142 results on '"Turecki, G."'
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2. Transthyretin orchestrates vitamin B12-induced stress resilience
- Author
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Stein, G., primary, Aly, J.S., additional, Manzolillo, A., additional, Lange, L., additional, Riege, K., additional, Hussain, I., additional, Heller, E.A., additional, Cubillos, S., additional, Ernst, T., additional, Hübner, C.A., additional, Turecki, G., additional, Hoffmann, S., additional, and Engmann, O., additional
- Published
- 2024
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- View/download PDF
3. Associations between epigenetic aging and childhood peer victimization, depression, and suicidal ideation in adolescence and adulthood: A study of two population-based samples
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Perret, L. C., primary, Geoffroy, M-C., additional, Barr, E., additional, Parnet, F., additional, Provencal, N., additional, Boivin, M., additional, O’Donnell, K. J., additional, Suderman, M., additional, Power, C., additional, Turecki, G., additional, and Ouellet-Morin, I., additional
- Published
- 2023
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- View/download PDF
4. Association of childhood externalizing, internalizing and comorbid symptoms with long-term economic outcomes
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Vergunst, F., primary, Commisso, M., additional, Geoffroy, M.-C., additional, Temcheff, C., additional, Scardera, S., additional, Poirier, M., additional, Côté, S., additional, Vitaro, F., additional, Turecki, G., additional, Tremblay, R., additional, and Orri, M., additional
- Published
- 2022
- Full Text
- View/download PDF
5. P.0696 Nuclei RNAseq reveals transcriptional alterations of prefrontal cortex astrocytes in a subpopulation of suicide completers.
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Dalbeyler, S., primary, Viollet, C., additional, Piechota, M., additional, Hoinkis, D., additional, Lawless, N., additional, Kuner, T., additional, Turecki, G., additional, Korostyński, M., additional, Hengerer, B., additional, and Ślęzak, M., additional
- Published
- 2021
- Full Text
- View/download PDF
6. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
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Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. Casas, Moser, Jennifer, Whitbourne, Stacey B., Brewer, Jessica V., Aslan, Mihaela, Connor, Todd, Argyres, Dean P., Stephens, Brady, Brophy, Mary T., Humphries, Donald E., Selva, Luis E., Do, Nhan, Shayan, Shahpoor, Cho, Kelly, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Mattocks, Kristin, Harley, John, Zablocki, Clement J., Whittle, Jeffrey, Jacono, Frank, Gutierrez, Salvador, Gibson, Gretchen, Hammer, Kimberly, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Mathew, Roy, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Ivins, Douglas, Mastorides, Stephen, Moorman, Jonathan, Gappy, Saib, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Okusaga, Olaoluwa, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Tandon, Neeraj, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Liangpunsakul, Suthat, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Constans, Joseph, Meyer, Paul, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Gaddy, Melinda, Wallbom, Agnes, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Ross, George, Tsao, Philip, Strollo, Patrick, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Huq, Mostaqul, Fayad, Joseph, Hung, Adriana, Lichy, Jack, Hurley, Robin, Robey, Brooks, Striker, Robert, Wray, Naomi R., Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F. M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Howard, David M., Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A., Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O'Reilly, Paul F., Oskarsson, Hogni, Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A. F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O'Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C. B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Penninx, Brenda W. J. H., Perlis, Roy H., Porteous, David J., Potash, James B., Preisig, Martin, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., O'Connell, Kevin S., Coombes, Brandon, Qiao, Zhen, Als, Thomas D., Børte, Sigrid, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Ferrier, I. 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P., Stephens, B., Brophy, M. T., Humphries, D. E., Selva, L. E., Do, N., Shayan, S., Cho, K., Pyarajan, S., Hauser, E., Sun, Y., Zhao, H., Wilson, P., Mcardle, R., Dellitalia, L., Mattocks, K., Harley, J., Zablocki, C. J., Whittle, J., Jacono, F., Gutierrez, S., Gibson, G., Hammer, K., Kaminsky, L., Villareal, G., Kinlay, S., Xu, J., Hamner, M., Mathew, R., Bhushan, S., Iruvanti, P., Godschalk, M., Ballas, Z., Ivins, D., Mastorides, S., Moorman, J., Gappy, S., Klein, J., Ratcliffe, N., Florez, H., Okusaga, O., Murdoch, M., Sriram, P., Yeh, S. S., Tandon, N., Jhala, D., Aguayo, S., Cohen, D., Sharma, S., Liangpunsakul, S., Oursler, K. A., Whooley, M., Ahuja, S., Constans, J., Meyer, P., Greco, J., Rauchman, M., Servatius, R., Gaddy, M., Wallbom, A., Morgan, T., Stapley, T., Sherman, S., Ross, G., Tsao, P., Strollo, P., Boyko, E., Meyer, L., Gupta, S., Huq, M., Fayad, J., Hung, A., Lichy, J., Hurley, R., Robey, B., Striker, R., Erlangsen, A., Kessler, R. C., Porteous, D., Ursano, R. J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards A.C., Galfalvy H., Levey D.F., Lori A., Shabalin A., Starnawska A., Su M.-H., Watson H.J., Adams M., Awasthi S., Gandal M., Hafferty J.D., Hishimoto A., Kim M., Okazaki S., Otsuka I., Ripke S., Ware E.B., Bergen A.W., Berrettini W.H., Bohus M., Brandt H., Chang X., Chen W.J., Chen H.-C., Crawford S., Crow S., DiBlasi E., Duriez P., Fernandez-Aranda F., Fichter M.M., Gallinger S., Glatt S.J., Gorwood P., Guo Y., Hakonarson H., Halmi K.A., Hwu H.-G., Jain S., Jamain S., Jimenez-Murcia S., Johnson C., Kaplan A.S., Kaye W.H., Keel P.K., Kennedy J.L., Klump K.L., Li D., Liao S.-C., Lieb K., Lilenfeld L., Liu C.-M., Magistretti P.J., Marshall C.R., Mitchell J.E., Monson E.T., Myers R.M., Pinto D., Powers A., Ramoz N., Roepke S., Rozanov V., Scherer S.W., Schmahl C., Sokolowski M., Strober M., Thornton L.M., Treasure J., Tsuang M.T., Witt S.H., Woodside D.B., Yilmaz Z., Zillich L., Adolfsson R., Agartz I., Air T.M., Alda M., Alfredsson L., Andreassen O.A., Anjorin A., Appadurai V., Soler 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Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.
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LD SCORE REGRESSION ,Genome-wide association study ,Suicide, Attempted ,3124 Neurology and psychiatry ,0302 clinical medicine ,Risk Factors ,Insomnia ,Suicide attempt ,GWAS ,Suïcidi ,Depression (differential diagnoses) ,Cause of death ,Psychiatry ,0303 health sciences ,Factors de risc en les malalties ,Mental Disorders ,Genetic Correlation ,Genome-wide Association Study ,Pleiotropy ,Polygenicity ,Suicide ,Suicide Attempt ,DEPRESSION ,3. Good health ,Genetic correlation ,Genome-Wide Association Study ,Humans ,Polymorphism, Single Nucleotide ,Depressive Disorder, Major ,Mental illness ,Cohort ,SEX ,medicine.symptom ,Human ,medicine.medical_specialty ,Risk factors in diseases ,BF ,Locus (genetics) ,BEHAVIORS ,Psykiatri ,EVENTS ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,medicine ,ddc:610 ,GENOME-WIDE ASSOCIATION ,IDEATION ,Socioeconomic status ,METAANALYSIS ,Biological Psychiatry ,030304 developmental biology ,business.industry ,Risk Factor ,Genetic architecture ,THOUGHTS ,RC0321 ,business ,Malalties mentals ,030217 neurology & neurosurgery - Abstract
Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551
- Published
- 2022
7. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
- Author
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Michael McCarthy, Claire O'Donovan, Urs Heilbronner, Ichiro Kusumi, Eduard Vieta, Liping Hou, Hsi-Chung Chen, Claire Slaney, Maria Grigoroiu-Serbanescu, Kazufumi Akiyama, Michael Bauer, Janusz K. Rybakowski, Frank Bellivier, Marion Leboyer, Katzutaka Shimoda, Palmiero Monteleone, Cristiana Cruceanu, Alessio Squassina, Stephanie H. Witt, Tadafumi Kato, Giovanni Severino, Alfonso Tortorella, J. Raymond DePaulo, Martin Alda, Louise Frisén, Mazda Adl, Martin Schalling, Per Hoffmann, Susan G. Leckband, Jean-Pierre Kahn, Jean-Michel Aubry, Francis J. McMahon, Sven Cichon, Alexandre Dayer, Tatyana Shekhtman, Franziska Degenhardt, James B. Potash, Bruno Etain, Joseph Frank, Antonio Benabarre, Bernhard T. Baune, Gloria Roberts, Ryota Hashimoto, Tomas Novak, Paul D. Shilling, Julia Veeh, Joanna M. Biernacka, Barbara König, Peter Falkai, Philip B. Mitchell, Urban Ösby, Esther Jiménez, Sébastien Gard, Mark A. Frye, Sarah Kittel-Schneider, Layla Kassem, Fasil Tekola-Ayele, Armin Birner, Cynthia Marie-Claire, Raffaella Ardau, Abesh Kumar Bhattacharjee, Stéphane Jamain, Julie Garnham, Guy A. Rouleau, Caterina Chillotti, Piotr M. Czerski, Thomas G. Schulze, Gustavo Turecki, Anbupalam Thalamuthu, Claudia Pisanu, Azmeraw T. Amare, Marina Mitjans, Sergi Papiol, Mario Maj, Bárbara Arias, Janice M. Fullerton, Nina Dalkner, Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Francis M. Mondimore, Eva Z. Reininghaus, Fernando S. Goes, Lena Backlund, Francesc Colom, Catharina Lavebratt, Christian Simhandl, Marcella Rietschel, Micah Cearns, Mikael Landén, Norio Ozaki, Gonzalo Laje, Barbara W. Schweizer, Nirmala Akula, Andrea Pfennig, Yi-Hsiang Hsu, John R. Kelsoe, Lina Martinsson, Markus M. Nöthen, Caroline M. Nievergelt, Pavla Stopkova, Mirko Manchia, Susan L. McElroy, Peter P. Zandi, Scott R. Clark, Joanna Hauser, Andreas J. Forstner, Po-Hsiu Kuo, Andreas Reif, Maria Del Zompo, Paul Grof, Fabian Streit, Ewa Ferensztajn-Rochowiak, Pablo Cervantes, Thomas Stamm, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Digital Health, Schubert, K. O., Thalamuthu, A., Amare, A. T., Frank, J., Streit, F., Adl, M., Akula, N., Akiyama, K., Ardau, R., Arias, B., Aubry, J. -M., Backlund, L., Bhattacharjee, A. K., Bellivier, F., Benabarre, A., Bengesser, S., Biernacka, J. M., Birner, A., Marie-Claire, C., Cearns, M., Cervantes, P., Chen, H. -C., Chillotti, C., Cichon, S., Clark, S. R., Cruceanu, C., Czerski, P. M., Dalkner, N., Dayer, A., Degenhardt, F., Del Zompo, M., Depaulo, J. R., Etain, B., Falkai, P., Forstner, A. J., Frisen, L., Frye, M. A., Fullerton, J. M., Gard, S., Garnham, J. S., Goes, F. S., Grigoroiu-Serbanescu, M., Grof, P., Hashimoto, R., Hauser, J., Heilbronner, U., Herms, S., Hoffmann, P., Hou, L., Hsu, Y. -H., Jamain, S., Jimenez, E., Kahn, J. -P., Kassem, L., Kuo, P. -H., Kato, T., Kelsoe, J., Kittel-Schneider, S., Ferensztajn-Rochowiak, E., Konig, B., Kusumi, I., Laje, G., Landen, M., Lavebratt, C., Leboyer, M., Leckband, S. G., Maj, M., Manchia, M., Martinsson, L., Mccarthy, M. J., Mcelroy, S., Colom, F., Mitjans, M., Mondimore, F. M., Monteleone, P., Nievergelt, C. M., Nothen, M. M., Novak, T., O'Donovan, C., Ozaki, N., Osby, U., Papiol, S., Pfennig, A., Pisanu, C., Potash, J. B., Reif, A., Reininghaus, E., Rouleau, G. A., Rybakowski, J. K., Schalling, M., Schofield, P. R., Schweizer, B. W., Severino, G., Shekhtman, T., Shilling, P. D., Shimoda, K., Simhandl, C., Slaney, C. M., Squassina, A., Stamm, T., Stopkova, P., Tekola-Ayele, F., Tortorella, A., Turecki, G., Veeh, J., Vieta, E., Witt, S. H., Roberts, G., Zandi, P. P., Alda, M., Bauer, M., Mcmahon, F. J., Mitchell, P. B., Schulze, T. G., Rietschel, M., and Baune, B. T.
