Review: Serotonin by stress interaction: a susceptibility factor for the development of depression?

Abstract

A genetic predisposition to depression may be a potential risk factor in the development of depression. Although the neurobiological equivalent of the predisposition remains unclear, it seems as though the brain serotonin (5-HT) system plays an important mediating role. Therefore, individuals with a family history of depression (FH+) may be more likely to develop depression due to an innate vulnerability related to altered serotonergic neurotransmission in the brain. A major problem, however, is that the role of brain 5-HT in depression is complex and this serotonin-related innate vulnerability, by itself, is not sufficient enough to cause a depressive episode. In the search for additional factors, stress has received particular attention. Stressful life events influence and precede the onset of depression. Furthermore, depression is associated with stress hormone dysregulation and bidirectional interactions are thought to occur between stress-related changes in the neuroendocrine stress system and the 5-HT system. In the current review, we argue that healthy individuals with a positive family history of depression are more prone to develop depression due to a genetic 5-HT susceptibility, which deteriorates stress coping mechanisms and increases stress vulnerability.

Differential effects of 5-HTTLPR genotypes on mood, memory, and attention bias following acute tryptophan depletion and stress exposure

“…Acute stress increases 5-HT neurotransmission (Davis et al 1995;De Kloet et al 1982, 1983, which promotes stress adaptation by mediating negative feedback control of cortisol on the HPA axis (Nuller and Ostroumova 1980;Van Praag 2004). In accord with the current findings, s allele carriers are thought to be 5-HT vulnerable and to be susceptible to depression symptoms particularly in the face of stress (Caspi et al 2003;Firk and Markus 2007;Van Praag 2004). Although hypothetically, stress and enhanced HPA activation, particularly in s allele carriers, may further undermine 5-HT function, which then may lead to reduced stress coping and subsequently result in negative mood (e.g., Dayan and Huys 2008;Firk and Markus 2007;Van Praag 2004).…”

“…In accord with the current findings, s allele carriers are thought to be 5-HT vulnerable and to be susceptible to depression symptoms particularly in the face of stress (Caspi et al 2003;Firk and Markus 2007;Van Praag 2004). Although hypothetically, stress and enhanced HPA activation, particularly in s allele carriers, may further undermine 5-HT function, which then may lead to reduced stress coping and subsequently result in negative mood (e.g., Dayan and Huys 2008;Firk and Markus 2007;Van Praag 2004). In further support, Gotlib et al (2008) found that only girls homozygous for the s allele showed a cortisol response following acute stress exposure, which also supports the hypothesis that 5-HTTLPR affects HPA activity and hence, stress reactivity.…”

“…This suggests that s allele carriers may only have a predisposition to serotonergic vulnerability that may be unmasked through challenges to the serotonergic system. This is also in line with contemporary theoretical models of gene involvement in depression that postulate that genetic vulnerability does not affect depression directly; rather, 5-HTTLPR may enhance susceptibility for depression particularly in the face of severe life events or stressful experiences, which may also challenge the brain serotonergic system (Firk and Markus 2007). Hence, depression is often preceded by stress (Van Praag 2004), and epidemiological studies have already demonstrated a positive association between the s allele of the 5-HTTLPR and a depressive reaction to stressful life events (e.g., Caspi et al 2003; for a recent review see Uher and McGuffin 2008).…”

“…Hence, depression is often preceded by stress (Van Praag 2004), and epidemiological studies have already demonstrated a positive association between the s allele of the 5-HTTLPR and a depressive reaction to stressful life events (e.g., Caspi et al 2003; for a recent review see Uher and McGuffin 2008). This is in line with the hypothesis that stress may cause depression due to complex interactions between the neuroendocrine stress system and the serotonergic system, particularly in individuals with a biological (genetic) vulnerability related to their serotonergic system (Firk and Markus 2007;Van Praag 2004). Although explorations of the involvement of interactions between serotonergic vulnerability in s allele 5-HTTLPR and stress in the onset of affective symptoms are a major challenge in biological psychiatry today, this interaction has not yet been experimentally investigated.…”

An Integrative Common Liabilities Model for the Comorbidity of Substance Use Disorders with Externalizing and Internalizing Disorders

“…Complex interactions between genetic susceptibility to serotonergic and noradrenergic system dysfunction and stress-related changes in the HPA axis have been implicated in the etiology of depression (Firk, Markus, Firk, & Markus, 2007;Porter et al, 2004), and psychopharmacological treatment studies support the role of reduced neurotransmission of serotonin and norepinephrine in the pathophysiology of GAD (Nutt, Argyropoulos, Hood, & Potokar, 2006). Despite the extensive body of research linking corticotrophin-releasing factor and the HPA axis to depression (Hankin, Badanes, Abela, & Watamura, 2010;Nemeroff & Vale, 2005;Wardenaar, et al, 2011), almost 24 no research has investigated the role of the HPA axis in the etiology of GAD separate from the INT-FA anxiety disorders.…”