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Background: At the beginning of COVID-19 pandemic, specific COVID/PSY wards were created in France to provide care for inpatients with COVID-19 and psychiatric disorders. In this multi-center prospective study, we set out to assess the clinical features and risk factors of somatic aggravation in patients hospitalized in COVID/PSY wards. Methods: Data were collected between 28 February and 30 May, 2020. We collected demographic data, psychiatric diagnoses, medical data and COVID-19-related clinical data. Somatic aggravation was estimated by the number of patients transferred to intensive care or medicine units, the number of deaths and the number of patients presenting a confusional state. A multivariate logistic model was used to assess the risk factors of confusional state and transfer to intensive care or medicine units. The risk of death was analysed by the univariate predictors of this outcome. Outcomes: 350 patients were included in the study. The number of inclusions peaked one week after that of the general population and declined more slowly. Overall, 24 (7%) were transferred to medicine units, 7 (2%) died and 51 (15%) patients presented a confusional state. Severe respiratory symptoms predicted the transfer to a medicine unit (OR 17.1; CI 4.9-59.3). Older age, an organic mental disorder, a confusional state, and severe respiratory symptoms predicted mortality in univariate analysis. Age > 55 (OR 4.9; CI 2.1-11.4), an affective disorder (OR 4.1; CI 1.6-10.9), and severe respiratory symptoms (OR 4.6; CI 2.2-9.7) predicted a higher risk, while smoking (OR 0.3; CI 0.1-0.9) predicted a lower risk of a confusional state. Interpretation: COVID-19 patients with severe psychiatric disorders have multiple somatic comorbidities and a high risk of confusion. COVID/PSY wards may play a role in reducing the mortality of COVID-19 in patients with psychiatric disorders. Funding Statement: There was no funding source for this study. Declaration of Interests: There are no conflicts of interest to be declared. Ethics Approval Statement: This observational study was conducted according to the principles of the Declaration of Helsinki. In accordance with French bioethics laws, it was classified as a non- interventional study, since it concerned anonymized clinical data that are routinely compiled in medical records. Compliance with French regulations on personal data collection was supervised by the personal data referent of the Centre Psychotherapique de Nancy. Patients, and their legal guardian when appropriate, were informed in writing, in agreement with national regulations for observational studies.

International audience; Importance: Breast cancer (BC) diagnosis and treatment expose patients to a 5-fold higher risk of depression compared with the general population, with an estimated prevalence of 10% to 25%. A depressive episode in patients with BC has implications for the tolerance of and adherence to treatment, impairing quality of life and reducing life expectancy.Objective: To identify and characterize distinct longitudinal patterns of depressive symptoms in patients with BC from diagnosis to 3 years after treatment.Design, settings, and participants: The CANTO-DEePRESS (Deeper in the Understanding and Prevention of Depression in Breast Cancer Patients) cohort study included women in the French multicenter CANTO (CANcer TOxicities) cohort study (conducted between March 20, 2012 and December 11, 2018), who were 18 years or older with invasive stage I to III BC and no previous BC treatment. The study aimed to characterize toxicities over a 5-year period following stage I to III primary BC treatment. Assessments of depressive symptoms were performed on a subset of patients with available data at diagnosis and at least 2 other time points. All data were extracted from the CANTO database on October 1, 2020.Main outcomes and measures: The primary outcome was the level of depressive symptoms at each assessment time point measured with the Hospital Anxiety and Depression Scale and depression subscale at BC diagnosis and at 3 to 6, 12, and 36 months after the end of treatment. The group-based trajectory modeling was used to identify trajectory groups, and multinomial logistic regression models were used to characterize the following factors associated with trajectory group affiliation: demographic, socioeconomic, clinical, lifestyle, and quality-of-life data.Results: A total of 4803 women (mean [SD] age, 56.2 [11.2] years; 2441 patients [50.8%] with stage I BC) were included in the study. Six trajectory groups that described the heterogeneity in the expression of depressive symptoms were identified: noncases with no expression of symptoms (n = 2634 [54.8%]), intermediate worsening (1076 [22.4%]), intermediate improvement (480 [10.0%]), remission (261 [5.4%]), delayed occurrence (200 [4.2%]), and stable depression (152 [3.2%]). HADS-D scores at diagnosis were consistently associated with the 5 depressive trajectory group affiliations, with an estimated higher probability per point increase of experiencing subthreshold or clinically significant depressive symptoms between diagnosis and the 3 years after the end of BC treatment. The higher probabilities ranged from 1.49 (95% CI, 1.43-1.54) for the intermediate worsening group to 10.53 (95% CI, 8.84-12.55) for the stable depression group. Trajectory groups with depressive symptoms differed from the noncases group without symptoms by demographic and clinical factors, such as having dependent children, lower household income, cancer stage, family history of BC, previous psychiatric hospitalizations, obesity, smoking status, higher levels of fatigue, and depression at diagnosis.Conclusions and relevance: In this cohort study, nearly a third of patients with BC experienced temporary or lasting significant depressive symptoms during and after treatment. Improving early identification of women at risk of developing long-term or delayed depression is therefore critical to increase quality of life and overall survival. Subjected to validation, this study is an important first step toward personalized care of patients with BC at risk of depression.

Bradycardia is one of the common cardiac abnormalities in patients with eating disorders. It ensues from hypometabolism, which results from reduced caloric intake and consequential weight loss. Hypothermia is another consequence of hypometabolism. While at-rest metabolism and body mass index (BMI) are typically used to assess hypometabolism and estimate potential bradycardia, we hypothesised that body temperature, which is easy to measure, could also capture the presence of this threatening cardiovascular condition. We monitored heart rate continuously for 72 h, measured resting energy expenditure (REE) and assessed body temperature in 12 body parts for 58 patients with anorexia nervosa (AN) and 29 patients with bulimia nervosa (BN). Palm temperature reflects bradycardia in both AN and BN, explaining 18% of its variance (p

ObjectiveTo confirm the rapid onset anti-suicidal benefits of ketamine in the short term and at six weeks, overall and according to diagnostic group.DesignProspective, double blind, superiority, randomised placebo controlled trial.SettingSeven French teaching hospitals between 13 April 2015 and 12 March 2019.Eligibility criteria for participantsAged 18 or older with current suicidal ideation, admitted to hospital voluntarily. Exclusion criteria included a history of schizophrenia or other psychotic disorders, substance dependence, and contraindications for ketamine.Participants156 participants were recruited and randomised to placebo (n=83) or ketamine (n=73), stratified by centre and diagnosis: bipolar, depressive, or other disorders.InterventionTwo 40 minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) were administered at baseline and 24 hours, in addition to usual treatment.Main outcome measuresThe primary outcome was the rate of patients in full suicidal remission at day 3, according to the scale for suicidal ideation total score ≤3. Analyses were conducted on an intention-to-treat basis.ResultsMore participants receiving ketamine reached full remission of suicidal ideas at day 3 than those receiving placebo: 46 (63.0%) of 83 participants in the ketamine arm and 25 (31.6%) of 73 in the placebo arm (odds ratio 3.7 (95% confidence interval 1.9 to 7.3), Pv56.3%; odds ratio 0.8 (95% confidence interval 0.3 to 2.5), P=0.7).ConclusionsThe findings indicate that ketamine is rapid, safe in the short term, and has persistent benefits for acute care in suicidal patients. Comorbid mental disorders appear to be important moderators. An analgesic effect on mental pain might explain the anti-suicidal effects of ketamine.Trial registrationClinicalTrials.govNCT02299440.

International audience; Background: Growing evidences suggest that depression with suicidal ideation (SI) could be a specific phenotype with its own characteristics. Moreover, opioid system deregulation might be implicated in suicidal behaviour (SB). The aim of this study was to determine whether the A118G polymorphism (rs1799971) in ORPM1 (the gene encoding opioid receptor mu 1) is associated with suicidal depression (ie, moderate to severe depression with SI) in a large cohort of outpatients with depression.Methods: GENESE is a large, prospective, naturalistic cohort of French adult outpatients with depression (DSM-IV criteria), treated and followed for 6 weeks. Depression severity was assessed with the Hospital Anxiety and Depression Scale (HADS), and SI with the suicidal item of the Montgomery-Åsberg Depression Rating Scale (MADRS-SI). From this cohort, patients with moderate or severe depression (HADS-D subscale score >11) were selected and classified as without SI (MADRS-SI < 2), or with SI (MADRS-SI ≥ 2).Results: The AA/AG genotypes of the A118G polymorphism were significantly associated with suicidal depression in the non-adjusted (OR = 2.32, 95% CI = [1.28; 4.18]; p-value = 0.005) and in the adjusted models (OR = 2.54, 95% CI = [1.35; 4.78]; p-value = 0.004).Conclusion: Outpatients with depression harbouring the A allele are at higher risk of SI (and possibly SB) than those carrying the G allele. More studies are needed to better understand the link between this polymorphism and SB.

International audience; Objective: Poor cognitive flexibility has been highlighted in patients with anorexia nervosa (AN), contributing to the development and maintenance of symptoms. The aim of the present study is to investigate how enhanced cognitive flexibility is involved in treatment outcomes in patients with AN.Method: One hundred thirty female out-patients treated for AN have been assessed at baseline and after 4 months of treatment. Path analyses were used to investigate the mediating role of cognitive flexibility, measured through the Brixton test, on a wide range of outcomes: body mass index, eating disorder symptoms, daily life functioning, anxiety, depression, emotions, self-rated silhouette.Results: Cognitive flexibility was improved during treatment, and enhanced cognitive flexibility explains a significant part of level of the improvement in daily life functioning (26%), reduction of eating disorder symptoms (18%) and reduction of depressive symptoms (17%). Others outcomes were also improved, but these improvements were not mediated by cognitive flexibility.Conclusions: Results suggest that enhancing cognitive flexibility could help reduce rigid cognitive and behavioural patterns involved in AN, thus improving everyday functioning and clinical severity. Further studies combining different types of cognitive flexibility evaluation as well as neuroimaging may be necessary to better establish which of its aspects are involved in patients' improvement.

