.” Arch Pediat Adol Med 2003;157:1134–5.
15. Wolke D, Lereya ST, Fisher HL, Lewis G, Zammit S. Bullying in elementary school and psychotic experiences at 18 years: a longitudinal, population-based cohort study. Psychol Med 2014;44:2199–211.
16. Schwartz D, Lansford JE, Dodge KA, Pettit GS, Bates JE. Peer victimization during middle childhood as a lead indicator of internalizing problems and diagnostic outcomes in late adolescence. J Clin Child Adolesc Psychol 2015;44:393–404.
17. Zwierzynska K, Wolke D, Lereya TS. Peer victimization in childhood and internalizing problems in adolescence: a prospective longitudinal study. J Abnorm Child Psychol 2013;41:309–23.
18. Biggs BK, Vernberg E, Little TD, Dill EJ, Fonagy P, Twemlow SW. Peer victimization trajectories and their association with children’s affect in late elementary school. Int J Behav Dev 2010;34:136–46.
19. Kochenderfer-Ladd B, Wardrop JL. Chronicity and instability of children’s peer victimization experiences as predictors of loneliness and social satisfaction trajectories. Child Dev 2001;72:134–51.
20. Rose AJ, Rudolph KD. A review of sex differences in peer relationship processes: potential trade-offs for the emotional and behavioral development of girls and boys. Psychol Bull 2006;132:98–131.
21. Copeland WE, Wolke D, Angold A, Costello EJ. Adult psychiatric outcomes of bullying and being bullied by peers in childhood and adolescence. JAMA Psychiatry 2013;70:419–26.
22. Jansen DEMC, Veenstra R, Ormel J, Verhulst FC, Reijneveld SA. Early risk factors for being a bully, victim, or bully/victim in late elementary and early secondary education. The longitudinal TRAILS study. BMC Public Health 2011;11.
23. Lereya ST, Copeland WE, Costello EJ, Wolke D. Adult mental health consequences of peer bullying and maltreatment in childhood: two cohorts in two countries. Lancet Psychiatry 2015;2:524–31.
24. Lereya ST, Samara M, Wolke D. Parenting behavior and the risk of becoming a victim and a bully/victim: a meta-analysis study. Child Abuse Negl 2013;37:1091–108.
25. Lereya ST, Wolke D. Prenatal family adversity and maternal mental health and vulnerability to peer victimisation at school. J Child Psychol Psychiatry 2013;54:644–52.
26. Mayes SD, Calhoun SL, Baweja R, Mahr F. Maternal ratings of bullying and victimization: differences in frequencies between psychiatric diagnoses in a large sample of children. Psychol Rep 2015;116:710–22.
27. Silberg JL, Copeland W, Linker J, Moore AA, Roberson-Nay R, York TP. Psychiatric outcomes of bullying victimization: a study of discordant monozygotic twins. Psychol Med 2016:1–9.
28. Copeland WE, Bulik CM, Zucker N, Wolke D, Lereya ST, Costello EJ. Does childhood bullying predict eating disorder symptoms? A prospective, longitudinal analysis. Int J Eat Disord 2015;48:1141–9.
29. Copeland WE, Wolke D, Lereya ST, Shanahan L, Worthman C, Costello EJ. Childhood bullying involvement predicts low-grade systemic inflammation into adulthood. Proc Natl Acad Sci U S A 2014;111:7570–5.
30. Gini G, Pozzoli T. Association between bullying and psychosomatic problems: a meta-analysis. Pediatrics 2009;123:1059–65.
31. Sigurdson JF, Wallander J, Sund AM. Is involvement in school bullying associated with general health and psychosocial adjustment outcomes in adulthood? Child Abuse Negl 2014;38:1607–17.
32. Boynton-Jarrett R, Ryan LM, Berkman LF, Wright RJ. Cumulative violence exposure and self-rated health: longitudinal study of adolescents in the United States. Pediatrics 2008;122:961–70.
33. Menrath I, Prussmann M, Muller-Godeffroy E, et al. Subjective health, school victimization, and protective factors in a high-risk school sample. J Dev Behav Pediatr 2015;36:305–12.
34. Ilola AM, Lempinen L, Huttunen J, Ristkari T, Sourander A. Bullying and victimisation are common in four-year-old children and are associated with somatic symptoms and conduct and peer problems. Acta Paediatr 2016;105:522–8.
35. Gini G, Pozzoli T, Lenzi M, Vieno A. Bullying victimization at school and headache: a meta-analysis of observational studies. Headache 2014;54:976–86.
36. Sansone RA, Sansone LA. Bully victims: psychological and somatic aftermaths. Psychiatry (Edgmont) 2008;5:62–4.
37. Troop-Gordon W, Rudolph KD, Sugimura N, Little TD. Peer victimization in middle childhood impedes adaptive responses to stress: a pathway to depressive symptoms. J Clin Child Adolesc Psychol 2015;44:432–45.
38. Korte SM, Koolhaas JM, Wingfield JC, McEwen BS. The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci Biobehav Rev 2005;29:3–38.
