Hostname: page-component-546b4f848f-lx7sf Total loading time: 0 Render date: 2023-06-03T21:27:11.734Z Has data issue: false Feature Flags: { "useRatesEcommerce": true } hasContentIssue false

The role of limbic system irritability in linking history of childhood maltreatment and psychiatric outcomes in low-income, high-risk women: Moderation by FK506 binding protein 5 haplotype

Published online by Cambridge University Press:  15 October 2012

Melissa N. Dackis*
University of Rochester
Fred A. Rogosch*
University of Rochester
Assaf Oshri
University of Rochester
Dante Cicchetti
University of Rochester University of Minnesota
Address correspondence and reprint requests to: Melissa Dackis or Fred Rogosch, Mt. Hope Family Center, 187 Edinburgh Street, Rochester, NY, 14608; E-mail: or
Address correspondence and reprint requests to: Melissa Dackis or Fred Rogosch, Mt. Hope Family Center, 187 Edinburgh Street, Rochester, NY, 14608; E-mail: or


Childhood maltreatment is associated with lasting changes in neuroendocrine regulation, alterations in brain structure and function, and symptoms of “limbic irritability.” Limbic irritability symptoms include somatic, sensory, and behavioral phenomena and may stem from increased excitatory neurotransmission following maltreatment. We tested the hypotheses that child maltreatment is indirectly associated with depressive and dissociative symptomatology via indicators of limbic irritability and that variation within the FK506 binding protein 5 gene (FKBP5), a gene involved in glucorticoid receptor functioning, moderates these effects. The sample consisted of high-risk, low-income women (N = 236) living in an inner-city environment. Child maltreatment, limbic irritability, and symptoms of depression and dissociation were measured cross-sectionally using self-report assessments. Haplotype analyses were conducted across four FKBP5 single nucleotide polymorphisms: rs3800373, rs9296158, rs1360870, and rs9470080. Path analysis using bootstrapping procedures was performed to test hypotheses regarding indirect and conditional indirect effects. We found significant indirect effects of maltreatment on depression (β = 0.088, p < .01) and dissociation (β = 0.105, p < .01) via limbic irritability. In addition, variation within FKBP5 moderated these significant indirect effects. For individuals with one to two copies of the CATT haplotype, the indirect effects of maltreatment on depression (β = 0.137, p < .01) and dissociation (β = 0.132, p < .01) via limbic irritability were significant, whereas the indirect paths were not significant for individuals with no copies of this haplotype (depression: β = 0.037, p > .05; dissociation: β = 0.002, p > .05). These results add to the growing evidence that child maltreatment may lead to symptoms of internalizing psychopathology through its impact on the limbic system. In addition, this study revealed a potential role of FKBP5 gene variants in contributing to risk for limbic system dysfunction.

Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Amico, F., Meisenzahl, E., Koutsouleris, N., Reiser, M., Moller, H. J., & Frodl, T. (2011). Structural MRI correlates for vulnerability and resilience to major depressive disorder. Journal of Psychiatry and Neuroscience, 36, 1522.CrossRefGoogle ScholarPubMed
Andersen, S. L., & Teicher, M. H. (2004). Delayed effects of early stress on hippocampal development. Neuropsychopharmacology, 29, 19881993.CrossRefGoogle ScholarPubMed
Andersen, S. L., Tomada, A., Vincow, E. S., Valente, E., Polcari, A., & Teicher, M. H. (2008). Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. Journal of Neuropsychiatry and Clinical Neuroscience, 20, 292301.CrossRefGoogle ScholarPubMed
Anderson, C. M., Teicher, M. H., Polcari, A., & Renshaw, P. F. (2002). Abnormal T2 relaxation time in the cerebellar vermis of adults sexually abused in childhood: Potential role of the vermis in stress-enhanced risk for drug abuse. Psychoneuroendocrinology, 27, 231244.CrossRefGoogle Scholar
Appel, K., Schwahn, C., Mahler, J., Schulz, A., Spitzer, C., Fenske, K., et al. (2011). Moderation of adult depression by a polymorphism in the FKBP5 gene and childhood physical abuse in the general population. Neuropsychopharmacology, 36, 19821991.CrossRefGoogle ScholarPubMed
Aslund, C., Leppert, J., Comasco, E., Nordquist, N., Oreland, L., & Nilsson, K. W. (2009). Impact of the interaction between the 5HTTLPR polymorphism and maltreatment on adolescent depression: A population-based study. Behavioral Genetics, 39, 524531.CrossRefGoogle Scholar
Barrett, J. C., Fry, B., Maller, J., & Daly, M. J. (2005). Haploview analysis and visualization of LD and haplotype maps. Bioinformatics, 21, 263265.CrossRefGoogle Scholar
Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Manual for the Beck Depression Inventory—II. San Antonio, TX: Psychological Corporation.Google Scholar