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Oncology ,Multifactorial Inheritance ,Treatment response ,medicine.medical_specialty ,Lithium (medication) ,Bipolar disorder ,Poor responder ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Lithium ,DISEASE ,Article ,Cellular and Molecular Neuroscience ,Risk Factors ,Internal medicine ,medicine ,Humans ,Manic-depressive illness ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Depressió psíquica ,METAANALYSIS ,Biological Psychiatry ,Depression (differential diagnoses) ,MANIA ,Depressive Disorder ,Depressive Disorder, Major ,Trastorn bipolar ,Depression ,business.industry ,Major ,medicine.disease ,Pathway analysis ,Liti ,COMPARATIVE EFFICACY ,Psychiatry and Mental health ,Mental depression ,Schizophrenia ,Polygenic risk score ,Esquizofrènia ,Pharmacogenomics ,business ,RC321-571 ,medicine.drug - Abstract
Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
- Published
- 2021
8. The impact of antidepressant treatment on the network structure of neurocognition and core emotional depressive symptoms among depressed individuals with a history of suicide attempt: An 8-week clinical study.
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Richard-Devantoy S, Berlim MT, Garel N, Inja A, and Turecki G
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- Humans, Adult, Male, Female, Middle Aged, Escitalopram therapeutic use, Escitalopram pharmacology, Desvenlafaxine Succinate therapeutic use, Young Adult, Aged, Adolescent, Neuropsychological Tests, Emotions drug effects, Suicide, Attempted statistics & numerical data, Suicide, Attempted psychology, Depressive Disorder, Major drug therapy, Depressive Disorder, Major psychology, Antidepressive Agents therapeutic use
- Abstract
Background: A more in-depth understanding of the relationship between depressive symptoms, neurocognition and suicidal behavior could provide insights into the prognosis and treatment of major depressive disorder (MDD) and suicide. We conducted a network analysis among depressed patients examining associations between history of suicide attempt (HSA), core emotional major depression disorder, and key neurocognitive domains., Method: Depressed patients (n = 120) aged 18-65 years were recruited from a larger randomized clinical trial conducted at the Douglas Institute in Montreal, Canada. They were randomly assigned to receive one of two antidepressant treatments (i.e., escitalopram or desvenlafaxine) for 8 weeks. Core emotional MDD and key neurocognitive domains were assessed pre-post treatment., Results: At baseline, an association between history of suicide attempt (HSA) and phonemic verbal fluency (PVF) suggested that HSA patients reported lower levels of the latter. After 8 weeks of antidepressant treatment, HSA became conditionally independent from PVF. Similar results were found for both the HAM-D and the QIDS-SR core emotional MDD/neurocognitive networks., Conclusion: Network analysis revealed a pre-treatment relationship between a HSA and decreased phonemic VF among depressed patients, which was no longer present after 8 weeks of antidepressant treatment., Competing Interests: Declaration of competing interest All authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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9. Depression-Anxiety Coupling Strength as a predictor of relapse in major depressive disorder: A CAN-BIND wellness monitoring study report.
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Nunes A, Pavlova B, Cunningham JEA, Nuñez JJ, Quilty LC, Foster JA, Harkness KL, Ho K, Lam RW, Li QS, Milev R, Rotzinger S, Soares CN, Taylor VH, Turecki G, Kennedy SH, Frey BN, Rudzicz F, and Uher R
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- Humans, Male, Female, Adult, Middle Aged, Proportional Hazards Models, Depression psychology, Anxiety Disorders psychology, Psychiatric Status Rating Scales, Depressive Disorder, Major psychology, Recurrence, Anxiety psychology
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Background: A critical challenge in the study and management of major depressive disorder (MDD) is predicting relapse. We examined the temporal correlation/coupling between depression and anxiety (called Depression-Anxiety Coupling Strength, DACS) as a predictor of relapse in patients with MDD., Methods: We followed 97 patients with remitted MDD for an average of 394 days. Patients completed weekly self-ratings of depression and anxiety symptoms using the Quick Inventory of Depressive Symptoms (QIDS-SR) and the Generalized Anxiety Disorder 7-item scale (GAD-7). Using these longitudinal ratings we computed DACS as random slopes in a linear mixed effects model reflecting individual-specific degree of correlation between depression and anxiety across time points. We then tested DACS as an independent variable in a Cox proportional hazards model to predict relapse., Results: A total of 28 patients (29 %) relapsed during the follow-up period. DACS significantly predicted confirmed relapse (hazard ratio [HR] 1.5, 95 % CI [1.01, 2.22], p = 0.043; Concordance 0.79 [SE 0.04]). This effect was independent of baseline depressive or anxiety symptoms or their average levels over the follow-up period, and was identifiable more than one month before relapse onset., Limitations: Small sample size, in a single study. Narrow phenotype and comorbidity profiles., Conclusions: DACS may offer opportunities for developing novel strategies for personalized monitoring, early detection, and intervention. Future studies should replicate our findings in larger, diverse patient populations, develop individual patient prediction models, and explore the underlying mechanisms that govern the relationship of DACS and relapse., Competing Interests: Declaration of competing interest RM has received consulting and speaking honoraria from AbbVie, Eisai, Janssen, Lallemand, Lundbeck, Neonmind, and Otsuka, and research grants from CAN-BIND, CIHR, Janssen, Nubiyota, OBI and OMHF. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from: Abbvie, Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, CAN-BIND Solutions, Carnot, Grand Challenges Canada, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Medscape, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute, Otsuka, Pfizer/Viatris, Shanghai Mental Health Center, Sunnybrook Health Sciences Center, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. JAF has served on the Scientific Advisory Board for MRM Health NL and has received consulting/speaker fees from Klaire Labs, WebMD, Takeda Canada and Rothman, Benson, Hedges Inc. QSL is an employee of Janssen Research & Development, LLC and is a shareholder in Johnson & Johnson, which is the parent company of the Janssen companies. QSL declares that, except for income received from her primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. JJN is partially supported by a Marshall Fellowship Award from the UBC Institute of Mental Health. RU is supported by the Canada Research Chairs program. CS has received research funds from Clairvoyant Therapeutics, Otsuka, Eisai Inc. and served as an Advisory Board Member for Bayer, Pfizer, Eisai, Boheringer-Ingelheim. SHK has received engagements from Boehringer-Ingelheim, Janssen, Lundbeck, Merck, Neurotorium, Otsuka. CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Additional funding is provided by the Canadian Institutes of Health Research (CIHR), Lundbeck, Servier. Funding and/or in kind support is also provided by the investigators' universities and academic institutions. All study medications for the CAN-BIND-1 Trial were independently purchased at wholesale market values. The Wellness Monitoring Study was partially funded by Janssen Research & Development, LLC with research funding from Janssen to University Health Network., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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10. Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.
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Islam F, Lisoway A, Oh ES, Fiori LM, Magarbeh L, Elsheikh SSM, Kim HK, Kloiber S, Kennedy JL, Frey BN, Milev R, Soares CN, Parikh SV, Placenza F, Hassel S, Taylor VH, Leri F, Blier P, Uher R, Farzan F, Lam RW, Turecki G, Foster JA, Rotzinger S, Kennedy SH, and Müller DJ
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- Humans, Female, Male, Adult, Treatment Outcome, Middle Aged, Cytochrome P-450 CYP2C19 genetics, Quantitative Trait Loci, CpG Islands genetics, Antidepressive Agents therapeutic use, Antidepressive Agents pharmacokinetics, Citalopram therapeutic use, Citalopram pharmacokinetics, Citalopram blood, DNA Methylation drug effects, Polymorphism, Single Nucleotide, Aripiprazole therapeutic use, Aripiprazole pharmacokinetics, Depressive Disorder, Major drug therapy, Depressive Disorder, Major genetics, Escitalopram therapeutic use
- Abstract
Introduction: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19 , CYP2D6 , CYP3A4 , and ABCB1 , and its effect on these outcomes., Methods: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects., Results: Eleven cis- SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain ( q =0.027) and serum concentrations of ESC
adj ( q <0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated., Discussion: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored., Competing Interests: Dr. Benicio N. Frey has no conflicts to disclose. Dr. Roumen V. Milev has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE Pharmaceuticals, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes of Health Research (CIHR), Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute (OBI), and Ontario Mental Health Foundation (OMHF). Dr. Sagar V. Parikh has received research support or consulting income from Aifred, Assurex (Myriad), Janssen, Mensante, Otsuka, Sage, and Takeda. Dr. Stefanie Hassel has no conflicts of interest to disclose. Dr. Pierre Blier received honoraria for participation in advisory boards, giving lectures, and/or expert consultation from Allergan, Bristol Myers Squibb, Janssen, Lundbeck, Otsuka, Pierre Fabre Medicaments, Pfizer and Sunovion; he received grants from Allergan, Janssen, and Lundbeck/Otsuka. Dr. Faranak Farzan received funding from Michael Smith Foundation for Health Research, Natural Sciences and Engineering Research Council of Canada Discovery, and Canadian Institutes of Health Research. Dr. Raymond W. Lam has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Abbvie, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Boehringer-Ingelheim, Canadian Institutes of Health Research (CIHR), Canadian Network for Mood and Anxiety Treatments, Carnot, Healthy Minds Canada, Janssen, Lundbeck, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute (OBI), Otsuka, Pfizer, Unity Health, and VGH-UBCH Foundation. Dr. Gustavo Turecki has received an Investigator-initiated grant from Pfizer Canada, and honoraria from Bristol-Meyers Squibb Canada and Janssen Canada. Dr. Susan Rotzinger has received grant funding from the Ontario Brain Institute (OBI), and Canadian Institutes of Health Research (CIHR), and holds a patent Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Dr. Stefan Kloiber has received honorarium for past consultation from EmpowerPharm. Dr. Sidney H. Kennedy has received research funding or honoraria from the following sources: Abbott, Alkermes, Allergan, Bristol-Myers Squibb (BMS), Brain Canada, Canadian Institutes for Health Research (CIHR), Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute (OBI), Ontario Research Fund (ORF), Otsuka, Pfizer, Servier, Sunovion and holds stock in Field Trip Health. Dr. Daniel J. Müller reports to be a co-investigator on two pharmacogenetic studies where genetic test kits were provided as in-kind contributions by Myriad Neuroscience. All other authors report no conflicts of interest related to this work., (Thieme. All rights reserved.)- Published
- 2024
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11. Proteomic evidence of depression-associated astrocytic dysfunction in the human male olfactory bulb.
