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3. Decreased telomere length in a subgroup of young individuals with bipolar disorders: replication in the FACE-BD cohort and association with the shelterin component POT1

Author

Spano, Luana, Marie-Claire, Cynthia, Godin, Ophélia, Lebras, Apolline, Courtin, Cindie, Laplanche, Jean-Louis, Leboyer, Marion, Aouizerate, Bruno, Lefrere, Antoine, Belzeaux, Raoul, Courtet, Philippe, Olié, Emilie, Dubertret, Caroline, Schwan, Raymund, Aubin, Valérie, Roux, Paul, Polosan, Mircea, Samalin, Ludovic, Haffen, Emmanuel, Bellivier, Frank, and Etain, Bruno

Published
2024
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4. Violent suicide attempt history in elderly patients with bipolar disorder: The role of sex, abdominal obesity, and verbal memory: Results from the FACE-BD cohort (FondaMental Advanced center of Expertise for Bipolar Disorders)

Author

Lengvenyte, Aiste, Aouizerate, Bruno, Aubin, Valerie, Loftus, Joséphine, Marlinge, Emeline, Belzeaux, Raoul, Dubertret, Caroline, Gard, Sebastien, Haffen, Emmanuel, Schwan, Raymund, Llorca, Pierre-Michel, Passerieux, Christine, Roux, Paul, Polosan, Mircea, Etain, Bruno, Leboyer, Marion, Courtet, Philippe, and Olié, Emilie

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

Background: Bipolar disorder (BD) is a chronic, lifelong condition, associated with increased risk of obesity, cognitive impairment, and suicidal behaviors. Abdominal obesity and a higher risk of violent suicide attempt (SA) seem to be shared correlates with older age, BD, and male sex until middle age when menopause-related female body changes occur. This study aimed at assessing the role of abdominal obesity and cognition in the violent SA burden of individuals with BD.Methods: From the well-defined nationwide cohort FACE-BD (FondaMental Advanced center of Expertise for Bipolar Disorders), we extracted data on 619 euthymic BD patients that were 50 years or older at inclusion. Cross-sectional clinical, cognitive, and metabolic assessments were performed. SA history was based on self-report.Results: Violent SA, in contrast to non-violent and no SA, was associated with higher waist circumference, abdominal obesity and poorer California Verbal Learning Test short-delay free recall (CVLT-SDFR) (ANOVA, p < .001, p = .014, and p = .006). Waist circumference and abdominal obesity were associated with violent SA history independently of sex, BD type and anxiety disorder (Exp(B) 1.02, CI 1.00-1.05, p = .018; Exp(B) 2.16, CI 1.00-4.64, p = .009, accordingly). In an exploratory model, waist circumference and CVLT-SDFR performance mediated the association between male sex and violent SA.Limitations: Cross-sectional design and retrospective reporting.Conclusions: Violent SA history was associated with abdominal obesity and poorer verbal memory in older age BD patients. These factors were interlinked and might mediate the association between male sex and violent SA.

Published
2022
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5. Predictors of functional impairment in bipolar disorder: Results from 13 cohorts from seven countries by the global bipolar cohort collaborative.

Author

Burdick, Katherine, Millett, Caitlin, Yocum, Anastasia, Altimus, Cara, Andreassen, Ole, Aubin, Valerie, Belzeaux, Raoul, Berk, Michael, Biernacka, Joanna, Blumberg, Hilary, Cleare, Anthony, Diaz-Byrd, Claudia, Dubertret, Caroline, Etain, Bruno, Lagerberg, Trine, Leboyer, Marion, Martinez-Aran, Anabel, McElroy, Susan, Mitchell, Philip, Olie, Emilie, Olorunfemi, Phebe, Passerieux, Christine, Peters, Amy, Pham, Daniel, Polosan, Mircea, Potter, Julia, Sajatovic, Martha, Samalin, Ludovic, Schwan, Raymund, Shanahan, Megan, Solé, Brisa, Strawbridge, Rebecca, Stuart, Amanda, Torres, Ivan, Ueland, Torrill, Vieta, Eduard, Williams, Lana, Wrobel, Anna, Yatham, Lakshmi, Young, Allan, Nierenberg, Andrew, McInnis, Melvin, Forester, Brent, Fullerton, Janice, Frye, Mark, Gard, Sébastien, Godin, Ophelia, Haffen, Emmanuel, Eyler, Lisa, and Klaus, Federica