Depressed patients often do not respond to the first antidepressant prescribed, resulting in sequential trials of different medications. Personalised medicine offers a means of reducing this delay; however, the clinical effectiveness of personalised approaches to antidepressant treatment has not previously been tested. We assessed the clinical effectiveness of using a predictive algorithm, based on behavioural tests of affective cognition and subjective symptoms, to guide antidepressant treatment. We conducted a multicentre, open-label, randomised controlled trial in 913 medication-free depressed patients. Patients were randomly assigned to have their antidepressant treatment guided by a predictive algorithm or treatment as usual (TaU). The primary outcome was the response of depression symptoms, defined as a 50% or greater reduction in baseline score of the QIDS-SR-16 scale, at week 8. Additional prespecified outcomes included symptoms of anxiety at week 8, and symptoms of depression and functional outcome at weeks 8, 24 and 48. The response rate of depressive symptoms at week 8 in the PReDicT (55.9%) and TaU (51.8%) arms did not differ significantly (odds ratio: 1.18 (95% CI: 0.89-1.56), P = 0.25). However, there was a significantly greater reduction of anxiety in week 8 and a greater improvement in functional outcome at week 24 in the PReDicT arm. Use of the PReDicT test did not increase the rate of response to antidepressant treatment estimated by depressive symptoms but did improve symptoms of anxiety at week 8 and functional outcome at week 24. Our findings indicate that personalisation of antidepressant treatment may improve outcomes in depressed patients. This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 696802.

Quantifying changes in DNA and RNA levels is an essential component of any molecular biology toolkit. Quantitative real time PCR (qPCR) techniques, in both clinical and basic research labs, have evolved to become both routine and standardized. However, the analysis of qPCR data includes many steps that are time consuming and cumbersome, which can lead to mistakes and misinterpretation of data. To address this bottleneck, we have developed an open source software, written in Python, to automate the processing of csv output files from any qPCR machine, using standard calculations that are usually performed manually. Auto-qPCR is a tool that saves time when computing this type of data, helping to ensure standardization of qPCR experiment analyses. Unlike other software packages that process qPCR data, our web-based app (http://auto-q-pcr.com/) is easy to use and does not require programming knowledge or software installation. Additionally, we provide examples of four different data processing modes within one program: (1) cDNA quantification to identify genomic deletion or duplication events, (2) assessment of gene expression levels using an absolute model, (3) relative quantification, and (4) relative quantification with a reference sample. Auto-qPCR also includes options for statistical analysis of the data. Using this software, we performed analysis of differential gene expression following an initial data processing and provide graphs of the findings prepared through the Auto-qPCR program. Thus, our open access Auto-qPCR software saves the time of manual data analysis and provides a more systematic workflow, minimizing the risk of errors when done manually. Our program constitutes a new tool that can be incorporated into bioinformatic and molecular biology pipelines in clinical and research labs.

International audience; 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.

International audience; Background: The literature suggests that cognitive reactivity in bipolar patients can increase relapse vulnerability, is enhanced by depressive mood and dysfunctional attitudes, and could be improved with MBCT. Autobiographical memory (AM) could be involved in cognitive reactivity, and improved with MBCT training. This study aims to investigate the effect of MBCT for bipolar patients on depressive and anxious symptoms, dysfunctional attitudes and AM, and the predictive versus mediating role of AM in the impact of MBCT on clinical symptoms. Methods: Sixty-two outpatients diagnosed with bipolar I disorder were assigned to MBCT and were compared to 37 bipolar patients on a waiting list. Affective symptoms and dysfunctional attitudes were explored using self-report inventories (BDI, BAI, DAS) and AM was assessed using the Autobiographical Memory Test. Results: Patients receiving MBCT demonstrated significantly decreased depressive symptoms, dysfunctional attitudes, overgeneral memories and omissions, and increased specific memories. General AM and omissions at baseline respectively predicted lower anxiety and dysfunctional attitudes improvement following therapy, but the improvement of AM did not explain the impact of MBCT on depression and dysfunctional attitudes improvement. Limits: Further studies should consider patients' therapeutic adherence and mechanisms involved in MBCT in order to better apprehend how MBCT may reduce dysfunctional attitudes and improve AM in bipolar patients. Conclusion: Results are consistent with the hypothesis that MBCT reduces cognitive reactivity and AM impairment in bipolar disorders. Findings suggest that AM training prior to MBCT may influence MBCT efficacy, but that MBCT efficacy on AM and clinical symptoms are non-related phenomena.

As a polygenic psychiatric disorder, the genetics of anorexia nervosa (AN) remains largely unexplored. Recently a large GWAS meta-analysis identified a significant SNP (rs6589488) as associated with AN. We suggested that rs6589488 might have gotten its association as being in linkage disequilibrium with unknown variants or functional intronic variants. In a selective cohort containing 51 patients diagnosed with restrictive subtype AN, we screened the whole coding region of the CADM1gene by Sanger sequencing and further investigated if these variants are associated with specific outcome. Only 13 single nucleotide polymorphisms, including 2 missense variants, 2 synonymous variants, 2 variants located at 5′-UTR and 7 intronic variants, including rs6589488, were identified in our AN cohort. The 2 missense variants, p.Val5Leu and p.Asp285Glu were not predicted to be deleterious. In conclusion, the intronic initial variant appears to be not associated with causative coding variant in the vicinity. If CADM1 is not the AN predisposition factor, the causative variant probably lies within 1 Mb of CADM1. Interestingly, among the 7 closest genes to CADM1, the nicotinamide N-methyltransferase (NNMT) gene is known to be associated with obesity. We suggest that the intronic variant in CADM1 could be in linkage disequilibrium with other causative variants located in NNMT.

The unpredictability and uncertainty of the COVID-19 pandemic; the associated lockdowns, physical distancing, and other containment strategies; and the resulting economic breakdown could increase the risk of mental health problems and exacerbate health inequalities. Preliminary findings suggest adverse mental health effects in previously healthy people and especially in people with pre-existing mental health disorders. Despite the heterogeneity of worldwide health systems, efforts have been made to adapt the delivery of mental health care to the demands of COVID-19. Mental health concerns have been addressed via the public mental health response and by adapting mental health services, mostly focusing on infection control, modifying access to diagnosis and treatment, ensuring continuity of care for mental health service users, and paying attention to new cases of mental ill health and populations at high risk of mental health problems. Sustainable adaptations of delivery systems for mental health care should be developed by experts, clinicians, and service users, and should be specifically designed to mitigate disparities in health-care provision. Thorough and continuous assessment of health and service-use outcomes in mental health clinical practice will be crucial for defining which practices should be further developed and which discontinued. For this Position Paper, an international group of clinicians, mental health experts, and users of mental health services has come together to reflect on the challenges for mental health that COVID-19 poses. The interconnectedness of the world made society vulnerable to this infection, but it also provides the infrastructure to address previous system failings by disseminating good practices that can result in sustained, efficient, and equitable delivery of mental health-care delivery. Thus, the COVID-19 pandemic could be an opportunity to improve mental health services. CM and CA are co-financed by the European Regional Development Fund; have received support from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI17/02227, and PI19/024), the European Commission; CIBERSAM, the Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), Fundación Familia Alonso, Fundación Alicia Koplowitz, and Fundación Mutua Madrileña; and have received European Union Structural Funds via the European Union Seventh Framework (FP7-4-HEALTH-2009-2.2.1-2-241909, FP7-HEALTH-2013-2.2.1-2-603196, and FP7-HEALTH-2013-2.2.1-2-602478) and the European Union H2020 programme under the Innovative Medicines Initiative 2 Joint Undertaking (115916 and 777394). TW acknowledges support from the National Institute for Health Research Maudsley Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King’s College London (IS-BRC-1215-20018) and the National Institute for Health Research Senior Investigator Award (NF-SI-0514-10028). MRP acknowledges support from the National Natural Science Foundation of China (81371502 and 81761128031). EV acknowledges the support of the Spanish Ministry of Science and Innovation (PI15/00283 and PI18/00805), funding that was integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional; the Instituto de Salud Carlos III; CIBERSAM; the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2017 SGR 1365); the CERCA Programme; and the Departament de Salut de la Generalitat de Catalunya (PERIS grant SLT006/17/00357). MC is supported by a European Research Council Consolidator Award (iHear 724809). We acknowledge Giulia Maria Giordano (University of Campania “Luigi Vanvitelli”, Naples, Italy) and Pasquale Pezzella (University of Campania “Luigi Vanvitelli”, Naples, Italy).

International audience; The management of eating disorders (EDs) is still difficult and few treatments are effective. Recently, several studies have described the important contribution of non-invasive brain stimulation (repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and electroconvulsive therapy) and invasive brain stimulation (deep brain stimulation and vagal nerve stimulation) for ED management. This review summarizes the available evidence supporting the use of brain stimulation in ED. All published studies on brain stimulation in ED as well as ongoing trials registered at clinicaltrials.gov were examined. Articles on neuromodulation research and perspective articles were also included. This analysis indicates that brain stimulation in EDs is still in its infancy. Literature data consist mainly of case reports, cases series, open studies, and only a few randomized controlled trials. Consequently, the evidence supporting the use of brain stimulation in EDs remains weak. Finally, this review discusses future directions in this research domain (e.g., sites of modulation, how to enhance neuromodulation efficacy, personalized protocols).

International audience; Anorexia nervosa (AN) is an eating disorder characterized by excessive weight loss, persistent food restriction and inappropriate physical activity relative to declining energy balance. The comorbidity with depression and/ or anxiety disorders might contribute to the "chronicization" of the disease. We aimed here to question first the link between physical activity and anxiety from a clinical investigation of AN patients (n = 206). Then, using a rodent model mimicking numerous physiological and metabolic alterations commonly seen in AN patients, we examined whether 1) chronic food restriction increased anxiety-like behaviour and 2) physical activity plays a role in regulating anxiety levels. To this end, we exposed young female mice to a chronic food restriction (FR, n = 8) paradigm combined or not with access to a running wheel (FRW, n = 8) for two weeks. The mice were compared to a group of mice fed ad libitum without (AL, n = 6) or with running wheel access (ALW, n = 8). We explored anxiety-like behaviour of all mice in the following tests: hyponeophagia, marble burying, elevated plus maze, open field, and the light and dark box. On the last day, we used a restraint test of 30 min duration and measured their stress reactivity by assaying plasma corticosterone. In the open field and the elevated plus-maze, we found that FRW mice behaved similarly to AL and ALW mice whereas FR mice did not express anxiety-like behaviour. The FRW mice displayed the lowest latency to reach the food in the hyponeophagia test. Regarding stress reactivity, FRW mice exhibited corticosterone reactivity after acute stress that was similar to the control mice, while FR mice did not fully return to basal corticosterone at one hour after the restraint stress. Taken together, these data demonstrate a differential reactivity to acute stress in FR conditions and a beneficial effect of running wheel activity in ALW and FRW conditions. Moreover, we report the absence of a typical anxiety-like behaviour associated with the food restriction (FR and FRW groups). We conclude that this model (FR and FRW mice) did not express typical anxiety-like behaviour, but that physical activity linked to food restriction improved coping strategies in an anxiogenic context.