Bernstein, D. P., & Fink, L. (1994). Childhood trauma questionnaire: A retrospective self-report manual. New York: Psychological Corporation.Google Scholar
Bernstein, D. P., & Putnam, F. W. (1986). Development, reliability, and validity of a dissociation scale. Journal of Nervous and Mental Disease, 174, 727735.CrossRefGoogle ScholarPubMed
Bernstein, D. P., Stein, J. A., Newcomb, M. D., Walker, E., Pogge, D., Ahluvalia, T., et al. (2003). Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse & Neglect, 27, 169190.CrossRefGoogle ScholarPubMed
Bevilacqua, L., Carli, V., Sarchiapone, M., George, D., Goldman, D., Roy, A., et al. (2012). Interaction between FKBP5 and childhood trauma and risk of aggressive behavior. Archives of General Psychiatry, 69, 6270.CrossRefGoogle Scholar
Binder, E. B. (2009). The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology, 34, S186S195.CrossRefGoogle ScholarPubMed
Binder, E. B., Bradley, R. C., Liu, W., Epstein, M. P., Deveau, T. C., Mercer, K. B., et al. (2008). Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. Journal of the American Medical Association, 299, 12911305.CrossRefGoogle ScholarPubMed
Binder, E. B., Salyakina, D., Lichtner, P., Wochnik, G. M., Ising, M., Putz, B., et al. (2004). Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genetics, 36, 13191325.CrossRefGoogle ScholarPubMed
Bollen, K. A., & Stine, R. (1990). Direct and indirect effects: Classical and bootstrap estimates of variability. Sociological Methodology, 20, 115140.CrossRefGoogle Scholar
Bradley, B., Westen, D., Mercer, K. B., Binder, E. B., Jovanovic, T., Crain, D., et al. (2011). Association between childhood maltreatment and adult emotional dysregulation in a low-income, urban, African American sample: Moderation by oxytocin receptor gene. Development and Psychopathology, 23, 439452.CrossRefGoogle Scholar
Bremner, J. D., Licinio, J., Darnell, A., Krystal, J. H., & Owens, M. J. (1997). Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. American Journal of Psychiatry, 154, 624629.Google ScholarPubMed
Briere, J. (1992). Child abuse trauma: Theory and treatment of the lasting effects. Newbury Park, CA: Sage.Google Scholar
Caldji, C., Francis, D., Sharma, S., Plotsky, P. M., & Meaney, M. J. (2000). The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology, 22, 219229.CrossRefGoogle ScholarPubMed
Caldji, C., Tannenbaum, B., Sharma, S., Francis, D., Plotsky, P. M., & Meaney, M. J. (1998). Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proceedings of the National Academy of Sciences, 95, 53355340.CrossRefGoogle Scholar
Carlson, E. B., & Putnam, F. W. (1993). An update on the Dissociative Experiences Scale. Dissociation, 6, 1627.Google Scholar
Caspi, A., McClay, J., Moffitt, T. E., Martin, J., Craig, I. W., & Taylor, A. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851854.CrossRefGoogle ScholarPubMed
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HT gene. Science, 301, 386389.CrossRefGoogle ScholarPubMed
Chen, M. C., Hamilton, J. P., & Gotlib, I. H. (2010). Decreased hippocampal volume in healthy girls at risk for depression. Archives of General Psychiatry, 67, 270276.CrossRefGoogle Scholar
Choi, J., Jeong, B., Polcari, A., Rohan, M. L., & Teicher, M. H. (2012). Reduced fractional anisotrophy in the visual limbic pathway of young adults witnessing domestic violence in childhood. NeuroImage, 59, 10711079.CrossRefGoogle Scholar
Choi, J., Jeong, B., Rohan, M. L., Polcari, A. M., & Teicher, M. H. (2009). Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biological Psychiatry, 65, 227234.CrossRefGoogle ScholarPubMed
Cicchetti, D. (1989). How research on child maltreatment has informed the study of child development: Perspectives from developmental psychopathology. In Cicchetti, D. & Carlson, V. (Eds.), Child maltreatment: Theory and research on the causes and consequences of child abuse and neglect (pp. 377431). New York: Cambridge University Press.CrossRefGoogle ScholarPubMed
Cicchetti, D. (2010). Resilience under conditions of extreme stress: A multilevel perspective. World Psychiatry, 9, 145154.CrossRefGoogle ScholarPubMed
Cicchetti, D., & Curtis, W. J. (2005). An event-related potential study of the processing of affective facial expressions in young children who experienced maltreatment during the first year of life. Development and Psychopathology, 17, 641677.CrossRefGoogle Scholar
Cicchetti, D., & Lynch, M. (1995). Failures in the expectable environment and their impact on individual development: The case of child maltreatment. In Cicchetti, D. & Cohen, D. J. (Eds.), Developmental psychopathology: Vol. 2. Risk, disorder, and adaptation (pp. 3271). New York: Wiley.Google Scholar
Cicchetti, D., Rogosch, F. A., & Oshri, A. (2011). Interactive effects of corticotropin-releasing hormone receptor 1, serortonin transporter linked polymorphic region, and child maltreatment on diurnal cortisol regulation and internalizing symptomatology. Development and Psychopathology, 23, 11251138.CrossRefGoogle Scholar
