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

Suicidalité sous antidépresseurs : aspects cliniques et étude cas-témoin pharmacogénétique

Antidepressant-worsening suicidal ideation (AWSI) is a rare but serious phenomenon. Multiple hypotheses have been suggested to explain AWSI: pharmacokinetic profile of antidepressants (AD), mixed states mistaken for unipolar depressive episodes, paradoxical action of benzodiazepines, and non or partial response to AD. The BDNF/NTRK2 neurotrophin pathway is involved in the pathophysiology of depression, suicide and in antidepressants mechanism of action. The aim of this study was to test for association between genetic polymorphisms of BDNF/NTRK2 pathway genes and (AWSI). This is a case-control study comparing patients with AWSI to patients without AWSI. Patients were collected from a cohort (3771 outpatients diagnosed for Major Depression and treated with tianeptine). AWSI was defined by an increase of at least 2 points on MADRS-item10 (item “suicidal thoughts”) during the treatment (N=78). 13 SNPs covering 5 BDNF/NTRK2 pathway genes were genotyped. 78 cases matched inclusion criteria and 312 controls matched for age, sex and suicidal thoughts at baseline were selected. 2 SNPs of the NTRK2 gene were significantly associated to the onset of AWSI: rs1439050 (p=0.01) and rs1867283 (p=0.04). The association remained significant for rs1439050 after adjustment for 4 potentially confounding factors: suicide attempt history (p<0.01), first episodes (p=0.02) benzodiazepines co-prescription (p=0.04) and alcohol abuse (p=0.02). This prospective study highlights the potential role of the neurotrophin pathway, and especially of NTRK2, in AWSI. It is also consistent with previous studies supporting the role of NTRK2 in suicidality.La recrudescence de la suicidalité sous antidépresseurs (RSAD) est un phénomène rare mais grave. Plusieurs hypothèses ont été évoquées pour le comprendre : le profil pharmacocinétique des antidépresseurs (AD), l’existence d’un trouble du spectre bipolaire passé, un effet paradoxal désinhibiteur des benzodiazépines, et enfin la mauvaise réponse au traitement AD. Cette étude pharmacogénétique cherche à mettre en évidence des facteurs génétiques de vulnérabilité à la RSAD, par l’étude de polymorphismes de gènes de la voie neurotrophique, qui a été impliquée dans la physiopathologie de la dépression, du suicide, et dans le mode d’action des antidépresseurs Il s’agit d’une étude cas-témoins comparant des patients issus de la cohorte GENESE (3771 patients traités par tianeptine pour un épisode dépressif majeur) avec ou sans RSAD. La RSAD était définie par une augmentation d’au moins 2 points du score de suicidalité sur l’item 10 de la MADRS. 13 SNPs de 5 gènes de la voie neurotrophique ont été génotypés. 78 cas et 312 témoins ont été inclus. Deux SNPs de NTRK2, étaient significativement associés à l’augmentation de la suicidalité sous antidépresseurs : rs1439050 (p=0,01) et rs1867283 (p=0,04). L’association restait statistiquement significative pour rs1439050 après ajustement sur des variables potentiellement contaminantes: antécédents de tentatives de suicides (p<0,01), premiers épisodes (p=0,02), coprescription de benzodiazépines (p=0,04), et abus d’alcool au cours de l’étude (p=0,02). Ce travail souligne le rôle de la voie neurotrophique et en particulier de NTRK2 dans la RSAD

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

International audienceBACKGROUND: 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

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

International audiencePolymorphisms 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

Additional file 1: of The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial

PReDiCT SPIRIT Checklist v0.2 6 Jan 2017. (DOCX 49 kb