International audience

Objective To determine the characteristics of the activation syndrome (AS) that predict the emergence or worsening of suicidal ideation (SI) in the first month of antidepressant treatment with tianeptine, as well as the temporal relationship between both conditions. Method A naturalistic sample of 2422 depressed outpatients starting a new antidepressant treatment with tianeptine was assessed at 2, 4 and 6 weeks of follow-up using validated questionnaires. Four main dimensions of AS were examined: impulsivity, sleep problems, anxiety and agitation. Results The emergence of an AS was more likely in long-lasting depressive episodes, but less likely if the patient responded to the antidepressant or benzodiazepines were added as an add-on treatment. Treatment-emergent SI was strongly associated to the presence of an AS, particularly in case of sleep problems (OR = 8.42) or impulsivity upsurges (OR = 3.89), even after adjustment for all relevant confounding factors. Conclusions Our findings suggest a dose-effect mechanism modulating the relationship between treatment-related SI and AS. AS symptoms may need to be monitored closely in the weeks that follow the introduction of an antidepressant treatment.

International audience; A drive for physical activity despite underweight is a core feature of anorexia nervosa. This pilot study detects which aspect of physical activity, if any, could be related to cognitive rigidity in anorexia nervosa. Twenty-eight outpatients with anorexia nervosa and 24 healthy participants were assessed for cognitive flexibility with the Trail Making Test (TMT) and for multiple dimensions of physical activity by subjective and objective assessments. Correlation analysis was conducted to disentangle the relationship between cognitive rigidity and the different aspects of physical activity, then, the moderating effect of anorexia nervosa on this relationship was assessed. A principal component analysis was performed to incorporate all variables of physical activity in (a) global factor(s) reflecting the multidimensional nature of this construct. Cognitive rigidity (TMT b - a score) was significantly correlated to the amount of objectively assessed physical activity estimated, only in the sample of patients with anorexia nervosa. The principal component analysis confirms the correlation between a single construct of "physical activity" and cognitive rigidity in anorexia nervosa only. This pilot study suggests a relationship between cognitive rigidity and physical activity that could help explain the persistence of the latter despite ongoing malnutrition in patients with anorexia nervosa.

International audience; Schizophrenia is a multifactorial disease associated with widespread cognitive impairment. Although cognitive deficits are one of the factors most strongly associated with functional impairment in schizophrenia (SZ), current treatment strategies hardly tackle these impairments. To develop more efficient treatment strategies in patients, a better understanding of their pathogenesis is needed. Recent progress in genetics, driven by large genome-wide association studies (GWAS) and the use of polygenic risk scores (PRS), has provided new insights about the genetic architecture of complex human traits, including cognition and SZ. Here, we review the recent findings examining the genetic links between SZ and cognitive functions in population-based samples as well as in participants with SZ. The performed meta-analysis showed a negative correlation between the polygenetic risk score of schizophrenia and global cognition (p < 0.001) when the samples rely on general and healthy participants, while no significant correlation was detected when the three studies devoted to schizophrenia patients were meta-analysed (p > 0.05). Our review and meta-analysis therefore argues against universal pleiotropy for schizophrenia alleles and cognition, since cognition in SZ patients would be underpinned by the same genetic factors than in the general population, and substantially independent of common variant liability to the disorder.

Anorexia nervosa (AN) is the psychiatric disorder with the highest mortality rate; however, the mechanisms responsible for its pathogenesis remain largely unknown. Large-scale genome-wide association studies (GWAS) have identified genetic loci associated with metabolic features in AN. Metabolic alterations that occur in AN have been mostly considered as consequences of the chronic undernutrition state but until recently have not been linked to the etiology of the disorder. We review the molecular basis of AN based on human genetics, with an emphasis on the molecular components controlling energy homeostasis, highlight the main metabolic and endocrine alterations occurring in AN, and decipher the possible connection between metabolic factors and abnormalities of reward processes that are central in AN. 30;12

International audience; Clinical and cognitive factors associated with clinical insight regarding both baseline level and its time-related changes, in outpatients treated for anorexia nervosa. The 193 participants were recruited at 13 French centers specializing in eating disorders (FFAB network) and assessed for insight (SAI-ED), body mass index (BMI), eating disorder severity, symptoms of depression and anxiety, emotional state, silhouette, and functionality; two cognitive tests were also administered. The 137 patients were then re-assessed 18 weeks later. Minimum and ideal subjective BMI and premorbid intelligence were associated with poor baseline insight. Contrary to nearly all other clinical factors, the level of insight revealed no improvement after four months of care. Only the higher value of the minimum lifetime BMI was significantly predictive of increased insight. More positive emotions (PANAS), less symptoms of depression and anxiety (HADS scores), and fewer syndromes (HADS above threshold) were the only factors that covaried with the changes in the level of insight. In conclusion, poor insight has little time variability, contrary to nearly all clinical and cognitive factors. As increased insight is mainly accompanied by improvements in the emotional domain, the latter could represent potential targets for patients with lack of awareness about their eating disorder.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness 1, affecting 0.9–4% of women and 0.3% of men 2–4, with twin-based heritability estimates of 50–60% 5. Mortality rates are higher than those in other psychiatric disorders 6, and outcomes are unacceptably poor 7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) 8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Background Time perspective (TP) can be described as an individual's attitude towards his personal past, present and future. Literature suggests that it plays a role in several areas of psychological functioning (self-efficacy, coping) and impacts actual thoughts and behaviors. However, TP has seldom been studied in mental health, despite previous studies suggesting that the temporal profile is altered in depressed patients. This study investigates the differences of TP between depressed patients and non-depressed participants, and its relationship with depressive and anxiety symptoms. Methods 45 patients diagnosed with major depressive disorder were compared to 43 non-depressed participants recruited in the general population. Participants were asked to answer time perspective (ZTPI), depression (BDI-13) and anxiety (STAI-Y) self-report inventories. Statistical analysis included comparisons of scores between depressed patients and non-depressed participants, correlation and regression analysis. Results Results indicate that TP is significantly altered in depressed patients. They display a more negative view of their past, a less hedonistic perspective towards their present, and a more fatalistic perspective when compared to non-depressed participants. Regression analysis shows that depressive and anxiety symptoms are associated with negative past and fatalistic present, and similar results are found with correlation analysis. Limitations The size of the sample was small, and longitudinal studies are needed to understand the dynamics and causal relationship between TP and depression. Conclusions These results underline the importance of considering TP in depressed patients, and encourage an in depth study of the relationship between TP and mood disorders. Therapeutic perspectives are discussed.

ObjectivesWe previously developed the Functional Remission Of General Schizophrenia (FROGS) scale demonstrating first, reliable assessment in a cross-sectional study and second, good time-stability. The purpose of the present analysis was to propose a shorter version (mini-FROGS), more compatible with the limited time available in a psychiatric visit, focusing on the functional domains that have higher likelihood of being improved with higher and/or longer symptomatic remission in different cultural backgrounds.MethodsWe used multiple regressions to find the most informative items explaining increased length of symptomatic remission, using prospective data from a national observational multicenter survey. Then, the mini-FROGS was used in different European countries to test its between-center reliability, compared to other scales.ResultsFour domains were retained as capturing the maximum of symptomatic remission, namely (1) travel and communication, (2) management of illness and treatment, (3) self-esteem and sense of independence and (4) respect of biological rhythms. First, the mini-FROG was evaluated in 443 French patients with clinical remission and 22 without, and 12/18 months later in 140 patients still in clinical remission and 23 in relapse. In Europe, 295 schizophrenia patients were assessed with the mini-FROGS and other scales devoted to functional remission, allowing comparisons. The mini-FROGS showed good correlations with other scales in different countries and demonstrated good psychometric properties.ConclusionThese results give evidence that a 4 items-only version of the FROGS scale may be useful to assess important aspects of functional remission, tightly linked to the length of clinical remission.

The concept of quality of life is an old one, but used extensively in the literature since the 90s with a growing number of instruments. Such diversity makes it difficult for clinicians to choose the most appropriate one regarding their divergence on different aspects including how to use them (especially self-questionnaire versus clinician based semi-structure interview), for what aim (from cost perspective, to functionality and/or subjective well-beingness), relying on what dimensions (as the covered quality of life dimensions are not always overlapping), and in which clinical settings (especially according to the availability or not of trained clinicians, and depending of the available time for such assessments). The aim of the literature review is to describe the most frequently used and/or quoted quality of life instruments in schizophrenia, and to describe their different characteristics and specificities in order to help clinicians to find the most appropriate one according to expectancies, possibilities and interests. In this review, we were able to collect 23 instruments, which need between 3 and 60min to fill-in, are relying in between 5 and 146 items, and allowing the assessment of 1 to 14 different quality of life dimensions. The two extremes could be the EuroQOL, which only has 5 self-report questions (with a visual analogical scale, for the rating procedure) and therefore needing only a couple of minutes, and the Quality of Life Scale which needs an initial training for quotation, relies on a semi-structured interview screening 21 items that are used to assess four different dimensions. Because of the heterogeneity of the broad concept of quality of life, and especially the diversity of the expectancies of the different instruments, it is not surprising that so many instruments are being proposed. But this statement reinforces the requirement that clinicians use the most adequate one, not only according to the expectancies, but also taking into account the local possibilities, especially regarding time to fill in the instrument and the possibility for clinicians to be trained if needed.

International audience; Anorexia nervosa (AN) is classically defined as a condition in which an abnormally low body weight is associated with an intense fear of gaining weight and distorted cognitions regarding weight, shape, and drive for thinness. This article reviews recent evidences from physiology, genetics, epigenetics, and brain imaging which allow to consider AN as an abnormality of reward pathways or an attempt to preserve mental homeostasis. Special emphasis is put on ghrelino-resistance and the importance of orexigenic peptides of the lateral hypothalamus, the gut microbiota and a dysimmune disorder of neuropeptide signaling. Physiological processes, secondary to underlying, and premorbid vulnerability factors—the “pondero-nutritional-feeding basements”- are also discussed.