Cicchetti, D., Rogosch, F. A., & Sturge-Apple, M. L. (2010). Interaction of child maltreatment and 5-HT polymorphisms: Suicidal ideation among children from low-SES backgrounds. Journal of Pediatric Psychology, 35, 536546.CrossRefGoogle Scholar
Cicchetti, D., Rogosch, F. A., & Thibodeau, E. L. (2012). The effects of child maltreatment on early signs of antisocial behavior: Genetic moderation by tryptophan hydroxylase, serotonin transporter, and monoamine oxidase A genes. Development and Psychopathology, 24, 907928.CrossRefGoogle Scholar
Cicchetti, D., Rogosch, F. A., & Toth, S. L. (1997). Ontonogenesis, depressotypic organization, and the depressive spectrum. In Luthar, S. S., Burack, J. A., Cicchetti, D., & Weisz, J. R. (Eds). Developmental psychopathology: Perspective on adjustment, risk, and disorder (pp. 273349). Cambridge: Cambridge University Press.Google Scholar
Cicchetti, D., & Toth, S. L. (1995). Developmental psychopathology and disorders of affect. In Cicchetti, D. & Cohen, D. J. (Eds.), Developmental psychopathology: Vol. 2. Risk, disorder, and adaptation (pp. 369420). New York: Wiley.Google Scholar
Cicchetti, D., & Toth, S. L. (1998). The development of depression in children and adolescents. American Psychologist, 53, 221241.CrossRefGoogle ScholarPubMed
Cicchetti, D., & Toth, S. L. (2005). Child maltreatment. Annual Review of Clinical Psychology, 1, 409438.CrossRefGoogle Scholar
Cicchetti, D., & Toth, S. L. (2009). The past achievements and future promises of developmental psychopathology: The coming of age of a discipline. Journal of Child Psychology and Psychiatry, 50, 1625.CrossRefGoogle ScholarPubMed
Cicchetti, D., Toth, S., & Manly, J. T. (2003). Maternal Maltreatment Interview. Unpublished manuscript.Google Scholar
Cicchetti, D., & Tucker, D. (1994). Development and self-regulatory structures of the mind. Development and Psychopathology, 6, 533549.CrossRefGoogle Scholar
Cicchetti, D., & Valentino, K. (2006). An ecological–transactional perspective on child maltreatment: Failure of the average expectable environment and its influences on child development. In Cicchetti, D. & Cohen, D. (Eds.), Development and psychopathology: Vol. 3. Risk, disorder, and adaptation (2nd ed., pp. 129201). New York: Wiley.Google Scholar
Cicchetti, D., & Valentino, K. (2007). Toward the application of a multiple-levels-of-analysis perspective to research in development and psychopathology. In Masten, A. S. (Ed.), Minnesota symposia on child psychology: Vol. 34. Multilevel dynamics in developmental psychopathology (pp. 243284). Mahwah, NJ: Erlbaum.Google Scholar
Cohen, P., Brown, J., & Smaile, E. (2001). Child abuse and neglect and development of mental disorders in the general population. Development and Psychopathology, 13, 981999.Google ScholarPubMed
Collishaw, S., Pickles, A., Messer, J., Rutter, M., Shearer, C., & Maughan, B. (2007). Resilience to adult psychopathology following childhood maltreatment: Evidence from a community sample. Child Abuse & Neglect, 31, 211229.CrossRefGoogle Scholar
Crews, F., He, J., & Hodge, C. (2007). Adolescent cortical development: A critical period of vulnerability for addiction. Pharmacology, Biochemistry, & Behavior, 86, 189199.CrossRefGoogle ScholarPubMed
Dannlowski, U., Ohrmann, P, Bauer, J., Kugel, H., Arolt, V., Heindel, W., et al. (2007). Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: A 3T fMRI study. Journal of Psychiatry and Neuroscience, 32, 423439.Google Scholar
Dannlowski, U., Stuhrmann, A., Beutelmann, V., Zwanzger, P., Lenzen, T., Grotegerd, D., et al. (2012). Limbic scars: Long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biological Psychiatry, 71, 286293.CrossRefGoogle Scholar
Davies, T. H., Ning, Y. M., & Sanchez, E. R. (2002). A new first step in activation of steroid receptors: Hormone-induced switching of FKBP51 and FKBP52 immunophilins. Journal of Biological Chemistry, 277, 45974600.CrossRefGoogle ScholarPubMed
DeBellis, M. D., Keshavan, M. S., Clark, D. B., Case, B. J., Giedd, J. N., Boring, A. M., et al. (1999). Developmental traumatology: Part II. Brain development. Biological Psychiatry, 45, 12711284.CrossRefGoogle Scholar
Denny, W. B., Valentine, D. L., Reynolds, P. D., Smith, D. F., & Scammel, J. G. (2000). Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology, 141, 41074113.CrossRefGoogle ScholarPubMed
Dixon, L., Browne, K., & Hamilton-Giachritsis, C. (2005). Risk factors of parents abused as children: A mediational analysis of the intergenerational continuity of child maltreatment (Part 1). Journal of Child Psychology and Psychiatry, 46, 4757.CrossRefGoogle Scholar
Edwards, V., Holden, G., Felitti, V., & Anda, R. (2003). Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: Results from the Adverse Childhood Experiences study. American Journal of Psychiatry, 160, 14531460.CrossRefGoogle Scholar