Subjects
Humans, Bipolar Disorder, Prospective Studies, Longitudinal Studies, Affect, Cohort Studies
Abstract

OBJECTIVES: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. METHODS: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived higher versus lower function as the dependent variable and selected clinical and demographic variables as predictors. RESULTS: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. CONCLUSIONS: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Published
2022

7. The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice

Author

Becker, Léa J., Fillinger, Clémentine, Waegaert, Robin, Journée, Sarah H., Hener, Pierre, Ayazgok, Beyza, Humo, Muris, Karatas, Meltem, Thouaye, Maxime, Gaikwad, Mithil, Degiorgis, Laetitia, Santin, Marie des Neiges, Mondino, Mary, Barrot, Michel, Ibrahim, El Chérif, Turecki, Gustavo, Belzeaux, Raoul, Veinante, Pierre, Harsan, Laura A., Hugel, Sylvain, Lutz, Pierre-Eric, and Yalcin, Ipek

Published
2023
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10. Crossed clinical features between eating disorders and types of bipolar disorder: Results from the FondaMental Advanced Centers of Expertise - Bipolar Disorder cohort

Author

Flaudias, Valentin, Samalin, Ludovic, Godin, Ophélia, Gard, Sébastien, Brousse, Georges, Loftus, Joséphine, Aubin, Valérie, Belzeaux, Raoul, Dubertret, Caroline, Le Strat, Yann, Mazer, Nicolas, de Prémorel, Alix, Roux, Paul, Polosan, Mircea, Schwitzer, Thomas, Aouizerate, Bruno, Llorca, Pierre-Michel, Biseul, Isabelle, Etain, Bruno, Moirand, Remi, Olié, Emilie, Haffen, Emmanuel, Leboyer, Marion, Courtet, Philippe, Icick, Romain, and Guillaume, Sébastien

Published
2023
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12. Clinical characteristics associated with discrepancies between self- and clinician-rated suicidal ideation in patients with bipolar disorder (FACE-BD cohort)

Author

Nobile, Bénédicte, Belzeaux, Raoul, Aouizerate, Bruno, Dubertret, Caroline, Haffen, Emmanuel, Llorca, Pierre-Michel, Roux, Paul, Polosan, Mircea, Schwan, Raymund, Walter, Michel, Rey, Romain, Januel, Dominique, Leboyer, Marion, Bellivier, Frank, Etain, Bruno, Courtet, Philippe, and Olié, Emilie

Published
2023
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13. Associations of white blood cell and platelet counts with specific depressive symptom dimensions in patients with bipolar disorder: Analysis of data from the FACE-BD cohort

Author

Lengvenyte, Aiste, Strumila, Robertas, Belzeaux, Raoul, Aouizerate, Bruno, Dubertret, Caroline, Haffen, Emmanuel, Llorca, Pierre-Michel, Roux, Paul, Polosan, Mircea, Schwan, Raymund, Walter, Michel, D'Amato, Thierry, Januel, Dominique, Leboyer, Marion, Bellivier, Frank, Etain, Bruno, Navickas, Alvydas, Olié, Emilie, and Courtet, Philippe

Published
2023
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14. Handedness in bipolar disorders is associated with specific neurodevelopmental features: results of the BD-FACE cohort

Author

Mallet, Jasmina, Godin, Ophélia, Mazer, Nicolas, Le Strat, Yann, Bellivier, Frank, Belzeaux, Raoul, Etain, Bruno, Fond, Guillaume, Gard, Sébastien, Henry, Chantal, Leboyer, Marion, Llorca, Pierre-Michel, Loftus, Joséphine, Olié, Emilie, Passerieux, Christine, Polosan, Mircea, Schwan, Raymund, Roux, Paul, and Dubertret, Caroline

Published
2022
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16. External Evaluation of Population Pharmacokinetics Models of Lithium in the Bipolar Population

