Neurodevelopmental origins of depressive disorders
Introduction
Depression is characterized by enduring sadness, anhedonia, guilt, low self-esteem, disturbed sleep, disturbed appetite, low energy, poor concentration and suicidal thoughts. With an approximately 20% lifetime incidence, depressive disorders are estimated to be the fourth largest contributor to the global burden of disease (according to the World Health Organization and the National Institute of Health).
The pathophysiological theories of depression are manifold and include Freud's model of inwardly turned aggression, Beck's model of cognitive distortion and, recently, Zubin and Spring's stress-diathesis model and Engel's biopsychosocial model, both of which have been embraced by the authors of DSM IV (Diagnostic and Statistical Manual of Mental Disorders IV). Modern hypotheses recognize that genetic and environmental factors both contribute to the vulnerability of an individual to depression. These factors are heterogeneous and interact in a complex fashion, as currently no single genetic or environmental factor can account for more than 5% of the variance between depressed and normal subjects (for reviews, see [1, 2]).
The development of an organism is determined both by its genetic makeup and by the environment to which it is exposed. The importance of development in the etiology of depression has been recognized, but has been often under emphasized. In this review, we consider several models of depression and examine advances that take developmental dimensions of environmental and genetic factors into account. We argue that environmental and genetic factors can affect the maturation of brain circuits involved in affective function and, ultimately, increase the likelihood of depressive disorders in adulthood. Increased recognition of the role that development plays in the etiology of depression should lead to a better understanding of disease pathophysiology and, subsequently, to better treatment and prevention strategies.
Section snippets
The monoamine model of depression
Reduced monoaminergic signaling has long been thought to underlie depressive disorders. For example, reduced monoamine metabolite levels have been found in the cerebrospinal fluid of depressed individuals; likewise, serotonin (or 5-HT) or norepinephrine depletion exerts pro-depressive effects (for reviews, see [3, 4]). These findings are in line with the observation that clinically effective antidepressants increase monoaminergic signaling. Although most of these measurements and manipulations
The HPA model of depression
Dysregulation of the hypothalamic–pituitary–adrenocortical (HPA) system has also been implicated in the pathophysiology of depression. For example, chronic adult stress is a risk factor for depression; baseline measures of the HPA system are abnormal in many depressed subjects; and depressed patients exhibit abnormal stress hormone responses to diverse challenge tests such as dexamethasone suppression (for reviews, see [35, 36]).
In the HPA system (Figure 2), the hypothalamic paraventricular
The neurotrophic model of depression
During development, neurotrophic factors regulate naturally occurring cell death, synaptic connectivity, fiber guidance and dendritic morphology, often in an activity-dependent manner. By fulfilling those same functions in the adult organism, neurotrophic factors contribute to the plasticity of the adult brain. Several lines of evidence suggest that reduced neurotrophic factor signaling in the adult brain may be implicated in the pathophysiology of depression. For example, environmental
Conclusions
Depression is a devastating, complex and highly prevalent disorder that requires better insights into its pathophysiology to improve treatment and prevention. Several models of depression that identify abnormalities in depressed subjects have been discussed in this review. These mainly static pathophysiological models can be further enhanced if developmental considerations are better integrated. For example, we have discussed several genetic and environmental vulnerability factors that are
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors thank Noelia Weisstaub, Maria Milekic, Neil Gray, Jeff Muller and Emanuela Morelli for critical reading of the manuscript. MSA is supported by NARSAD, Sackler and NIMH grants.
References (73)
- et al.
Effects of genes and stress on the neurobiology of depression
Int Rev Neurobiol
(2006) The genetics of depression: a review
Biol Psychiatry
(2006)- et al.
Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice
Biol Psychiatry
(2003) - et al.
Decreased dorsal raphe nucleus neuronal activity in adult chloral hydrate anesthetized rats following neonatal clomipramine treatment: implications for endogenous depression
Brain Res
(1997) - et al.
Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response
Int J Neuropsychopharmacol
(2004) - et al.
Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression
Biol Psychiatry
(2006) - et al.
Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels
J Neurosci
(2006) - et al.
Requirement of tryptophan hydroxylase during development for maturation of sensorimotor gating
J Mol Biol
(2006) - et al.
Adverse childhood experiences and the risk of depressive disorders in adulthood
J Affect Disord
(2004) - et al.
The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: a multiple regression analysis
Depress Anxiety
(2002)
Maternal care and the development of stress responses
Curr Opin Neurobiol
Effects of a non-peptide CRF antagonist (DMP696) on the behavioral and endocrine sequelae of maternal separation
Neuropsychopharmacology
Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development
Neuron
Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation
Biol Psychiatry
Regulation of glucocorticoid and mineralocorticoid receptor mRNAs in the hippocampus of the maternally deprived infant rat
Brain Res
Natural variations in maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity in the medial preoptic area
Endocrinology
A neurotrophic model for stress-related mood disorders
Biol Psychiatry
Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients
Psychoneuroendocrinology
Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior
Science
Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning
J Neurosci
Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress
Science
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Science
Genetics of affective and anxiety disorders
Annu Rev Psychol
The neuropharmacology of serotonin and noradrenaline in depression
Int Clin Psychopharmacol
Evidence for a biochemical lesion in depression
J Clin Psychiatry
Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region
Science
A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders
Mol Psychiatry
Variability in the serotonin transporter gene and increased risk for major depression with melancholia
Hum Genet
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Science
The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication
Arch Gen Psychiatry
Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background
Genes Brain Behav
The regulation of neurite outgrowth, growth cone motility, and electrical synaptogenesis by serotonin
J Neurobiol
Serotonin selectively inhibits growth cone motility and synaptogenesis of specific identified neurons
Science
The developmental role of serotonin: news from mouse molecular genetics
Nat Rev Neurosci
Ontogeny of the serotonergic system in the rat: serotonin as a developmental signal
Ann N Y Acad Sci
Cited by (161)
Can neuroimaging measures differentiate the disease course of anorexia nervosa? A systematic review
2023, Journal of Psychiatric ResearchMicroglial activation mediates maternal separation-induced depressive-like behavior in rats: A neurodevelopmental depression model
2023, Journal of Affective Disorders ReportsAssociation between childhood cognitive skills & adult suicidal behavior: A systematic review and meta-analysis
2023, Journal of Affective Disorders