39. McEwen BS, Stellar E. Stress and the individual. Mechanisms leading to disease. Arch Intern Med 1993;153:2093–101.
40. Borsook D, Maleki N, Becerra L, McEwen B. Understanding migraine through the lens of maladaptive stress responses: a model disease of allostatic load. Neuron 2012;73:219–34.
41. Power ML, Schulkin J. Maternal obesity, metabolic disease, and allostatic load. Physiol Behav 2012;106:22–8.
42. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav 2012;106:29–39.
43. Logan JG, Barksdale DJ. Allostasis and allostatic load: expanding the discourse on stress and cardiovascular disease. J Clin Nurs 2008;17:201–8.
44. Sabbah W, Watt RG, Sheiham A, Tsakos G. Effects of allostatic load on the social gradient in ischaemic heart disease and periodontal disease: evidence from the Third National Health and Nutrition Examination Survey. J Epidemiol Community Health 2008;62:415–20.
45. Nelson KM, Reiber G, Kohler T, Boyko EJ. Peripheral arterial disease in a multiethnic national sample: the role of conventional risk factors and allostatic load. Ethn Dis 2007;17:669–75.
46. Vieta E, Popovic D, Rosa AR, et al. The clinical implications of cognitive impairment and allostatic load in bipolar disorder. Eur Psychiatry 2013;28:21–9.
47. Brietzke E, Kapczinski F, Grassi-Oliveira R, Grande I, Vieta E, McIntyre RS. Insulin dysfunction and allostatic load in bipolar disorder. Expert Rev Neurother 2011;11:1017–28.
48. Sylvia LG, Ametrano RM, Nierenberg AA. Exercise treatment for bipolar disorder: potential mechanisms of action mediated through increased neurogenesis and decreased allostatic load. Psychother Psychosom 2010;79:87–96.
49. Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 2008;32:675–92.
50. Nugent KL, Chiappelli J, Rowland LM, Hong LE. Cumulative stress pathophysiology in schizophrenia as indexed by allostatic load. Psychoneuroendocrinology 2015;60:120–9.
51. Misiak B, Frydecka D, Zawadzki M, Krefft M, Kiejna A. Refining and integrating schizophrenia pathophysiology—relevance of the allostatic load concept. Neurosci Biobehav Rev 2014;45:183–201.
52. Lolich M, Holtzman JN, Rago CM, Vazquez GH. [Neuroprogression and cognition in bipolar disorders: a systematic review of cognitive performance in euthymic patients]. Vertex 2015;26:265–75.
53. da Costa SC, Passos IC, Lowri C, Soares JC, Kapczinski F. Refractory bipolar disorder and neuroprogression. Prog Neuropsychopharmacol Biol Psychiatry 2016;70:103–10.
54. Inal-Emiroglu FN, Resmi H, Karabay N, et al. Decreased right hippocampal volumes and neuroprogression markers in adolescents with bipolar disorder. Neuropsychobiology 2015;71:140–8.
55. Stein K, Broome MR. Neuroprogression in schizophrenia: pathways and underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 2015;49:183–4.
56. Budni J, Valvassori SS, Quevedo J. Biological mechanisms underlying neuroprogression in bipolar disorder. Rev Bras Psiquiatr 2013;35:1–2.
57. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med 1998;14:245–58.
58. Power C, Hypponen E, Smith GD. Socioeconomic position in childhood and early adult life and risk of mortality: a prospective study of the mothers of the 1958 British birth cohort. Am J Public Health 2005;95:1396–402.
59. Hertz MF, Everett Jones S, Barrios L, David-Ferdon C, Holt M. Association between bullying victimization and health risk behaviors among high school students in the United States. J Sch Health 2015;85:833–42.
60. Lantos JD, Halpern J. Bullying, social hierarchies, poverty, and health outcomes. Pediatrics 2015;135 suppl 2:S21–3.
61. Politis S, Bellou V, Belbasis L, Skapinakis P. The association between bullying-related behaviours and subjective health complaints in late adolescence: cross-sectional study in Greece. BMC Res Notes 2014;7:523.
62. Fekkes M, Pijpers FI, Fredriks AM, Vogels T, Verloove-Vanhorick SP. Do bullied children get ill, or do ill children get bullied? A prospective cohort study on the relationship between bullying and health-related symptoms. Pediatrics 2006;117:1568–74.
63. Wilkins-Shurmer A, O’Callaghan MJ, Najman JM, Bor W, Williams GM, Anderson MJ. Association of bullying with adolescent health-related quality of life. J Paediatr Child Health 2003;39:436–41.
64. Weir E. The health impact of bullying. CMAJ 2001;165:1249.
65. Wolke D, Woods S, Bloomfield L, Karstadt L. Bullying involvement in primary school and common health problems. Arch Dis Child 2001;85:197–201.
66. Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A 2007;104:1319–24.
67. Slopen N, Koenen KC, Kubzansky LD. Childhood adversity and immune and inflammatory biomarkers associated with cardiovascular risk in youth: a systematic review. Brain Behav Immun 2012;26:239–50.
