Altered brain processing of decision-making in healthy first-degree biological relatives of suicide completers.

Suicidal behavior is heritable, with the transmission of risk being related to the transmission of vulnerability traits. Previous studies suggest that risky decision-making may be an endophenotype of suicide. Here, we aimed at investigating brain processing of decision-making in relatives of suicide completers in order to shed light on heritable mechanisms of suicidal vulnerability. Seventeen healthy first-degree biological relatives of suicide completers with no personal history of suicidal behavior, 16 relatives of depressed patients without any personal or family history of suicidal behavior, and 19 healthy controls were recruited. Functional 3 T magnetic resonance imaging scans were acquired while participants underwent the Iowa Gambling Task, an economic decision-making test. Whole-brain analyses contrasting activations during risky vs safe choices were conducted with AFNI and FSL. Individuals with a family history of suicide in comparison to control groups showed altered contrasts in left medial orbitofrontal cortex, and right dorsomedial prefrontal cortex. This pattern was different from the neural basis of familial depression. Moreover, controls in comparison to relatives showed increased contrast in several regions including the post-central gyrus, posterior cingulate and parietal cortices, and cerebellum (culmen) in familial suicide; and inferior parietal, temporal, occipital, anteromedial and dorsolateral prefrontal cortices, and cerebellum (vermis) in familial depression. These findings most likely represent a complex combination of vulnerability and protective mechanisms in relatives. They also support a significant role for deficient risk processing, and ventral and dorsal prefrontal cortex functioning in the suicidal diathesis.

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.