Elsevier

Experimental Neurology

Volume 233, Issue 1, January 2012, Pages 102-111
Experimental Neurology

Review
Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene–environment interactions, and epigenetics

https://doi.org/10.1016/j.expneurol.2011.10.032Get rights and content

Abstract

Early life stress, such as childhood abuse, neglect and loss, is a well established major risk factor for developing depressive disorders later in life. We here summarize and discuss current developments in human research regarding the link between early life stress and depression. Specifically, we review the evidence for the existence of sensitive periods for the adverse effects of early life stress in humans. We further review the current state of knowledge regarding gene × environment (G × E) interactions in the effects of early life stress. While multiple genes operate in multiple environments to induce risk for depression after early life stress, these same genes also seem to enhance the beneficial effects of a positive early environment. Also, we discuss the epigenetic mechanisms that might underlie these G × E interactions. Finally, we discuss the potential importance of identifying sensitive time periods of opportunity, as well as G × E interactions and epigenetic mechanisms, for early interventions that might prevent or reverse the detrimental outcomes of early life stress and its transmission across generations.

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

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