Etkin, A., & Wagner, T. D. (2007). Functional neuroimagining of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. American Journal of Psychiatry, 164, 14761488.CrossRefGoogle Scholar
Evans, G. W. (2003). A multimethodological analysis of cumulative risk and allostatic load among rural children. Developmental Psychology, 39, 924933.CrossRefGoogle ScholarPubMed
Fitzgerald, P. B., Laird, A. R., Maller, J., & Daskalakis, Z. J. (2008). A meta-analytic study of changes in brain activation in depression. Human Brain Mapping, 29, 683695.CrossRefGoogle ScholarPubMed
Frodl, T., Reinhold, E., Koutsouleris, N., Donohoe, G., Bondy, B., Reiser, M., et al. (2010). Childhood stress, serotonin transporter gene, and brain structures in major depression. Neuropsychopharmacology, 35, 13831390.CrossRefGoogle ScholarPubMed
Gibb, B. E., Uhrlass, D. J., Grassia, M., Benas, J. S., & McGeary, J. (2010). Children's inferential styles, 5-HTTLPR genotype, and maternal expressed emotion-criticism: An integrated model for the intergenerational transmission of depression. Journal of Abnormal Psychology, 118, 734745.CrossRefGoogle ScholarPubMed
Gilbertson, M. W., Shenton, M. E., Ciszewski, A., Kasai, K., Lasko, N. B., Orr, S. P., et al. (2002). Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nature Neuroscience, 5, 12421247.CrossRefGoogle ScholarPubMed
Gillespie, C. F., Phifer, J., Bradley, B., & Ressler, K. J. (2009). Risk and resilience: Genetic and environmental influences on development of the stress response. Depression and Anxiety, 26, 984992.CrossRefGoogle ScholarPubMed
Gogtay, N., Nugent, T. F., Herman, D. H., Ordonez, A., Greenstein, D., Hayashi, K. M., et al. (2006). Dynamic mapping of normal human hippocampal development. Hippocampus, 16, 664672.CrossRefGoogle ScholarPubMed
Green, A., Voeller, K., Gaines, R., & Kulsie, J. (1981). Neurological impairment in maltreated children. Child Abuse & Neglect, 5, 129134.CrossRefGoogle Scholar
Green, J. G., McLaughlin, K. A., Berglund, P. A, Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., et al. (2010). Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication 1: Associations with first onset of DSM-IV disorders. Archives of General Psychiatry, 67, 113123.CrossRefGoogle Scholar
Heim, C., & Nemeroff, C. B. (2001). The role of childhood trauma in the neurobiology of mood and anxiety disorders: Preclinical and clinical studies. Biological Psychiatry, 49, 10231039.CrossRefGoogle ScholarPubMed
Heim, C., Newport, D. J., Bonsall, R., Miller, A. H., & Nemeroff, C. B. (2001). Altered pituitary–adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. American Journal of Psychiatry, 158, 575581.CrossRefGoogle Scholar
Heim, C., Newport, D. J., Heit, S., Graham, Y. P., Wilcox, M., Bonsall, R., et al. (2000). Pituitary–adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. Journal of the American Medical Association, 284, 592597.CrossRefGoogle ScholarPubMed
Horstmann, S., Lucae, S., Menke, A., Hennings, J. M., Ising, M., Roeske, D., et al. (2010). Polymorphisms in GRIK4, HTA21, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology, 35, 727740.CrossRefGoogle ScholarPubMed
Hyman, S. M., Garcia, M., Kemp, K., Mazure, C. M., & Sinha, R. (2005). A gender specific psychometric analysis of the early trauma inventory short form in cocaine dependent adults. Addictive Behavior, 30, 847852.CrossRefGoogle ScholarPubMed
Ising, M., Depping, A. M., Siebertz, A., Lucae, S., Unschuld, P. G., Kloiber, , et al. (2008). Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. European Journal of Neuroscience, 28, 389398.CrossRefGoogle Scholar
Ito, Y., Teicher, M. H., Glod, C. A., & Ackerman, E. (1998). Preliminary evidence for aberrant cortical development in abused children: A quantitative EEG study. Neuropsychiatric Clinical Neuroscience, 10, 298307.CrossRefGoogle ScholarPubMed
Ito, Y., Teicher, M. H., Glod, C. A., Harper, D., Magnus, E., & Gelbard, H. A. (1993). Increased prevalence of electrophysiological abnormalities in children with psychological, physical, and sexual abuse. Neuropsychiatric Clinical Neuroscience, 5, 401408.Google ScholarPubMed
Johnson, A. L., Gibb, B. E., & McGeary, J. (2010). Reports of childhood physical abuse, 5-HTTLPR genotype, and women's attentional biases for angry faces. Cognitive Therapy Research, 34, 380387.CrossRefGoogle Scholar
Jovanovic, T., Blanding, N. Q., Norrholm, S. D., Duncan, E., Bradley, B., & Ressler, K. J. (2009). Childhood abuse is associated with increased startle reactivity in adulthood. Depression and Anxiety, 26, 10181026.CrossRefGoogle ScholarPubMed
Kang, J. I., Chung, H. C., Jeung, H. C., Kim, S. J., & An, S. K. (in press). FKBP5 polymorphisms as vulnerability to anxiety and depression in patients with advanced gastric cancer: A controlled and prospective study. Psychoneuroendocrinology.Google Scholar
Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry, 68, 444454.CrossRefGoogle ScholarPubMed