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Rahimian R, Perlman K, Fakhfouri G, Mpai R, Richard VR, Hercher C, Penney L, Davoli MA, Nagy C, Zahedi RP, Borchers CH, Giros B, Turecki G, and Mechawar N
- Abstract
The olfactory bulb (OB), a major structure of the limbic system, has been understudied in human investigations of psychopathologies such as depression. To explore more directly the molecular features of the OB in depression, a global comparative proteome analysis was carried out with human post-mortem OB samples from 11 males having suffered from depression and 12 healthy controls. We identified 188 differentially abundant proteins (with adjusted p < 0.05) between depressed cases and controls. Gene ontology and gene enrichment analyses suggested that these proteins are involved in biological processes including the complement and coagulation cascades. Cell type enrichment analysis displayed a significant reduction in several canonical astrocytic proteins in OBs from depressed patients. Furthermore, using RNA-fluorescence in-situ hybridization, we observed a decrease in the percentage of ALDH1L1
+ cells expressing canonical astrocytic markers including ALDOC, NFIA, GJA1 (connexin 43) and SLC1A3 (EAAT1). These results are consistent with previous reports of downregulated astrocytic marker expression in other brain regions in depressed patients. We also conducted a comparative phosphoproteomic analysis of OB samples and found a dysregulation of proteins involved in neuronal and astrocytic functions. To determine whether OB astrocytic abnormalities is specific to humans, we also performed proteomics on the OB of socially defeated male mice, a commonly used model of depression. Cell-type specific analysis revealed that in socially defeated animals, the most striking OB protein alterations were associated with oligodendrocyte-lineage cells rather than with astrocytes, highlighting an important species difference. Overall, this study further highlights cerebral astrocytic abnormalities as a consistent feature of depression in humans., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [CHB is the CSO of MRM Proteomics Inc., and the VP of Proteomics at Molecular You. RPZ is CEO of MRM Proteomics. The remaining authors declare no conflict of interest]., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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12. Transthyretin Orchestrates Vitamin B12-Induced Stress Resilience.
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Stein G, Aly JS, Manzolillo A, Lange L, Riege K, Hussain I, Heller EA, Cubillos S, Ernst T, Hübner CA, Turecki G, Hoffmann S, and Engmann O
- Abstract
Background: Chronic stress significantly contributes to mood and anxiety disorders. Previous data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood., Methods: Using the chronic variable stress mouse model coupled with RNA sequencing, we identified vitamin B12-induced transcriptional changes related to stress resilience. Using viral-mediated gene transfer and in vivo epigenome editing, we revealed a functional pathway linking vitamin B12, DNA methylation (DNAme), and depression-like symptoms., Results: We identified Ttr (transthyretin) as a key sex-specific target of vitamin B12 in chronic stress. Accordingly, TTR expression was increased postmortem in the prefrontal cortex of male but not female patients with depression. Virally altered Ttr in the prefrontal cortex functionally contributed to stress- and depression-related behaviors, changes in dendritic spine morphology, and gene expression. In stressed mice, vitamin B12 reduced DNAme in the Ttr promoter region. Importantly, using in vivo epigenome editing to alter DNAme in the brains of living mice for the first time, we established a direct causal link between DNAme and Ttr and stress-associated behaviors., Conclusions: Using state-of-the-art techniques, this study uncovered a mechanistic link between vitamin B12 supplementation, Ttr, and markers of chronic stress and depression, encouraging further studies into dietary interventions for mood disorders., (Copyright © 2024 Society of Biological Psychiatry. All rights reserved.)
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- 2024
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13. Chondroitin sulfate glycan sulfation patterns influence histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain.
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Belliveau C, Théberge S, Netto S, Rahimian R, Fakhfouri G, Hosdey C, Davoli MA, Hendrickson A, Hao K, Giros B, Turecki G, Alonge KM, and Mechawar N
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- Humans, Animals, Mice, Male, Female, Extracellular Matrix metabolism, Extracellular Matrix chemistry, Adult, Middle Aged, Receptors, N-Acetylglucosamine, Plant Lectins, Chondroitin Sulfates metabolism, Chondroitin Sulfates chemistry, Brain metabolism
- Abstract
Perineuronal nets (PNNs) are a condensed subtype of extracellular matrix that form a net-like coverings around certain neurons in the brain. PNNs are primarily composed of chondroitin sulfate (CS) proteoglycans from the lectican family that consist of CS-glycosaminoglycan side chains attached to a core protein. CS disaccharides can exist in various isoforms with different sulfation patterns. Literature suggests that CS disaccharide sulfation patterns can influence the function of PNNs as well as their labeling. This study was conducted to characterize such interregional CS disaccharide sulfation pattern differences in adult human (n = 81) and mouse (n = 19) brains. Liquid chromatography tandem mass spectrometry was used to quantify five different CS disaccharide sulfation patterns, which were then compared to immunolabeling of PNNs using Wisteria Floribunda Lectin (WFL) to identify CS-glycosaminoglycans and anti-aggrecan to identify CS proteoglycans. In healthy brains, significant regional and species-specific differences in CS disaccharide sulfation and single versus double-labeling pattern were identified. A secondary analysis to investigate how early-life stress impacts these PNN features discovered that although early-life stress increases WFL+ PNN density, the CS-glycosaminoglycan sulfation code and single versus double PNN-labeling distributions remained unaffected in both species. These results underscore PNN complexity in traditional research, emphasizing the need to consider their heterogeneity in future experiments., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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14. Development of a differential treatment selection model for depression on consolidated and transformed clinical trial datasets.
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Perlman K, Mehltretter J, Benrimoh D, Armstrong C, Fratila R, Popescu C, Tunteng JF, Williams J, Rollins C, Golden G, and Turecki G
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- Humans, Clinical Trials as Topic, Female, Male, Antidepressive Agents therapeutic use, Adult, Middle Aged, Neural Networks, Computer, Depressive Disorder, Major therapy, Machine Learning, Bayes Theorem
- Abstract
Major depressive disorder (MDD) is the leading cause of disability worldwide, yet treatment selection still proceeds via "trial and error". Given the varied presentation of MDD and heterogeneity of treatment response, the use of machine learning to understand complex, non-linear relationships in data may be key for treatment personalization. Well-organized, structured data from clinical trials with standardized outcome measures is useful for training machine learning models; however, combining data across trials poses numerous challenges. There is also persistent concern that machine learning models can propagate harmful biases. We have created a methodology for organizing and preprocessing depression clinical trial data such that transformed variables harmonized across disparate datasets can be used as input for feature selection. Using Bayesian optimization, we identified an optimal multi-layer dense neural network that used data from 21 clinical and sociodemographic features as input in order to perform differential treatment benefit prediction. With this combined dataset of 5032 individuals and 6 drugs, we created a differential treatment benefit prediction model. Our model generalized well to the held-out test set and produced similar accuracy metrics in the test and validation set with an AUC of 0.7 when predicting binary remission. To address the potential for bias propagation, we used a bias testing performance metric to evaluate the model for harmful biases related to ethnicity, age, or sex. We present a full pipeline from data preprocessing to model validation that was employed to create the first differential treatment benefit prediction model for MDD containing 6 treatment options., (© 2024. The Author(s).)
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- 2024
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15. Exploring the genetics of lithium response in bipolar disorders.
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Herrera-Rivero M, Adli M, Akiyama K, Akula N, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O'Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Streit F, Tekola-Ayele F, Thalamuthu A, Tortorella A, Turecki G, Veeh J, Vieta E, Viswanath B, Witt SH, Zandi PP, Alda M, Bauer M, McMahon FJ, Mitchell PB, Rietschel M, Schulze TG, and Baune BT
- Abstract
Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., (© 2024. The Author(s).)
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- 2024
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16. Two polygenic mouse models of major depressive disorders identify TMEM161B as a potential biomarker of disease in humans.
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El Yacoubi M, Altersitz C, Latapie V, Rizkallah E, Arthaud S, Bougarel L, Pereira M, Wierinckx A, El-Hage W, Belzeaux R, Turecki G, Svenningsson P, Martin B, Lachuer J, Vaugeois JM, and Jamain S
- Subjects
- Animals, Humans, Mice, Male, Female, Adult, Membrane Proteins genetics, Mice, Inbred C57BL, Middle Aged, Brain metabolism, Depressive Disorder, Major genetics, Depressive Disorder, Major drug therapy, Disease Models, Animal, Multifactorial Inheritance, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Biomarkers blood
- 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 Tmem161b in brain and blood of our two mouse models. Changes in TMEM161B expression 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., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
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- 2024
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17. Omics Approaches to Investigate the Pathogenesis of Suicide.
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Boldrini M, Xiao Y, Sing T, Zhu C, Jabbi M, Pantazopoulos H, Gürsoy G, Martinowich K, Punzi G, Vallender EJ, Zody M, Berretta S, Hyde TM, Kleinman JE, Marenco S, Roussos P, Lewis DA, Turecki G, Lehner T, and Mann JJ
- Abstract
Suicide is the second leading cause of death in U.S. adolescents and young adults and is generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This article is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that while bulk tissue studies provide comprehensive information, single-nucleus approaches that identify cell type-specific changes are needed. While single-nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches that combine cell type-specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression and how these interact with epigenetic marks, single-nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole-genome sequencing and genome-wide association databases. The workshop concluded with a recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarker discovery to guide suicide prevention., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2024
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18. Parvalbumin interneurons in human ventromedial prefrontal cortex: a comprehensive post-mortem study of myelination and perineuronal nets in neurotypical individuals and depressed suicides with and without a history of child abuse.
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Théberge S, Belliveau C, Xie D, Khalaf R, Perlman K, Rahimian R, Davoli MA, Turecki G, and Mechawar N
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- Humans, Male, Female, Adult, Middle Aged, Myelin Sheath pathology, Myelin Sheath metabolism, Suicide, Aged, Autopsy, Child Abuse psychology, Young Adult, Prefrontal Cortex pathology, Prefrontal Cortex metabolism, Parvalbumins metabolism, Interneurons pathology, Interneurons metabolism
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Cortical parvalbumin interneurons (PV+) are major regulators of excitatory/inhibitory information processing, and their maturation is associated with the opening of developmental critical periods (CP). Recent studies reveal that cortical PV+ axons are myelinated, and that myelination along with perineuronal net (PNN) maturation around PV+ cells is associated with the closures of CP. Although PV+ interneurons are susceptible to early-life stress, their relationship between their myelination and PNN coverage remains unexplored. This study compared the fine features of PV+ interneurons in well-characterized human post-mortem ventromedial prefrontal cortex samples (n = 31) from depressed suicides with or without a history of child abuse (CA) and matched controls. In healthy controls, 81% of all sampled PV+ interneurons displayed a myelinated axon, while a subset (66%) of these cells also displayed a PNN, proposing a relationship between both attributes. Intriguingly, a 3-fold increase in the proportion of unmyelinated PV+ interneurons with a PNN was observed in CA victims, along with greater PV-immunofluorescence intensity in myelinated PV+ cells with a PNN. This study, which is the first to provide normative data on myelination and PNNs around PV+ interneurons in human neocortex, sheds further light on the cellular and molecular consequences of early-life adversity on cortical PV+ interneurons., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)
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- 2024
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19. Changes in Expression of Key Genes in Alzheimer's Disease: A Specific Brain Tissue Change.
