Satisfaction with follow-up consultations among Swiss childhood cancer survivors: A prospective cohort study.

Depression is the leading cause of disability worldwide [], and approximately 15–30% of patients experiencing depressive episodes respond inadequately to first-line therapeutics []. Inflammation can induce depressive episodes [], and increased inflammation can predict depressive symptoms []. Depressed patients with defective anti-inflammatory immune responses respond inadequately to antidepressant treatment [], and the blockade of inflammation (tumor necrosis factor antagonist-infliximab) has shown antidepressant efficacy in depressed patients with elevated C-reactive protein (CRP) levels []. Meta-analyses indicate that the inflammatory marker CRP is frequently elevated in individuals experiencing depression despite adjustment for epidemiological and other confounding factors. The increased CRP levels are associated with physical (appetite and energy) and cognitive symptoms of depression (lack of interest in activities); however, peripheral inflammation is not associated with the emotional symptoms (hopelessness and feeling like a failure) of depression []. Thus, the variability in the severity of depressive symptoms experienced by individuals could be related to interactions between biological risk factors, such as genetics, and other environmental factors, such as inflammation or chronic stress. An understanding of the mechanisms underlying such interactions is needed to advance the tools required for personalized psychiatric and clinical care. The neurotrophin hypothesis of depression postulates that brain-derived neurotrophic factor (BDNF) is involved in depression, and the implications of reduced/impaired BDNF are well established in human and animal studies []. Reduced serum levels of BDNF were observed in patients suffering from major depressive disorder [], and reduced brain gene transcript and protein levels of BDNF were documented in young suicide victims []. Increased DNA methylation of the BDNF gene in peripheral blood cells of major depressive disorder patients suppresses BDNF expression, suggesting that epigenetic changes to this neurotrophic gene may disrupt physiological BDNF-Tropomyosin receptor kinase B (TrkB) signaling []. Patients with depressive episodes exhibit reduced BDNF levels in the serum [] and in the brain [], while effective treatment with antidepressants increases BDNF levels in the brains of depressed patients []. In rodent models, chronic unpredictable stress induces depressive-like behaviors concomitant with reduced levels of mature BDNF and its receptor TrkB in the neocortex and the hippocampus []. However, the efficacy of an antidepressant, like fluoxetine, to rescue depressive behaviors and increase BDNF mRNA is dependent on the environmental factors in which treatment is presented, and outcomes vary between stressful and stress-free conditions []. Furthermore, previous investigations studying BDNF heterozygous mice suggest that exposure to stress induces the development of depressive-like behaviors [,], and that a genetic reduction in BDNF is associated with an exaggerated neuroimmune response to peripheral immune challenge []. While the relationship between the BDNF and neuroinflammation may be bidirectional in nature [], the cellular and molecular mechanisms altered by such a gene (BDNF) and environment (immune challenge) interaction remain widely unknown. A common single-nucleotide polymorphism (SNP), rs6265, involving a valine for methionine substitution at amino acid position 66 (Val66Met) on the brain-derived neurotrophic factor (BDNF) gene is associated with the development of dysthymic mood disorders [] and the onset of cognitive [] and memory deficits []. The Val66Met SNP impairs neuronal processing and reduces activity-dependent release of mature BDNF [–]. The BDNF Val66Met genotype is also linked to a negative modulation of early life experiences, increasing the risk of developing depression in adulthood [,]. As such, the Val66Met SNP may be a vulnerability factor for stress-induced [] or inflammation-induced depression []. Patients carrying the Val66Met allele were more likely to develop depressive symptoms after treatment with interferon-α [], and the Met allele predicted inflammation-associated depressive symptoms in women with breast cancer []. In preclinical models, mice expressing the human BDNF Val66Met SNP under the endogenous BDNF promoter are more susceptible to anxiogenic stimuli, stress-induced depressive-like behaviors, and less responsive to antidepressant treatment [,]. These data suggest that the Val66Met SNP may sensitize the development of depressed mood associated with an aberrant inflammatory tone.