Kendler, K. S., Kuhn, J. W., & Prescott, C. A. (2004). Childhood sexual abuse, stressful life events, and risk for major depression in women. Psychological Medicine, 34, 14751482.CrossRefGoogle ScholarPubMed
Kessler, R. C., Chiu, W. T., Demler, O., & Walters, E. E. (2005). Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry, 62, 617627.CrossRefGoogle Scholar
Keyes, K. M., Eaton, N. R., Krueger, R. F., McLaughlin, K. A., Wall, M. M., Grant, B. F., et al. (2012). Child maltreatment and the structure of common psychiatric disorders. British Journal of Psychiatry, 200, 107115.CrossRefGoogle Scholar
Kim, J., & Cicchetti, D. (2010). Longitudinal pathways linking child maltreatment, emotion regulation, peer relations, and psychopathology. Journal of Child Psychology & Psychiatry, 51, 706716.CrossRefGoogle Scholar
Kim-Cohen, J., Caspi, A., Taylor, A., Williams, B., Newcombe, R., Craig, I. W., et al. (2006). MAOA, maltreatment, and gene–environment interaction predicting children's mental health: New evidence and a meta-analysis. Molecular Psychiatry, 11, 903913.CrossRefGoogle Scholar
Kim-Spoon, J., Cicchetti, D., & Rogosch, F. A. (in press). A longitudinal study of emotion regulation, negative emotionality, and internalizing symptomatology in maltreated and nonmaltreated children. Child Development.Google Scholar
Koenen, K. C., Amstadter, A. B., & Nugent, N. R. (2009). Gene–environment interaction in posttraumatic stress disorder: An update. Journal of Traumatic Stress, 22, 416426.CrossRefGoogle ScholarPubMed
Koenen, K. C., Saxe, G., Purcell, S., Smoller, J. W., Bartholomew, D., Miller, A., et al. (2005). Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children. Molecular Psychiatry, 10, 10581059.CrossRefGoogle ScholarPubMed
Krämer, U. M., Cunillera, T., Caàmara, E., Marco-Pallarés, J., Cucurell, D., Nager, W., et al. (2007). The impact of catechol-O-methyltransferase and dopamine D4 receptor genotypes on neurophysiological markers of performance monitoring. Journal of Neuroscience, 27, 1419014198.CrossRefGoogle Scholar
Lekman, M., Laje, G., Charney, D., Rush, A. J., Wilson, A. F., Sorant, A. J., et al. (2008). The FKBP5-gene in depression and treatment response—An association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) cohort. Biological Psychiatry, 63, 11031110.CrossRefGoogle ScholarPubMed
Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., et al. (1997). Maternal care, hippocampal glucocorticoid receptors, and hypothalamic–pituitary–adrenal responses to stress. Science, 277, 16591662.CrossRefGoogle Scholar
Lowy, M. T., Wittenberg, L., & Yamamoto, B. K. (1995). Effect of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats. Journal of Neurochemistry, 65, 268274.CrossRefGoogle Scholar
Ludwig, A. M. (1983). The psychobiological functions of dissociation. American Journal of Clinical Hypnosis, 26, 9399.CrossRefGoogle ScholarPubMed
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience, 10, 434445.CrossRefGoogle ScholarPubMed
Lupien, S. J., Ouellet-Morin, I., Hupbach, A., Tu, M. T., Buss, C., Walker, D., et al. (2006). Beyond the stress concept: Allostatic load—A developmental biological and cognitive perspective. In Cicchetti, D. & Cohen, D. (Eds.), Developmental psychopathology: Vol. 2. Developmental neuroscience (2nd ed., pp. 578628). New York: Wiley.Google Scholar
Lyons-Ruth, K., & Spielman, E. (2004). Disorganized infant attachment strategies and helpless–fearful profiles of parenting: Integrating attachment research with clinical intervention. Infant Mental Health Journal, 25, 318335.CrossRefGoogle ScholarPubMed
Macfie, J., Cicchetti, D., & Toth, S. L. (2001a). The development of dissociation in maltreated preschool-aged children. Development and Psychopathology, 13, 233254.CrossRefGoogle ScholarPubMed
Macfie, J., Cicchetti, D., & Toth, S. L. (2001b). Dissociation in maltreated versus nonmaltreated preschool-aged children. Child Abuse & Neglect, 25, 12531267.CrossRefGoogle Scholar
MacKinnon, D. P. (2008). An introduction to statistical mediation analysis. New York: Erlbaum.Google Scholar
MacQueen, G. M., & Frodl, T. (2010). The hippocampus in major depression: Evidence for the convergence of the bench and bedside in psychiatric research? Molecular Psychiatry, 16, 252264.CrossRefGoogle Scholar
McCrory, E. J., De Brito, S. A., Sebastian, C. L., Mechelli, A., Bird, G., Kelly, P. A., et al. (2011). Heightened neural reactivity to threat in child victims of family violence. Current Biology, 21, R947R948.CrossRefGoogle Scholar
McEwen, B. S. (1998). Stress, adaptation, and disease: Allostasis and allostatic load. Annals of the New York Academy of Sciences, 840, 3344.CrossRefGoogle ScholarPubMed
McEwen, B. S., & Stellar, E. (1993). Stress and the individual: Mechanisms leading to disease. Archives of Internal Medicine, 153, 20932101.CrossRefGoogle ScholarPubMed
