Corticotropin releasing hormone receptor CRHR1 gene is associated with tianeptine antidepressant response in a large sample of outpatients from real-life settings.

Polymorphisms of genes involved in the hypothalamic-pituitary-adrenocortical (HPA) axis have been associated with response to several antidepressant treatments in patients suffering of depression. These pharmacogenetics findings have been reported from independent cohorts of patients mostly treated with selective serotonin reuptake inhibitors, tricyclic antidepressant, and mirtazapine. Tianeptine, an atypical antidepressant, recently identified as a mu opioid receptor agonist, which prevents and reverses the stress induced by glucocorticoids, has been investigated in this present pharmacogenetics study. More than 3200 Caucasian outpatients with a major depressive episode (MDE) from real-life settings were herein analyzed for clinical response to tianeptine, a treatment initiated from 79.5% of the subjects, during 6-8 weeks follow-up, assessing polymorphisms targeting four genes involved in the HPA axis (NR3C1, FKPB5, CRHR1, and AVPR1B). We found a significant association (p < 0.001) between CRHR1 gene variants rs878886 and rs16940665, or haplotype rs878886*C-rs16940665*T, and tianeptine antidepressant response and remission according to the hospital anxiety and depression scale. Analyses, including a structural equation model with simple mediation, suggest a moderate effect of sociodemographic characteristics and depressive disorder features on treatment response in individuals carrying the antidepressant responder allele rs8788861 (allele C). These findings suggest direct pharmacological consequences of CRHR1 polymorphisms in the antidepressant tianeptine response and remission, in MDE patients. This study replicates the association of the CRHR1 gene, involved in the HPA axis, with (1) a specificity attributed to treatment response, (2) a lower risk of chance finding, and in (3) an ecological situation.

A visual analog scale to measure psychological and physical pain: A preliminary validation of the PPP-VAS in two independent samples of depressed patients.

OBJECTIVE: Psychological pain lies at the heart of human experience. However, it may also be abnormally intense and/or prolonged in pathological states, with negative outcomes. A simple and reliable measure of psychological pain for clinical use would be useful. In this study, we present a preliminary validation of a simple visual analog scale jointly measuring psychological and physical pain. METHODS: Two samples of adult (non elderly) depressed patients and healthy controls were independently recruited in two locations in Canada and the USA (N = 46/48 and 200/20, respectively). Six dimensions were successively scored on a paper visual analog scale measuring current, mean and worst pain over the last 15 days, for physical then psychological pain. RESULTS: All physical and psychological pain dimensions discriminated depressed from non-depressed subjects. Among depressed patients, psychological pain scores were higher than physical pain scores for a given period of assessment. Moreover, correlations between dimensions from the same pain category (physical or psychological) were higher than between different pain categories. Psychological pain was mainly correlated with depression and hopelessness scales while physical pain was mainly correlated with anxiety scales. Secondary analyses showed that psychological (and some physical) pain measures were correlated with suicidal ideas in one location, but no difference in pain scores was found between patients with vs. without a history of suicidal acts in both samples. Childhood trauma positively correlated with several pain dimensions. CONCLUSION: The PPP-VAS appears to be a valid tool in terms of discriminative capacities and convergent-divergent validities. Validation in different samples, including adolescents and elderly, and in various psychiatric and medical conditions will have to be conducted, in addition to the assessment of concurrent and predictive validities, and the confirmation of sensitivity to change. The role of psychological pain in the suicidal process needs to be further elucidated.

The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial.

BACKGROUND: Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4-6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual. METHODS/DESIGN: The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient's antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depression measured using the Quick Inventory of Depressive Symptoms - Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed. DISCUSSION: This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02790970 . Registered on 30 March 2016.

Neurotrophin Genes and Antidepressant-Worsening Suicidal Ideation: A Prospective Case-Control Study.

BACKGROUND: Antidepressant-worsening suicidal ideation is a rare but serious phenomenon. This study aimed to test for association between antidepressant-worsening suicidal ideation and polymorphisms of BDNF/NTRK2 neurotrophin pathway genes, known to be involved in depression and suicide. METHODS: This was a case-control study comparing patients with antidepressant-worsening suicidal ideation to patients without. Patients were collected from the GENESE cohort (3771 depressed tianeptine-treated outpatients). Antidepressant-worsening suicidal ideation was defined by an increase of at least 2 points on the Montgomery-Åsberg Depression Rating Scale-item10 during treatment. Controls were matched for age, sex, and baseline Montgomery-Åsberg Depression Rating Scale-item10 score. Thirteen single nucleotide polymorphisms covering 5 BDNF/NTRK2 pathway genes were genotyped. RESULTS: A total 78 cases and 312 controls were included. Two NTRK2 single nucleotide polymorphisms were associated to antidepressant-worsening suicidal ideation: rs1439050 (P=.01) and rs1867283 (P=.04). Association with rs1439050 remained significant after adjustment for potentially confounding factors, including previous suicide attempts (P<.01). CONCLUSIONS: This naturalistic prospective study is consistent with previous studies on highlighting the potential role of the neurotrophin pathway, and especially of NTRK2, in antidepressant-worsening suicidal ideation.

Association between genetic variants of DVWA and osteoarthritis of the knee and hip: a comprehensive meta-analysis.

Recently, double von Willebrand factor domain A (DVWA) gene, a previously unknown gene, was revealed to contain several single nucleotide polymorphisms (SNPs) that showed consistent association with knee osteoarthritis (OA) in Japanese and Chinese cohorts. However, subsequent studies failed to confirm this result in several different populations. To deal with the issues raised by inconsistent results among those studies, we investigated the association between DVWA and OA using meta-analytic techniques, combining all published data up to December 2014. 10 independent samples from 4 teams contributed data for a possible association between SNP rs7639618 and knee or hip OA. The total number of cases and controls of this SNP was respectively 4,142 versus 6,575 for knee OA, and 2,325 versus 2,914 for hip OA. A trend of significant association was observed in the combined population with knee OA (P=0.06), and a significant difference was identified between patients with knee OA and controls for the G-allele of rs7639618 (P=0.02). Together with the reported functional studies, our results indicate that DVWA may have a small but strong effect on the susceptibility to knee OA, at least in Asian population. Further functional studies are needed to determine the underlying variation of DVWA and to relate this to the pathophysiology of OA.