EDITORIAL
The Preeminent Role of Childhood Abuse and Neglect in Vulnerability to Major Psychiatric Disorders: Toward Elucidating the Underlying Neurobiological Mechanisms Charles B. Nemeroff,
MD, PhD, AND
In the little world in which children have their existence, whosoever brings them up, there is nothing so finely perceived and so finely felt as injustice. —Charles Dickens
M
ore than 3 decades ago, our group and others1,2 suggested, based on results from laboratory animal studies, that trauma early in life in the form of child abuse and/or neglect was associated with persistent alterations in the central nervous system (CNS) that likely mediated the increased diathesis for mood and anxiety disorders in individuals who experienced significant early adversity. Although the seminal role of early life experiences in psychopathology was posited by Freud3 early in his career and by other psychoanalysts, it was not firmly established until the appearance of more recent epidemiological studies, including the Adverse Childhood Experiences (ACE) Study. There have now been multiple replications of these findings in diverse populations, and this work has been extended to include not only depression and posttraumatic stress disorder (PTSD), but schizophrenia and bipolar disorder as well.4 Despite the overwhelming evidence of a link between childhood adversity and adult psychopathology, the recognition that this vulnerability is mediated by persistent biological consequences of the trauma on the developing organism, brain and body, has been accepted only in the last decade. Indeed, there is an analogy here between the reluctance of our field to accept the fact that the adult brain is capable of new neuron formation, that is, neurogenesis,5 and the reluctance to accept the long-term biological
Elisabeth Binder,
MD, PhD
consequences of early adversity. There is now overwhelming evidence from preclinical and clinical studies that exposure to a variety of stressors early in life results in alterations in hypothalamic– pituitary–adrenal (HPA) axis activity, a number of neurotransmitter systems (e.g., corticotrophinreleasing factor [CRF], monoamines, substance P, and others), and increased markers of inflammation including inflammatory cytokines (interleukin-6, C-reactive protein, and others). In addition, structural magnetic resonance imaging (MRI) and functional MRI (fMRI) and positron emission tomography (PET) brain imaging studies have revealed changes in limbic (amygdala, hippocampus) and cortical brain areas6,7 in adults exposed to child abuse and neglect. One of the most impressive breakthroughs in the field has been the identification of single nucleotide polymorphisms (SNPs) that mediate the depressogenic and anxiogenic effects of early life trauma. Thus the CRF R1 receptor polymorphism has been shown, in several studies, to mediate the increased risk of depression and suicide in these patients.8 The FKBP5 gene has been shown to mediate the risk for PTSD in patients exposed to abuse and neglect.9 In addition, polymorphisms of the BDNF, PAC1, 5HT3, and oxytocin receptors, serotonin transporter, and others have all been implicated in the diathesis for mood and anxiety disorders in individuals exposed to early life trauma.10-12 In addition to the aforementioned studies are a series of recent experiments that have sought to determine whether epigenetics plays a role in the pathophysiological consequences of early life stress. Epigenetics refers to changes in gene activity and expression that are not caused by changes in the DNA sequence. A variety of
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 4 APRIL 2014
www.jaacap.org
395
NEMEROFF AND BINDER
epigenetic mechanisms have been identified including the following: first, changes in histone proteins that control gene expression, and second, the addition of methyl groups to the DNA, mostly at CpG sites. Highly methylated areas of DNA tend to be less transcriptionally active. Third, noncoding RNAs are now known to modulate gene expression. In a recent study, our group demonstrated for the first time the interaction of genetic and epigenetic factors in mediating the risk for PTSD in adults with a history of early life trauma, with trauma-triggered demethylation occurring only in the context of a specific FKBP5 genotype.13 The report in this issue of the Journal by Weder et al. further extends our knowledge of epigenetics and depression in maltreated children in a study of slightly less than 200 children with half exposed to child abuse and half participating as controls.14 Methylation in 3 genes (i.e., DNA-binding protein inhibitor 1D-3; glutamate receptor, ionotropic NMDA1 [Grin1]; and tubulin polymerizationpromoting protein [TPPP]) were predictors of depression. Lower depression severity was associated with greater methylation at the CpG sites within the 3 genes. Of note, each of these genes is involved in biological systems involved in stress including neuroendocrine mechanisms and neural plasticity. Clearly, investigations of epigenetic changes have generated great interest in the last few years, and it has become