Author

Lereclus Aurélie, Boniffay Andréa, Kallée Gauvind, Blin Olivier, Belzeaux Raoul, Frédéric Dayan, Benito Sylvain, and Guilhaumou Romain

Subjects
lithium, bipolar disorder, population pharmacokinetics, external evaluation, therapeutic drug monitoring, treatment optimization, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Lithium has been used in the treatment of bipolar disorder for several decades. Treatment optimization is recommended for this drug, due to its narrow therapeutic range and a large pharmacokinetics (PK) variability. In addition to therapeutic drug monitoring, attempts have been made to predict individual lithium doses using population pharmacokinetics (popPK) models. This study aims to assess the clinical applicability of published lithium popPK models by testing their predictive performance on two different external datasets. Available PopPK models were identified and their predictive performance was determined using a clinical dataset (46 patients/samples) and the literature dataset (89 patients/samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated, and the results of both external evaluations compared. Only one model met the acceptability criteria for both datasets. Overall, there was a lack of predictability of models; median PE and median absolute PE, respectively, ranged from −6.6% to 111.2% and from 24.4% to 111.2% for the literature dataset, and from −4.5% to 137.6% and from 24.9% to 137.6% for the clinical dataset. Most models underpredicted the observed concentrations (7 out of 10 models presented a negative bias). Renal status was included as a covariate of lithium’s clearance in only two models. To conclude, most of lithium’s PopPK models had limited predictive performances related to the absence of covariates of interest included, such as renal status. A solution to this problem could be to improve the models with methodologies such as metamodeling. This could be useful in the perspective of model-informed precision dosing.

Published
2023
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18. The course of bipolar disorder as a function of the presence and sequence of onset of comorbid alcohol use disorders in outpatients attending the Fondamental Advanced Centres of Expertise

Author

Icick, Romain, Gard, Sébastien, M'Bailara, Katia, Biseul, Isabelle, Samalin, Ludovic, Brousse, Georges, Flaudias, Valentin, Llorca, Pierre-Michel, Loftus, Joséphine, Cussac, Iréna, Aubin, Valérie, Schwan, Raymund, Roux, Paul, Polosan, Mircea, Courtet, Philippe, Olié, Emilie, Henry, Chantal, Mazer, Nicolas, Haffen, Emmanuel, Etain, Bruno, Leboyer, Marion, Bellivier, Frank, Belzeaux, Raoul, Godin, Ophélia, and Guillaume, Sébastien

Published
2021
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19. Pharmacological treatment profiles in the FACE-BD cohort: An unsupervised machine learning study, applied to a nationwide bipolar cohort✰

Author

Brodeur, Sébastien, Terrisse, Hugo, Pouchon, Arnaud, Godin, Ophelia, Aouizerate, Bruno, Aubin, Valerie, Bellivier, Frank, Belzeaux, Raoul, Bougerol, Thierry, Courtet, Philippe, Dubertret, Caroline, Gard, Sebastien, Haffen, Emmanuel, Henry, Chantal, Leboyer, Marion, Olié, Emilie, Roux, Paul, Samalin, Ludovic, Schwan, Raymund, Etain, Bruno, Bosson, Jean-Luc, and Polosan, Mircea

Published
2021
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20. Clinical characteristics of bipolar disorders with postpartum depressive onset