International audience; BACKGROUND:Suicidal thoughts and behaviors could be associated to a poor response to antidepressant treatment, but the exclusion of suicidal patients from randomized clinical trials restricts the available knowledge. In this study, we aimed at defining more precisely the response to antidepressants among suicidal patients and the threshold of suicidality that best predicts a poor response.METHOD:We investigated the short-term response to a new antidepressant treatment of 4,041 depressed outpatients depending on their suicidal status (passive or active suicidal ideation (SI), history of suicide attempts [SAs]), either self-rated or clinician-rated. Depression outcomes, measured with the Hospital Anxiety and Depression Scale, and remission rates were compared depending on suicidal status at baseline using logistic regression models.RESULTS:Using either a qualitative or a quantitative approach to measure SI, we found that suicidal patients were less likely to improve or attain remission, but not more likely to worsen, than nonsuicidal patients. In the multivariate analyses, SI (odds ratio [OR] = 1.40; 95% confidence interval [CI]: 1.18-1.65) and a history of SA (OR = 1.39; 95% CI: 1.16-1.66) were the best predictors of nonremission, independently of the class of antidepressant treatment.CONCLUSION:Antidepressant treatment seems to be less effective among those patients that need it most. Clinical trials including suicidal patients are needed to investigate specific treatment options.

Background Telephone-administered psychotherapies (T-P) provided as an adjunct to antidepressant medication may improve response rates in major depressive disorder (MDD). The goal of this study was to compare telephone-administered social rhythm therapy (T-SRT) and telephone-administered intensive clinical management (T-ICM) as adjuncts to antidepressant medication for MDD. A secondary goal was to compare T-P with Treatment as Usual (TAU) as adjunctive treatment to medication for MDD. Methods 221 adult out-patients with MDD, currently depressed, were randomly assigned to 8 sessions of weekly T-SRT ( n =110) or T-ICM ( n =111), administered as an adjunct to agomelatine. Both psychotherapies were administered entirely by telephone, by trained psychologists who were blind to other aspects of treatment. The 221 patients were a posteriori matched with 221 depressed outpatients receiving TAU (controls). The primary outcome measure was the percentage of responders at 8 weeks post-treatment. Results No significant differences were found between T-SRT and T-ICM. But T-P was associated with higher response rates (65.4% vs 54.8%, p =0.02) and a trend toward higher remission rates (33.2% vs 25.1%; p =0.06) compared to TAU. Limitations Short term study. Conclusions This study is the first assessing the short-term effects of an add-on, brief, telephone-administered psychotherapy in depressed patients treated with antidepressant medication. Eight sessions of weekly telephone-delivered psychotherapy as an adjunct to antidepressant medication resulted in improved response rates relative to medication alone.

International audience; BACKGROUND:Early improvement in positive emotions-more than decreases in negative emotions-was highly predictive of treatment response in an ecologically valid prospective manner. This result needs replication with simpler assessments to determine whether it can be translated into clinical practice.METHODS:2049 adult depressed outpatients receiving agomelatine were assessed at inclusion, week 2, and week 6 using the clinician-rated Quick Inventory of Depressive Symptomatology, Sheehan Disability Scale, Clinical Global Impression scale, and Multidimensional Assessment of Thymic States (MATHYS), an auto-questionnaire rating the frequency of emotions, including sadness and joy, over the previous week.RESULTS:Joy and sadness had a relatively low correlation coefficient at baseline (r=-0.277), joy (r=-0.160) being less correlated with clinical severity than sadness (r=0.317). An increase in joy at week 2 had higher specificity (85.04%) and positive predictive value (70.55%) for treatment response than decreased sadness (57.92% and 66.04%, respectively), and the global capacity of the former to predict remission, either clinical (Yule Q coefficient, 39.96%) or functional (44.35%), was even better compared to the prediction of clinical response (37.38%).LIMITATIONS:MATHYS retrospectively assesses emotions, with five possible ratings only, relying on self-rated frequencies. With only a 6-week follow-up, conclusions are limited to short-term aspects of clinical and functional remission.CONCLUSIONS:Early improvement in joy during the first 2 weeks of treatment is strongly specific for treatment response and remission. The frequency of joy captures the predictivity and may deserve further study regarding inclusion in depressive rating scales.

Le binge drinking (consommation ponctuelle importante d’alcool) est un mode de consommation d’alcool frequemment utilise par les etudiants. Les consequences d’une consommation excessive sont nombreuses et il est important d’aider les jeunes qui en souffrent. Les interventions sur Internet (IBI) semblent etre une methode efficace pour les aider a prendre conscience de la dangerosite du binge drinking. Les bases de donnees Medline et PsycINFO ont ete consultees pour effectuer cette revue de la litterature. Le composant principal des IBI est le compte rendu personnalise, accompagne d’informations, de comparaisons normatives, de conseils, etc. Les IBI analysees ont, dans l’ensemble, ete efficaces sur la population etudiante. Malgre une efficacite averee et de nombreux avantages, ce type d’intervention est peu repandu et doit encore se developper, afin de mieux s’adapter aux jeunes.

Context:A delay of 4–8 weeks before modifying the prescribed antidepressant treatment is usually proposed when incomplete treatment response is observed. A number of studies nevertheless proposed that the lack of early improvement (usually 20% decrease of severity at week 2) is predictive of the absence of subsequent treatment response, potentially saving weeks of inadequate treatment, but with no information for non-interventional studies devoted to outpatients.Method:Two thousand nine hundred and thirty-eight outpatients with major depressive disorder were included in a multicentre, non-interventional study, assessing at inclusion, week 2 and week 6, mood (QIDS-C, CGI, PGI and VAS) sleep (LSEQ) and functionality (SDS). All metrics at week 2 were tested for their capacity to predict response (and then remission) at week 6, all patients being treated by agomelatine. A meta-analysis of all studies (n = 12) assessing the predictive role of improvement at week 2 was also performed, assessing specific effect size of published studies and the weight of the different parameters they used.Results:The QIDS-C and the CGI-I were the only instruments with an area under the curve over 0.7, with different cut-offs for treatment response and remission. A decrease of more than five points at the QIDS-C had the highest positive predictive value for treatment response, and a CGI-I over three had the highest negative predictive value, which would favour relying on the clinicians for warning (too high CGI-I), and on instruments for confidence (favourable decrease of the QIDS-C). The meta-analysis of all studies also detected a large effect size of early improvement, stressing how rating week 2 severity could be beneficial in clinical practice.Conclusions:Previous reports stressing the interest of an assessment at week 2 were reinforced by the present results, which also defined more accurately what could be the most appropriate cut-offs, and how combining these early results could be more effective.

Impairment of executive functions (EFs) mediated by the prefrontal lobe is regarded as a cognitive endophenotype of alcohol dependence, being observed both in probands and in healthy offspring. Given its impact on the anatomy of the prefrontal cortex, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may well be involved in this specific endophenotype. Forty-six healthy adult children of alcoholics (HACA) and 82 healthy controls (HC) took part in the study. All the participants were assessed with the Diagnostic Interview for Genetic Studies, and their family histories of alcohol and substance use were assessed with the Family Informant Schedule and Criteria. The Trail Making Test, Arithmetic Switching Task, Stroop Color-Word Test and Wisconsin Card Sorting Test were administered to assess EFs. An overall executive factor score was calculated using factorial analyses. Genotyping of the BDNF Val66Met polymorphism was performed using the TaqMan ® allelic discrimination assay. HACA had significantly lower EFs performance than HC. Genetic analysis showed that BDNF genotype distributions were in Hardy–Weinberg equilibrium in the HACA and HC. Genotype and allele distributions did not differ significantly between the two groups. Participants with the Met allele performed significantly more poorly than participants with the Val allele, and a group by allele interaction was observed, the BDNF Met allele being associated with a poorer executive factor score in the HACA group. These results suggest that the BDNF Val66Met polymorphism may contribute to alcohol dependence vulnerability via lower EFs performance.

Background: It has been estimated that as many as two thirds of patients with schizophrenia are unable to perform basic personal and social roles or activities. Occupational functioning and social functioning, as well as independent living, are considered as core domains of patient functioning. Improvement in patient functioning has also been recognized as an important treatment goal in guidelines and an important outcome by regulatory agencies. Nevertheless, information is lacking on how these aspects are being considered by psychiatrists across the world and how they are being assessed and managed.Methods: The 'Europe, the Middle East and Africa functioning survey' was designed to canvas opinions of psychiatrists across these regions to ascertain their perceptions of the clinical importance, assessment and management of functioning amongst their patients with schizophrenia. The survey comprised 17 questions and was conducted from March to April 2011 in 42 countries. Data collected included the demographics of respondents and their opinions regarding personal and social functioning in patients with schizophrenia.Results: Results were obtained from 4,163 clinicians. Psychiatrists estimated that more than two thirds (70%) of their patients with schizophrenia showed impaired or very poor levels of functioning. The majority of psychiatrists (92%) believed that personal and social functioning was an important treatment goal for patients with schizophrenia, and 91% believed it was an important goal for patients' families. The majority of psychiatrists (55%) assess the personal and social functioning of their patient at each visit; however, 81% reported that they determine the level of functioning through clinical interview and not by using a specific assessment scale. To manage personal and social functioning in their patients, 26% of psychiatrists prefer pharmacological interventions, whereas 46% prefer psychosocial interventions.Conclusion: Psychiatrists recognize that functioning is impaired/very poor in patients with schizophrenia, and there is still an important need to address functioning as a main treatment goal for patients with schizophrenia. © 2013 Gorwood et al.; licensee BioMed Central Ltd.

