Gene expression biomarkers of response to citalopram treatment in major depressive disorder

There is significant variability in antidepressant treatment outcome, with ∼30–40% of patients with major depressive disorder (MDD) not presenting with adequate response even following several trials. To identify potential biomarkers of response, we investigated peripheral gene expression patterns of response to antidepressant treatment in MDD. We did this using Affymetrix HG-U133 Plus2 microarrays in blood samples, from untreated individuals with MDD (N=63) ascertained at a community outpatient clinic, pre and post 8-week treatment with citalopram, and used a regression model to assess the impact of gene expression differences on antidepressant response. We carried out technical validation of significant probesets by quantitative reverse transcriptase PCR and conducted central nervous system follow-up of the most significant result in post-mortem brain samples from 15 subjects who died during a current MDD episode and 11 sudden-death controls. A total of 32 probesets were differentially expressed according to response to citalopram treatment following false discovery rate correction. Interferon regulatory factor 7 (IRF7) was the most significant differentially expressed gene and its expression was upregulated by citalopram treatment in individuals who responded to treatment. We found these results to be concordant with our observation of decreased expression of IRF7 in the prefrontal cortex of MDDs with negative toxicological evidence for antidepressant treatment at the time of death. These findings point to IRF7 as a gene of interest in studies investigating genomic factors associated with antidepressant response

Endogenous Serotonin Acts on 5-HT2C-Like Receptors in Key Vocal Areas of the Brain Stem to Initiate Vocalizations in Xenopus laevis

Serotonin initiates various rhythmic behaviors in vertebrates. Previously we have shown that serotonergic neurons innervate the central vocal pathway in the African clawed frog (Xenopus laevis). We also discovered that exogenous serotonin applied to isolated brains in vitro activates fictive vocalizations by activating 5-HT2C-like receptors. In this study, we examined the location of 5-HT2C-like receptors and determined whether endogenously released serotonin also initiates vocalizations by activating 5-HT2C-like receptors in male Xenopus brains. To this end, we first identified the specific location of 5-HT2C-like receptors using immunohistochemistry. We next examined which of the populations of neurons that express 5-HT2C-like receptors are functionally relevant for initiating fictive vocalizations by applying a 5-HT2C receptor agonist to brains transected at various levels. Of four populations of immunopositive neurons, we showed that 5-HT2C-like receptors located in two areas of the brain stem vocal circuit, the raphe nucleus and motor nucleus IX-X, initiate fictive vocalizations. We next showed that endogenous serotonin can also activate fictive vocalizations by increasing the extracellular concentration of endogenous serotonin using a selective serotonin reuptake inhibitor (SSRI). The SSRI-induced vocal initiation is also mediated by activation of 5-HT2C-like receptors because blockade of these receptors prevents fictive vocalization. The results suggest that in vivo release of serotonin initiates male vocalizations by activating 5-HT2C-like receptors in the brain stem vocal nuclei