increasingly clear that epigenetic alterations encode genetic and environmental factors and can reflect risk and resilience to psychopathology. In humans, however, the issue of tissue and cell specificity remains an important consideration because epigenetic patterns are mostly cell type-specific, and access to brain tissue is limited. Although some overlap of environment-induced epigenetic changes have been observed between blood cells and the brain,13,15 the exact extent and mechanisms of these overlapping changes have not yet been identified. Analyses of peripheral epigenetic changes can certainly be used as biomarkers; however, to use them as potential sources of insight into disease mechanisms, additional studies investigating the relationship of environment-responsive epigenetic changes across tissues will be necessary. It is possible that systemwide changes in transcription factor activation, including, for example, the glucocorticoid receptor in response to stress and trauma, could mediate such global epigenetic effects. It is also important to note that DNA methylation can be affected by a number of factors, with
age and gender being important influences, as well as ethnicity, and that genetic population differences are strongly reflected in epigenetic differences.16 These factors need to be considered in such analyses. Furthermore, differences in cell types analyzed within a single tissue are also an important confounding factor, such as different blood cell types in peripheral blood, neurons and glia in brain tissue and blood cells versus epithelial cells in DNA from saliva. Because preselection of these cell types is often difficult or impossible, bioinformatic strategies have been devised to assess the relative cell fractions and to control for these in the analyses.17-20 Controlling for such differences in cell type allows an understanding of whether group differences in DNA methylation are related to differences in the tissue composition or, indeed, to the environmental or disease factor in question. Overall, although the assessment of peripheral DNA methylation changes is an exciting tool for psychiatric research, the above-mentioned caveats need to be kept in mind when interpreting such results. In summary, these new findings, coupled with the seminal studies of Meaney and colleagues,21 as well as our own contributions, highlight the importance of epigenetic mechanisms in mediating the untoward effects of early adversity. These findings may lead to novel treatment and prevention strategies. &
JOURNAL 396
www.jaacap.org
Accepted February 18, 2014. This article was reviewed under and accepted by Deputy Editor Stephen V. Faraone, PhD. Dr. Nemeroff is with the Miller School of Medicine, University of Miami; Dr. Binder is with Max Planck Institute for Psychiatry, Munich. Disclosure: Dr. Nemeroff has received research/grant support from the National Institutes of Health (NIH). He has served as a consultant to Xhale, Takeda, SK Pharma, Shire, Roche, Eli Lilly and Co., Allergan, Mitsubishi Tanabe Pharma, Development America, Taisho Pharmaceutical Inc., and Lundbeck. He has held stock in CeNeRx BioPharma, PharmaNeuroBoost, Revaax Pharma, Xhale, Celgene, and Seattle Genetics. He has served on the advisory boards of American Foundation for Suicide Prevention (AFSP), CeNeRx BioPharma, National Alliance for Research on Schizophrenia and Depression (NARSAD), Xhale, PharmaNeuroBoost, Anxiety Disorders Association of America (ADAA), and Skyland Trail. He has served on the Board of Directors of AFSP, NovaDel, Skyland Trail, Gratitude America, and ADAA. He has received income sources or equity from PharmaNeuroBoost, CeNeRx BioPharma, NovaDel Pharma, Reevax Pharma, American Psychiatric Publishing, and Xhale. He holds patents in Method and devices for transdermal delivery of lithium (US 6,375,990B1) and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2). He has received honoraria from the Florida Council for Community Mental Health, the Las Vegas Psychiatric Society, the World Psychiatric Association, the Saudi Psychiatric Association, the Kenes MP Asia, the American Physician Institute for Advanced Professional Studies, Asociacion de Psiquiatras de la Region de Bayamon, Florida Partners in
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 4 APRIL 2014
EDITORIAL
of America, Scuola Superiore di Neuroscienze e Neuroscience School of Advanced Studies, American Psychiatric Publishing, 20th National Congress on Child Maltreatment, Bogota, Colombia, Lundbeck, Max Planck Institute, Medical Education Speaker Network, and Guarant International. He has received royalties from the American Psychiatric Association, John Wiley and Sons, Inc., The Authors Registry, Elsevier, Oxford University Press, and Cambridge University Press. He has served as an expert witness and/or legal advice consultant to Edward Health Services Corporation, Penn and Seaborn, LLC, Schochor, Federico, and Staton, PA, Great Northern Insurance Agency, Douberly and Cicero, Sotolongo, PA, and Kirby Johnson, PC. Dr. Binder reports no biomedical financial interests or potential conflicts of interest.