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

Aims: Different vulnerability genes have been proposed in alcohol dependence, but replications are sparse, probably due to 1) phenotypical heterogeneity and 2) difficulties to rely on reliable definition of the correct phenotype. Indeed, specific subgroups of patients may be more directly concerned with some vulnerability genes, the actions of these genes being more directly related to their function. We postulated that three potential vulnerability genes, that were at least twice associated with alcohol dependence, influence the extreme of the severity of alcohol dependence, i.e. mortality, through traits with which they were previously associated, namely impulsivity and antisocial personality disorder and the 5-HT1B gene, suicide attempt and the short allele of 5-HTTLPR, and addictive disorder comorbidity and the DRD2 gene. Methods: We analysed the survival status of a male alcohol-dependent sample (n = 126) recruited 9 years before, and could compare 61 surviving patients to 41 patients who died during this period (representing 81.0% of the initial sample). Results: The main clinical characteristic that was associated with an increased mortality rate was a larger cumulative tobacco use (pack-years). We also found that the C allele of the 5-HT1b was the only one in excess in the non-surviving patients. Contrary to our hypothesis, impulsivity and antisocial personality disorder were not explaining the role of this gene. Conclusions: Even if there is a significant involvement of the 5- HT1B C allele, no intermediate phenotype was detected in our sample. The relatively short delay of 9 years and the somewhat old age at baseline of our patients could have limited the influence of psychiatric comorbidity or the specificities of alcohol dependence, explaining why the only detected co-factor was tobacco consumption. Tobacco dependence is therefore the main factor to explain mortality within the first decade, and the effect of this comorbid condition is not explained by three vulnerability genes previously associated to alcohol dependence.

Background Massively Multiplayer Online Role-Playing Games (MMORPGs) are a very popular and enjoyable leisure activity, and there is a lack of international validated instruments to assess excessive gaming. With the growing number of gamers worldwide, adverse effects (isolation, hospitalizations, excessive use, etc.) are observed in a minority of gamers, which is a concern for society and for the scientific community. In the present study, we focused on screening gamers at potential risk of MMORPG addiction. Methods In this exploratory study, we focused on characteristics, online habits and problematic overuse in adult MMORPG gamers. In addition to socio-demographical data and gamer behavioral patterns, 3 different instruments for screening addiction were used in French MMORPG gamers recruited online over 10 consecutive months: the substance dependence criteria for the Diagnostic and Statistical Manual of Mental Disorder, fourth revised edition (DSM-IV-TR) that has been adapted for MMORPG (DAS), the qualitative Goldberg Internet Addiction Disorder scale (GIAD) and the quantitative Orman Internet Stress Scale (ISS). For all scales, a score above a specific threshold defined positivity. Results The 448 participating adult gamers were mainly young adult university graduates living alone in urban areas. Participants showed high rates of both Internet addiction (44.2% for GIAD, 32.6% for ISS) and DAS positivity (27.5%). Compared to the DAS negative group, DAS positive gamers reported significantly higher rates of tolerance phenomenon (increased amount of time in online gaming to obtain the desired effect) and declared significantly more social, financial (OR: 4.85), marital (OR: 4.61), family (OR: 4.69) and/or professional difficulties (OR: 4.42) since they started online gaming. Furthermore, these gamers self-reported significantly higher rates (3 times more) of irritability, daytime sleepiness, sleep deprivation due to play, low mood and emotional changes since online gaming onset. Conclusions The DAS appeared to be a good first-line instrument to screen MMORPG addiction in online gamers. This study found high MMORPG addiction rates, and self-reported adverse symptoms in important aspects of life, including mood and sleep. This confirms the need to set up relevant prevention programs against online game overuse.

International audience; OBJECTIVES: Autism (MIM#209850) and schizophrenia (MIM#181500) are both neurodevelopmental psychiatric disorders characterized by a highly genetic component. Homeogenes and forkhead genes encode transcription factors, which have been involved in brain development and cell differentiation. Thus, they are relevant candidate genes for psychiatric disorders. Genetic studies have reported an association between autism and DLX2, HOXA1, EN2, ARX, and FOXP2 genes whereas only three studies of EN2, OTX2, and FOXP2 were performed on schizophrenia. Interestingly, most of these candidate genes contain trinucleotide repeats coding for polyamino acid stretch in which instability can be the cause of neurodevelopmental disorders. Our goal was to identify variations of coding trinucleotide repeats in schizophrenia, autism, and idiopathic mental retardation. METHODS: We screened the coding trinucleotide repeats of OTX1, EN1, DLX2, HOXA1, and FOXP2 genes in populations suffering from schizophrenia (247 patients), autism (98 patients), and idiopathic mental retardation (56 patients), and compared them with control populations (112 super controls and 202 healthy controls). RESULTS: Novel deletions and insertions of coding trinucleotide repeats were found in the DLX2, HOXA1, and FOXP2 genes. Most of these variations were detected in controls and no difference in their distribution was observed between patient and control groups. Two different polymorphisms in FOXP2 were, however, found only in autistic patients and the functional consequences of these variations of repeats have to be characterized and correlated to particular clinical features. CONCLUSION: This study did not identify specific disease risk variants of trinucleotide repeats in OTX1, EN1, DLX2, HOXA1, and FOXP2 candidate genes in neurodevelopmental psychiatric disorders.

Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptin's effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.

SIR—Recently, a rare functional variant, I425V, in the serotonin transporter gene (SLC6A4) has been reported to be associated with a complex neuropsychiatric phenotype that includes obsessive-compulsive disorder (OCD), alcohol abuse/dependence, anorexia nervosa, and pervasive developmental disorder (PDD).1 Our study, performed in a large population of patients with these disorders, confirms the occurrence and the segregation of V425 in OCD. The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in numerous psychiatric disorders, mostly because of the efficacy of serotonin reuptake inhibitors (SRIs). Among the polymorphisms identified in SLC6A4, three have been shown to be functional. The rare I425V variation, located in exon 9, increases the transport activity of the protein2, whereas the two more frequent polymorphisms, 5-HTTLPR located in the 5′-UTR of the gene, and STin2 located in intron 2, modify the transcriptional activity of the gene3,4. Despite a large number of studies, the functional implications of the two frequent SLC6A4 polymorphisms in psychiatric disorders are still a matter of debate. In the present study, we sought to further explore the influence of the rare but clearly functional I425V variant in a large sample of patients with OCD and other psychiatric conditions previously reported in the two families carrying I425V, i.e., FDD, anorexia nervosa, and alcohol abuse/dependence. To be included in the study, patients had to meet the DSM-IV criteria for OCD, anorexia nervosa, alcohol abuse/dependence, or FDD. The diagnosis of FDD was confirmed using the Autism Diagnostic Interview-Revised.5 For the other disorders, lifetime psychiatric evaluation was carried out using the Diagnostic Interview for Genetic Studies (DIGS)6 for adult patients, or the Kiddie Schedule for Affective Disorders and Schizophrenia for children.7 Healthy controls were included after being interviewed with the DIGS and the Family Interview for Genetic Studies8 to confirm the absence of both personal and family history of major psychiatric disorders. The local Research Ethics Boards reviewed and approved the study. The V425 was found in 3/254 probands with OCD, 1/284 with PDD, 1/124 with anorexia nervosa, in 1/285 healthy controls, but not in alcohol abusers/dependents (0/128) (Table 1). In OCD family 1, V425 was transmitted by the father who also had a lifetime history of OCD and single phobia. The paternal grandfather was alcoholic and tobacco dependant. No genotypic information was available for the paternal grandparents since the grandfather died of throat cancer and the grandmother of breast cancer. In OCD family 2, the mother and two siblings of the proband had committed suicide and the father was also dead, so no genotypic information was available for these individuals. OCD case 1 had only one brother, who committed suicide some years ago, so no genotypic information was available for him. No other clinical data were available concerning the first-degree relatives of OCD case 1. In FDD family 1, V425 was transmitted by the father and was present in the proband and two brothers. The father and one of the brothers carrying the V425 were both alcohol dependent. However, the youngest brother (19 years old), also carrying the V425 variant, did not suffer from alcoholism or any other psychiatric disorder at the time of evaluation. Table 1 SCL6A4 genotypes and clinical features of the subjects included in the study Our results are in accordance with those previously reported by Ozaki et al1 on four points. First, we report a possibly higher occurrence of the V425 variant in OCD compared to controls. Although the variant is rare, the combined results of the two studies indicate a significantly higher frequency of V425 in OCD compared to controls1,9 (5/457 vs. 2/884, Fisher exact test, P= 0.02). Second, despite the limited clinical and genotypic information on the families carrying the V425 variant, our results suggest a possible co-segregation between the V425 and neuropsychiatric phenotypes, specifically in OCD. Third, Ozaki et al. hypothesized that the V425 variant may confer treatment-resistance to SRIs. This was indirectly supported by our findings since all OCD probands carrying the V425 variant in our study were considered resistant to SRIs, i.e., the severity of their obsessive and compulsive symptoms decreased less than 25% with multiple trials of a high dose of SRIs and a good compliance. Specifically, the three probands with OCD carrying the variant showed poor or no response to multiple trials of SRIs at adequate doses over several years. Fourth, the analysis of the two additional polymorphisms of the SCL6A4 gene indicated that the V425 polymorphism might be associated with the L allele of 5-HTTLPR. However, our results do not confirm the hypothesis of a combined gain of function effect of both V425 and L/L genotype as a genetic risk for OCD, since this combined genotype was not present in all affected patients and, by contrast, was present in the control subject carrying the V425 variant. In conclusion, our results are similar to those of the original report by Ozaki et al. and, therefore, lend support for a role of SLC6A4 V425 in the susceptibility to complex neuropsychiatric phenotypes. However, due to its global low frequency and to the fact that it was detected in a few controls, the role of V425 remains uncertain and should be interpreted with caution. We encourage other investigators, especially in the field of OCD, to screen for V425 in their samples. Indeed, the replication of these findings could ultimately implicate SLC6A4 as a true susceptibility gene to complex neuropsychiatric disorders, and consequently shed further light on the results obtained with the more frequent polymorphisms.