McEwen, B. S., & Wingfield, J. C. (2003). The concept of allostasis in biology and biomedicine. Hormones and Behavior, 43, 215.CrossRefGoogle ScholarPubMed
McLaughlin, K. A., Green, J. G., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., & Kessler, R. C. (2010a). Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication: II. Associations with persistence of DSM-IV disorders. Archives of General Psychiatry, 67, 124132.CrossRefGoogle ScholarPubMed
McLaughlin, K. A., Green, J. G., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., & Kessler, R. C. (2010b). Childhood adversities and adult psychiatric disorders in the National Comorbidity Survey replication (NCR): III. Associations with functional impairment related to DSM-IV disorders. Psychological Medicine, 40, 847859.CrossRefGoogle Scholar
Meaney, M. J., Stewart, J., & Beatty, W. W. (1981). The effects of gluococorticoids during the neonatal period on the development of social play in juvenile rats. Hormones and Behavior, 16, 475491.CrossRefGoogle Scholar
Mehta, D., & Binder, E. B. (2012). Gene × Environment vulnerability factors for PTSD: The HPA-axis. Neuropharmacology, 62, 654662.CrossRefGoogle ScholarPubMed
Muthén, B. (2011). Applications of causally defined direct and indirect effects in mediation analysis using SEM in Mplus. Manuscript submitted for publication.Google Scholar
Muthén, L. K., & Muthén, D. O. (1998–2011). Mplus Version 6.11 [Computer software]. Los Angeles: Author.Google Scholar
Myers, J., Berliner, L., Briere, L., Hendrix, C., Jenny, C., & Reid, T. A. (2002). The APSAC handbook on child maltreatment. Thousand Oaks, CA: Sage.Google Scholar
Nemeroff, C. B., & Vale, W.W. (2005). The neurobiology of depression: Inroads to treatment and new drug discovery. Journal of Clinical Psychiatry, 66, 513.Google Scholar
Orr, S. P., Lasko, N. B., Metzger, L. J., Berry, N. J., Ahern, C. E., & Pitman, R. K. (1998). Psychophysiological assessment of women with posttraumatic stress disorder resulting from childhood sexual abuse. Journal of Consulting and Clinical Psychology, 66, 906913.CrossRefGoogle Scholar
Pariante, C. M., & Lightman, S. L. (2008). The HPA axis in major depression: Classical theories and new developments. Trends in Neurosciences, 31, 464468.CrossRefGoogle ScholarPubMed
Pariante, C. M., & Miller, A. H. (2001). Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment. Biological Psychiatry, 49, 391404.CrossRefGoogle ScholarPubMed
Pollak, S. D., Klorman, R., Thatcher, J. E., & Cicchetti, D. (2001). P3b reflects maltreated children's reactions to facial displays of emotion. Psychophysiology, 38, 267274.CrossRefGoogle ScholarPubMed
Post, R. M. (1992). Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. American Journal of Psychiatry, 149, 9991010.Google ScholarPubMed
Putnam, F. W. (1997). Dissociation in children and adolescents: A developmental perspective. New York: Guilford Press.Google Scholar
Rao, H., Betancourt, L., Giannetta, J. M., Brodsky, N. L., Korczykowski, M., Avants, B. B., et al. (2010). Early parental care is important for hippocampal maturation: Evidence from brain morphology in humans. NeuroImage, 49, 11441150.CrossRefGoogle Scholar
Roy, A., Gilman, S. E., Brslau, J., Breslau, N., & Koenen, K. C. (2010). Race–ethnic differences in exposure to traumatic events, development of posttraumatic stress disorder, and treatment seeking in the United States population. Psychological Medicine, 29, 113.Google Scholar
Roy, A., Gorodetsky, E., Yuan, Q., Goldman, D., & Enoch, M. (2010). Interaction of FKBP5, a stress-related gene, with childhood trauma increases trauma increases the risk for attempting suicide. Neuropsychopharmacology, 35, 16741683.Google ScholarPubMed
Rutter, M., Moffitt, T. E., & Caspi, A. (2006). Gene–environment interplay and psychopathology: Multiple varieties but real effects. Journal of Child Psychology and Psychiatry, 47, 226261.CrossRefGoogle ScholarPubMed
Sanchez, M. M., Young, L. J., Plotsky, P. M., & Insel, T. R. (2000). Distribution of corticosteroid receptors in the rhesus brain: Relative absence of glucocorticoid receptors in the hippocampal formation. Journal of Neuroscience, 20, 46574668.Google ScholarPubMed
Sarapas, C., Cai, G., Bierer, L. M., Golier, J. A., Galea, S., Ising, M., et al. (2011). Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks. Disease Markers, 30, 101110.CrossRefGoogle ScholarPubMed
Scammell, J. G., Denny, W. B., Valentine, D. L., & Smith, D. F. (2001). Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. General and Comparative Endocrinology, 124, 152165.CrossRefGoogle ScholarPubMed
Schapiro, S. (1971). Hormonal and environmental influences on rat brain and behavior. In Sterman, M. B. & McGinty, O. J. (Eds.), Brain development and behavior (pp. 307334). New York: Academic Press.Google Scholar
Seckl, J. R. (1998). Physiologic programming of the fetus. Clinical Perinatology, 25, 939962.Google ScholarPubMed
