ReviewCurrent research trends in early life stress and depression: Review of human studies on sensitive periods, gene–environment interactions, and epigenetics
Introduction
Stress or trauma is associated with dramatic increases in the risk to develop depressive disorders. In addition, it is estimated that 30–40% of the risk for depression is genetically determined. Other risk factors of depressive disorders include a family history of depression, past episodes of depression, female gender, and neuroticism among others. It is now well-accepted that genetic diathesis (genes, gender, personality, family history) and environmental influences (stress, abuse, neglect, adverse family relations) across the lifespan together likely underlie vulnerability for depression (see, for example, Kendler et al., 2002, Merikangas and Swendsen, 1997, Nestler et al., 2002). Of note, the childhood period seems to be particularly sensitive to environmental disturbances that increase depression risk (for example, Heim et al., 2010). Early programming of neurobiological systems that are implicated in regulating emotion and stress responses appears to mediate increased stress vulnerability and depression risk later in life. However, not all cases with early adverse experiences develop depression later in life and there is substantial variability in the outcomes of early life stress, including resilience. Potential factors that might explain outcome variability or resilience to the effects of early life stress in humans remain poorly understood. The present review article discusses several current research developments concerning the complex link between early life stress and depression. After providing a general overview of the epidemiology of early life stress and its main clinical and neurobiological consequences, we specifically focus on discussing (a) the potential role of sensitive periods for the effects of early life stress in humans, (b) known genotypic moderators of the effects of early life stress on depression risk versus resilience, and (c) epigenetic programming of the stress responses by early life stress.
Section snippets
Prevalence of early life stress
Childhood adversity is unfortunately common in our society. According to the National Child Abuse and Neglect Data System (NCANDS), in 2009, approximately 3,300,000 referrals, involving alleged maltreatment of approximately 6,000,000 children, were received by child protective agencies across the US. Of those, 61% were screened to receive a response and roughly a quarter of cases were confirmed cases of maltreatment (NCANDS, 2009). These numbers reflect only the tip of the iceberg, as most
Relationship between early life stress and depression
Numerous epidemiologic and clinical studies have provided compelling evidence for a strong association between various forms of early life stress and depressive symptoms or disorders. The large CDC study conducted in an HMO population provided evidence for a strong dose–response relationship between childhood adversities (sexual abuse, physical abuse, witnessing paternal violence) and general mental health problems in adulthood (Edwards et al., 2003). An earlier study in the same population
Brief overview of neurobiological effects of early life stress
The precise mechanisms that mediate the detrimental and persistent impact of early adversity on depression risk have been the subject of intense inquiry over decades. Advances from neuroscience research have provided compelling insights into the enormous plasticity of the developing brain as a function of experience. Enduring effects of early life stress on the brain and its stress regulatory outflow systems, including the autonomic, endocrine and immune systems, may lead to the development of
Timing as a critical factor: sensitive periods for the effects of early life stress
Few clinical studies have revealed that there might be timing-dependent effects of early life stress on depression risk. For example, Maercker et al. (2004) reported that political traumatization before the age of 12 years was associated with risk for major depression in adulthood, whereas traumatization from 12 years throughout adolescence was associated with increased risk for PTSD. Similarly, a study by Agid et al. (1999) has suggested that parental loss before 9 years of age was associated
Gene × environment interactions
In addition to timing effects of early life stress, depending on sensitive periods of the developing brain, individual genotypic variations interacting with early life stress may contribute to variability in clinical outcomes. While the overall heritability of major depression is estimated to be between 30 and 40%, so far all genetic studies have documented that common variants of intermediate or large effect do not seem to play a major role in the genetics of this disorder. This is supported
Epigenetics
While several G × E interactions in the prediction of depression have been reported as described above, the biological or molecular mechanism behind these G × E interactions has not yet been resolved. A plausible model could involve allele-specific moderation of experience-dependent alteration of epigenetic marks, such as DNA methylation or histone modification, which will be discussed next.
Epigenetics refers to the regulation of DNA transcription without alteration of the original sequence and is
Conclusion
We here provide a selective review of current research developments concerning the relationship between early life stress and depression. Prevalence data suggests that early life stress occurs throughout different age groups in childhood, with the youngest age group of 1–3 years being most affected. However, very little is known as to whether timing of early life stress throughout childhood has an impact on neurobiological and behavioral outcomes. There is a reasonable foundation to believe that
References (146)
- et al.