La dépendance à l’exercice physique (EP) fait partie des addictions comportementales tout comme le jeu pathologique, qui a récemment intégré le cadre diagnostic dans le DSM-5 des « troubles de l’usage », mais son cadre reste mal défini. Cette étude épidémiologique, observationnelle et transversale réalisée sur 3 mois (2016-2017) évalue la prévalence de la dépendance à l’EP avec l’Exercice Addiction Inventory ainsi que ses liens avec certaines comorbidités psychiatriques (anxiété, dépression, alcool, cannabis, TCA), la gestion de la douleur et l’interdiction de pratique du sport. Les athlètes interrogés sont des adultes recrutés via des clubs (triathlon, trail) ou réseaux sociaux, ils ont répondu à un auto-questionnaire par internet. Selon l’EAI 12,7% des sportifs étaient «à risque de dépendance» et se caractérisaient par le fait d’être plus jeunes (p=0,04), plus à risque de TCA (p=0,02) et de mésusage de l’alcool (p=0,02). Plus le score de l’EAI était élevé, moins les sportifs pratiquaient (r=0,01) mais plus ils avaient de risque d’avoir des troubles anxieux (p

Introduction: Suicide is a major Public Health concern and self-esteem is given growing interest in our society.Objectives: To assess the correlation between self-esteem and suicidal intent, independently of depression, and to examine the relationship between the different dimensions of self-esteem (total, general, familial, professional and social). We also studied whether poor self-esteem was predictive of suicidal risk.Methods: Two studies were conducted among a Suicide Prevention Department. The first one (N=132) was cross sectional. We sought for correlations (with and without adjusting for depression) between self-esteem (assessed with the Coopersmith scale (SEI)) and suicidal intent. The second study (N=42) compared the reappearance of ideation or suicidal behavior within the month following hospitalization, distinguishing two groups with low (SEI total ≤ 16) versus moderate (SEI total ≥ 33) self-esteem.Results: Suicidal intent was correlated with total self-esteem (r=-0.227, p=0.009), social self-esteem (r=-0.331, p

Through its cerebral localization, its anatomical and functional connectivity, the hippocampus is involved in memory (coding and storing) and in emotion regulation. Cell proliferation in the dentate gyrus, new synaptic connections and the modulation of the efficiency of existing synaptic connections by the Long Term Potentiation and Long Term Depression, participate in memory function. Negative retro feedback that the hippocampus has on the hypothalamic-pituitary-adrenal axis allows a regulation of the reaction of the organism to stress it undergoes. Depression can in fact be considered as a state of stress for the organism.Neuron progenitor proliferation and neuronal plasticity are essential characteristics of the hippocampus ‘functioning. The effect of antidepressant therapeutics, medicinal ones as well as electro convulsive therapy, underlies the importance of this characteristic.Concerning more precisely an endogenous subtype of depression, melancholia, numerous genetic factors have been found as being vulnerability factors. Traumatic events, especially during childhood, are at the origin of the expression of this vulnerability.Memory impairments are found inconstantly in relation to depression. The repetitive character of depression, which is pathology with a high rate of recurrence, could explain that these impairments are only found after several depressive episodes. This is a cumulative or quantitative hypothesis. Or, specificities linked to melancholia could make this subtype more neurotoxic and could explain that memory impairments would be linked to melancholia. This is a qualitative hypothesis.Willing to explore the influence of each of these hypotheses, but one of them requiring studying subjects with different lifetimes being depressed and different ages, we first studied the impact of age on memory impairment. Age is not an independent factor explaining worse memory recovery after a depressive episode once remaining symptoms and memory at baseline are controlled for.Studying the respective influence of the quantitative hypothesis and the qualitative hypothesis we found that the lifetime being depressed is correlated to delayed verbal memory impairment and size of the right hippocampus, whereas the score at scale of melancholia is not. However, lifetime being depressed and the rate of melancholia are correlated.Depression appears to be neurotoxic through a cumulative mechanism, each depressive episode being a stress for the organism with a hyper activation of the hypothalamic-pituitary-adrenal axis and a hyper secretion of cortisol. But taking into account the genetic vulnerability factors, which are linked to endogenous subtype of depression, and the kindling hypothesis with smaller and smaller stressful life events preceding a depressive episode, it could be the same subjects that both have depressive episodes with melancholic characteristics and depression with a high rate of recurrence. This is only a statistic correlation between lifetime being depressed and hippocampal atrophy, biological mechanisms explaining causality for this correlation are not yet known. Only a part of the subjects could be exposed to genetic vulnerability and high recurrence of the depressive episodes or depressive episodes could become melancholic after several recurrences. Further research on this topic is needed. Moreover, looking at the high cost of depression and the high influence of life conditions during childhood, maternal care and traumas, special attention must be payed to them., De par sa localisation anatomique, ses connexions anatomiques et fonctionnelles, l’hippocampe est une structure impliquée dans la mémoire (encodage et stockage de l’information) et dans la régulation des émotions. La prolifération des cellules au niveau du gyrus denté, les nouvelles connexions synaptiques et la modulation de l’efficacité des synapses déjà existantes par la Long Term Potentiantion (LTP) et la Long Term Depression (LTD) participent aux fonctions mnésiques. Le rétro-feedback négatif qu’exerce l’hippocampe sur l’axe hypothalamo-hypophyso-surrénalien permet une régulation de la réaction à un stress auquel est soumis l’organisme. La dépression est en outre considérée comme étant un état de stress pour l’organisme.La prolifération de progéniteurs neuronaux, la plasticité neuronale, sont des caractéristiques essentielles du fonctionnement de l’hippocampe. L’effet des traitements antidépresseurs, aussi bien médicamenteux que l’électro-convulsivo-thérapie (ECT) soulignent l’importance de cette caractéristique.Concernant plus particulièrement une forme de dépression dite endogène, la mélancolie, de nombreux facteurs génétiques sont retrouvés comme étant des facteurs de vulnérabilité. Des évènements traumatiques, particulièrement dans l’enfance, sont à l’origine de l’expression de cette vulnérabilité.Des troubles de la mémoire sont retrouvés de manière inconstante en lien avec la dépression. Le caractère répétitif de la dépression, qui est une maladie récurrente, pourrait expliquer que ces troubles mnésiques ne soient retrouvés qu’après plusieurs épisodes dépressifs, il s’agirait d’un caractère cumulatif, quantitatif. Ou bien, les spécificités liées à la mélancolie seraient à l’origine d’une plus grande neuro-toxicité de cette forme de dépression et expliqueraient que les troubles de la mémoire soient liés à ce type d’épisode, de manière cette fois qualitative.Voulant étudier le poids respectif de ces deux hypothèses, l’une impliquant d’étudier des sujets ayant des temps de vie passés en dépression variables et donc des âges variables, et la fonction testée étant la mémoire qui est altérée avec le vieillissement, nous avons tout d’abord étudié l’impact de l’âge. L’âge n’est pas un facteur indépendant pouvant expliquer une moins bonne récupération de la fonction mnésique après un épisode dépressif majeur lorsque sont pris en compte le niveau de performance mnésique de base et les symptômes persistants.L’étude du poids de l’hypothèse qualitative et quantitative a montré que le temps de vie passé en dépression est corrélé à la performance en mémoire déclarative différée et à la taille de l’hippocampe droit, le score de mélancolie ne l’est pas. En revanche temps de vie passé en dépression et score de mélancolie sont corrélés.La dépression apparaît donc être toxique par un mécanisme cumulatif de chaque épisode qui représente un état de stress pour l’organisme avec une hyper activation de l’axe hypothalamo-hypophyso-surrénalien et une sécrétion accrue de cortisol. Mais du fait des facteurs de vulnérabilité génétique, qui sont liés au type endogène de dépression, et à la théorie de l’embrasement, des évènements de stress de moins en moins importants précédant un épisode dépressif majeur, ce pourrait être les mêmes sujets qui sont à la fois soumis à des épisodes dépressifs à caractéristique mélancolique et à un trouble dépressif multi-récurrent. Il s’agit cependant d’une corrélation statistique entre temps de vie passé en dépression et atteinte de l’hippocampe, les mécanismes biologiques de causalité expliquant ce constat ne sont pas connus. Seule une partie de la population pourrait être exposée à une vulnérabilité génétique et à un grand nombre d’épisodes dépressifs, ou bien les épisodes dépressifs pourraient prendre une caractéristique mélancolique après un certain nombre de récurrence. Des recherches dans ce domaine sont à développer.