Sedlak, A. J., Mettenburg, J., Basena, M., Petta, I., McPherson, K., Greene, A., et al. (2010). Fourth National Incidence Study of Child Abuse and Neglect (NIS-4): Report to Congress, Executive Summary. Washington DC: US Department of Health and Human Services, Administration for Children and Families.Google Scholar
Segman, R. H., Shefi, N., Goltser-Dubner, T., Friedman, N., Kaminski, N., & Shalev, A. Y. (2005). Peripheral blood mononuclear cell gene expression profiles identify emergent posttraumatic stress disorder among trauma survivors. Molecular Psychiatry, 10, 500513.CrossRefGoogle ScholarPubMed
Shields, A., & Cicchetti, D. (1997). Emotion regulation among school-age children: The development and validation of a new criterion Q-sort scale. Developmental Psychology, 33, 906916.CrossRefGoogle ScholarPubMed
Shields, A., & Cicchetti, D. (1998). Reactive aggression among maltreated children: The contributions of attention and emotion dysregulation. Journal of Clinical Child Psychology, 27, 381395.CrossRefGoogle ScholarPubMed
Shields, A., & Cicchetti, D. (2001). Parental maltreatment and emotion dysregulation as risk factors for bullying and victimization in middle childhood. Journal of Clinical Child Psychology, 30, 349363.CrossRefGoogle Scholar
Shields, A., Ryan, R. M., & Cicchetti, D. (2001). Narrative representations of caregivers and emotion regulation as predictors of maltreated children's rejection by peers. Developmental Psychology, 37, 321337.CrossRefGoogle ScholarPubMed
Shrout, P. E., & Bolger, N. (2002). Mediation in experimental and nonexperimental studies: New procedures and recommendation. Psychological Methods, 7, 422445.CrossRefGoogle Scholar
Simeon, D., Knutelska, M., Yehuda, R., Putnam, F., Schmeidler, J., & Smith, L. M. (2007). Hypothalamic–pituitary–adrenal axis dysfunction in dissociative disorders, posttraumatic stress disorder, and health volunteers. Biological Psychiatry, 61, 966973.CrossRefGoogle Scholar
Skelton, K., Ressler, K. J., Norrholm, S. D., Jovanovic, T., & Bradley-Davino, B. (2012). PTSD and gene variants: New pathways and new thinking. Neuropharmacology, 62, 628637.CrossRefGoogle Scholar
Spear, L. (2000). The adolescent brain and age-related behavioral manifestations. Neuroscience & Biobehavioral Reviews, 24, 417463.CrossRefGoogle ScholarPubMed
Sroufe, L. A., & Fleeson, J. (1986). Attachment and the construction of relationships. In Hartup, N. W. & Rubin, Z. (Eds.), Relationships and development (pp. 273308). Hillsdale, NJ: Erlbaum.Google Scholar
Stein, M. B. (1997). Hippocampal volume in women victimized by childhood sexual abuse. Psychological Medicine, 27, 951959.CrossRefGoogle ScholarPubMed
Stephens, M., & Scheet, P. (2005). Accounting for decay of linkage disequilibrium in haplotype interference and missing-data imputation. American Journal of Human Genetics, 76, 449462.CrossRefGoogle Scholar
Stephens, M., Smith, N., & Donnelly, P. (2001). A new statistical method for haplotype reconstruction from population data. American Journal of Human Genetics, 68, 978989.CrossRefGoogle Scholar
Storch, E. A., Roberti, J. W., & Roth, D. A. (2004). Factor structure, concurrent validity, and internal consistency of the Beck Depression Inventory—Second Edition in a sample of college students. Depression and Anxiety, 19, 187189.CrossRefGoogle Scholar
Suprianto, I., Sasada, T., Fukutake, M., Asano, M., Ueno, Y., Nagasaki, Y., et al. (2011). Association of FKBP5 gene haplotypes with completed suicide in the Japanese population. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35, 252256.CrossRefGoogle Scholar
Teicher, M. H., Andersen, S. L., Polcari, A., Anderson, C. M., & Navalta, C. P. (2002). Developmental neurobiology of childhood stress and trauma. Psychiatric Clinics of North America, 25, 397426.CrossRefGoogle ScholarPubMed
Teicher, M. H., Andersen, S. L., Polcari, A., Anderson, C. M., Navalta, C. P., & Kim, D. M. (2003). The neurobiological consequences of early stress and childhood maltreatment. Neuroscience and Biobehavioral Reviews, 27, 3344.CrossRefGoogle ScholarPubMed
Teicher, M. H., Dumont, N. L., Ito, Y., Vaituzis, C., Gledd, J. N., & Andersen, S. L. (2004). Childhood neglect is associated with reduced corpus callosum area. Biological Psychiatry, 15, 8085.CrossRefGoogle Scholar
Teicher, M. H., Glod, C. A., Surrey, J., & Swett, C. (1993). Early childhood abuse and limbic system ratings in adult psychiatric outpatients. Journal of Neuropsychiatry, 5, 301306.Google ScholarPubMed
Teicher, M. H., Ito, Y., Glod, C. A., Anderson, S. L., Dumont, N., & Ackerman, E. (1997). Preliminary evidence for abnormal cortical development in physically and sexually abused children using EEG coherence and MRI. Annals of the New York Academy of Science, 821, 160175.CrossRefGoogle ScholarPubMed
Teicher, M. H., Samson, J. A., Polcari, A., & McGreenery, C. E. (2006). Sticks, stones, and hurtful words: Relative effects of various forms of childhood maltreatment. American Journal of Psychiatry, 163, 9931000.CrossRefGoogle ScholarPubMed