Author

Etain, B., Henry, C., Olié, E., Leboyer, M., Haffen, E., Llorca, P.M., Barteau, V., Bensalem, S., Godin, O., Laouamri, H., Souryis, K., Hotier, S., Pelletier, A., Drancourt, N., Sanchez, J.P., Saliou, E., Hebbache, C., Petrucci, J., Willaume, L., Bourdin, E., Bellivier, F., Carminati, M., Marlinge, E., Meheust, J., Antoniol, B., Desage, A., Gard, S., Jutant, A., Mbailara, K., Minois, I., Zanouy, L., Abettan, C., Bardin, L., Cazals, A., Courtet, P., Deffinis, B., Ducasse, D., Gachet, M., Henrion, A., Martinerie, E., Molière, F., Noisette, B., Tarquini, G., Azorin, J.M., Belzeaux, R., Correard, N., Consoloni, J.L., Groppi, F., Lescalier, L., Montant, J., Rebattu, M., Viglianese, N., Cohen, R., Kahn, J.P., Milazzo, M., Wajsbrot-Elgrabli, O., Bougerol, T., Fredembach, B., Suisse, A., Halili, B., Pouchon, A., Polosan, M., Galliot, A.M., Grévin, I., Cannavo, A.S., Kayser, N., Passerieux, C., Roux, P., Aubin, V., Cussac, I., Dupont, M.A., Loftus, J., Medecin, I., Dubertret, C., Mazer, N., Portalier, C., Scognamiglio, C., Bing, A., Tebeka, Sarah, Godin, Ophelia, Mazer, Nicolas, Bellivier, Frank, Courtet, Philippe, Etain, Bruno, Gard, Sébastien, Leboyer, Marion, Llorca, Pierre-Michel, Loftus, Joséphine, Olié, Emilie, Passerieux, Christine, Polosan, Mircea, Schwan, Raymund, Belzeaux, Raoul, and Dubertret, Caroline

Published
2021
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21. Trajectories of medication adherence in patients with Bipolar Disorder along 2 years-follow-up

Author

Consoloni, Julia-Lou, M'Bailara, Katia, Perchec, Cyrille, Aouizerate, Bruno, Aubin, Valérie, Azorin, Jean-Michel, Bellivier, Frank, Correard, Nadia, Courtet, Philippe, Dubertret, Caroline, Etain, Bruno, Gard, Sébastien, Haffen, Emmanuel, Leboyer, Marion, Llorca, Pierre-Michel, Olié, Emilie, Polosan, Mircea, Roux, Paul, Schwan, Raymund, Samalin, Ludovic, and Belzeaux, Raoul

Published
2021
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27. Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative

Author

Burdick, Katherine E., primary, Millett, Caitlin E., additional, Yocum, Anastasia K., additional, Altimus, Cara M., additional, Andreassen, Ole A., additional, Aubin, Valerie, additional, Belzeaux, Raoul, additional, Berk, Michael, additional, Biernacka, Joanna M., additional, Blumberg, Hilary P., additional, Cleare, Anthony J., additional, Diaz-Byrd, Claudia, additional, Dubertret, Caroline, additional, Etain, Bruno, additional, Eyler, Lisa T., additional, Forester, Brent P., additional, Fullerton, Janice M., additional, Frye, Mark A., additional, Gard, Sébastien, additional, Godin, Ophelia, additional, Haffen, Emmanuel, additional, Klaus, Federica, additional, Lagerberg, Trine Vik, additional, Leboyer, Marion, additional, Martinez-Aran, Anabel, additional, McElroy, Susan, additional, Mitchell, Philip B., additional, Olie, Emilie, additional, Olorunfemi, Phebe, additional, Passerieux, Christine, additional, Peters, Amy T., additional, Pham, Daniel L., additional, Polosan, Mircea, additional, Potter, Julia R., additional, Sajatovic, Martha, additional, Samalin, Ludovic, additional, Schwan, Raymund, additional, Shanahan, Megan, additional, Solé, Brisa, additional, Strawbridge, Rebecca, additional, Stuart, Amanda L., additional, Torres, Ivan, additional, Ueland, Torrill, additional, Vieta, Eduard, additional, Williams, Lana J., additional, Wrobel, Anna L., additional, Yatham, Lakshmi N., additional, Young, Allan H., additional, Nierenberg, Andrew A., additional, and McInnis, Melvin G., additional

Published
2023
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31. Subjects suffering from bipolar disorder taking lithium are less likely to report physical pain: a FACE-BD study.

