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1. Exploring the genetics of lithium response in bipolar disorders

Author

Marisol Herrera-Rivero, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Azmeraw T. Amare, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Joanna M. Biernacka, Armin Birner, Micah Cearns, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Bruno Etain, Peter Falkai, Ewa Ferensztajn-Rochowiak, Andreas J. Forstner, Josef Frank, Louise Frisén, Mark A. Frye, Janice M. Fullerton, Carla Gallo, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Roland Hasler, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Liping Hou, Yi-Hsiang Hsu, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Po-Hsiu Kuo, Ichiro Kusumi, Barbara König, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, Mirko Manchia, Cynthia Marie-Claire, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Vincent Millischer, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Tomas Novák, Markus M. Nöthen, Claire O’Donovan, Norio Ozaki, Sergi Papiol, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, Hélène Richard-Lepouriel, Gloria Roberts, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Klaus Oliver Schubert, Eva C. Schulte, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fabian Streit, Fasil Tekola-Ayele, Anbupalam Thalamuthu, Alfonso Tortorella, Gustavo Turecki, Julia Veeh, Eduard Vieta, Biju Viswanath, Stephanie H. Witt, Peter P. Zandi, Martin Alda, Michael Bauer, Francis J. McMahon, Philip B. Mitchell, Marcella Rietschel, Thomas G. Schulze, and Bernhard T. Baune

Subjects
Bipolar disorder, Lithium treatment, Psychiatric symptoms, Comorbidity, Genetics, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

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.

Published
2024
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2. Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study

Author

Anna H. Ou, Sara B. Rosenthal, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Martin Alda, Azmeraw T. Amare, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Michael Bauer, Bernhard T. Baune, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Joanna M. Biernacka, Pablo Cervantes, Guo-Bo Chen, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, David A. Cousins, Cristiana Cruceanu, Piotr M. Czerski, Clarissa R. Dantas, Alexandre Dayer, Maria Del Zompo, Franziska Degenhardt, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Frederike Tabea Fellendorf, Ewa Ferensztajn-Rochowiak, Andreas J. Forstner, Louise Frisén, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Andrea Hofmann, Liping Hou, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Tadafumi Kato, Sarah Kittel-Schneider, Barbara König, Po-Hsiu Kuo, Ichiro Kusumi, Nina Lackner, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A. López Jaramillo, Glenda MacQueen, Mario Maj, Mirko Manchia, Cynthia Marie-Claire, Lina Martinsson, Manuel Mattheisen, Michael J. McCarthy, Susan L. McElroy, Francis J. McMahon, Philip B. Mitchell, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Urban Ösby, Norio Ozaki, Sergi Papiol, Roy H. Perlis, Claudia Pisanu, James B. Potash, Andrea Pfennig, Daniela Reich-Erkelenz, Andreas Reif, Eva Z. Reininghaus, Marcella Rietschel, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, K. Oliver Schubert, Thomas G. Schulze, Barbara W. Schweizer, Florian Seemüller, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Kazutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Eduard Vieta, Julia Volkert, Stephanie Witt, Naomi R. Wray, Adam Wright, L. Trevor Young, Peter P. Zandi, and John R. Kelsoe

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

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.

Published
2024
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3. Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder

