Significant Need for a French Network of Expert Centers Enabling a Better Characterization and Management of Treatment-Resistant Depression (Fondation FondaMental)

Background Major 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. Methods The 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. Discussion This 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.

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.
discussion: This 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.
Keywords: treatment-resistant depression, depressive disorder, assessment, network, innovative strategies introduCtion Major depression is characterized by a high lifetime prevalence of 16-17% in the general population (1) with the possibility of evolution into a recurrent or chronic course (2) and a negative impact on the general functioning and quality of life (3). Major depression also has a high level of comorbidity with various psychiatric and non-psychiatric disorders (1,4), with a high occurrence of completed suicide (4), and significant burden associated with the heavy personal, societal, and economic costs (4). Treatment-resistant depression (TRD) has been estimated to represent half of the overall treatment costs for major depression (5,6). Although not clearly established in France, it can be assumed that approximately 20-30% of depressed patients experience TRD, as reported in Anglo-Saxon countries (7), and up to one half of patients responding only partially (8). TRD is currently defined by the failure of at least two attempts of antidepressant treatments administered sequentially at adequate dose and duration (8). Patients may be unresponsive to usual therapeutic strategies because of clinical features of the condition itself, factors interfering with the proper delivery of an optimal treatment such as under-dosing or poor adherence related to side effects, cognitions, comorbid disorders (psychiatric and nonpsychiatric), etc. (5,6,(8)(9)(10)(11)(12). Although controversial (13), one of the major issue relies on the misdiagnosis of TRD instead of BP-II because hypomanic symptoms are difficult to detect, especially on a retrospective basis (14). Indeed, as reported by Judd et al. (15), patients with BP-II were symptomatic more than half of all follow-up weeks while depressive symptoms were largely more preponderant during the course as compared with hypomanic and cycling/mixed symptoms. Unrecognized bipolar spectrum illness increases substantially the risk for the inappropriate prescription of antidepressant treatment known to be associated with the occurrence of short-term resistance, poor tolerance, cycle acceleration, manic switch as well as late response loss after several months of recovery (13,14,16,17). Thus, an inaccurate diagnosis almost always means a significant delay in appropriate and effective treatment based on mood stabilizers for bipolar patients. However, in this study, the adopted procedure tends to minimize hidden bipolar disorders behind TRD cases by using the structured Mini International Neuropsychiatric Interview (MINI) for the diagnostic evaluations coupled with the Mood Disorder Questionnaire (MDQ) useful for screening signs and symptoms of bipolar spectrum disorders. Also, there is a heterogeneous etiology of TRD, including different environmental risk factors like childhood adversities coupled with multiple genetic determinants related to numerous genetic loci, and various epigenetic contributors involving a wide range of biological systems including the hypothalamic-pituitary-adrenal axis, immune function, monoamines, neurotrophic factors, etc. (5,6,8,9,18). These factors can significantly modulate the therapeutic response while remission remains the aim of treatment for depression, given its implications for recovery of daily functioning and better long-term prognosis (7,(19)(20)(21)(22). The absence of appropriate treatment increases the burden of depression and the resulting costs. This burden manifests itself in many ways including residual symptoms, cognitive impairment, relapse and recurrence, decreased quality of life, suicide, cardio-and cerebrovascular morbimortality, psychosocial alteration, work days lost, family impact, and economic costs (4,23). Taken together, all these considerations underlie the particular relevance for the determination of contributing factors by a large and exhaustive assessment of patients suffering from TRD.
Many recommendations for clinical practice have been developed by various psychiatric societies around the world (24)(25)(26)(27)(28). These recommendations are primarily based on the analysis and classification of the scientific literature. They consider randomized, controlled and double-blind studies on large samples as offering the highest level of evidence. In spite of their rigor from a methodological and scientific point of view, the adaptability of these recommendations in everyday clinical practice can raise questions (29). High-level evidence studies, in fact, refer to selected samples of subjects, often free from comorbidities. They exclude characteristics such as advanced age, increased suicidal risk or high level of pharmacological resistance. These clinical situations are, however, frequently observed in daily clinical practice in the patient population suffering from TRD (12,30).
In France, the need for improving the diagnosis, assessment, and management of psychiatric pathologies has led both the Ministry of Research and the Ministry of Health to support jointly the development of a national network of expert centers for Bipolar disorder (31), schizophrenia, TRD, and autism under the leadership of the foundation of scientific cooperation named "FondaMental" created in 2007. This article describes a new model of clinical collaboration between the expert centers and the regional community of clinicians, especially those general practitioners and psychiatrists who provide the first point of contact with health services for most TRD patients. Thus, within this network, we propose a systematic, comprehensive, longitudinal, and multidimensional assessment for patients who have failed to achieve remission after at least two adequate trials using different classes of antidepressants. The psychiatric, non-psychiatric, socioenvironmental, metabolic, biological, and cognitive dimensions of the current depressive episode are explored. A personalized evaluation and care program is delivered by a clinical expert highly specialized in the field of TRD. It also intends to narrow the gap between research knowledge and clinical practice. This represents an additional and locally accessible approach to the patients and their referent physician. The objective of this article is to disseminate information about this highly relevant project and to describe the standardized evaluation as proposed within the French network of centers specifically dedicated to TRD.