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

Previous models of Attention Deficit / Hyperactivity Disorder (ADHD) such as Barkley’s or Brown’s conceptualized ADHD as essentially a developmental impairment of executive function. Against this view, it is now recognized that ADHD is a heterogeneous disorder, involving multiple deficits and multiple neuronal pathways. Despite this current theoretical framework, most structural brain imaging studies in ADHD have compared groups of children with ADHD with typically developing children, without trying to identify subgroups within the diagnostic category. This approach has yielded heterogeneous findings, possibly due to inter-studies variations in the type and number of comorbidities, the percentage of medicated participants included, the number of girls included, and/or methodological and statistical differences. Patients participating in these studies were also often exposed to methylphenidate, and potential medication effects on grey matter volumes are still unclear in certain brain regions such as the frontal lobe, despite a therapeutic action involving the preferential activation of catecholamine neurotransmission within the prefrontal cortex. In this thesis, we used voxel-based morphometry to study the influence of two important risk factors for the development of comorbid conditions in ADHD. The first of these two factors was gender, and the second a genetic polymorphism of the Catechol-O-methyltransferase gene known to put children with ADHD at risk for developing a conduct disorder (Val158Met). We also compared grey matter volumes in children with ADHD exposed to methylphenidate, never-medicated children with ADHD and typically developing children. These experimental studies were part of a more general discussion of ADHD neuropsychological and neurobiological heterogeneity. In our study exploring the influence of gender on the structural correlates of ADHD, we report for the first time a gender-by-diagnosis interaction, with grey matter volume differences in boys and girls with ADHD in midline cortical structures, involved in emotional regulation and part of the default mode network. We propose that these differences may contribute to explain why girls with ADHD more often develop inattentive and internalizing symptoms, whereas externalizing symptoms are predominant in boys with ADHD. In our study investigating the effects of Val158Met in ADHD, we report the first evidence of a COMT-related genetic modulation of ADHD-related grey matter volume alterations. Indeed, children with ADHD at higher risk for developing a conduct disorder (children homozygotes for the Val158 allele) presented increased grey matter volumes in the caudate nucleus when compared with typically developing children, whereas children carrying a Met158 allele presented with decreased grey matter volumes in the right inferior frontal cortex, a region known for its key role in attention. Finally, we measured grey matter volumes in medicated children with ADHD, never-medicated children with ADHD and typically developing children using both whole-brain voxel-based morphometry and automated tracing procedures in chosen regions of interest. We document potential methylphenidate-related grey matter volume normalization and deviation in previously unexplored frontal and temporal regions, and report a positive association between treatment history and grey matter volume in the nucleus accumbens, a key region for reward processing. Our first two experimental studies therefore contribute to a better understanding of the influence of important sources of within-category heterogeneity, while the third helps clarifying the potential confounding effect of medication exposure in previous structural brain imaging studies in ADHD.; Succédant à une théorisation centrée sur le rôle des déficits des fonctions exécutives, les modèles contemporains du trouble déficit de l'attention / hyperactivité (TDAH) mettent en avant l’hétérogénéité d’une catégorie diagnostique impliquant des déficits neuropsychologiques, voies cérébrales et mécanismes étiopathogéniques multiples. En dépit de cette évolution, la majorité des études d'imagerie cérébrale des corrélats structurels du trouble menées à ce jour ont été conduites au niveau de la catégorie diagnostique, sans spécification supplémentaire. Cette approche comparant en moyenne un groupe de patients avec TDAH à un groupe de sujets sains a donné des résultats très variables d'une étude à l'autre, la comparaison inter-étude étant toutefois rendue difficile par la présence de facteurs confondants, tels que des différences en terme de régions d’intérêt examinées, de comorbidités acceptées chez les patients, de pourcentages de sujets masculins et féminins, de fenêtre d’âge sélectionnée, de méthodologie d'analyse ou encore de pourcentage de patients traités par méthylphénidate. Dans ce doctorat, nous nous sommes appuyés sur la morphométrie voxel-à-voxel pour isoler l’influence sur les volumes de matière grise de deux facteurs d’hétérogénéité intra-catégorielle dans le TDAH : le genre d’une part, et un polymorphisme génétique (Val158Met du gène Catéchol-O-méthyltransferase (COMT)) d’autre part ; ces deux facteurs présentant l’intérêt de moduler le risque associé de développer un trouble de type externalisé. Nous avons également comparé les volumes de matière grise d’enfants avec TDAH ayant reçu un traitement par méthylphénidate, de patients n'ayant jamais été exposé à la médication, et de sujet sains. Ces recherches expérimentales ont été inscrites dans une discussion plus générale de l’hétérogénéité des résultats de la littérature structurelle consacrée au TDAH et des sources neuropsychologiques de cette hétérogénéité. Dans notre étude des effets du genre sur les volumes de matière grise dans le TDAH, nous reportons pour la première fois une interaction entre genre et diagnostic, avec des corrélats structurels du trouble différents chez les garçons et les filles avec TDAH dans des régions de la ligne médiane du cerveau, impliquées à la fois dans la régulation émotionnelle et dans le fonctionnement du mode de réseau par défaut. Nous suggérons que ces différences structurelles pourraient contribuer aux différences de risque associé pour les troubles internalisés et externalisés présentées par les garçons et filles avec TDAH. Dans notre étude explorant l'influence du polymorphisme Val158Met sur les volumes de matière grise, nous mettons en évidence une modulation génétique des corrélats structurels du trouble : les sujets homozygotes pour l'allèle Val158, identifiés dans la littérature comme à risque pour le développement d'un trouble des conduites, présentent des volumes de matière grise supérieurs dans le noyau caudé comparativement aux sujets sains, tandis que les patients avec TDAH porteurs d'un allèle Met158 présentent des volumes de matière grise plus faibles dans le cortex préfrontal inférieur droit, une région cruciale pour les processus de contrôle attentionnel. Enfin, dans notre étude des corrélats structurels de l'exposition au méthylphénidate, nous reportons un effet potentiellement normalisateur du traitement sur les volumes de matière grise de l'insula et du pole temporal, des volumes de matière grise plus faibles chez les patients traités comparativement aux sujets sains dans le gyrus frontal moyen et dans le gyrus précentral, et une association entre volume de matière grise dans le nucleus accumbens gauche et durée d'exposition au méthylphénidate chez les sujets traités. (...)

Through its cerebral localization, its anatomical and functional connectivity, the hippocampus is involved in memory (coding and storing) and in emotion regulation. Cell proliferation in the dentate gyrus, new synaptic connections and the modulation of the efficiency of existing synaptic connections by the Long Term Potentiation and Long Term Depression, participate in memory function. Negative retro feedback that the hippocampus has on the hypothalamic-pituitary-adrenal axis allows a regulation of the reaction of the organism to stress it undergoes. Depression can in fact be considered as a state of stress for the organism.Neuron progenitor proliferation and neuronal plasticity are essential characteristics of the hippocampus ‘functioning. The effect of antidepressant therapeutics, medicinal ones as well as electro convulsive therapy, underlies the importance of this characteristic.Concerning more precisely an endogenous subtype of depression, melancholia, numerous genetic factors have been found as being vulnerability factors. Traumatic events, especially during childhood, are at the origin of the expression of this vulnerability.Memory impairments are found inconstantly in relation to depression. The repetitive character of depression, which is pathology with a high rate of recurrence, could explain that these impairments are only found after several depressive episodes. This is a cumulative or quantitative hypothesis. Or, specificities linked to melancholia could make this subtype more neurotoxic and could explain that memory impairments would be linked to melancholia. This is a qualitative hypothesis.Willing to explore the influence of each of these hypotheses, but one of them requiring studying subjects with different lifetimes being depressed and different ages, we first studied the impact of age on memory impairment. Age is not an independent factor explaining worse memory recovery after a depressive episode once remaining symptoms and memory at baseline are controlled for.Studying the respective influence of the quantitative hypothesis and the qualitative hypothesis we found that the lifetime being depressed is correlated to delayed verbal memory impairment and size of the right hippocampus, whereas the score at scale of melancholia is not. However, lifetime being depressed and the rate of melancholia are correlated.Depression appears to be neurotoxic through a cumulative mechanism, each depressive episode being a stress for the organism with a hyper activation of the hypothalamic-pituitary-adrenal axis and a hyper secretion of cortisol. But taking into account the genetic vulnerability factors, which are linked to endogenous subtype of depression, and the kindling hypothesis with smaller and smaller stressful life events preceding a depressive episode, it could be the same subjects that both have depressive episodes with melancholic characteristics and depression with a high rate of recurrence. This is only a statistic correlation between lifetime being depressed and hippocampal atrophy, biological mechanisms explaining causality for this correlation are not yet known. Only a part of the subjects could be exposed to genetic vulnerability and high recurrence of the depressive episodes or depressive episodes could become melancholic after several recurrences. Further research on this topic is needed. Moreover, looking at the high cost of depression and the high influence of life conditions during childhood, maternal care and traumas, special attention must be payed to them., De par sa localisation anatomique, ses connexions anatomiques et fonctionnelles, l’hippocampe est une structure impliquée dans la mémoire (encodage et stockage de l’information) et dans la régulation des émotions. La prolifération des cellules au niveau du gyrus denté, les nouvelles connexions synaptiques et la modulation de l’efficacité des synapses déjà existantes par la Long Term Potentiantion (LTP) et la Long Term Depression (LTD) participent aux fonctions mnésiques. Le rétro-feedback négatif qu’exerce l’hippocampe sur l’axe hypothalamo-hypophyso-surrénalien permet une régulation de la réaction à un stress auquel est soumis l’organisme. La dépression est en outre considérée comme étant un état de stress pour l’organisme.La prolifération de progéniteurs neuronaux, la plasticité neuronale, sont des caractéristiques essentielles du fonctionnement de l’hippocampe. L’effet des traitements antidépresseurs, aussi bien médicamenteux que l’électro-convulsivo-thérapie (ECT) soulignent l’importance de cette caractéristique.Concernant plus particulièrement une forme de dépression dite endogène, la mélancolie, de nombreux facteurs génétiques sont retrouvés comme étant des facteurs de vulnérabilité. Des évènements traumatiques, particulièrement dans l’enfance, sont à l’origine de l’expression de cette vulnérabilité.Des troubles de la mémoire sont retrouvés de manière inconstante en lien avec la dépression. Le caractère répétitif de la dépression, qui est une maladie récurrente, pourrait expliquer que ces troubles mnésiques ne soient retrouvés qu’après plusieurs épisodes dépressifs, il s’agirait d’un caractère cumulatif, quantitatif. Ou bien, les spécificités liées à la mélancolie seraient à l’origine d’une plus grande neuro-toxicité de cette forme de dépression et expliqueraient que les troubles de la mémoire soient liés à ce type d’épisode, de manière cette fois qualitative.Voulant étudier le poids respectif de ces deux hypothèses, l’une impliquant d’étudier des sujets ayant des temps de vie passés en dépression variables et donc des âges variables, et la fonction testée étant la mémoire qui est altérée avec le vieillissement, nous avons tout d’abord étudié l’impact de l’âge. L’âge n’est pas un facteur indépendant pouvant expliquer une moins bonne récupération de la fonction mnésique après un épisode dépressif majeur lorsque sont pris en compte le niveau de performance mnésique de base et les symptômes persistants.L’étude du poids de l’hypothèse qualitative et quantitative a montré que le temps de vie passé en dépression est corrélé à la performance en mémoire déclarative différée et à la taille de l’hippocampe droit, le score de mélancolie ne l’est pas. En revanche temps de vie passé en dépression et score de mélancolie sont corrélés.La dépression apparaît donc être toxique par un mécanisme cumulatif de chaque épisode qui représente un état de stress pour l’organisme avec une hyper activation de l’axe hypothalamo-hypophyso-surrénalien et une sécrétion accrue de cortisol. Mais du fait des facteurs de vulnérabilité génétique, qui sont liés au type endogène de dépression, et à la théorie de l’embrasement, des évènements de stress de moins en moins importants précédant un épisode dépressif majeur, ce pourrait être les mêmes sujets qui sont à la fois soumis à des épisodes dépressifs à caractéristique mélancolique et à un trouble dépressif multi-récurrent. Il s’agit cependant d’une corrélation statistique entre temps de vie passé en dépression et atteinte de l’hippocampe, les mécanismes biologiques de causalité expliquant ce constat ne sont pas connus. Seule une partie de la population pourrait être exposée à une vulnérabilité génétique et à un grand nombre d’épisodes dépressifs, ou bien les épisodes dépressifs pourraient prendre une caractéristique mélancolique après un certain nombre de récurrence. Des recherches dans ce domaine sont à développer.

