Neurodevelopmental origins of depressive disorders

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Depression is a common and devastating neuropsychiatric disorder, and a better understanding of its pathophysiology is needed to improve diagnosis, treatment and prevention. By considering the developmental dimensions of genetic and environmental factors, new insights have been found into the etiology and pathophysiology of depression. Specifically, we begin to understand how certain vulnerability factors affect the maturation of brain circuits involved in emotional function to increase the risk for depressive disorders later in life. These new findings might help us to better categorize and manage this complex disease.

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.

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