Mission of the national Expert Centers for trd
The principal mission of this national network is to establish a genuine prevention, screening, and diagnosis policy for TRD: • Care: setting up a national and European network of expert centers-pluridisciplinary diagnosis and screening platforms-making it possible to follow patient cohorts with the contribution of an individual computerized medical file system common to all centers (e-Resistant Depression). This should allow access to personalized medicine primarily based on the elaboration of a strategy of care consistent with available data of the Evidence-Based Medicine and the monitoring of clinical outcomes via repeated assessments over time. • Research: bringing together a national network of public and private researchers, linked to fundamental research platforms (mainly referring to biochemistry, molecular biology, genetic, and brain imaging), an approach that has already led to major discoveries. One of the aims is to improve staging and evaluation of innovative therapeutic options according to new scientific hypotheses, such as the inflammation theory of major depression and treatment failure (32). • Training health-care professionals and raising awareness in the workplace: disseminating knowledge about the risk fac tors for mental illnesses and about novel treatment strategies. • Communication: changing the way in which psychiatric diseases are generally perceived by the general population, and by opinion leaders, to substantially decrease stigmatization. This operating care system offers a systematic, comprehensive, longitudinal, and multidimensional evaluation of cases of TRD by sharing a common set of assessment tools exploring separately psychiatric, non-psychiatric, metabolic, biological, genetic and cognitive dimensions of major depression. This is paralleled by a medico-economic evaluation for examining the global economic burden of the disease and related health-care resource utilization. For this purpose, the shared e-resistant depression medical file (e-Resistant Depression) and database (FACE-DR) were developed by the Fondation FondaMental to collect and store all these data. In addition, an integrated biobank intimately connected to FACE-DR is now being established with the primary goal of the collection of serum, plasma, DNA, RNA samples for the measurement of several biomarkers that could further be associated with treatment resistance in depressed patients (Figure 1).

network of Centers
The French network of expert centers for resistant depression consists of 13 specialized care centers hosted within academic departments of Psychiatry widely distributed across France (Paris/Créteil, Paris Fernand-Widal, Besançon, Bordeaux, Brest, Clermont-Ferrand, Grenoble, Marseille, Montpellier, Lille, Lyon, Toulouse, and Tours). A multidisciplinary team of clinical representatives from FondaMental formed a working group to select the appropriate instruments for the clinical and biological assessments. These teams are composed of, at least, a psychiatrist, a nurse, a neuropsychologist and a secretary within each center. Valid and reliable observer-and self-rating scales were prioritized, and all those involved in patient assessments received intensive training in the use of the measures they employ.