Crisis, Global Technology Community, LLC, the International Society of Psychoneuroendocrinology, CPO Hanser Service, 1er Congreso de la Sociedad Internacional de Trastornos Bipolares, Venezuela, APA/ Egyptian Psychiatric Association, YPO Partners Forum, Lieber Institute, Inc., Nevada Psychiatric Association, the University of New Mexico, World Congress of Biological Psychiatry, the University of Texas Medical Branch Galveston Grand Rounds, the Volkswagen Foundation/Herrenhausen Conference, Rush University Grand Rounds, 5th International Cardio Event 2013, CCM International Saudi Arabia/ APA Meetings, CME Outfitters, CINP World Congress, the Medical University of South Carolina, Harvard Medical School/Psychopharmacology: A Master Class, the Florida Psychiatric Association, the International Society for Bipolar Disorders, 16th Annual Laura Evans Memorial Breast Cancer Symposium, Delaware State University, the University of North Carolina, New York University, NARSAD/the Brain and Behavior Research Foundation, the American Foundation for Suicide Prevention, the University of Chicago, King’s College, Beth Israel Deaconess, Wright State University, the University of Texas Medical Branch, Physicians Practice Group, Augusta, GA, Londocor Event Management e South African Biological Psychiatry Congress Education SPA, Psychiatric Foundation of North Carolina, Colombian Psychiatric Association Meeting, the Anxiety and Depression Association
Correspondence to Charles B. Nemeroff, MD, PhD, Department of Psychiatry and Behavioral Sciences, 1120 NW 14 Street #1455, University of Miami, Miami, FL 33136; e-mail: CNemeroff@med. miami.edu 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.02.004
REFERENCES 1. Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology. 1996;137:1212-1218. 2. Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropinreleasing factor in adult non-human primates exposed to early life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci. 1996;93: 1619-1623. 3. Freud S. Further remarks on the neuro-psychosis of defense. In: The Standard Edition of the Complete Psychological Works of Sigmund Freud, Vol. 3. London: Hogarth Press and the Institute of Psycho-Analysis; 1962 [originally published 1896]. 4. Nemeroff CB, Seligman F. The pervasive and persistent neurobiological and clinical aftermath of child abuse and neglect. J Clin Psychiatry. 2013;74:10. 5. Hanson ND, Owens MJ, Nemeroff CB. Depression, antidepressants, and neurogenesis: a critical reappraisal. Neuropsychopharmacology. 2011;36:2589-2602. 6. Heim C, Shugart M, Craighead WE, Nemeroff CB. Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol. 2010;52:671-690. 7. Heim CM, Mayberg HS, Mletzko T, Nemeroff CB, Pruessner JC. Decreased cortical representation of genital somatosensory field after childhood sexual abuse. Am J Psychiatry. 2013;170: 616-623. 8. Bradley RG, Binder EB, Epstein MP, et al. Influence of child abuse on adult depression. Moderation by the corticotropinreleasing hormone receptor gene. Arch Gen Psychiatry. 2008; 65:190-200. 9. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291-1305. 10. Caspi A, Sugden K, Moffit TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5HTT gene. Science. 2003;301:386-389.