Les troubles de la mémoire déclarative verbale sont très souvent retrouvés au cours comme au décours d’un épisode dépressif majeur, dans le cadre d’un trouble de l’humeur unipolaire ou bipolaire. Ces troubles mnésiques peuvent être significativement aggravés par la sévérité de l’épisode et par la présence de caractéristiques mélancoliques. La sévérité évolutive du trouble dépressif a aussi une influence négative, qui peut cependant être masquée au moment d’un épisode dépressif par la sévérité clinique de l’épisode et des troubles de l’attention et de la motivation associés. Une étude sur 30 patients soutient ces données et suggère qu’il existe une influence à la fois d’un facteur « trait » et d’un facteur « état » sur les capacités de mémoire déclarative verbale des patients déprimés. Une hypothèse explicative serait celle d’une neurotoxicité de la maladie dépressive sur les cognitions et notamment sur la mémoire déclarative verbale, via une atteinte de l’hippocampe, retrouvé atrophié dans la dépression. Plusieurs mécanismes physiopathologiques ont été impliqués, comme une dysrégulation de l’axe hypothalamo-hypophyso-cortico-surrénalien et/ou des processus inflammatoires, associés à des troubles de la neurogénèse et de la plasticité neuronale hippocampique. L’existence d’une vulnérabilité génétique préalable pourrait agir par différents biais sur le volume de l’hippocampe et la survenue de la dépression. Les traitements utilisés dans la dépression sont associés à des effets neurotrophiques et de neurogénèse au niveau de l’hippocampe, ce qui pourrait rendre compte de l’amélioration des troubles de mémoire déclarative verbale observée au décours de la prise en charge.

Since the serendipitous discovery of typical antipsychotics in the treatment of schizophrenia, several molecules have been developed for their tolerance and a specific action. However, before any prescription of these molecules, in the spirit of the disorder, the concept of resistance to the treatment was evoked. Indeed, there is an inter-individual variation of response to antipsychotics in schizophrenic subjects that was described by specific scales of evaluation. It appears that clinical factors seem to contribute to the non response of treatment and they are not appreciated so well. Psychotics follow specific pathways and it is know that physiological and biochemical effects depend on factors. Thus, smoking habits, alcohol and diet have been described as factors influencing variability in drug response. While age, gender and genetic factors seem to contribute to the quality of therapeutic response. Evidence from family, twin and adoption studies clearly demonstrate the involvement of genetic factors in schizophrenia. Both linkage and association studies support this hypothesis. Although the results of such studies remain inconsistent regarding the heterogeneity of the disease. Refinement of the phenotype using the pharmacogenetic approach could thus be useful in the genetic studies of schizophrenia. Pharmacogenetic research claim to assess a possible interaction between the therapeutic targets of antispychotics and their specific mutations in candidate genes. High affinity of atypical antipsychotics for 5-HT2A receptors may explain their specific efficacy/tolerability profile compared to conventional antipsychotics. A number of reports have associated a silent 5-HT2A polymorphism (T102) with response to clozapine or risperidone. This polymorphism is in complete linkage disequilibrium with a -1438A/G polymorphism, located within the promoter region of the gene, with conflicting results. Phenotypical heterogeneity of schizophrenia might explain such discrepancies. For example, negative symptoms are known to reflect severity of illness and to restrain therapeutic response. On this basis, we re-assessed the possible influence of the −1438A/G polymorphism of the 5-HT2A receptor gene on the clinical efficacy of atypical antipsychotics with focus on several relevant dimensions. The A allele and the AA genotype of the −1438A/G polymorphism of the gene coding for the 5-HT2A receptor were not associated with therapeutic response to atypical antipsychotics in our sample. Furthermore, the AA genotype appeared to be associated with the SANS score, raising the possibility that negative symptoms in schizophrenia constitute a confounding factor between the 5-HT2A gene and atypical antipsychotic response. Traditionally, dopaminergic and serotoninergic sytems have been used as targets for antipsychotic therapy. Although, most available antipsychotics have a multitarget profile without any clear mechanism of action. Recently, atypical antispychotics have been found to display a wide range of affinities for several neurotransmitters. Neurobiological research suggest a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Epidemiology studies show that patients consume twice more of cannabis than the general population. An increase of the density of receptors is observed in the dorsolateral prefrontal cortex of schizophrenic post mortem samples. The CNR1 gene, that encodes the CB1 receptor, is located on chromosome 6q14-15, which has been considered as a susceptibility locus for schizophrenia. Recent progress in pharmacogenetics, evaluating the individual risk for antipsychotic refractoriness, has focused notably on the dopaminergic and serotoninergic systems. However, so far, these studies led to discrepant data. This led us to assess the possible influence of the 1359G/A polymorphism as a haplotype tagging SNP of the CNR1 gene, in comparison with three other SNPs covering 14kb across this gene, on the risk of schizophrenia and/or therapeutic response to atypical antipsychotics. We found no difference in 1359G/A polymorphism between patients and control subjects, and no relationships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor. However, the G allele frequency was significantly higher among non-responsive vs responsive patients, with a dose effect of the G allele. In contrast, no association was found for three other genetic polymorphisms of the CNR1 gene. Pharmacogenetics may in future lead to individualized pharmacotherapy based on the specific genetic, environmental and demographic characteristics of each patient. Pharmacogenetics could thus increase the patient comfort in terms of both higher initial response rates and reduced propensity to developing debilitating side-effects., Depuis la découverte, fruit du hasard des neuroleptiques pour traiter la schizophrénie, de nombreuses molécules ont été développées pour une meilleure tolérance et une meilleure efficacité. Toutefois, bien avant la prescription de ces molécules, à l'essence même de la pathologie, le concept de résistance a été évoqué. La variabilité interindividuelle de réponse aux antipsychotiques des sujets schizophrènes a pu être ainsi conceptualisée grâce à des échelles spécifiques d'évaluation. Il apparait que ces sujets non répondeurs se caractérisent par une symptomatologie clinique plus bruyante qui n'est pas toujours évaluée de manière spécifique par ce type d'échelles. Les psychotropes empruntent des voies bien définies et il est reconnu que les effets physiologiques et biochimiques de ces substances sont soumis à certaines influences. Ainsi, le type d'alimentation, l'alcool et le tabac sont autant de facteurs extrinsèques influant la réponse aux traitements tandis que l'âge, le sexe, le poids ou d'autres facteurs physiopathologiques (incluant les facteurs héréditaires) sont d'importants facteurs intrinsèques. L'hypothèse d'un sous bassement génétique de la schizophrénie est étayé par plusieurs travaux comme les études épidémiologiques, de liaison génétique et des gènes candidats. Toutefois, l'hétérogénéité phénotypique de la maladie amène à des résultats variables. De fait, le cloisonnement phénotypique à la non réponse aux antipsychotiques chez les patients schizophrènes, pourrait être contributif à ce type d'approche. La pharmacogénétique se base sur les connaissances pharmacologiques des antipsychotiques et des gènes candidats des récepteurs cibles de ces molécules. Se basant sur l'hypothèse sérotoninergique de la schizophrénie et le tropisme préférentiel des antipsychotiques atypiques pour le récepteur sérotoninergique 5-HT2A, les premières études dans ce domaine ont testé la qualité de la réponse à la clozapine avec les polymorphismes T102C -1438A/G de la région promotrice et du gène du récepteur 5-HT2A. On peut toutefois noter l'inconsistance des résultats. L'hétérogénéité phénotypique de la maladie pourrait, au travers de symptômes cliniques, souligner ces différences. Par exemple, les symptômes négatifs dont la constance au cours de la maladie et l'association avec une moins bonne réponse thérapeutique sont reconnus. Notre hypothèse était que la disparité des résultats des études pharmacogénétiques testant le gène du récepteur 5-HT2A était liée à l'interférence des symptômes négatifs eux-mêmes sous influence génétique. Nous avons donc choisi de tester le polymorphisme -1438A/G de la région promotrice du gène codant pour le récepteur 5-HT2A et la réponse aux antipsychotiques, évaluant de manière parallèle les variables cliniques pouvant aggraver la réponse aux traitements. Dans ce premier travail, nous avons constaté que les sujets mauvais répondeurs se définissent surtout par la gravité des symptômes négatifs. Nous ne retrouvons pas d'association positive entre le polymorphisme génétique -1438A/G et la réponse aux antipsychotiques atypiques. Toutefois, l'allèle A et le génotype AA semblent être significativement associés à l'intensité des symptômes négatifs intervenant ainsi comme potentiel facteur confusionnant dans les études pharmacogénétiques testant le récepteur 5-HT2A. Les théories dopaminergiques et sérotoninergiques dans la schizophrénie ont été enrichies d'autres hypothèses pharmacologiques comme l'implication des systèmes adrénergiques, histaminiques, muscariniques ou cannabinoides. Plusieurs arguments permettaient d'envisager le gène du récepteur CB1 comme potentiellement impliqué dans la réponse médicamenteuse chez les patients schizophrènes. La plupart des études épidémiologiques montrent que les patients schizophrènes consomment jusqu'à deux fois plus de cannabis que dans la population générale. Les études post mortem réalisées chez les patients schizophrènes montrent une augmentation de la densité de ces récepteurs au niveau du cortex préfrontal dorsolatéral et cela de manière indépendante à la consommation récente de cannabis. La localisation cérébrale des récepteurs CB1, leur rôle interactif avec d'autres neurotransmetteurs en particulier la dopamine ou le glutamate ont permis d'envisager l'hypothèse endocannabinoide de la schizophrénie. Le gène du récepteur CB1 est localisé sur la région chromosomique 6q14-15, une région potentiellement impliquée dans la schizophrénie. Dans un second travail, nous avons analysé le polymorphisme 1359G/A du récepteur CB1 (étant donné sa caractéristique de tag-SNP) dans la réponse aux antipsychotiques. Parallèlement, nous avons choisi de tester trois autres polymorphismes couvrant environ 14kb du gène du CB1. Nous trouvons une association significative entre l'allèle G et la mauvaise réponse aux antipsychotiques mais pas d'association avec la maladie. Les travaux de recherche en pharmacogénétique semblent pertinents dans la prédiction de la qualité de la réponse aux traitements chez les patients schizophrènes. Dans la mesure où les mécanismes d'actions des antipsychotiques sont connus, il semble aisé de tester les gènes des récepteurs cibles dans la prédiction de la réponse médicamenteuse. Ce type d'approche pourrait être contributive comme outil complémentaire au psychiatre afin d'améliorer le confort des patients à travers une meilleure compliance.