Cohort of Patients
A general practitioner or psychiatrist, who afterward will receive a detailed evaluation report along with some suggestions for clinical issues and therapeutic interventions, refers patients to be assessed in expert centers. Patients are clinically unresponsive to two successive and adequate sequences of antidepressants from two different pharmacological classes corresponding to at least stage II of the staging criteria proposed by Thase for defining TRD (33). Before participating in the full assessment, patients are interviewed by a psychiatrist at the expert center to: -Confirm the diagnosis of TRD according to the DSM-IV (34) criteria with moderate to severe symptoms (MADRS ≥ 20), the level of resistance indicated by the classification of Thase and Rush (33) (≥2), and assess the need to perform the full evaluation. -Exclude bipolar disorders, psychotic disorders, OCD, eating disorders (with BMI < 15), somatoform disorders, and mood disorders related to substance abuse or misuse. -Inform the patient about the formal assessment procedure and schedule the appointments with different health professionals within the expert centers comprising at least a psychiatrist, a nurse, and a neuropsychologist. Patients with TRD are then invited to participate and complete the assessment protocol over a period of two consecutive days.

data Collection
An electronic health-care record system for a common national database was implemented through the development of a webbased application, e-resistant depression© designed to collate all assessment data for clinical monitoring, research, and treatment purposes. Access to the system is carefully regulated and approval was obtained from the ethical committee and the committee in charge of the safety of computerized databases (French CNIL: DR-2015-673). To optimize data entry and retrieval, free text input has been minimized, and drops down lists and other approaches leading to standardized inputs chosen when possible. The XML format is used to transfer data from e-resistant-depression© into an anonymous national database.

assessment Procedure
Patients benefit at inclusion from an exhaustive clinical assessment (e-Resistant Depression) followed by systematic evaluations during four consecutive years, which are designed to identify: (i) clinical characteristics of resistance with psychological, non-psychiatric and metabolic data, (ii) socioenvironmental factors including daily routines, sport exercise, diet and stress-related factors such as early life traumatic experiences conferring high sensitivity to subsequent negative events over the lifespan which is expected to further influence the course of major depression and therapeutic response, and (iii) economic impact assessed by several indicators including number and duration of hospitalizations, number of visits to psychiatrists, general practitioners, pharmacological and nonpharmacological treatment consumption, work productivity, and health-related quality of life. For this purpose, all centers have adopted the same package of evaluations and the different members of the center perform the full assessment. Table 1 provides a list of the self-and

Feedback to the Clinicians
One of the major roles of the expert centers is to provide feedback to the clinicians regarding the proposals for care. These reports cover both diagnosis, clinical and treatment issues. As the evaluation is carried out by several different experts, the document sent to the clinicians is structured as the report of a multidisciplinary clinical meeting. In addition, the network intends to propose formalized recommendations on TRD for clinicians through joined sponsorship with the French Association of Biological Psychiatry and Neuropsychopharmacology.

Biobanking
A biobank was gradually developed and implemented within the network of the expert centers for resistant depression. After collecting signed written informed consent, each included patient is sampled at the beginning of the first visit within the Center of Clinical Investigation working locally in close collaboration with each of the expert centers. Samples are then transferred and stored at the Mondor CRB (Créteil) for further research projects developed within the network.
Building this biobank should enable the identification of new biomarkers and precise mechanisms of resistance with the identification of immunological, neuroendocrine, biochemical, genetic, epigenetic and cellular mechanisms regulating the signaling pathways that are supposed to be impaired in resistant depression. For this purpose, the biobank is composed of serum, plasma, DNA, RNA, etc. to be able to measure several biomarkers associated with the immune (pro-inflammatory cytokines and enzymatic pathways), neuroendocrine (pituitary-adrenal and thyroid axes), and monoaminergic systems (serotonin, norepinephrine, dopamine), or implicated in neurogenesis, neuroprotection (e.g., BDNF), and in genetic/epigenetic mechanisms.