11. Gatt JM, Williams LM, Schofield PR, et al. Impact of the HTR3A gene with early life trauma on emotional networks and depressed mood. Depress Anxiety. 2010;27:752-759. 12. Gatt JM, Nemeroff CB, Schofield PR, et al. Early life stress combined with serotonin 3A receptor and brain-derived neurotrophic factor valine 66 to methionine genotypes impacts emotional brain and arousal correlates of risk for depression. Biol Psychiatry. 2010; 68:818-824. 13. Klengel T, Mehta D, Anacker C, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neurosci. 2013;16:33-41. 14. Weder N, Zhang H, Jensen K, et al. Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. J. Am. Acad. Child Adolesc. Psychiatry. 2014;53:417-424. 15. Provenc¸al N, Suderman MJ, Guillemin C, et al. The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J Neurosci. 2012;44:15626-15642. 16. Barfield RT, Almli LM, Kilaru V, et al. Accounting for population stratification in DNA methylation studies. Genet Epidemiol. 2014 Jan 29. http://dx.doi.org/10.1002/gepi.21789. PubMed PMID: 24478250. 17. Houseman EA, Accomando WP, Koestler DC, et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform. 2012;13:86. 18. Lam LL, Emberly E, Fraser HB, et al. Factors underlying variable DNA methylation in a human community cohort. Proc Natl Acad Sci U S A. 2012;109(Suppl 2):17253-17260. 19. Suderman M, Borghol N, Pappas JJ, et al. Epigenomic socioeconomic studies more similar than different. Proc Natl Acad Sci U S A. 2013;110:E1246. 20. Guintivano J, Aryee MJ, Kaminsky ZA. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013;8:290-302. 21. Meaney MJ. Epigenetics and the biological definition of gene environment interactions. Child Dev. 2010;81:41-79.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 4 APRIL 2014
www.jaacap.org
397
The Preeminent Role of Childhood Abuse and Neglect in Vulnerability to Major Psychiatric Disorders: Toward Elucidating the Underlying Neurobiological Mechanisms Charles B. Nemeroff,
MD, PhD, AND
In the little world in which children have their existence, whosoever brings them up, there is nothing so finely perceived and so finely felt as injustice. —Charles Dickens
M
ore than 3 decades ago, our group and others1,2 suggested, based on results from laboratory animal studies, that trauma early in life in the form of child abuse and/or neglect was associated with persistent alterations in the central nervous system (CNS) that likely mediated the increased diathesis for mood and anxiety disorders in individuals who experienced significant early adversity. Although the seminal role of early life experiences in psychopathology was posited by Freud3 early in his career and by other psychoanalysts, it was not firmly established until the appearance of more recent epidemiological studies, including the Adverse Childhood Experiences (ACE) Study. There have now been multiple replications of these findings in diverse populations, and this work has been extended to include not only depression and posttraumatic stress disorder (PTSD), but schizophrenia and bipolar disorder as well.4 Despite the overwhelming evidence of a link between childhood adversity and adult psychopathology, the recognition that this vulnerability is mediated by persistent biological consequences of the trauma on the developing organism, brain and body, has been accepted only in the last decade. Indeed, there is an analogy here between the reluctance of our field to accept the fact that the adult brain is capable of new neuron formation, that is, neurogenesis,5 and the reluctance to accept the long-term biological
Elisabeth Binder,
MD, PhD