Stress, sensitive periods and maturational events in adolescent depression
Trends Neurosci.
(2008) - et al.
Puberty and depression
Child Adolesc. Psychiatr. Clin. N. Am.
(2006) - et al.
Development and validation of a brief screening version of the Childhood Trauma Questionnaire
Child Abuse Negl.
(2003) The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders
Psychoneuroendocrinology
(2009)- et al.
Prevalence and psychological sequelae of self-reported childhood physical and sexual abuse in a general population sample of men and women
Child Abuse Negl.
(2003) - et al.
Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment
Biol. Psychiatry
(2007) - et al.
Effect of childhood emotional abuse and age on cortisol responsivity in adulthood
Biol. Psychiatry
(2009) - et al.
Adverse childhood experiences and the risk of depressive disorders in adulthood
J. Affect. Disord.
(2004) - et al.
Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects
Psychoneuroendocrinology
(2008) - 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)
Early impact of 5-HTTLPR polymorphism on the neural correlates of sadness
Neurosci. Lett.
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
Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain
Neuroscience
Childhood trauma history differentiates amygdala response to sad faces within MDD
J. Psychiatr. Res.
The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma
Biol. Psychiatry
The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies
Biol. Psychiatry
The link between childhood trauma and depression: insights from HPA axis studies in humans
Psychoneuroendocrinology
The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
Serotonin transporter promoter gain-of-function genotypes are linked to obsessive–compulsive disorder
Am. J. Hum. Genet.
Brain-derived neurotrophic factor–5-HTTLPR gene interactions and environmental modifiers of depression in children
Biol. Psychiatry
Brain development in children and adolescents: insights from anatomical magnetic resonance imaging
Neurosci. Biobehav. Rev.
The genetics of depression: a review
Biol. Psychiatry
FKBP5 and resistant attachment predict cortisol reactivity in infants: gene–environment interaction
Psychoneuroendocrinology
Neuroimaging studies of normal brain development and their relevance for understanding childhood neuropsychiatric disorders
J. Am. Acad. Child Adolesc. Psychiatry
The long-term impact of the physical, emotional, and sexual abuse of children: a community study
Child Abuse Negl.
Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis
Biol. Psychiatry
Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia
Mol. Psychiatry
Early adversity and 5-HTT/BDNF genes: new evidence of gene–environment interactions on depressive symptoms in a general population
Psychol. Med.
Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development
J. Neuropsychiatry Clin. Neurosci.
Vulnerability genes or plasticity genes?
Mol. Psychiatry
Myelination of cortical–hippocampal relays during late adolescence
Schizophr. Bull.
Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: new evidence for a gene–environment interaction
Am. J. Med. Genet. B Neuropsychiatr. Genet.
The role of puberty in the developing adolescent brain
Hum. Brain Mapp.
Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene
Arch. Gen. Psychiatry
Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men
J. Neurosci.
Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects
Neuropsychopharmacology
Genetic–environmental interaction in the genesis of aggressivity and conduct disorders
Arch. Gen. Psychiatry
Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits
Am. J. Psychiatry
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Science
Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2
Science
Interaction of chronic stress with serotonin transporter and catechol-O-methyltransferase polymorphisms in predicting youth depression
Depress. Anxiety
Maternal–infant response to variable foraging demand in nonhuman primates: effects of timing of stressor on cerebrospinal fluid corticotropin-releasing factor and circulating glucocorticoid concentrations
Ann. N.Y. Acad. Sci.
Amygdalo-cortical sprouting continues into early adulthood: implications for the development of normal and abnormal function during adolescence
J. Comp. Neurol.
Elevated inflammation levels in depressed adults with a history of childhood maltreatment
Arch. Gen. Psychiatry
Biological embedding of stress through inflammation processes in childhood
Mol. Psychiatry
Quantitative growth and development of human brain
Arch. Dis. Child.
Childhood abuse, household dysfunction, and the risk of attempted suicide throughout the life span: findings from the Adverse Childhood Experiences Study
JAMA
Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: results from the adverse childhood experiences study
Am. J. Psychiatry
Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice
Nat. Neurosci.
Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety
Mol. Psychiatry
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