Trends in Neurosciences
ReviewStress, sensitive periods and maturational events in adolescent depression
Introduction
The overriding issue of this review is to understand why depression emerges with such force and frequency in adolescence, particularly in young women. Conceivably, a host of psychosocial factors can render adolescents especially vulnerable, but our focus will be on neurobiological factors. In particular, we will examine the interplay of genetic, maturational and experiential factors affecting mood using a translational perspective that melds clinical and basic laboratory findings.
Section snippets
Basic epidemiology of adolescent depression
Major depression disorder is a common and serious disorder of adolescence [1]. Lifetime prevalence increases dramatically from 1% of the population under age 12 to ∼17%–25% of the population by the end of adolescence [2]. The greatest surge in newly emergent cases occurs between 15 and 18 years [3].
Cross-sectional and prospective epidemiological studies indicate that anxiety disorders often precede the emergence of depression and identify children at risk for developing depression 4, 5. It is
Etiology of depression
Although the specific etiology of major depression remains unknown, both heredity and early experience are critical determinants. Further, maturational events might potentially increase prevalence or trigger episodes (see Box 1). It is important to distinguish between specific etiological factors (e.g. genetic polymorphisms, childhood adversity) that increase risk in selective recipients and universal phenomena (e.g. puberty) that exert moderating effects on the entire population.
Effects of early stress on brain development—evidence for sensitive periods
Early stress stemming from childhood adversity is a predisposing risk factor for the development of major depression [15], and depression is the most common adult sequela of early abuse [35]. Whether exposure to adversity leads to the eventual development of depression is likely to be determined by genetic susceptibilities [16], frequency, severity and multiplicity of the stressors 16, 36, gender and timing of insult [37]. Exposure to physical or sexual abuse resulting in psychopathology has
Maturation and onset of depression
Depression is the most extensively documented outcome of exposure to CSA in adults but is not a common occurrence in children [35]. This suggests that a substantial time lag, or incubation period, occurs between early stress exposure and eventual development of depression. In a prospective study, rates of depression were increased by physical abuse or neglect (n = 676), which lead to an earlier emergence of depression relative to controls (n = 520) [48]. In a separate cohort exposed to CSA but no
Delayed effects of early stress on the hippocampus
The role of the hippocampus in adolescent depression is highly likely, given its susceptibility to the effects of stress [50] and its role in mood regulation and antidepressant response [51]. Reduced hippocampal size has been observed in most studies of adults with major depression [39], and can vary as a function of episode number [39] or duration of time spent depressed but untreated [32]. We propose that the hippocampus contributes to the burden of depression by failing to provide an
Late-maturing prefrontal cortex
Multiple components of the prefrontal cortex (PFC) are involved in the emergence of depression as it matures during the periadolescent period. A primary role of the PFC is to modulate activity of limbic structures. The PFC has a protracted postnatal ontogeny and does not attain adult volume until the early 20s [58]. The complexity of the region and its developmental time course render it vulnerable, especially to stress during adolescence [46]. PFC development is also affected by early
The amygdala: fear, irritability and anxiety
The amygdala has become an increasingly important component of theories of depression, based largely on imaging studies of mood regulation. The amygdala is over-responsive to fearful stimuli in depression [66], and insufficiently regulated by PFC controls [67]. This leads to an excessive and persistent degree of negative affectivity, which is a significant but nonspecific feature of depression. Alteration in the genes encoding 5-HTT and 5HT1 is associated with augmented amygdala response to
Conclusions
Recent studies have emphasized the importance of gene x environment in the genesis of depression. Time is another crucial factor, both in terms of windows of vulnerability when brain regions might be maximally sensitive to environmental influences and in the cascade of maturational events that lead to the unfolding of depression. The hippocampus and PFC can have early and late windows of vulnerability, and serve respectively as targets for the predisposing and precipitating effects of stress.
Acknowledgements
This work was supported, in part, by awards from NARSAD (2001, 2002, 2005), NIDA (RO1DA-017846), NIMH (RO1MH-66222) and the Simches and Rosenberg Families.
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