consequences of early adversity. There is now overwhelming evidence from preclinical and clinical studies that exposure to a variety of stressors early in life results in alterations in hypothalamic– pituitary–adrenal (HPA) axis activity, a number of neurotransmitter systems (e.g., corticotrophinreleasing factor [CRF], monoamines, substance P, and others), and increased markers of inflammation including inflammatory cytokines (interleukin-6, C-reactive protein, and others). In addition, structural magnetic resonance imaging (MRI) and functional MRI (fMRI) and positron emission tomography (PET) brain imaging studies have revealed changes in limbic (amygdala, hippocampus) and cortical brain areas6,7 in adults exposed to child abuse and neglect. One of the most impressive breakthroughs in the field has been the identification of single nucleotide polymorphisms (SNPs) that mediate the depressogenic and anxiogenic effects of early life trauma. Thus the CRF R1 receptor polymorphism has been shown, in several studies, to mediate the increased risk of depression and suicide in these patients.8 The FKBP5 gene has been shown to mediate the risk for PTSD in patients exposed to abuse and neglect.9 In addition, polymorphisms of the BDNF, PAC1, 5HT3, and oxytocin receptors, serotonin transporter, and others have all been implicated in the diathesis for mood and anxiety disorders in individuals exposed to early life trauma.10-12 In addition to the aforementioned studies are a series of recent experiments that have sought to determine whether epigenetics plays a role in the pathophysiological consequences of early life stress. Epigenetics refers to changes in gene activity and expression that are not caused by changes in the DNA sequence. A variety of
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 4 APRIL 2014
www.jaacap.org
395
NEMEROFF AND BINDER
epigenetic mechanisms have been identified including the following: first, changes in histone proteins that control gene expression, and second, the addition of methyl groups to the DNA, mostly at CpG sites. Highly methylated areas of DNA tend to be less transcriptionally active. Third, noncoding RNAs are now known to modulate gene expression. In a recent study, our group demonstrated for the first time the interaction of genetic and epigenetic factors in mediating the risk for PTSD in adults with a history of early life trauma, with trauma-triggered demethylation occurring only in the context of a specific FKBP5 genotype.13 The report in this issue of the Journal by Weder et al. further extends our knowledge of epigenetics and depression in maltreated children in a study of slightly less than 200 children with half exposed to child abuse and half participating as controls.14 Methylation in 3 genes (i.e., DNA-binding protein inhibitor 1D-3; glutamate receptor, ionotropic NMDA1 [Grin1]; and tubulin polymerizationpromoting protein [TPPP]) were predictors of depression. Lower depression severity was associated with greater methylation at the CpG sites within the 3 genes. Of note, each of these genes is involved in biological systems involved in stress including neuroendocrine mechanisms and neural plasticity. Clearly, investigations of epigenetic changes have generated great interest in the last few years, and it has become increasingly clear that epigenetic alterations encode genetic and environmental factors and can reflect risk and resilience to psychopathology. In humans, however, the issue of tissue and cell specificity remains an important consideration because epigenetic patterns are mostly cell type-specific, and access to brain tissue is limited. Although some overlap of environment-induced epigenetic changes have been observed between blood cells and the brain,13,15 the exact extent and mechanisms of these overlapping changes have not yet been identified. Analyses of peripheral epigenetic changes can certainly be used as biomarkers; however, to use them as potential sources of insight into disease mechanisms, additional studies investigating the relationship of environment-responsive epigenetic changes across tissues will be necessary. It is possible that systemwide changes in transcription factor activation, including, for example, the glucocorticoid receptor in response to stress and trauma, could mediate such global epigenetic effects. It is also important to note that DNA methylation can be affected by a number of factors, with