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Rasmussen LT, de Labio RW, Dos Santos MP, Fredi BM, Baisi Chagas EF, Chen ES, Turecki G, Smith MAC, and Payão SLM
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- Humans, Male, Female, Aged, Cerebellum metabolism, Receptors, N-Methyl-D-Aspartate genetics, Receptor, Insulin genetics, Receptor, Insulin metabolism, Auditory Cortex metabolism, Amyloid beta-Protein Precursor genetics, Aged, 80 and over, Apolipoproteins E genetics, Gene Expression genetics, Case-Control Studies, Alzheimer Disease genetics, Alzheimer Disease metabolism, Low Density Lipoprotein Receptor-Related Protein-1 genetics, Antigens, CD
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Alzheimer's disease (AD) is an irreversible and neurodegenerative disorder. Its etiology is not clear, but the involvement of genetic components plays a central role in the onset of the disease. In the present study, the expression of 10 genes (APP, PS1 and PS2, APOE, APBA2, LRP1, GRIN2B, INSR, GJB1, and IDE) involved in the main pathways related to AD were analyzed in auditory cortices and cerebellum from 29 AD patients and 29 healthy older adults. Raw analysis revealed tissue-specific changes in genes LRP1, INSR, and APP. A correlation analysis showed a significant effect also tissue-specific AD in APP, GRIN2B, INSR, and LRP1. Furthermore, the E4 allele of the APOE gene revealed a significant correlation with change expression tissue-specific in ABPA2, APP, GRIN2B, LRP1, and INSR genes. To assess the existence of a correction between changes in target gene expression and a probability of AD in each tissue (auditory cortices and cerebellum) an analysis of the effect of expressions was realized and showed that the reduction in the expression of the APP in auditory cortex and GRIN2B cerebellum had a significant effect in increasing the probability of AD, in the same logic, our result also suggesting that increased expression of the LRP1 and INSR genes had a significant effect on increasing the probability of AD. Our results showed tissue-specific gene expression alterations associated with AD and certainly opened new perspectives to characterize factors involved in gene regulation and to obtain possible biomarkers for AD., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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20. Relationship of Major Depressive Disorder and Schizophrenia Polygenic Risk Scores to Suicide: A Comparison Between European and Asian Ancestry Populations.
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Otsuka I, Galfalvy H, Guo J, Akiyama M, Okazaki S, Terao C, Rujescu D, Turecki G, Hishimoto A, and Mann JJ
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Psychiatric diagnosis rates in suicide decedents appear higher in European ancestry populations compared with East Asians. Shared genetic components exist between major depressive disorder (MDD)/schizophrenia (SCZ) and suicide, but no study has compared these shared polygenic architectures between Europeans and East Asians. We compared polygenic risk scores (PRSs) for MDD/SCZ determined from large data sets specific to each ancestry in European and East Asian suicide decedent samples. MDD/SCZ PRSs appeared more prominent in European suicides compared with Japanese suicides. A greater coexistence of psychiatric disorders in European suicide decedents than in East Asian suicide decedents may be partly explained by genetics. Our results are limited by the smaller sample size of our suicide decedents and sample size disparities between the European discovery data set and the East Asian data set for MDD/SCZ, resulting in less statistical power to detect robust difference between the two ancestries.
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- 2024
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21. SNORA69 is up-regulated in the lateral habenula of individuals with major depressive disorder.
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Lin R, Mitsuhashi H, Fiori LM, Denniston R, Ibrahim EC, Belzung C, Mechawar N, and Turecki G
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- Humans, Animals, Mice, Base Sequence, RNA, Ribosomal, 18S, RNA, Small Nucleolar genetics, RNA, Small Nucleolar metabolism, Depressive Disorder, Major genetics, Habenula metabolism
- Abstract
Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69's role in MDD pathology is warranted., (© 2024. The Author(s).)
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- 2024
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22. Towards Outcome-Driven Patient Subgroups: A Machine Learning Analysis Across Six Depression Treatment Studies.
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Benrimoh D, Kleinerman A, Furukawa TA, Iii CFR, Lenze EJ, Karp J, Mulsant B, Armstrong C, Mehltretter J, Fratila R, Perlman K, Israel S, Popescu C, Golden G, Qassim S, Anacleto A, Tanguay-Sela M, Kapelner A, Rosenfeld A, and Turecki G
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- Humans, Female, Antidepressive Agents therapeutic use, Depression, Suicidal Ideation, Anxiety therapy, Depressive Disorder, Major therapy
- Abstract
Background: Major depressive disorder (MDD) is a heterogeneous condition; multiple underlying neurobiological and behavioral substrates are associated with treatment response variability. Understanding the sources of this variability and predicting outcomes has been elusive. Machine learning (ML) shows promise in predicting treatment response in MDD, but its application is limited by challenges to the clinical interpretability of ML models, and clinicians often lack confidence in model results. In order to improve the interpretability of ML models in clinical practice, our goal was to demonstrate the derivation of treatment-relevant patient profiles comprised of clinical and demographic information using a novel ML approach., Methods: We analyzed data from six clinical trials of pharmacological treatment for depression (total n = 5438) using the Differential Prototypes Neural Network (DPNN), a ML model that derives patient prototypes which can be used to derive treatment-relevant patient clusters while learning to generate probabilities for differential treatment response. A model classifying remission and outputting individual remission probabilities for five first-line monotherapies and three combination treatments was trained using clinical and demographic data. Prototypes were evaluated for interpretability by assessing differences in feature distributions (e.g. age, sex, symptom severity) and treatment-specific outcomes., Results: A 3-prototype model achieved an area under the receiver operating curve of 0.66 and an expected absolute improvement in remission rate for those receiving the best predicted treatment of 6.5% (relative improvement of 15.6%) compared to the population remission rate. We identified three treatment-relevant patient clusters. Cluster A patients tended to be younger, to have increased levels of fatigue, and more severe symptoms. Cluster B patients tended to be older, female, have less severe symptoms, and the highest remission rates. Cluster C patients had more severe symptoms, lower remission rates, more psychomotor agitation, more intense suicidal ideation, and more somatic genital symptoms., Conclusion: It is possible to produce novel treatment-relevant patient profiles using ML models; doing so may improve interpretability of ML models and the quality of precision medicine treatments for MDD., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2024
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23. Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression.
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Ibrahim P, Denniston R, Mitsuhashi H, Yang J, Fiori LM, Żurawek D, Mechawar N, Nagy C, and Turecki G
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- Humans, Depression, Brain metabolism, Depressive Disorder, Major metabolism, MicroRNAs genetics, Extracellular Vesicles genetics
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Background: Major depressive disorder (MDD) is a leading cause of disability with significant mortality risk. Despite progress in our understanding of the etiology of MDD, the underlying molecular changes in the brain remain poorly understood. Extracellular vesicles (EVs) are lipid-bound particles that can reflect the molecular signatures of the tissue of origin. We aimed to optimize a streamlined EV isolation protocol from postmortem brain tissue and determine whether EV RNA cargo, particularly microRNAs (miRNAs), have an MDD-specific profile., Methods: EVs were isolated from postmortem human brain tissue. Quality was assessed using western blots, transmission electron microscopy, and microfluidic resistive pulse sensing. EV RNA was extracted and sequenced on Illumina platforms. Functional follow-up was performed in silico., Results: Quality assessment showed an enrichment of EV markers, as well as a size distribution of 30 to 200 nm in diameter, and no contamination with cellular debris. Small RNA profiling indicated the presence of several RNA biotypes, with miRNAs and transfer RNAs being the most prominent. Exploring miRNA levels between groups revealed decreased expression of miR-92a-3p and miR-129-5p, which was validated by qPCR and was specific to EVs and not seen in bulk tissue. Finally, in silico functional analyses indicate potential roles for these 2 miRNAs in neurotransmission and synaptic plasticity., Conclusion: We provide a streamlined isolation protocol that yields EVs of high quality that are suitable for molecular follow-up. Our findings warrant future investigations into brain EV miRNA dysregulation in MDD., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)
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- 2024
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24. Influence of CYP2C19 , CYP2D6 , and ABCB1 Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study.
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Islam F, Magarbeh L, Elsheikh SSM, Kloiber S, Espinola CW, Bhat V, Frey BN, Milev R, Soares CN, Parikh SV, Placenza F, Hassel S, Taylor VH, Leri F, Blier P, Uher R, Farzan F, Lam RW, Turecki G, Foster JA, Rotzinger S, Kennedy SH, and Müller DJ
- Subjects
- Adult, Male, Female, Humans, Aripiprazole adverse effects, Escitalopram, Citalopram adverse effects, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2C19 metabolism, Depression, Canada, Biomarkers, ATP Binding Cassette Transporter, Subfamily B, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism, Depressive Disorder, Major drug therapy, Depressive Disorder, Major genetics
- Abstract
Objectives: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6 , and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1 ), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample., Methods: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models., Results: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F (2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF ( r = -0.42, p = 0.004, q = 0.034) and SS ( r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction ( r = -0.39, p = 0.009, q = 0.052)., Conclusions: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.
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- 2024
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25. Perception of social inclusion/exclusion and response inhibition in adolescents with past suicide attempt: a multidomain task-based fMRI study.
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Gifuni AJ, Pereira F, Chakravarty MM, Lepage M, Chase HW, Geoffroy MC, Lacourse E, Phillips ML, Turecki G, Renaud J, and Jollant F
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The occurrence of suicidal behaviors increases during adolescence. Hypersensitivity to negative social signals and deficits in cognitive control are putative mechanisms of suicidal behaviors, which necessitate confirmation in youths. Multidomain functional neuroimaging could enhance the identification of patients at suicidal risk beyond standard clinical measures. Three groups of adolescents (N = 96; 78% females, age = 11.6-18.1) were included: patients with depressive disorders and previous suicide attempts (SA, n = 29); patient controls with depressive disorders but without any suicide attempt history (PC, n = 35); and healthy controls (HC, n = 32). We scanned participants with 3T-MRI during social inclusion/exclusion (Cyberball Game) and response inhibition (Go-NoGo) tasks. Neural activation was indexed by the blood-oxygenation-level dependent (BOLD) of the hemodynamic response during three conditions in the Cyberball Game ("Control condition", "Social Inclusion", and "Social Exclusion"), and two conditions in Go-NoGo task ("Go" and "NoGo" blocks). ANCOVA-style analysis identified group effects across three whole-brain contrasts: 1) NoGo vs. Go, 2) Social inclusion vs. control condition, 3) Social exclusion vs. control condition. We found that SA had lower activation in the left insula during social inclusion vs. control condition compared to PC and HC. Moreover, SA compared to PC had higher activity in the right middle prefrontal gyrus during social exclusion vs. control condition, and in bilateral precentral gyri during NoGo vs. Go conditions. Task-related behavioral and self-report measures (Self-reported emotional reactivity in the Cyberball Game, response times and number of errors in the Go-NoGo Task) did not discriminate groups. In conclusion, adolescent suicidal behaviors are likely associated with neural alterations related to the processing of social perception and response inhibition. Further research, involving prospective designs and diverse cohorts of patients, is necessary to explore the potential of neuroimaging as a tool in understanding the emergence and progression of suicidal behaviors., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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26. Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.
