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Abstract Background It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the “in vivo” measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. Methods/design This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2–3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50–70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. Discussion By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. Trial registration ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

Background: Major depressive disorder (MDD) is among the most common psychiatric disorders. One-third of patients are usually unresponsive to several lines of treatment. This study aimed to describe the FondaMental French cohort of patients with treatment-resistant depression (TRD) and to estimate utility and healthcare resource use outcomes. Methods: Patients with TRD were evaluated prospectively over four years (baseline, 6, 12, 18, 24, 36 and 48 months) in a real-world clinical setting. Interim analyses focused on the first two consecutive years. Four MDD-related states (major depressive episode (MDE), response, remission, recovery) were defined based on the MADRS (Montgomery–Åsberg depression rating scale) and other clinical events. Health status was assessed with the EuroQol 5 Dimensions 5 Level (EQ-5D-5L) questionnaire. Utility values were estimated as preference measures that the patients assigned to their overall health status. Results: This study was based on 252 patients with TRD. The mean utility value by health state was 0.41, 0.63, 0.80, and 0.90, for MDE, response, remission, and recovery, respectively. At baseline, 59% of patients had an MADRS score of at least 28. Their baseline average utility value was lower compared to the other patients (0.43 versus 0.58, p < 0.001). This significant difference persisted at the following visits. The rate of patients in MDEs having at least one hospitalisation for depression or other reasons than depression was generally higher than that in the other health states. Conclusion: This study documented patterns in healthcare resource consumption, quality of life, and other characteristics in patients with TRD, both globally and by health state and depression severity.

BackgroundMajor depression is characterized by (i) a high lifetime prevalence of 16–17% in the general population; (ii) a high frequency of treatment resistance in around 20–30% of cases; (iii) a recurrent or chronic course; (iv) a negative impact on the general functioning and quality of life; and (v) a high level of comorbidity with various psychiatric and non-psychiatric disorders, high occurrence of completed suicide, significant burden along with the personal, societal, and economic costs. In this context, there is an important need for the development of a network of expert centers for treatment-resistant depression (TRD), as performed under the leadership of the Fondation FondaMental.MethodsThe principal mission of this national network is to establish a genuine prevention, screening, and diagnosis policy for TRD to offer a systematic, comprehensive, longitudinal, and multidimensional evaluation of cases. A shared electronic medical file is used referring to a common exhaustive and standardized set of assessment tools exploring psychiatric, non-psychiatric, metabolic, biological, and cognitive dimensions of TRD. This is paralleled by a medico-economic evaluation to examine the global economic burden of the disease and related health-care resource utilization. In addition, an integrated biobank has been built by the collection of serum and DNA samples for the measurement of several biomarkers that could further be associated with the treatment resistance in the recruited depressed patients. A French observational long-term follow-up cohort study is currently in progress enabling the extensive assessment of resistant depressed patients. In those unresponsive cases, each expert center proposes relevant therapeutic options that are classically aligned to the international guidelines referring to recognized scientific societies.DiscussionThis approach is expected to improve the overall clinical assessments and to provide evidence-based information to those clinicians most closely involved in the management of TRD thereby facilitating treatment decisions and choice in everyday clinical practice. This could contribute to significantly improve the poor prognosis, the relapsing course, daily functioning and heavy burden of TRD. Moreover, the newly created French network of expert centers for TRD will be particularly helpful for a better characterization of sociodemographic, clinical, neuropsychological, and biological markers of treatment resistance required for the further development of personalized therapeutic strategies in TRD.