age and gender being important influences, as well as ethnicity, and that genetic population differences are strongly reflected in epigenetic differences.16 These factors need to be considered in such analyses. Furthermore, differences in cell types analyzed within a single tissue are also an important confounding factor, such as different blood cell types in peripheral blood, neurons and glia in brain tissue and blood cells versus epithelial cells in DNA from saliva. Because preselection of these cell types is often difficult or impossible, bioinformatic strategies have been devised to assess the relative cell fractions and to control for these in the analyses.17-20 Controlling for such differences in cell type allows an understanding of whether group differences in DNA methylation are related to differences in the tissue composition or, indeed, to the environmental or disease factor in question. Overall, although the assessment of peripheral DNA methylation changes is an exciting tool for psychiatric research, the above-mentioned caveats need to be kept in mind when interpreting such results. In summary, these new findings, coupled with the seminal studies of Meaney and colleagues,21 as well as our own contributions, highlight the importance of epigenetic mechanisms in mediating the untoward effects of early adversity. These findings may lead to novel treatment and prevention strategies. &
JOURNAL 396
www.jaacap.org
Accepted February 18, 2014. This article was reviewed under and accepted by Deputy Editor Stephen V. Faraone, PhD. Dr. Nemeroff is with the Miller School of Medicine, University of Miami; Dr. Binder is with Max Planck Institute for Psychiatry, Munich. Disclosure: Dr. Nemeroff has received research/grant support from the National Institutes of Health (NIH). He has served as a consultant to Xhale, Takeda, SK Pharma, Shire, Roche, Eli Lilly and Co., Allergan, Mitsubishi Tanabe Pharma, Development America, Taisho Pharmaceutical Inc., and Lundbeck. He has held stock in CeNeRx BioPharma, PharmaNeuroBoost, Revaax Pharma, Xhale, Celgene, and Seattle Genetics. He has served on the advisory boards of American Foundation for Suicide Prevention (AFSP), CeNeRx BioPharma, National Alliance for Research on Schizophrenia and Depression (NARSAD), Xhale, PharmaNeuroBoost, Anxiety Disorders Association of America (ADAA), and Skyland Trail. He has served on the Board of Directors of AFSP, NovaDel, Skyland Trail, Gratitude America, and ADAA. He has received income sources or equity from PharmaNeuroBoost, CeNeRx BioPharma, NovaDel Pharma, Reevax Pharma, American Psychiatric Publishing, and Xhale. He holds patents in Method and devices for transdermal delivery of lithium (US 6,375,990B1) and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2). He has received honoraria from the Florida Council for Community Mental Health, the Las Vegas Psychiatric Society, the World Psychiatric Association, the Saudi Psychiatric Association, the Kenes MP Asia, the American Physician Institute for Advanced Professional Studies, Asociacion de Psiquiatras de la Region de Bayamon, Florida Partners in
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 4 APRIL 2014
EDITORIAL
of America, Scuola Superiore di Neuroscienze e Neuroscience School of Advanced Studies, American Psychiatric Publishing, 20th National Congress on Child Maltreatment, Bogota, Colombia, Lundbeck, Max Planck Institute, Medical Education Speaker Network, and Guarant International. He has received royalties from the American Psychiatric Association, John Wiley and Sons, Inc., The Authors Registry, Elsevier, Oxford University Press, and Cambridge University Press. He has served as an expert witness and/or legal advice consultant to Edward Health Services Corporation, Penn and Seaborn, LLC, Schochor, Federico, and Staton, PA, Great Northern Insurance Agency, Douberly and Cicero, Sotolongo, PA, and Kirby Johnson, PC. Dr. Binder reports no biomedical financial interests or potential conflicts of interest.