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Ou AH, Rosenthal SB, Adli M, Akiyama K, Akula N, Alda M, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bauer M, Baune BT, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dantas CR, Dayer A, Del Zompo M, Degenhardt F, DePaulo JR, Étain B, Falkai P, Fellendorf FT, Ferensztajn-Rochowiak E, Forstner AJ, Frisén L, Frye MA, Fullerton JM, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Gruber O, Hashimoto R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hofmann A, Hou L, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kittel-Schneider S, König B, Kuo PH, Kusumi I, Lackner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CAL, MacQueen G, Maj M, Manchia M, Marie-Claire C, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, McMahon FJ, Mitchell PB, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, Ösby U, Ozaki N, Papiol S, Perlis RH, Pisanu C, Potash JB, Pfennig A, Reich-Erkelenz D, Reif A, Reininghaus EZ, Rietschel M, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulze TG, Schweizer BW, Seemüller F, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Tighe SK, Tortorella A, Turecki G, Vieta E, Volkert J, Witt S, Wray NR, Wright A, Young LT, Zandi PP, and Kelsoe JR
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- Humans, Proto-Oncogene Proteins c-akt genetics, Phosphatidylinositol 3-Kinases genetics, Genome-Wide Association Study, Multiomics, Focal Adhesions, Lithium pharmacology, Lithium therapeutic use, Bipolar Disorder drug therapy, Bipolar Disorder genetics
- Abstract
Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)
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- 2024
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27. Association of chronic pain with suicide attempt and death by suicide: a two-sample Mendelian randomization.
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Balit J, Erlangsen A, Docherty A, Turecki G, and Orri M
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Prior studies have suggested an association between chronic pain and suicidal behavior. However, evidence supporting the causal nature of this association, and the role played by depression, remain difficult to establish due to confounding. We investigated associations of chronic pain with suicide attempt and death by suicide as well as the mediating role of depression in this association using a genetically informed method strengthening causal inference. We conducted a two-sample Mendelian randomization. Independent SNPs (N = 97) from the multisite chronic pain GWAS (N
GWAS = 387,649) were used as instrumental variables to test associations of chronic pain with suicide attempt (measured from hospital records; NGWAS = 50,264) and death by suicide (measured from official death causes; NGWAS = 18,085). Indirect associations of chronic pain with suicide attempt and death by suicide via major depressive disorder (NGWAS = 173,005) were estimated. Primary analyses were supported by a range of sensitivity and outlier analyses. We found evidence supporting the contribution of chronic pain to increasing the risk of suicide attempt (OR = 1.67, CI = 1.21-2.35) and death by suicide (OR = 2.00, CI = 1.10-3.62). Associations were consistent across sensitivity analysis methods, and no evidence for outliers driving these associations was found. Through mediation analyses, we found that major depressive disorder explained a substantial proportion of the association between chronic pain and suicide attempt (proportion mediated = 39%; ORindirect association = 1.32, CI = 1.09-1.61) and death by suicide (proportion mediated = 34%; ORindirect association = 1.40, CI = 1.13-1.73). Our findings suggest that both pain management interventions and prevention of depression are likely to be effective strategies to reduce suicide risk in individuals with chronic pain., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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28. Correction: Is later‑life depression a risk factor for Alzheimer's disease or a prodromal symptom: a study using post‑mortem human brain tissue?
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Sinclair LI, Mohr A, Morisaki M, Edmondson M, Chan S, Bone-Connaughton A, Turecki G, and Love S
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- 2024
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29. Music as an Intervention to Improve the Hemodynamic Response of Ketamine in Depression: A Randomized Clinical Trial.
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Greenway KT, Garel N, Dinh-Williams LL, Beaulieu S, Turecki G, Rej S, and Richard-Devantoy S
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- Humans, Depression drug therapy, Treatment Outcome, Hemodynamics, Ketamine pharmacology, Ketamine therapeutic use, Music
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- 2024
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30. Impact of psychiatric follow-up frequency on outcomes and waiting times.
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Cousineau M, Verter V, and Turecki G
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- Humans, Retrospective Studies, Follow-Up Studies, Appointments and Schedules, Waiting Lists, Depressive Disorder, Major epidemiology, Depressive Disorder, Major therapy
- Abstract
Objectives: This study determined whether naturally occurring but significantly different outpatient follow-up frequencies are associated with clinical outcomes and service waiting times., Study Design: Longitudinal retrospective study., Methods: This study was conducted in an outpatient setting. Participants consisted of 340 patients with major depressive disorder who were randomly assigned to 4 psychiatrists and were followed at a variable frequency defined by the clinician. Patients were assessed at baseline and at every visit with structured interviews and self-reported questionnaires. These groups were also compared according to their baseline characteristics, treatment, and appointment frequencies. Little's law was used to estimate the impact of modifying the appointment frequencies on the service waiting time., Results: The demographic variables, prescriptions, and depression severity at intake of patients across the 4 groups were similar. The mean times between appointments of the 4 groups were significantly different (87.0, 46.9, 67.9, and 61.5 days, respectively; P < .001), but these differences in outpatient follow-up frequency were not associated with clinical outcomes (eg, mean last Quick Inventory of Depressive Symptomatology Self-Report score, 10.5, 10.0, 11.9, and 9.7; P = .25). However, different outpatient follow-up frequencies had an estimated impact on waiting times for access to care; using Little's law, it was observed that the waiting list would be eliminated by reducing by 23.9% the follow-up frequencies of the 3 psychiatrists with the highest frequencies., Conclusions: Although variations in appointment frequencies do not appear to have a major impact on clinical outcomes, they could be managed to achieve significant improvements in the accessibility of the clinic.
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- 2024
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31. Elevated triglycerides and low triiodothyronine: Key risk factors for coronary artery calcification in patients with schizophrenia.
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Huang TY, Chen LC, Li XP, Li WH, Xu SX, Nagy C, Ibrahim P, Nie ZW, Yang NY, Zeng L, Huang HW, Turecki G, and Xie XH
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- Humans, Triiodothyronine, Cross-Sectional Studies, Risk Factors, Triglycerides, Schizophrenia diagnostic imaging, Schizophrenia epidemiology, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease epidemiology
- Abstract
Objective: Coronary artery calcification (CAC) is a well-established independent predictor of coronary heart disease, and patients with schizophrenia have significantly higher rates compared to the general population. We performed this study to examine the population-specific risk factors associated with CAC in patients with schizophrenia., Methods: In this cross-sectional study, patients with schizophrenia who underwent low-dose chest CT scans between January 2020 and December 2021 were analyzed. Ordinary CAC scores and results of routine blood tests were obtained. Logistic regression was used to calculate the odds ratio (OR) for potential risk factors in patients with and without CAC, while the negative binomial additive model was used to explore the dose-response relationship between risk factors and CAC score., Results: Of the 916 patients, 233 (25.4 %) had CAC, while 683 (74.6 %) did not. After adjusting for confounding factors, higher triglyceride levels (OR = 1.20, 95 % confidence interval (CI): 1.04 to 1.38, p = 0.013) and low triiodothyronine levels (OR = 0.50, 95 % CI: 0.29 to 0.84; p = 0.010) were identified as risk factors for CAC. Both triglycerides (p = 0.021) and triiodothyronine (p = 0.010) were also found to have significant dose-response relationships with CAC scores according to the negative binomial additive model in the exploratory analysis., Conclusions: This study highlights elevated serum triglycerides and decreased triiodothyronine levels as population-specific risk factors for CAC in patients with schizophrenia, suggest the need for close monitoring of CAC in patients with schizophrenia and further prospective trials to provide additional evidence on this topic., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2024
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32. Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience.
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Zhang Y, Pan YD, Zheng WY, Li HY, Zhu MZ, Ou Yang WJ, Qian Y, Turecki G, Mechawar N, and Zhu XH
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- Humans, Mice, Animals, Dorsal Raphe Nucleus metabolism, Serotonergic Neurons metabolism, Serotonin metabolism, Serotonin pharmacology, Antidepressive Agents pharmacology, Hypoxia, Receptors, Purinergic P2X2 metabolism, Resilience, Psychological, Depressive Disorder, Major
- Abstract
Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN
5-HT ) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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33. Correction: Evaluating the Clinical Feasibility of an Artificial Intelligence-Powered, Web-Based Clinical Decision Support System for the Treatment of Depression in Adults: Longitudinal Feasibility Study.
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Popescu C, Golden G, Benrimoh D, Tanguay-Sela M, Slowey D, Lundrigan E, Williams J, Desormeau B, Kardani D, Perez T, Rollins C, Israel S, Perlman K, Armstrong C, Baxter J, Whitmore K, Fradette MJ, Felcarek-Hope K, Soufi G, Fratila R, Mehltretter J, Looper K, Steiner W, Rej S, Karp JF, Heller K, Parikh SV, McGuire-Snieckus R, Ferrari M, Margolese H, and Turecki G
- Abstract
[This corrects the article DOI: 10.2196/31862.]., (©Christina Popescu, Grace Golden, David Benrimoh, Myriam Tanguay-Sela, Dominique Slowey, Eryn Lundrigan, Jérôme Williams, Bennet Desormeau, Divyesh Kardani, Tamara Perez, Colleen Rollins, Sonia Israel, Kelly Perlman, Caitrin Armstrong, Jacob Baxter, Kate Whitmore, Marie-Jeanne Fradette, Kaelan Felcarek-Hope, Ghassen Soufi, Robert Fratila, Joseph Mehltretter, Karl Looper, Warren Steiner, Soham Rej, Jordan F Karp, Katherine Heller, Sagar V Parikh, Rebecca McGuire-Snieckus, Manuela Ferrari, Howard Margolese, Gustavo Turecki. Originally published in JMIR Formative Research (https://formative.jmir.org), 24.01.2024.)
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- 2024
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34. Association between greenspace exposure and suicide-related outcomes across the lifespan: A systematic review.