longitudinal Follow-up
Each patient enrolled into the cohort is evaluated every six months over the next 4 years (Figure 2). Table 2 summarizes the evaluation tools used at each visit. The objective of these followup visits is to evaluate the course of depressive symptoms and related clinical dimensions such as clinical remission, residual symptoms, relapses, recurrences, etc.
At the end of each visit, a report is sent to the doctor who referred the patient to the center. As described earlier, the results of the main evaluations are provided in these reports, and a clear diagnosis is given as well as a relevant proposal for therapeutic management. Therefore, from the overall clinical and paraclinical analysis Plan Data will be analyzed using SPSS version 22 (Armonk, NY, USA: IBM Corp.). As described elsewhere (7,12,64), means and SDs will be presented for continuous variables, and counts and percentages for discrete variables. Parametric analysis-ofvariance methods will be used for the repeated comparisons of the overall symptom severity (i.e., MADRS, QIDS-SR-16 scores) over the 4-year follow-up period. Post hoc tests will be conducted to make pairwise comparisons. Chi-square tests will be applied for the comparisons of sociodemographic characteristics, and percentages of depressed patients showing satisfactory response (i.e., ≥50% decrease in MADRS or QIDS-SR-16 score from baseline), achieving remission (i.e., MADRS score ≤10 or QIDS-SR-16 score ≤5) or experiencing relapse (i.e., MADRS score ≥15 or QIDS-SR-16 score ≥11) across experimental visits. For the calculation of sample size, we formulate the hypothesis that the depressed patients in our sample will be considered as remitters in at least 35% of cases at mid-term after the proposed treatment strategies referring to standard international guidelines, thereby enabling to obtain the remission rate observed following a first-line antidepressant therapy in the earlier collaborative study STAR*D (7). This therefore contrasts with the remission rate of less than 15% which was reported after failure of more than two previous antidepressant treatments in this pivotal STAR*D trial (7). On this basis, the required number of subjects is calculated for a two-sided test with a risk α of 5% and a power 1-β of 95% leading to the inclusion of a total of 130 resistant depressed subjects in our cohort to allow the demonstration of a difference at least equal to 20% in the remission rate as compared with that found in the STAR* study. We will recruit 130 additional subjects in our cohort to take into account and cover any protocol deviations, dropouts, or missing data, etc.

dissemination Plan
The significant findings will be disseminated through following three distinct and complementary strategies: (1) publications in international scientific journals, (2) communications in congress, and (3) symposia and conference for health care providers under supervision of the principle investigators within each university hospital affiliated to our national network. Other specific actions will be developed enabling the targeted diffusion of the most relevant results and including multidisciplinary brainstorming sessions in the setting of a regional coordination of care for difficult-to-treat depressed patients, teaching activity for medical students and residents in psychiatry, continuing medical education for mental health professionals (general practitioners, psychiatrists, psychologists, nurses, etc.), and educational training during summer schools for master and Ph.D. students, postdoctoral fellows, especially. Finally, more general informative meetings will be regularly conducted by the expert centers, designed for the affected patients with their caregivers and commonly focused on the presentation of major clinical, therapeutic, and functional issues related to resistant depression.