Teicher, M. H., Samson, J. A., Sheu, Y., Polcari, A., & McGreenery, C. E. (2010). Hurtful words: Association of exposure to peer verbal abuse with elevated psychiatric symptom scores and corpus callosum abnormalities. American Journal of Psychiatry, 167, 14641471.CrossRefGoogle ScholarPubMed
Tomoda, A., Navalta, C. P., Polcari, A., Sadato, N., & Teicher, M. H. (2009). Childhood sexual abuse is associated with reduced gray matter volume in visual cortex of young women. Biological Psychiatry, 66, 642648.CrossRefGoogle ScholarPubMed
Toth, S. L., Manly, J. T., & Cicchetti, D. (1992). Child maltreatment and vulnerability to depression. Development and Psychopathology, 4, 97112.CrossRefGoogle Scholar
Touma, C., Gassen, N. C., Herrman, L., Cheung-Flynn, J., Bull, D. R., Ionescu, I. A., et al. (2011). FK506 binding protein 5 shapes stress responsiveness: Modulation of neuroendocrine reactivity and coping behavior. Biological Psychiatry, 15, 928936.CrossRefGoogle Scholar
Trickett, P. K., & McBride-Chang, C. (1995). The developmental impact of different types of child abuse and neglect. Developmental Review, 15, 311337.CrossRefGoogle Scholar
van der Kolk, B., & Greenberg, M. S. (1987). The psychobiology of the trauma response: Hyperarousal, constriction, and addiction to traumatic reexposure. In van der Kolk, B. (Ed.), Psychological trauma (pp. 6387). Washington, DC: American Psychiatric Press.Google ScholarPubMed
van der Kolk, B. A., van der Hart, O. V., & Marmar, C. R. (1996). Dissociation and information processing in posttraumatic stress disorder. In van der Kolk, B. A., McFarlane, A. C., & Weisaeth, L. (Ed.), Traumatic stress: The effects of overwhelming experience on mind, body, and society (pp. 303327). New York: Guilford Press.Google Scholar
van IJzendoorn, M., & Schuengel, C. (1996). The measurement of dissociation in normal and clinical populations: Meta-analytic validation of the Dissociative Experiences Scale (DES). Clinical Psychology Review, 16, 362382.Google Scholar
Velders, F. P., Kunigas, M., Kumari, M., Dekker, M. J., Uitterlinden, A. G., Kirschbaum, C., et al. (2011). Genetics of cortisol secretion and depressive symptoms: A candidate gene and genome wide association approach. Psychoneuroendocrinology, 36, 10531061.CrossRefGoogle ScholarPubMed
Veltman, D. J., de Ruiter, M. B., Rombouts, S. A., Lazeron, R. H., Barkhof, F., van Dyck, R., et al. (2005). Neurophysiological correlates of increased verbal working memory in high-dissociative participants: A functional MRI study. Psychological Medicine, 35, 175185.CrossRefGoogle Scholar
Vermeer, H., Hendriks-Stegeman, B. I., van der Burg, B., van Buul-Offers, S. C., & Jansen, M. (2003). Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression. Journal of Clinical Endocrinology and Metabolism, 88, 277284.CrossRefGoogle Scholar
Vythilingam, M., Heim, C., Newport, J., Miller, A. H., Anderson, E., Bronen, R., et al. (2002). Childhood trauma is associated with smaller hippocampal volume in women with major depression. American Journal of Psychiatry, 159, 20722080.CrossRefGoogle Scholar
Welberg, L. A., & Seckl, J. R. (2001). Prenatal stress, glucocortioicds, and the programming of the brain. Journal of Neuroendocrinology, 13, 113128.CrossRefGoogle Scholar
Widom, C. S. (1999). Posttraumatic stress disorder in abused and neglected children grown up. American Journal of Psychiatry, 156, 12231229.Google ScholarPubMed
Widom, C. S., DuMont, K., & Czaja, S. J. (2007). A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Archives of General Psychiatry, 64, 4956.CrossRefGoogle Scholar
Wochnik, G. M., Ruegg, J., Abel, G. A., Schmidt, U., Holsboer, F., Rein, T., et al. (2005). FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. Journal of Biological Chemistry, 280, 46094616.CrossRefGoogle Scholar
Xie, P., Kianzler, H. R., Poling, J., Stein, M. B., Anton, R. F., Farrer, L. A., et al. (2010). Interaction of FKBP5 with childhood adversity on risk for posttraumatic stress disorder. Neuropsychopharmacology, 35, 16841694.Google Scholar
Yehuda, R. (2009). Status of glucocorticoid alterations in posttraumatic stress disorder. Annals of the New York Academy of Science, 1179, 5669.CrossRefGoogle Scholar
Yehuda, R., Golier, J. A., Yang, R., & Tischler, L. (2004). Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder. Biological Psychiatry, 55, 11101116.CrossRefGoogle ScholarPubMed
Zimmermann, P., Bruckl, T., Nocon, A., Pfister, H., & Binder, E. (2011). Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: Results form a 10-year prospective community sample. American Journal of Psychiatry, 168, 11071116.CrossRefGoogle Scholar
Zobel, A., Schuhmacher, A., Jessen, F., Hofels, S., von Widdern, O., Metten, M., et al. (2010). DNA sequence variants of the FKBP5 gene are associated with unipolar depression. International Journal of Neuropsychopharmacology, 13, 649660.CrossRefGoogle ScholarPubMed