Author

Risch, Nathan, Dubois, Jonathan, Etain, Bruno, Aouizerate, Bruno, Bellivier, Frank, Belzeaux, Raoul, Dubertret, Caroline, Haffen, Emmanuel, Januel, Dominique, Leboyer, Marion, Lefrere, Antoine, Samalin, Ludovic, Polosan, Mircea, Rey, Romain, Roux, Paul, Schwan, Raymund, Walter, Michel, Courtet, Philippe, and Olié, Emilie

Subjects
LITHIUM carbonate, BIPOLAR disorder, SLEEP quality, SUICIDE risk factors, ATTEMPTED suicide
Abstract

Background. Physical pain is a common issue in people with bipolar disorder (BD). It worsens mental health and quality of life, negatively impacts treatment response, and increases the risk of suicide. Lithium, which is prescribed in BD as a mood stabilizer, has shown promising effects on pain. Methods. This naturalistic study included 760 subjects with BD (FACE-BD cohort) divided in two groups: with and without self-reported pain (evaluated with the EQ-5D-5L questionnaire). In this sample, 176 subjects were treated with lithium salts. The objectives of the study were to determine whether patients receiving lithium reported less pain, and whether this effect was associated with the recommended mood-stabilizing blood concentration of lithium. Results. Subjects with lithium intake were less likely to report pain (odds ratio [OR] = 0.59, 95% confidence interval [CI], 0.35-0.95; p = 0.036) after controlling for sociodemographic variables, BD type, lifetime history of psychiatric disorders, suicide attempt, personality traits, current depression and anxiety levels, sleep quality, and psychomotor activity. Subjects taking lithium were even less likely to report pain when lithium concentration in blood was =0.5 mmol/l (OR = 0.45, 95% CI, 0.24-0.79; p = 0.008). Conclusions. This is the first naturalistic study to show lithium's promising effect on pain in subjects suffering from BD after controlling for many confounding variables. This analgesic effect seems independent of BD severity and comorbid conditions. Randomized controlled trials are needed to confirm the analgesic effect of lithium salts and to determine whether lithium decreases pain in other vulnerable populations. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Decreased telomere length in a subgroup of young individuals with bipolar disorders: replication in the FACE-BD cohort and association with the shelterin component POT1

Author

Marie-Claire, Cynthia, primary, Spano, Luana, additional, Godin, Ophelia, additional, Lebras, Apolline, additional, Courtin, Cindie, additional, Laplanche, Jean-Louis, additional, Leboyer, Marion, additional, Aouizerate, Bruno, additional, Lefrere, Antoine, additional, Belzeaux, Raoul, additional, Courtet, Philippe, additional, Olié, Emilie, additional, Dubertret, Caroline, additional, SCHWAN, Raymund, additional, Aubin, Valérie, additional, Roux, Paul, additional, Polosan, Mircea, additional, Samalin, Ludovic, additional, haffen, emmanuel, additional, Collaborators, FondaMental Advanced Centers of Expertise in Bipolar Disorde, additional, Bellivier, Frank, additional, and Etain, Bruno, additional

Published
2023
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35. Factors associated with lamotrigine concentration/dose ratio in individuals with bipolar disorders

Author

Chouchana, Margot, primary, Delage, Clément, additional, Godin, Ophélia, additional, Fontan, Jean- Eudes, additional, Bellivier, Frank, additional, Gard, Sebastien, additional, Aubin, Valérie, additional, Belzeaux, Raoul, additional, Dubertret, Caroline, additional, Haffen, Emmanuel, additional, Leboyer, Marion, additional, Olie, Emilie, additional, Courtet, Philippe, additional, Polosan, Mircea, additional, Roux, Paul, additional, Samalin, Ludovic, additional, Schwan, Raymund, additional, Lefrere, Antoine, additional, Bloch, Vanessa, additional, and Etain, Bruno, additional

Published
2023
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37. Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode

Author

Consoloni, Julia-Lou, Ibrahim, El Chérif, Lefebvre, Marie-Noëlle, Zendjidjian, Xavier, Olié, Emilie, Mazzola-Pomietto, Pascale, Desmidt, Thomas, Samalin, Ludovic, Llorca, Pierre-Michel, Abbar, Mocrane, Lopez-Castroman, Jorge, Haffen, Emmanuel, Baumstarck, Karine, Naudin, Jean, Azorin, Jean-Michel, El-Hage, Wissam, Courtet, Philippe, and Belzeaux, Raoul

Published
2018
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41. Two polygenic mouse models of major depressive disorders identify TMEM161Bas a potential biomarker of disease in humans