68. Turner RJ, Thomas CS, Brown TH. Childhood adversity and adult health: evaluating intervening mechanisms. Soc Sci Med 2016;156:114–24.
69. Friedman EM, Montez JK, Sheehan CM, Guenewald TL, Seeman TE. Childhood adversities and adult cardiometabolic health: does the quantity, timing, and type of adversity matter? J Aging Health 2015;27:1311–38.
70. Davis CR, Dearing E, Usher N, et al. Detailed assessments of childhood adversity enhance prediction of central obesity independent of gender, race, adult psychosocial risk and health behaviors. Metabolism 2014;63:199–206.
71. Oshio T, Umeda M, Kawakami N. Impact of interpersonal adversity in childhood on adult mental health: how much is mediated by social support and socio-economic status in Japan? Public Health 2013;127:754–60.
72. Scott J, Varghese D, McGrath J. As the twig is bent, the tree inclines: adult mental health consequences of childhood adversity. Arch Gen Psychiatry 2010;67:111–2.
73. Schilling EA, Aseltine RH, Gore S. The impact of cumulative childhood adversity on young adult mental health: measures, models, and interpretations. Soc Sci Med 2008;66:1140–51.
74. Power C. Childhood adversity still matters for adult health outcomes. Lancet 2002;360:1619–20.
75. Bifulco A, Moran PM, Ball C, Lillie A. Adult attachment style. II: Its relationship to psychosocial depressive-vulnerability. Soc Psychiatry Psychiatr Epidemiol 2002;37:60–7.
76. Oshri A, Rogosch FA, Cicchetti D. Child maltreatment and mediating influences of childhood personality types on the development of adolescent psychopathology. J Clin Child Adolesc Psychol 2013;42:287–301.
77. Turner RJ, Lloyd DA. Lifetime traumas and mental health: the significance of cumulative adversity. J Health Soc Behav 1995;36:360–76.
78. Campbell L, Simpson JA, Boldry J, Kashy DA. Perceptions of conflict and support in romantic relationships: the role of attachment anxiety. J Pers Soc Psychol 2005;88:510–31.
79. Raposa EB, Hammen CL, Brennan PA, O’Callaghan F, Najman JM. Early adversity and health outcomes in young adulthood: the role of ongoing stress. Health Psychol 2014;33:410–8.
80. Chen Y, Baram TZ. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology 2016;41:197–206.
81. Yam KY, Naninck EF, Schmidt MV, Lucassen PJ, Korosi A. Early-life adversity programs emotional functions and the neuroendocrine stress system: the contribution of nutrition, metabolic hormones and epigenetic mechanisms. Stress 2015;18:328–42.
82. Rudolph KD, Troop-Gordon W, Granger DA. Individual differences in biological stress responses moderate the contribution of early peer victimization to subsequent depressive symptoms. Psychopharmacology (Berl) 2011;214:209–19.
83. McGowan PO, Szyf M. The epigenetics of social adversity in early life: implications for mental health outcomes. Neurobiol Dis 2010;39:66–72.
84. Bale TL. Epigenetic and transgenerational reprogramming of brain development. Nat Rev Neurosci 2015;16:332–44.
85. Kelly MP, Kelly RS, Russo F. The integration of social, behavioral, and biological mechanisms in models of pathogenesis. Perspect Biol Med 2014;57:308–28.
86. Ouellet-Morin I, Wong CC, Danese A, et al. Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychol Med 2013;43:1813–23.
87. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull 2011;137:959–97.
88. Rutten BP, Mill J. Epigenetic mediation of environmental influences in major psychotic disorders. Schizophr Bull 2009;35:1045–56.
89. Raposa EB, Bower JE, Hammen CL, Najman JM, Brennan PA. A developmental pathway from early life stress to inflammation: the role of negative health behaviors. Psychol Sci 2014;25:1268–74.
90. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237–42.
91. Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun 2007;21:901–12.
92. O’Connor MF, Bower JE, Cho HJ, et al. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 2009;23:887–97.
93. Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010;375:132–40.
94. Shah T, Casas JP, Cooper JA, et al. Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts. Int J Epidemiol 2009;38:217–31.
95. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Jama 2001;286:327–34.
96. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003;107:391–7.
97. Takizawa R, Danese A, Maughan B, Arseneault L. Bullying victimization in childhood predicts inflammation and obesity at mid-life: a five-decade birth cohort study. Psychol Med 2015;45:2705–15.
98. Elks CM, Francis J. Central adiposity, systemic inflammation, and the metabolic syndrome. Curr Hypertens Rep 2010;12:99–104.
99. Takizawa R, Maughan B, Arseneault L. Adult health outcomes of childhood bullying victimization: evidence from a five-decade longitudinal British birth cohort. Am J Psychiatry 2014;171:777–84.
100. Dale J, Russell R, Wolke D. Intervening in primary care against childhood bullying: an increasingly pressing public health need. J R Soc Med 2014;107:219–23.
101. Srabstein JC, Leventhal BL. Medical recognition of bullying and its related morbidity. Lancet Psychiatry 2015;2:858–9.
Keywords:

bullying; health; inflammation; metabolism; stress

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