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Bolanis D, Vergunst F, Mavoa S, Schmelefske E, Khoury B, Turecki G, Orri M, and Geoffroy MC
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- Male, Female, Adolescent, Humans, Cross-Sectional Studies, Parks, Recreational, Suicidal Ideation, Longevity, Suicide
- Abstract
A growing number of studies have linked greenspace exposure to suicide, but findings are inconsistent. We conducted a systematic review on the associations between greenspace exposure and suicide-related outcomes (namely, suicide mortality, self-harm, and suicidal ideation) up until January 6, 2023. We used the Mixed Methods Appraisal Tool (or MMAT) to assess the quality of the included studies. In total, 23 studies met our inclusion criteria, consisting of 14 ecological, four cross-sectional, three longitudinal, and two experimental studies. Most studies were published in 2022 and conducted in Europe (n = 10), Asia (n = 7), and North America (n = 5), with one worldwide analysis. Various indicators were used to assess greenspace exposure including objective measures (e.g., level of surrounding greenness, quantity, structural features, tree canopy coverage), and greenspace use (e.g., duration and frequency). Suicide mortality was the most studied outcome (n = 14). Quality assessment showed that most (87 %) of the included observational studies used representative samples. Protective associations of exposure to greenspace were reported for suicide mortality (9/14 or 64 %), self-harm (n = 3/5 or 60 %) and suicidal ideation (n = 4/6 or 67 %), with nine or 36 % studies reporting no association. Most of the included studies adjusted for key covariates such as age, sex, and socioeconomic status at various aggregate levels (e.g., household, city). For greenspace exposure and suicide mortality, studies stratified by sex (n = 10) showed larger protective associations for females (n = 7) than for males (n = 4). However, the included studies showed high heterogeneity in terms of exposure indicators and greenspace definitions. Experimental studies and studies using youth samples were rare. While more research is warranted, preliminary findings suggest protective associations between greenspace exposure and suicide-related outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2024
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35. Relation of hippocampal volume and SGK1 gene expression to treatment remission in major depression is moderated by childhood maltreatment: A CAN-BIND-1 report.
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Mazurka R, Cunningham S, Hassel S, Foster JA, Nogovitsyn N, Fiori LM, Strother SC, Arnott SR, Frey BN, Lam RW, MacQueen GM, Milev RV, Rotzinger S, Turecki G, Kennedy SH, and Harkness KL
- Subjects
- Adult, Child, Humans, Biomarkers, Canada, Depression, Gene Expression, Glucocorticoids metabolism, Hippocampus diagnostic imaging, Magnetic Resonance Imaging methods, RNA, Messenger, Child Abuse, Depressive Disorder, Major drug therapy, Depressive Disorder, Major genetics
- Abstract
Preclinical research implicates stress-induced upregulation of the enzyme, serum- and glucocorticoid-regulated kinase 1 (SGK1), in reduced hippocampal volume. In the current study, we tested the hypothesis that greater SGK1 mRNA expression in humans would be associated with lower hippocampal volume, but only among those with a history of prolonged stress exposure, operationalized as childhood maltreatment (physical, sexual, and/or emotional abuse). Further, we examined whether baseline levels of SGK1 and hippocampal volume, or changes in these markers over the course of antidepressant treatment, would predict treatment outcomes in adults with major depression [MDD]. We assessed SGK1 mRNA expression from peripheral blood, and left and right hippocampal volume at baseline, as well as change in these markers over the first 8 weeks of a 16-week open-label trial of escitalopram as part of the Canadian Biomarker Integration Network in Depression program (MDD [n = 161] and healthy comparison participants [n = 91]). Childhood maltreatment was assessed via contextual interview with standardized ratings. In the full sample at baseline, greater SGK1 expression was associated with lower hippocampal volume, but only among those with more severe childhood maltreatment. In individuals with MDD, decreases in SGK1 expression predicted lower remission rates at week 16, again only among those with more severe maltreatment. Decreases in hippocampal volume predicted lower week 16 remission for those with low childhood maltreatment. These results suggest that both glucocorticoid-related neurobiological mechanisms of the stress response and history of childhood stress exposure may be critical to understanding differential treatment outcomes in MDD. ClinicalTrials.gov: NCT01655706 Canadian Biomarker Integration Network for Depression Study., Competing Interests: Declaration of Competing Interest RM, SC, SH, LF, NN, BNF, KH reported no relevant conflict of interests. RVM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes for Health Research, Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute and Ontario Mental Health Foundation. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes for Health Research, Canadian Network for Mood and Anxiety Treatments, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, Sanofi, Unity Health, and VGH-UBCH Foundation. SCS received funding from the Ontario Brain Institute and Canadian Institutes for Health Research (MOP137097) for neuroimaging analysis in CAN-BIND, and SCS is a Senior Scientific Advisor and co-owner of ADMdx, Inc., a neuroimaging consulting company. SRA has carried out consultancy work for Indoc Research. SR holds a patent "Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Inventors: David Lovejoy, R.B. Chewpoy, Dalia Barsyte, Susan Rotzinger." SHK has received research funding or honoraria from the following sources: Abbott, Alkermes, Abbvie, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen and holds stock in Field Trip Health., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)
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- 2024
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36. Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons.
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Barde S, Aguila J, Zhong W, Solarz A, Mei I, Prud'homme J, Palkovits M, Turecki G, Mulder J, Uhlén M, Nagy C, Mechawar N, Hedlund E, and Hökfelt T
- Subjects
- Female, Humans, Male, Dorsal Raphe Nucleus, Gene Expression Profiling, Locus Coeruleus metabolism, Neurons metabolism, Substance P metabolism, Cholecystokinin metabolism, Depressive Disorder, Major genetics, Depressive Disorder, Major metabolism, Neuropeptides metabolism
- Abstract
Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders., Competing Interests: Conflict of interest T.H. owns stock in H. Lundbeck A/S. All the other authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2024
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37. Transcriptional signatures of early-life stress and antidepressant treatment efficacy.
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Parel ST, Bennett SN, Cheng CJ, Timmermans OC, Fiori LM, Turecki G, and Peña CJ
- Subjects
- Humans, Male, Female, Mice, Animals, Depression drug therapy, Depression genetics, Escitalopram, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Treatment Outcome, Stress, Psychological drug therapy, Stress, Psychological genetics, Ketamine pharmacology, Adverse Childhood Experiences
- Abstract
Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters brain development, but the molecular changes in the brain following ELS that may mediate altered antidepressant response have not been systematically studied. Sex and gender also impact the risk of depression and treatment response. Here, we leveraged existing RNA sequencing datasets from 1) blood samples from depressed female- and male-identifying patients treated with escitalopram or desvenlafaxine and assessed for treatment response or failure; 2) the nucleus accumbens (NAc) of female and male mice exposed to ELS and/or adult stress; and 3) the NAc of mice after adult stress, antidepressant treatment with imipramine or ketamine, and assessed for treatment response or failure. We find that transcriptomic signatures of adult stress after a history of ELS correspond with transcriptomic signatures of treatment nonresponse, across species and multiple classes of antidepressants. Transcriptomic correspondence with treatment outcome was stronger among females and weaker among males. We next pharmacologically tested these predictions in our mouse model of early-life and adult social defeat stress and treatment with either chronic escitalopram or acute ketamine. Among female mice, the strongest predictor of behavior was an interaction between ELS and ketamine treatment. Among males, however, early experience and treatment were poor predictors of behavior, mirroring our bioinformatic predictions. These studies provide neurobiological evidence for molecular adaptations in the brain related to sex and ELS that contribute to antidepressant treatment response., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2023
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38. Exploring the genetics of lithium response in bipolar disorders.
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Herrera-Rivero M, Adli M, Akiyama K, Akula N, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O'Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Streit F, Tekola-Ayele F, Thalamuthu A, Tortorella A, Turecki G, Veeh J, Vieta E, Viswanath B, Witt SH, Zandi PP, Alda M, Bauer M, McMahon FJ, Mitchell PB, Rietschel M, Schulze TG, and Baune BT
- Abstract
Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., Competing Interests: Competing interests Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbvie, Almirall, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GH Research, Glaxo-Smith-Kline, Janssen, Lundbeck, Orion, Otsuka, Pfizer, Roche, Rovi, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Stanley Medical Research Institute and Viatris. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Takeda. Bernhard Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co, Ltd, Eli Lilly Japan K.K., Otsuka Pharmaceutical Co, Ltd, GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co, Ltd, Dainippon Sumitomo Pharma Co, Ltd, Meiji Seika Pharma Co, Ltd, Pfizer Japan Inc., Mochida Pharmaceutical Co, Ltd, Shionogi & Co, Ltd, Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc, Wako Pure Chemical Industries, Ltd, Wiley Publishing Japan, Nippon Boehringer Ingelheim Co Ltd, Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co, Ltd and Takeda Pharmaceutical Co, Ltd. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén has received lecture honoraria from Lundbeck. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. Scott Clark has received grants, or data and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia,Viatris. Bruno Etain received honoraria from Sanofi Aventis. The rest of authors have no conflicts of interest to disclose.
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- 2023
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39. Pro-inflammatory markers are associated with response to sequential pharmacotherapy in major depressive disorder: a CAN-BIND-1 report.
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Husain MI, Foster JA, Mason BL, Chen S, Zhao H, Wang W, Rotzinger S, Rizvi S, Ho K, Lam R, MacQueen G, Milev R, Frey BN, Müller D, Turecki G, Jha M, Trivedi M, and Kennedy SH
- Subjects
- Humans, Aripiprazole therapeutic use, Escitalopram, Tumor Necrosis Factor-alpha therapeutic use, Depressive Disorder, Major drug therapy
- Abstract
Objective: There is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies in major depressive disorder (MDD)., Methods: In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10-20 mg daily for 8 weeks. Responders continued escitalopram while non-responders received adjunctive aripiprazole 2-10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers-C-reactive protein, interleukin (IL)-1β, IL-6, IL-17, interferon-gamma (IFN)-Γ, tumor necrosis factor (TNF)-α, and Chemokine C-C motif ligand-2 (CCL-2)-measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyzes to assess associations between inflammatory markers and treatment response., Results: Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16., Conclusion: Higher pre-treatment levels of IFN-Γ and CCL-2 were associated with non-response to escitalopram. Increasing levels of these pro-inflammatory markers may be associated with non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
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- 2023
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40. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
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Amare AT, Thalamuthu A, Schubert KO, Fullerton JM, Ahmed M, Hartmann S, Papiol S, Heilbronner U, Degenhardt F, Tekola-Ayele F, Hou L, Hsu YH, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Aubry JM, Hasler R, Richard-Lepouriel H, Perroud N, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka JM, Birner A, Marie-Claire C, Cervantes P, Chen HC, Chillotti C, Cichon S, Cruceanu C, Czerski PM, Dalkner N, Del Zompo M, DePaulo JR, Étain B, Jamain S, Falkai P, Forstner AJ, Frisen L, Frye MA, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Fallgatter AJ, Stegmaier S, Ethofer T, Biere S, Petrova K, Schuster C, Adorjan K, Budde M, Heilbronner M, Kalman JL, Kohshour MO, Reich-Erkelenz D, Schaupp SK, Schulte EC, Senner F, Vogl T, Anghelescu IG, Arolt V, Dannlowski U, Dietrich D, Figge C, Jäger M, Lang FU, Juckel G, Konrad C, Reimer J, Schmauß M, Schmitt A, Spitzer C, von Hagen M, Wiltfang J, Zimmermann J, Andlauer TFM, Fischer A, Bermpohl F, Ritter P, Matura S, Gryaznova A, Falkenberg I, Yildiz C, Kircher T, Schmidt J, Koch M, Gade K, Trost S, Haussleiter IS, Lambert M, Rohenkohl AC, Kraft V, Grof P, Hashimoto R, Hauser J, Herms S, Hoffmann P, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe J, Kittel-Schneider S, Ferensztajn-Rochowiak E, König B, Kusumi I, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Tortorella A, Manchia M, Martinsson L, McCarthy MJ, McElroy S, Colom F, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, O'Donovan C, Ozaki N, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schweizer BW, Severino G, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Maj M, Turecki G, Vieta E, Veeh J, Witt SH, Wright A, Zandi PP, Mitchell PB, Bauer M, Alda M, Rietschel M, McMahon FJ, Schulze TG, Clark SR, and Baune BT
- Subjects
- Humans, Female, Male, Adult, Middle Aged, Treatment Outcome, Bayes Theorem, Genome-Wide Association Study methods, Glutamic Acid metabolism, Cohort Studies, Lithium Compounds therapeutic use, Lithium Compounds pharmacology, Acetylcholine metabolism, Polymorphism, Single Nucleotide genetics, Antimanic Agents therapeutic use, Antimanic Agents pharmacology, Bipolar Disorder drug therapy, Bipolar Disorder genetics, Multifactorial Inheritance genetics, Lithium therapeutic use, Lithium pharmacology
- Abstract
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li
+ PGS ) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+ PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+ Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+ PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+ PGS was positively associated with lithium treatment response in the ConLi+ Gen cohort, in both the categorical (P = 9.8 × 10- 12 , R2 = 1.9%) and continuous (P = 6.4 × 10- 9 , R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10- 4 , R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+ PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment., (© 2023. The Author(s).)- Published
- 2023
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41. Massively parallel functional dissection of schizophrenia-associated noncoding genetic variants.