Author

El Yacoubi, Malika, Altersitz, Claire, Latapie, Violaine, Rizkallah, Elari, Arthaud, Sébastien, Bougarel, Laure, Pereira, Marcela, Wierinckx, Anne, El-Hage, Wissam, Belzeaux, Raoul, Turecki, Gustavo, Svenningsson, Per, Martin, Benoît, Lachuer, Joël, Vaugeois, Jean-Marie, and Jamain, Stéphane

Abstract

Treatments are only partially effective in major depressive disorders (MDD) but no biomarker exists to predict symptom improvement in patients. Animal models are essential tools in the development of antidepressant medications, but while recent genetic studies have demonstrated the polygenic contribution to MDD, current models are limited to either mimic the effect of a single gene or environmental factor. We developed in the past a model of depressive-like behaviors in mice (H/Rouen), using selective breeding based on behavioral reaction after an acute mild stress in the tail suspension test. Here, we propose a new mouse model of depression (H-TST) generated from a more complex genetic background and based on the same selection process. We first demonstrated that H/Rouen and H-TST mice had similar phenotypes and were more sensitive to glutamate-related antidepressant medications than selective serotonin reuptake inhibitors. We then conducted an exome sequencing on the two mouse models and showed that they had damaging variants in 174 identical genes, which have also been associated with MDD in humans. Among these genes, we showed a higher expression level of Tmem161bin brain and blood of our two mouse models. Changes in TMEM161Bexpression level was also observed in blood of MDD patients when compared with controls, and after 8-week treatment with duloxetine, mainly in good responders to treatment. Altogether, our results introduce H/Rouen and H-TST as the two first polygenic animal models of MDD and demonstrate their ability to identify biomarkers of the disease and to develop rapid and effective antidepressant medications.

Published
2024
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43. GPR56/ADGRG1 is associated with response to antidepressant treatment

Author

Belzeaux, Raoul, Gorgievski, Victor, Fiori, Laura M., Lopez, Juan Pablo, Grenier, Julien, Lin, Rixing, Nagy, Corina, Ibrahim, El Chérif, Gascon, Eduardo, Courtet, Philippe, Richard-Devantoy, Stéphane, Berlim, Marcelo, Chachamovich, Eduardo, Théroux, Jean-François, Dumas, Sylvie, Giros, Bruno, Rotzinger, Susan, Soares, Claudio N., Foster, Jane A., Mechawar, Naguib, Tall, Gregory G., Tzavara, Eleni T., Kennedy, Sidney H., and Turecki, Gustavo

Published
2020
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44. Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants

Author

Ju, Chelsey, Fiori, Laura M., Belzeaux, Raoul, Theroux, Jean-Francois, Chen, Gary Gang, Aouabed, Zahia, Blier, Pierre, Farzan, Faranak, Frey, Benicio N., Giacobbe, Peter, Lam, Raymond W., Leri, Francesco, MacQueen, Glenda M., Milev, Roumen, Müller, Daniel J, Parikh, Sagar V., Rotzinger, Susan, Soares, Claudio N., Uher, Rudolf, Li, Qingqin, Foster, Jane A., Kennedy, Sidney H., and Turecki, Gustavo

Published
2019
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45. Childhood maltreatment contributes to the medical morbidity of individuals with bipolar disorders.

Author

Godin, Ophélia, Leboyer, Marion, Grillault Laroche, Diane, Aubin, Valérie, Belzeaux, Raoul, Courtet, Philippe, Dubertret, Caroline, Gard, Sébastien, Haffen, Emmanuel, Olie, Emilie, Polosan, Mircea, Roux, Paul, Samalin, Ludovic, Schwan, Raymund, Bellivier, Frank, and Etain, Bruno

Subjects
DISEASE risk factors, MIGRAINE complications, THYROID diseases, CHILD abuse, CROSS-sectional method, MULTIVARIATE analysis, RISK assessment, QUESTIONNAIRES, DESCRIPTIVE statistics, RESEARCH funding, HEADACHE, DUODENAL ulcers, BIPOLAR disorder, COMORBIDITY, DISEASE complications
Abstract