diSCuSSion
By offering a systematic, complete, longitudinal, and multidimensional evaluation of each TRD case, using shared medical records containing common assessment tools exploring separately the psychiatric, non-psychiatric dimensions, metabolic functions, biological, and cognitive impairments, we aim at making accessible to all patients with a diagnosis of TRD, the most personalized and adapted treatment strategies possible. Indeed, it seems important to be able to apply the therapeutic guidelines to improve the prognosis of TRD. Guo et al. (65) showed an improvement in the management using measurement-based care for outpatients with moderate to severe major depression. Indeed, the responses as well as remission rates are higher, and adjustment of therapeutic doses of antidepressant is more straightforward in the measurement-based care group. interleaved systematically with frequent rest periods to prevent sufficiently a gradual decline in concentration and excessive fatigability. Phone reminders are even scheduled at least one week before each visit to limit dropouts. As supported in the study by Rush (66), measurement-based care also offers the advantage of better preparing and engaging the patients in shared decision making and adherence to long-term care needs, thereby familiarizing themselves with relevant tools currently used for monitoring their clinical symptoms and side effects caused by standard treatments. Moreover, diagnostic and clinical heterogeneity appears to be a major obstacle for an exact understanding of the pathophysiology of mental illnesses and, in particular, major depression. Although there is a widely demonstrated hereditary component (67) the identification of genetic risk factors has proven difficult even in meta-analyses of genome-wide association studies (68).
Similarly, efforts to develop new treatments have stagnated, partly due to a lack of new biological targets and the choice of the people most likely to benefit from them (69). All these challenges have been attributed in part to the fact that our diagnostic system assigns a unique label to a syndrome that is not unitary but could be caused by distinct pathological processes, which would require different treatments. Indeed, major depression is a widespread disease presumably represented by a large number of patient subgroups that must be identified precisely to propose adapted therapeutic strategies.
Our national network must be part of the existing regional health care system. Although adherence to treatment guidelines has been shown to improve clinical outcomes (65), there are barriers to their application, including the fact that guidelines are often viewed as "top-down" measures. One aim of the network is to make available the standard recommendations derived from the currently used guidelines for each patient. It should bridge the gap between evidence-based medicine and routine practice.
In addition, clinical research is an important issue within the network. The electronic health-care record system for each expert center is connected to a national database and data on this large clinically representative cohort of TRD cases will allow prospective follow-up and comparative-effectiveness studies. Combination of clinical, biological, genetic, and epigenetic data could contribute to a more precise definition of separate clusters of major depression for a more specific and tailored management of this pathology. To refine the diagnostic and therapeutic approach, by focusing on more precise clusters, the main lines of future research are focused on: (i) the role of comorbidities, beyond what are now defined as risk factors for resistance [cardiovascular, neurological, metabolic pathologies, etc. (70)(71)(72)]; (ii) the role and impact of traumatic factors; (iii) the presence of suicidal ideation or behaviors; (iv) the functional repercussions; (v) resistance to treatments; (vi) neurocognitive profiles; (vii) genetic, epigenetic, immuno-inflammatory, neuroendocrine, and neurochemical markers, etc. In this context, patients benefiting from the evaluation within the expert centers, are asked to participate in various national and European research studies implemented in partnership with the "Fondation FondaMental" addressing jointly clinical, pathophysiological, and therapeutic issues (73).

ConCluSion
The adopted integrative approach shared within the network of expert centers for resistant depression is a compelling model for the precise characterization of sociodemographic, clinical, neuropsychological, biological, and metabolic factors of treatment resistance and to further develop innovative and personalized strategies through the multi-faceted questions of assessment, management, and treatment of major depression. This is one of the best options for changing the poor prognosis of TRD, reducing the deleterious impact on daily functioning and quality of life and thereby lowering the serious societal and economic burden related to high direct and indirect costs of TRD.

EtHiCS StatEMEnt
Ethics approval and consent to participate: the database (clinical data and biobanking) was validated by an ethics committee: CNIL (French CNIL: DR-2015-673). Consent for publication: all patients in the expert centers receive oral and written information on the possible use of their data for research purposes. Availability of data and material: all the material used for the assessment is validated in French.
autHor ContriButionS AY, DB, EH, WE-H, and BA realized the initial frame of the manuscript. The authors have made corrections after proofreading. All the authors participated in the recruitment of patients.

aCKnoWlEdgMEntS
The authors would like to thank Fondation FondaMental.

Funding
FondaMental Network is supported by AstraZeneca, Janssen, Lilly, Lundbeck, Otsuka, Sanofi, Servier, and Takeda. Through a scientific partnership, Fondation FondaMental and AstraZeneca join forces to fill the gap in clinical data on resistant depressive disorders Jansenn has been supporting the social missions of the "Fondation FondaMental" since 2008. Lilly France supports young researchers. Lundbeck is committed to supporting the "Fondation FondaMental" in disseminating knowledge through the support of the annual conference cycle. Otsuka Pharmaceutical France supports the Fondation FondaMental Foundation's knowledge dissemination mission. Servier has been providing institutional support since 2008 to the "Fondation FondaMental's" actions. Takeda supports the research mission of "Fondation FondaMental. "