Glucocorticoids and stress‐related depression: an evaluation of biological mechanisms and the potential for new therapeutics
| DOI | https://doi.org/10.1108/17465721111134529 |
| Date | 15 March 2011 |
| Pages | 17-33 |
| Published date | 15 March 2011 |
| Author | Andrew McVicar,John Clancy |
| Subject Matter | Health & social care |
Review
Glucocorticoids and stress-related
depression: an evaluation of biological
mechanisms and the potential for new
therapeutics
Andrew McVicar and John Clancy
Abstract
Purpose – Principles of epigenesis that provide a foundation for research into chronic medical
disorders are increasingly being applied in the context of mental health. The purpose of this paper is to
consider recent research evidence for epigenetic influences in the pathogenesis of depression, and the
putative links with stress biology during exposure to chronic stress, with the aim of placing this into a
context of potential new therapeutics.
Design/methodology/approach – Substantive reviews published during the last ten years were
identified in a search of the Pubmed database in September 2010 using the terms ‘‘epigenetics’ ’ or
‘‘epigenesis’’ with ‘ ‘mental health’’, ‘‘mood disorder’’, ‘ ‘depression’’, stress’, ‘‘chronic stress’’ or
‘‘environment’’, supplemented by hand-searching of citations in the reviews.
Findings – Epigenetic mechanisms are both heritable and acquired, and their impact on the underlying
genome helps explain individual vulnerability and patterns of occurrence of depression.
Originality/value – The paper shows that this relatively new field of research is in its infancy, and the
influence of adverse environments (i.e. stressors) on genetic/epigenetic predisposition has promise for
the advent of novel therapeutics based on epigenetic manipulation.
Keywords Depression, Stress, Human biology, Medical treatment
Paper type General review
Introduction
Depression is a widespread disorder that is strongly associated with stress (Hammen et al.,
1992) and commonly commences in the teenage years in response to adverse experiences,
when a first occurrence is associated with subsequent increased risk of persistence, or
recurrence, into adulthood (Kessler et al., 2005; Widom et al., 2007). Whilst a degree of
concordance in identical twins strengthens the case for a genetic cause, the linkage is
considerably lower than might be anticipated (Lau and Eley,2010) thus placing an emphasis
on an impact of ‘‘environmental’’ factors as being more influential.
In most individuals, severe mood disorder develops slowly but the changes are long-lasting,
a pattern that is indicative of cumulative and stable changes to brain functioning in the
pathogenesis. In this context, stress-related mood disorder has been associated with
long-term stress (Bondi et al., 2008), which contrasts starkly with the outcomes of acute
stress that enable adaptation to short-term adverse environmental factors, and so enable
DOI 10.1108/17465721111134529 VOL. 10 NO. 1 2011, pp. 17-33, QEmerald Group Publishing Limited, ISSN 1746-5729
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Andrew McVicar is based at
the Faculty of Health and
Social Care, Anglia Ruskin
University, Chelmsford, UK.
John Clancy is based at the
School of Nursing and
Midwifery, University of
East Anglia, Norwich, UK.
coping with trauma arising from them (Sapolsky et al., 2000). Transactional models of acute
stress emphasise the centrality of cognition in appraisal and psychological adaptation, but
recent research indicates that the release of glucocorticoid hormones as part of the acute
stress response also facilitates psychological adaptation, and their excessive secretion
during chronic stress possibly may be causative for the impact of chronic stress on mood
(Marques et al., 2009). An endocrinological contribution potentially puts a new perspective
on stress-related depression as a chronic disorder, and this paper, therefore, reviews the
physiological links between chronic stress and depression, and considers directions for new
therapeutic approaches based on research evidence that chronic stress impacts on gene
expression.
Genes and gene expression in the pathogenesis of mood disorder
A fundamental feature of all cells is that cell type, structure and function are the outcomes of
genotype and its expression. There is general consensus for a genetic basis to depression,
and the search for genetic linkage has identified regions on several chromosomes, but the
evidence from such linkage studies remains speculative (review Lau and Eley, 2010). This
inconsistency of genetic trait is highlighted in twin studies which indicate that genotypic
influences explain only 30-40 per cent of the variance in mental health disorders, much lower
than might be anticipated. The indications are that a direct influence of inherited genotype
makes only a moderate contribution to the occurrence of mood disorders.
The pattern of occurrence of depression is also difficult to reconcile with inheritance of a
specific causal genotype. It is often the case that adult cases of major depression emerge in
adolescence but having occurred once then that experience substantially increases the
likelihood of a second episode, which in turn increases the risk of a third (Kim-Cohen et al.,
2003; Widom et al., 2007) suggesting that an underlying susceptibility and cumulative risk is
a more likely explanation. Increased risk of depression in adolescents has been attributed to
various causes, but susceptibility appears to stem from an inherited liability involving multiple
susceptibility genes, none of which alone are sufficient for development of the disorder (Lau
and Eley, 2010), and so raises questions as to what factors might apply to that subset of
people whose symptoms persist from childhood or adolescence into adulthood, or recur as
adults.
Twin studies strongly support the notion that in most instances where there is genetic risk it
only predicts a likelihood of depressive symptoms following adverse life events or chronic
stressors (Nestler,2001), in particular associated with psychosocial difficulties (Kessler et al.,
2005), and in recent years the focus of research into the biological basis of depression has
moved away from seeking inherited causal genotypes towards increasing understanding
how the regulation of the genome may change as a consequence of environmental adversity.
Referred to as ‘‘epigenetic’’ regulation, it is recognised that alterations in its control are
implicated in chronic medical disorders (e.g. breast cancer, Lo and Sukumar (2008)), but it is
a relatively new approach to study the pathology of mental health problems (Graff and
Mansuy, 2009). The focus has largely been on the impact of early adverse events on
epigenetic control, and the resultant implications for vulnerability as adults, but there is
evidence from animal studies that epigenet ic modulation in adults might also be
transmissible to their offspring, producing neurological changes and depressive
behaviours consistent with those obser ved with post-pubertal epigenetic chan ges,
described below (Haihong et al., 2010); though not the focus of this paper, the occurrence
of intergeneration transmission suggests that new approaches may have to be considered in
evaluating the inheritance of mood disorder.
Epigenesis: an overview
Waddington (1953) described what he called the ‘‘epigenetic landscape’’ as a metaphor for
the pattern of gene expression required for cell differentiation during embryological
development. Subsequent research identified the role of promoter genes in controlling the
expression of structural genes, and eventually saw adoption of the term ‘‘epigenesis’ ’ to
describe the selective control of gene activation during embryological development and
later, that determined the pattern of cell division.
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