Background: Individuals with bipolar disorders (BD) are at risk of premature death, mainly due to medical comorbidities. Childhood maltreatment might contribute to this medical morbidity, which remains underexplored in the literature. Methods: We assessed 2891 outpatients with BD (according to DSM-IV criteria). Childhood maltreatment was assessed using the Childhood Trauma Questionnaire. Lifetime diagnoses for medical disorders were retrospectively assessed using a systematic interview and checked against medical notes. Medical morbidity was defined by the sum of medical disorders. We investigated associations between childhood maltreatment (neglect and abuse) and medical morbidity while adjusting for potential confounders. Results: One quarter of individuals had no medical comorbidities, while almost half of them had at least two. Multivariable regression showed that childhood maltreatment (mainly abuse, but also sexual abuse) was associated with a higher medical morbidity. Medical morbidity was also associated with sex, age, body mass index, sleep disturbances, lifetime anxiety disorders and lifetime density of mood episodes. Childhood maltreatment was associated with an increased prevalence of four (i.e. migraine/headache, drug eruption, duodenal ulcer, and thyroid diseases) of the fifteen most frequent medical disorders, however with no difference in terms of age at onset. Conclusions: This large cross-sectional study confirmed a high medical morbidity in BD and its association with childhood maltreatment. The assessment of childhood maltreatment in individuals with BD should be systematically included in routine care and the potential impact on physical health of psycho-social interventions targeting childhood maltreatment and its consequences should be evaluated. [ABSTRACT FROM AUTHOR]

Published
2023
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46. Definition of early age at onset in bipolar disorder according to distinctive neurodevelopmental pathways: insights from the FACE-BD study.

Author

Corponi, Filippo, Lefrere, Antoine, Leboyer, Marion, Bellivier, Frank, Godin, Ophelia, Loftus, Josephine, Courtet, Philippe, Dubertret, Caroline, Haffen, Emmanuel, Llorca, Pierre Michel, Roux, Paul, Polosan, Mircea, Schwan, Raymund, Samalin, Ludovic, Olié, Emilie, Etain, Bruno, Seriès, Peggy, and Belzeaux, Raoul

Subjects
DIAGNOSIS of bipolar disorder, REFERENCE values, PREDICTIVE tests, AGE distribution, RESEARCH methodology, AGE factors in disease, CHILD psychopathology, RESEARCH funding, DESCRIPTIVE statistics, RECEIVER operating characteristic curves, BIPOLAR disorder
Abstract

Background: Converging evidence suggests that a subgroup of bipolar disorder (BD) with an early age at onset (AAO) may develop from aberrant neurodevelopment. However, the definition of early AAO remains unprecise. We thus tested which age cut-off for early AAO best corresponds to distinguishable neurodevelopmental pathways. Methods: We analyzed data from the FondaMental Advanced Center of Expertise-Bipolar Disorder cohort, a naturalistic sample of 4421 patients. First, a supervised learning framework was applied in binary classification experiments using neurodevelopmental history to predict early AAO, defined either with Gaussian mixture models (GMM) clustering or with each of the different cut-offs in the range 14 to 25 years. Second, an unsupervised learning approach was used to find clusters based on neurodevelopmental factors and to examine the overlap between such data-driven groups and definitions of early AAO used for supervised learning. Results: A young cut-off, i.e. 14 up to 16 years, induced higher separability [mean nested cross-validation test AUROC = 0.7327 (± 0.0169) for ⩽16 years]. Predictive performance deteriorated increasing the cut-off or setting early AAO with GMM. Similarly, defining early AAO below 17 years was associated with a higher degree of overlap with data-driven clusters (Normalized Mutual Information = 0.41 for ⩽17 years) relatively to other definitions. Conclusions: Early AAO best captures distinctive neurodevelopmental patterns when defined as ⩽17 years. GMM-based definition of early AAO falls short of mapping to highly distinguishable neurodevelopmental pathways. These results should be used to improve patients' stratification in future studies of BD pathophysiology and biomarkers. [ABSTRACT FROM AUTHOR]

Published
2023
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48. Antidepressive effects of targeting ELK-1 signal transduction