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Rummel CK, Gagliardi M, Ahmad R, Herholt A, Jimenez-Barron L, Murek V, Weigert L, Hausruckinger A, Maidl S, Hauger B, Raabe FJ, Fürle C, Trastulla L, Turecki G, Eder M, Rossner MJ, and Ziller MJ
- Subjects
- Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, Neurons metabolism, Polymorphism, Single Nucleotide genetics, Animals, Mice, High-Throughput Nucleotide Sequencing, Schizophrenia genetics
- Abstract
Schizophrenia (SCZ) is a highly heritable mental disorder with thousands of associated genetic variants located mostly in the noncoding space of the genome. Translating these associations into insights regarding the underlying pathomechanisms has been challenging because the causal variants, their mechanisms of action, and their target genes remain largely unknown. We implemented a massively parallel variant annotation pipeline (MVAP) to perform SCZ variant-to-function mapping at scale in disease-relevant neural cell types. This approach identified 620 functional variants (1.7%) that operate in a highly developmental context and neuronal-activity-dependent manner. Multimodal integration of epigenomic and CRISPRi screening data enabled us to link these functional variants to target genes, biological processes, and ultimately alterations of neuronal physiology. These results provide a multistage prioritization strategy to map functional single-nucleotide polymorphism (SNP)-to-gene-to-endophenotype relations and offer biological insights into the context-dependent molecular processes modulated by SCZ-associated genetic variation., Competing Interests: Declaration of interests M.J.R. is a shareholder in and consultant to Systasy Bioscence GmbH. A. Herholt is employed by Systasy Bioscience GmbH, Munich, Germany., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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42. Intravenous ketamine for benzodiazepine deprescription and withdrawal management in treatment-resistant depression: a preliminary report.
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Garel N, Greenway KT, Dinh-Williams LL, Thibault-Levesque J, Jutras-Aswad D, Turecki G, Rej S, and Richard-Devantoy S
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- Humans, Benzodiazepines therapeutic use, Depression drug therapy, Cohort Studies, Infusions, Intravenous, Ketamine pharmacology, Depressive Disorder, Treatment-Resistant drug therapy, Deprescriptions, Substance Withdrawal Syndrome drug therapy
- Abstract
We present the first evidence that sub-anesthetic ketamine infusions for treatment resistant depression (TRD) may facilitate deprescription of long-term benzodiazepine/z-drugs (BZDRs). Long-term BZDR prescriptions are potentially harmful yet common, partly because of challenging withdrawal symptoms. Few pharmacological interventions have evidence for facilitating BZDR discontinuation, and none in patients actively suffering from TRD. In this ambi-directional cohort study, discontinuation of long-term (>6 month) BZDRs was attempted in 22 patients with severe unipolar or bipolar TRD receiving a course of six subanesthetic ketamine infusions over four weeks. We investigated the rates of successful BZDRs deprescription, trajectories of acute psychological withdrawal symptoms, and subsequent BZDRs abstinence during a mean follow-up of 1 year (primary outcome). Clinically significant deteriorations in depression, anxiety, sleep, and/or suicidality during the acute BZDR discontinuation phase were measured by repeated standardized scales and analyzed by latent growth curve models and percent correct classification analysis. Of the 22 eligible patients, all enrolled in this study and 91% (20/22) successfully discontinued all BZDRs by the end of the 4-week intervention, confirmed by urinary analyses. Less than 25% of discontinuers experienced any significant worsening of anxiety, depression, sleep difficulties, or suicidality during treatment. During follow-up (mean [range] duration, 12 [3-24] months), 64% (14/22) of patients remained abstinent from any BZDRs. These preliminary results suggest that ketamine infusions for TRD may facilitate the deprescription of BZDRs, even in patients with active depressive symptoms and significant comorbidity. Further investigation is warranted into this potential novel application of ketamine., (© 2023. The Author(s).)
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- 2023
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43. Transcriptional dissection of symptomatic profiles across the brain of men and women with depression.
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Mansouri S, Pessoni AM, Marroquín-Rivera A, Parise EM, Tamminga CA, Turecki G, Nestler EJ, Chen TH, and Labonté B
- Subjects
- Male, Humans, Female, Depression genetics, Brain metabolism, Synaptic Transmission, Signal Transduction, Magnetic Resonance Imaging, Depressive Disorder, Major
- Abstract
Major depressive disorder (MDD) is one of the most important causes of disability worldwide. While recent work provides insights into the molecular alterations in the brain of patients with MDD, whether these molecular signatures can be associated with the expression of specific symptom domains remains unclear. Here, we identified sex-specific gene modules associated with the expression of MDD, combining differential gene expression and co-expression network analyses in six cortical and subcortical brain regions. Our results show varying levels of network homology between males and females across brain regions, although the associations between these structures and the expression of MDD remain highly sex specific. We refined these associations to several symptom domains and identified transcriptional signatures associated with distinct functional pathways, including GABAergic and glutamatergic neurotransmission, metabolic processes and intracellular signal transduction, across brain regions associated with distinct symptomatic profiles in a sex-specific fashion. In most cases, these associations were specific to males or to females with MDD, although a subset of gene modules associated with common symptomatic features in both sexes were also identified. Together, our findings suggest that the expression of distinct MDD symptom domains associates with sex-specific transcriptional structures across brain regions., (© 2023. The Author(s).)
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- 2023
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44. Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.
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Kelsoe J, Ou A, Rosenthal S, Adli M, Akiyama K, Akula N, Alda M, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Banzato C, Bauer M, Baune B, Bellivier F, Benabarre A, Bengesser S, Abesh B, Biernacka J, Bui E, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark S, Colom F, Cousins D, Cruceanu C, Czerski P, Dantas C, Dayer A, Degenhardt F, DePaulo JR, Etain B, Falkai P, Fellendorf F, Ferensztajn-Rochowiak E, Forstner AJ, Frisen L, Frye M, Fullerton J, Gard S, Garnham J, Goes F, Grigoroiu-Serbanescu M, Grof P, Gruber O, Hashimoto R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hofmann A, Hou L, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kittel-Schneider S, König B, Kuo PH, Kusumi I, Dalkner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband S, Jaramillo CL, MacQueen G, Maj M, Manchia M, Marie-Claire C, Martinsson L, Mattheisen M, McCarthy M, McElroy S, McMahon F, Mitchell P, Mitjans M, Mondimore F, Monteleone P, Nievergelt C, Nöthen M, Novak T, Osby U, Ozaki N, Papiol S, Perlis R, Pfennig A, Potash J, Reich-Erkelenz D, Reif A, Reininghaus E, Rietschel M, Rouleau G, Rybakowski JK, Schalling M, Schofield P, Schubert KO, Schulze T, Schweizer B, Seemüller F, Severino G, Shekhtman T, Shilling P, Shimoda K, Simhandl C, Slaney C, Squassina A, Stamm T, Stopkova P, Tighe S, Tortorella A, Turecki G, Vieta E, Volkert J, Witt S, Wray N, Wright A, Young T, Zandi P, and Zompo MD
- Abstract
Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., Competing Interests: MAd has received a grant from Servier, speaker’s fees from Servier, Lundbeck, Aristo, Parexel, Gilead, ViiV, Deutsche Bank, MSD, and MyTomorrows, plus a non-financial support from Lundbeck. KA has received speaker’s fees from Taisho Toyama Pharmaceutical. MAl is funded by a grant of the Canadian Institutes of Health Research. MB has received speaker’s fees from AstraZeneca, Pfizer, Lilly, Lundbeck, GlaxoSmithKline, Servier, and Ferrer Internacional. BÉ received non-financial support from Labex Biopsy and Fondation Fondamental. RH received grants and speaker honoraria from Dainippon Sumitomo Pharma and Novartis plus speaker honoraria from Eli Lilly Japan, GlaxoSmithKline, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical, Astellas Pharma, Pfizer, and the Yoshitomiyakuhin Corporation. TK received a grant from Takeda Pharmaceutical and fees from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka Pharmaceutical, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma, Meiji Seika Pharma, PfizerJapan, Mochida Pharmaceutical, Shionogi & Co, Janssen Pharmaceutical, Yoshitomiyakuhin Corporation, Agilent Technologies, Astellas Pharma, and Wako Pure Chemical Industries. IK received grants and fees from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis, Otsuka, Ono Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Takeda Pharmaceutical, Shionogi, and Yoshitomi Pharmaceutical; he received grants from AbbVie GK, Asahi Kasei Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, and Daiichi Sankyo and fees from Astellas Pharma and Janssen Pharmaceutical. MJM served as unpaid consultant for Pathway Genomic (San Diego, USA). SLM received a grant and fees from Naurex and Shire, further grants from Alkermes, Cephalon, Forest, Marriott Foundation, Orexigen Therapeutics, and Takeda Pharmaceutical, he further has served on the advisory boards for Bracket, Hoffmann-La Roche, MedAvante, Sunovion and received fees from Novo Nordisk. RHP received personal fees from RID Ventures, Genomind LLC, Healthrageous, P zer, Perfect Health, Proteus, and Psybrain. PRS received a grant from NHMRC. TGS received a grant and fees from Roche Pharmaceuticals. TSt received personal fees from Servier, Lundbeck, and Bristol-Myers Squibb. MM has received grants from Lundbeck and Angelini. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. SRC has participated in advisory and educational boards and received speaker’s fees from Janssen-Cilag, Lundbeck, Otsuka, and Servier; research funding from Janssen-Cilag, Lundbeck, Otsuka, and Gilead; and data sharing from Viatris Australia. ML has received lecture honoraria from Lundbeck pharmaceuticals. All above listed interests are outside of the submitted work. All other authors declare no competing interests.
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- 2023
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45. DNA Methylation Signatures of Functional Somatic Syndromes: Systematic Review.