Crisis, Global Technology Community, LLC, the International Society of Psychoneuroendocrinology, CPO Hanser Service, 1er Congreso de la Sociedad Internacional de Trastornos Bipolares, Venezuela, APA/ Egyptian Psychiatric Association, YPO Partners Forum, Lieber Institute, Inc., Nevada Psychiatric Association, the University of New Mexico, World Congress of Biological Psychiatry, the University of Texas Medical Branch Galveston Grand Rounds, the Volkswagen Foundation/Herrenhausen Conference, Rush University Grand Rounds, 5th International Cardio Event 2013, CCM International Saudi Arabia/ APA Meetings, CME Outfitters, CINP World Congress, the Medical University of South Carolina, Harvard Medical School/Psychopharmacology: A Master Class, the Florida Psychiatric Association, the International Society for Bipolar Disorders, 16th Annual Laura Evans Memorial Breast Cancer Symposium, Delaware State University, the University of North Carolina, New York University, NARSAD/the Brain and Behavior Research Foundation, the American Foundation for Suicide Prevention, the University of Chicago, King’s College, Beth Israel Deaconess, Wright State University, the University of Texas Medical Branch, Physicians Practice Group, Augusta, GA, Londocor Event Management e South African Biological Psychiatry Congress Education SPA, Psychiatric Foundation of North Carolina, Colombian Psychiatric Association Meeting, the Anxiety and Depression Association
Correspondence to Charles B. Nemeroff, MD, PhD, Department of Psychiatry and Behavioral Sciences, 1120 NW 14 Street #1455, University of Miami, Miami, FL 33136; e-mail: CNemeroff@med. miami.edu 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.02.004
REFERENCES 1. Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology. 1996;137:1212-1218. 2. Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropinreleasing factor in adult non-human primates exposed to early life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci. 1996;93: 1619-1623. 3. Freud S. Further remarks on the neuro-psychosis of defense. In: The Standard Edition of the Complete Psychological Works of Sigmund Freud, Vol. 3. London: Hogarth Press and the Institute of Psycho-Analysis; 1962 [originally published 1896]. 4. Nemeroff CB, Seligman F. The pervasive and persistent neurobiological and clinical aftermath of child abuse and neglect. J Clin Psychiatry. 2013;74:10. 5. Hanson ND, Owens MJ, Nemeroff CB. Depression, antidepressants, and neurogenesis: a critical reappraisal. Neuropsychopharmacology. 2011;36:2589-2602. 6. Heim C, Shugart M, Craighead WE, Nemeroff CB. Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol. 2010;52:671-690. 7. Heim CM, Mayberg HS, Mletzko T, Nemeroff CB, Pruessner JC. Decreased cortical representation of genital somatosensory field after childhood sexual abuse. Am J Psychiatry. 2013;170: 616-623. 8. Bradley RG, Binder EB, Epstein MP, et al. Influence of child abuse on adult depression. Moderation by the corticotropinreleasing hormone receptor gene. Arch Gen Psychiatry. 2008; 65:190-200. 9. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291-1305. 10. Caspi A, Sugden K, Moffit TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5HTT gene. Science. 2003;301:386-389.
11. Gatt JM, Williams LM, Schofield PR, et al. Impact of the HTR3A gene with early life trauma on emotional networks and depressed mood. Depress Anxiety. 2010;27:752-759. 12. Gatt JM, Nemeroff CB, Schofield PR, et al. Early life stress combined with serotonin 3A receptor and brain-derived neurotrophic factor valine 66 to methionine genotypes impacts emotional brain and arousal correlates of risk for depression. Biol Psychiatry. 2010; 68:818-824. 13. Klengel T, Mehta D, Anacker C, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neurosci. 2013;16:33-41. 14. Weder N, Zhang H, Jensen K, et al. Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. J. Am. Acad. Child Adolesc. Psychiatry. 2014;53:417-424. 15. Provenc¸al N, Suderman MJ, Guillemin C, et al. The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J Neurosci. 2012;44:15626-15642. 16. Barfield RT, Almli LM, Kilaru V, et al. Accounting for population stratification in DNA methylation studies. Genet Epidemiol. 2014 Jan 29. http://dx.doi.org/10.1002/gepi.21789. PubMed PMID: 24478250. 17. Houseman EA, Accomando WP, Koestler DC, et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform. 2012;13:86. 18. Lam LL, Emberly E, Fraser HB, et al. Factors underlying variable DNA methylation in a human community cohort. Proc Natl Acad Sci U S A. 2012;109(Suppl 2):17253-17260. 19. Suderman M, Borghol N, Pappas JJ, et al. Epigenomic socioeconomic studies more similar than different. Proc Natl Acad Sci U S A. 2013;110:E1246. 20. Guintivano J, Aryee MJ, Kaminsky ZA. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013;8:290-302. 21. Meaney MJ. Epigenetics and the biological definition of gene environment interactions. Child Dev. 2010;81:41-79.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 4 APRIL 2014
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