Author

Apazoglou, Kallia, Farley, Séverine, Gorgievski, Victor, Belzeaux, Raoul, Lopez, Juan Pablo, Grenier, Julien, and Ibrahim, El Chérif

Subjects
Depression (Mood disorder) -- Drug therapy -- Development and progression, Extracellular signal-regulated kinases -- Health aspects -- Physiological aspects, Antidepressants -- Research, Pharmacological research, Transcription factors -- Physiological aspects -- Health aspects, Cellular signal transduction, Messenger RNA, Mental disorders, Job stress, Major depressive disorder, Tricyclic antidepressants, Suicide, RNA, Biological sciences, Health
Abstract

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement.sup.1. In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted.sup.2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation.sup.5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner.sup.8, as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1. The transcription factor ELK-1 is upregulated in patients with major depressive disorder, and selective inhibition of hippocampal ELK-1 produces rapid antidepressive effects in rodent models of depression., Author(s): Kallia Apazoglou [sup.1] , Séverine Farley [sup.1] , Victor Gorgievski [sup.1] , Raoul Belzeaux [sup.2] [sup.3] [sup.4] , Juan Pablo Lopez [sup.2] , Julien Grenier [sup.5] , El Chérif [...]

Published
2018
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50. Definition of early age at onset in bipolar disorder according to distinctive neurodevelopmental pathways:Insights from the FACE-BD study

Author

Corponi, Filippo, Lefrere, Antoine, Leboyer, Marion, Bellivier, Frank, Godin, Ophelia, Loftus, Josephine, Courtet, Philippe, Dubertret, Caroline, Haffen, Emmanuel, Llorca, Pierre Michel, Roux, Paul, Polosan, Mircea, Schwan, Raymund, Samalin, Ludovic, Olié, Émilie, Etain, Bruno, Seriès, Peggy, Belzeaux, Raoul, University of Edinburgh, Assistance Publique - Hôpitaux de Marseille (APHM), Fondation FondaMental [Créteil], Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pôle de Psychiatrie [Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital H. Mondor - A. Chenevier, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Princesse Grace, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Louis Mourier - AP-HP [Colombes], Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481) (NEURO), Université de Franche-Comté (UFC), CHU Clermont-Ferrand, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Centre Hospitalier de Versailles André Mignot (CHV), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Grenoble, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Psychothérapique de Nancy [Laxou] (CPN), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and Pôle Digestif [CHRU Montpellier]

Subjects
bipolar disorder, machine learning, neurodevelopment, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Age at onset, age at onset
Abstract

BackgroundConverging evidence suggests that a subgroup of bipolar disorder (BD) with an early age at onset (AAO) may develop from aberrant neurodevelopment. However, the definition of early AAO remains unprecise. We thus tested which age cut-off for early AAO best corresponds to distinguishable neurodevelopmental pathways.MethodsWe analyzed data from the FondaMental Advanced Center of Expertise-Bipolar Disorder cohort, a naturalistic sample of 4421 patients. First, a supervised learning framework was applied in binary classification experiments using neurodevelopmental history to predict early AAO, defined either with Gaussian mixture models (GMM) clustering or with each of the different cut-offs in the range 14 to 25 years. Second, an unsupervised learning approach was used to find clusters based on neurodevelopmental factors and to examine the overlap between such data-driven groups and definitions of early AAO used for supervised learning.ResultsA young cut-off, i.e. 14 up to 16 years, induced higher separability [mean nested cross-validation test AUROC = 0.7327 (± 0.0169) for ⩽16 years]. Predictive performance deteriorated increasing the cut-off or setting early AAO with GMM. Similarly, defining early AAO below 17 years was associated with a higher degree of overlap with data-driven clusters (Normalized Mutual Information = 0.41 for ⩽17 years) relatively to other definitions.ConclusionsEarly AAO best captures distinctive neurodevelopmental patterns when defined as ⩽17 years. GMM-based definition of early AAO falls short of mapping to highly distinguishable neurodevelopmental pathways. These results should be used to improve patients' stratification in future studies of BD pathophysiology and biomarkers.

Published
2023

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