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Fischer S, Kleinstäuber M, Fiori LM, Turecki G, Wagner J, and von Känel R
- Subjects
- Adult, Humans, DNA Methylation, Genome-Wide Association Study, Fatigue Syndrome, Chronic genetics, Fibromyalgia genetics, Irritable Bowel Syndrome genetics
- Abstract
Objective: Functional somatic syndromes (FSS) are highly prevalent across all levels of health care. The fact that they are characterized by medically unexplained symptoms, such as fatigue and pain, raises the important question of their underlying pathophysiology. Psychosocial stress represents a significant factor in the development of FSS and can induce long-term modifications at the epigenetic level. The aim of this review was to systematically review, for the first time, whether individuals with FSS are characterized by specific alterations in DNA methylation., Methods: MEDLINE and PsycINFO were searched from the first available date to September 2022. The inclusion criteria were as follows: a) adults fulfilling the research diagnostic criteria for chronic fatigue syndrome, fibromyalgia syndrome, and/or irritable bowel syndrome; b) healthy control group; and c) candidate-gene or genome-wide study of DNA methylation., Results: Sixteen studies ( N = 957) were included. In candidate-gene studies, specific sites within NR3C1 were identified, which were hypomethylated in individuals with chronic fatigue syndrome compared with healthy controls. In genome-wide studies in chronic fatigue syndrome, a hypomethylated site located to LY86 and hypermethylated sites within HLA-DQB1 were found. In genome-wide studies in fibromyalgia syndrome, differential methylation in sites related to HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , and LY6G5C was found., Conclusions: Individuals with chronic fatigue syndrome and fibromyalgia syndrome seem to be characterized by altered DNA methylation of genes regulating cellular signaling and immune functioning. In chronic fatigue syndrome, there is preliminary evidence for these to be implicated in key pathophysiological alterations, such as hypocortisolism and low-grade inflammation, and to contribute to the debilitating symptoms these individuals experience., Preregistration: PROSPERO identifier: CRD42022364720., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)
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- 2023
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46. Universal method for the isolation of microvessels from frozen brain tissue: A proof-of-concept multiomic investigation of the neurovasculature.
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Wakid M, Almeida D, Aouabed Z, Rahimian R, Davoli MA, Yerko V, Leonova-Erko E, Richard V, Zahedi R, Borchers C, Turecki G, and Mechawar N
- Abstract
The neurovascular unit, comprised of vascular cell types that collectively regulate cerebral blood flow to meet the needs of coupled neurons, is paramount for the proper function of the central nervous system. The neurovascular unit gatekeeps blood-brain barrier properties, which experiences impairment in several central nervous system diseases associated with neuroinflammation and contributes to pathogenesis. To better understand function and dysfunction at the neurovascular unit and how it may confer inflammatory processes within the brain, isolation and characterization of the neurovascular unit is needed. Here, we describe a singular, standardized protocol to enrich and isolate microvessels from archived snap-frozen human and frozen mouse cerebral cortex using mechanical homogenization and centrifugation-separation that preserves the structural integrity and multicellular composition of microvessel fragments. For the first time, microvessels are isolated from postmortem ventromedial prefrontal cortex tissue and are comprehensively investigated as a structural unit using both RNA sequencing and Liquid Chromatography with tandem mass spectrometry (LC-MS/MS). Both the transcriptome and proteome are obtained and compared, demonstrating that the isolated brain microvessel is a robust model for the NVU and can be used to generate highly informative datasets in both physiological and disease contexts., Competing Interests: None., (© 2023 The Authors.)
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- 2023
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47. Preparation and processing of dried blood spots for microRNA sequencing.
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Morgunova A, Ibrahim P, Chen GG, Coury SM, Turecki G, Meaney MJ, Gifuni A, Gotlib IH, Nagy C, Ho TC, and Flores C
- Abstract
Dried blood spots (DBS) are biological samples commonly collected from newborns and in geographic areas distanced from laboratory settings for the purposes of disease testing and identification. MicroRNAs (miRNAs)-small non-coding RNAs that regulate gene activity at the post-transcriptional level-are emerging as critical markers and mediators of disease, including cancer, infectious diseases, and mental disorders. This protocol describes optimized procedural steps for utilizing DBS as a reliable source of biological material for obtaining peripheral miRNA expression profiles. We outline key practices, such as the method of DBS rehydration that maximizes RNA extraction yield, and the use of degenerate oligonucleotide adapters to mitigate ligase-dependent biases that are associated with small RNA sequencing. The standardization of miRNA readout from DBS offers numerous benefits: cost-effectiveness in sample collection and processing, enhanced reliability and consistency of miRNA profiling, and minimal invasiveness that facilitates repeated testing and retention of participants. The use of DBS-based miRNA sequencing is a promising method to investigate disease mechanisms and to advance personalized medicine., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2023
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48. The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression.
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Garel N, Drury J, Thibault Lévesque J, Goyette N, Lehmann A, Looper K, Erritzoe D, Dames S, Turecki G, Rej S, Richard-Devantoy S, and Greenway KT
- Abstract
Background: Subanesthetic ketamine has accumulated meta-analytic evidence for rapid antidepressant effects in treatment-resistant depression (TRD), resulting in both excitement and debate. Many unanswered questions surround ketamine's mechanisms of action and its integration into real-world psychiatric care, resulting in diverse utilizations that variously resemble electroconvulsive therapy, conventional antidepressants, or serotonergic psychedelics. There is thus an unmet need for clinical approaches to ketamine that are tailored to its unique therapeutic properties., Methods: This article presents the Montreal model, a comprehensive biopsychosocial approach to ketamine for severe TRD refined over 6 years in public healthcare settings. To contextualize its development, we review the evidence for ketamine as a biomedical and as a psychedelic treatment of depression, emphasizing each perspectives' strengths, weaknesses, and distinct methods of utilization. We then describe the key clinical experiences and research findings that shaped the model's various components, which are presented in detail., Results: The Montreal model, as implemented in a recent randomized clinical trial, aims to synergistically pair ketamine infusions with conventional and psychedelic biopsychosocial care. Ketamine is broadly conceptualized as a brief intervention that can produce windows of opportunity for enhanced psychiatric care, as well as powerful occasions for psychological growth. The model combines structured psychiatric care and concomitant psychotherapy with six ketamine infusions, administered with psychedelic-inspired nonpharmacological adjuncts including rolling preparative and integrative psychological support., Discussion: Our integrative model aims to bridge the biomedical-psychedelic divide to offer a feasible, flexible, and standardized approach to ketamine for TRD. Our learnings from developing and implementing this psychedelic-inspired model for severe, real-world patients in two academic hospitals may offer valuable insights for the ongoing roll-out of a range of psychedelic therapies. Further research is needed to assess the Montreal model's effectiveness and hypothesized psychological mechanisms., Competing Interests: AL has received grant support from MED-EL and Oticon Medical. DE has received funding from NIHR and was scientific advisor for Mydecine, Entheon Biomedical, Clerkenwell Health, Smallpharma Ltd. and Field Trip Health Ltd. SR received a salary award from the Fonds de recherche du Québec - Santé, receives grant funding from Mitacs, is on a steering committee for AbbVie, and owns shares of Aifred Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Garel, Drury, Thibault Lévesque, Goyette, Lehmann, Looper, Erritzoe, Dames, Turecki, Rej, Richard-Devantoy and Greenway.)
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- 2023
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49. A standardized workflow for long-term longitudinal actigraphy data processing using one year of continuous actigraphy from the CAN-BIND Wellness Monitoring Study.
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Slyepchenko A, Uher R, Ho K, Hassel S, Matthews C, Lukus PK, Daros AR, Minarik A, Placenza F, Li QS, Rotzinger S, Parikh SV, Foster JA, Turecki G, Müller DJ, Taylor VH, Quilty LC, Milev R, Soares CN, Kennedy SH, Lam RW, and Frey BN
- Subjects
- Humans, Workflow, Polysomnography, Data Collection, Actigraphy, Algorithms
- Abstract
Monitoring sleep and activity through wearable devices such as wrist-worn actigraphs has the potential for long-term measurement in the individual's own environment. Long periods of data collection require a complex approach, including standardized pre-processing and data trimming, and robust algorithms to address non-wear and missing data. In this study, we used a data-driven approach to quality control, pre-processing and analysis of longitudinal actigraphy data collected over the course of 1 year in a sample of 95 participants. We implemented a data processing pipeline using open-source packages for longitudinal data thereby providing a framework for treating missing data patterns, non-wear scoring, sleep/wake scoring, and conducted a sensitivity analysis to demonstrate the impact of non-wear and missing data on the relationship between sleep variables and depressive symptoms. Compliance with actigraph wear decreased over time, with missing data proportion increasing from a mean of 4.8% in the first week to 23.6% at the end of the 12 months of data collection. Sensitivity analyses demonstrated the importance of defining a pre-processing threshold, as it substantially impacts the predictive value of variables on sleep-related outcomes. We developed a novel non-wear algorithm which outperformed several other algorithms and a capacitive wear sensor in quality control. These findings provide essential insight informing study design in digital health research., (© 2023. Springer Nature Limited.)
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- 2023
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50. Is later-life depression a risk factor for Alzheimer's disease or a prodromal symptom: a study using post-mortem human brain tissue?
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Sinclair LI, Mohr A, Morisaki M, Edmondson M, Chan S, Bone-Connaughton A, Turecki G, and Love S
- Subjects
- Adult, Humans, Middle Aged, Prodromal Symptoms, Depression, Brain, Blood-Brain Barrier, Alzheimer Disease
- Abstract
Background: Depression and dementia are both common diseases. Although new cases of depression are more common in younger adults, there is a second peak at the age of 50 years suggesting a different pathological process. Late-life depression (LLD) is associated with dementia. However, it remains unclear whether depression represents a dementia prodrome or is a true risk factor for its development. LLD is thought to have a vascular component and this may be a possible link between depression and dementia. We hypothesised that later-life depression is a prodromal manifestation of dementia and would therefore be associated with more AD, and/or ischaemic brain abnormalities that are present in earlier-life depression or in age- and sex-matched controls., Methods: We assessed post-mortem orbitofrontal cortex and dorsolateral pre-frontal cortex from 145 individuals in 4 groups: 28 18-50-year-olds with depression, 30 older individuals (ages 51-90) with depression, 28 with early AD (Braak tangle stages III-IV) and 57 matched controls (17 early-life, 42 later-life). Levels of Aβ, phospho-tau and α-synuclein were assessed by immunohistochemistry and ELISA. To quantify chronic ischaemia, VEGF, MAG and PLP1 were measured by ELISA. To assess pericyte damage, PDGFRB was measured by ELISA. For blood-brain barrier leakiness, JAM-A, claudin 5 and fibrinogen were measured by ELISA. To quantity endothelial activation, the ratio of ICAM1:collagen IV was assessed by immunohistochemistry., Results: There was no evidence of chronic cerebral hypoperfusion or increased Aβ/tau in either depression group. There was also no indication of pericyte damage, increased blood-brain barrier leakiness or endothelial activation in the OFC or DLPFC in the depression groups., Conclusions: Contrary to some previous findings, we have not found evidence of impaired vascular function or increased Aβ in LLD. Our study had a relatively small sample size and limitations in the availability of clinical data. These results suggest that depression is a risk factor for dementia rather than an early manifestation of AD or a consequence of cerebral vascular insufficiency., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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