Author

Michael Bauer, Tasha Glenn, Eric D. Achtyes, Martin Alda, Esen Agaoglu, Kürsat Altınbaş, Ole A. Andreassen, Elias Angelopoulos, Raffaella Ardau, Memduha Aydin, Yavuz Ayhan, Christopher Baethge, Rita Bauer, Bernhard T. Baune, Ceylan Balaban, Claudia Becerra-Palars, Aniruddh P. Behere, Prakash B. Behere, Habte Belete, Tilahun Belete, Gabriel Okawa Belizario, Frank Bellivier, Robert H. Belmaker, Francesco Benedetti, Michael Berk, Yuly Bersudsky, Şule Bicakci, Harriet Birabwa-Oketcho, Thomas D. Bjella, Conan Brady, Jorge Cabrera, Marco Cappucciati, Angela Marianne Paredes Castro, Wei-Ling Chen, Eric Y. W. Cheung, Silvia Chiesa, Marie Crowe, Alessandro Cuomo, Sara Dallaspezia, Maria Del Zompo, Pratikkumar Desai, Seetal Dodd, Bruno Etain, Andrea Fagiolini, Frederike T. Fellendorf, Ewa Ferensztajn-Rochowiak, Jess G. Fiedorowicz, Kostas N. Fountoulakis, Mark A. Frye, Pierre A. Geoffroy, Michael J. Gitlin, Ana Gonzalez-Pinto, John F. Gottlieb, Paul Grof, Bartholomeus C. M. Haarman, Hirohiko Harima, Mathias Hasse-Sousa, Chantal Henry, Lone Hoffding, Josselin Houenou, Massimiliano Imbesi, Erkki T. Isometsä, Maja Ivkovic, Sven Janno, Simon Johnsen, Flávio Kapczinski, Gregory N. Karakatsoulis, Mathias Kardell, Lars Vedel Kessing, Seong Jae Kim, Barbara König, Timur L. Kot, Michael Koval, Mauricio Kunz, Beny Lafer, Mikael Landén, Erik R. Larsen, Melanie Lenger, Rasmus W. Licht, Carlos Lopez-Jaramillo, Alan MacKenzie, Helle Østergaard Madsen, Simone Alberte Kongstad A. Madsen, Jayant Mahadevan, Agustine Mahardika, Mirko Manchia, Wendy Marsh, Monica Martinez-Cengotitabengoa, Julia Martini, Klaus Martiny, Yuki Mashima, Declan M. McLoughlin, Ybe Meesters, Ingrid Melle, Fátima Meza-Urzúa, Pavol Mikolas, Yee Ming Mok, Scott Monteith, Muthukumaran Moorthy, Gunnar Morken, Enrica Mosca, Anton A. Mozzhegorov, Rodrigo Munoz, Starlin V. Mythri, Fethi Nacef, Ravi K. Nadella, Takako Nakanotani, René Ernst Nielsen, Claire O’Donovan, Adel Omrani, Yamima Osher, Uta Ouali, Maja Pantovic-Stefanovic, Pornjira Pariwatcharakul, Joanne Petite, Johannes Petzold, Andrea Pfennig, Yolanda Pica Ruiz, Marco Pinna, Maurizio Pompili, Richard J. Porter, Danilo Quiroz, Francisco Diego Rabelo-da-Ponte, Raj Ramesar, Natalie Rasgon, Woraphat Ratta-apha, Michaela Ratzenhofer, Maria Redahan, M. S. Reddy, Andreas Reif, Eva Z. Reininghaus, Jenny Gringer Richards, Philipp Ritter, Janusz K. Rybakowski, Leela Sathyaputri, Angela M. Scippa, Christian Simhandl, Daniel Smith, José Smith, Paul W. Stackhouse, Dan J. Stein, Kellen Stilwell, Sergio Strejilevich, Kuan-Pin Su, Mythily Subramaniam, Ahmad Hatim Sulaiman, Kirsi Suominen, Andi J. Tanra, Yoshitaka Tatebayashi, Wen Lin Teh, Leonardo Tondo, Carla Torrent, Daniel Tuinstra, Takahito Uchida, Arne E. Vaaler, Eduard Vieta, Biju Viswanath, Maria Yoldi-Negrete, Oguz Kaan Yalcinkaya, Allan H. Young, Yosra Zgueb, and Peter C. Whybrow

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Published
2023
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4. Analysis on in vitro effect of lithium on telomere length in lymphoblastoid cell lines from bipolar disorder patients with different clinical response to long-term lithium treatment

Author

Alessio Squassina, Anna Meloni, Donatella Congiu, Panagiotis Bosganas, George P. Patrinos, Rixing Lin, Gustavo Turecki, Giovanni Severino, Raffaella Ardau, Caterina Chillotti, and Claudia Pisanu

Subjects
Bipolar disorder, Mood disorders, Accelerated aging, Cellular systems, Neural precursors, Lymphoblastoid cell liens, Medicine, Genetics, QH426-470
Abstract

Abstract Background It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15). Results There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors. Conclusions Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.

Published
2022
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5. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author

Klaus Oliver Schubert, Anbupalam Thalamuthu, Azmeraw T. Amare, Joseph Frank, Fabian Streit, Mazda Adl, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Cynthia Marie-Claire, Micah Cearns, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Liping Hou, Yi-Hsiang Hsu, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Ewa Ferensztajn-Rochowiak, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan McElroy, Francesc Colom, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O’Donovan, Norio Ozaki, Urban Ösby, Sergi Papiol, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fasil Tekola-Ayele, Alfonso Tortorella, Gustavo Turecki, Julia Veeh, Eduard Vieta, Stephanie H. Witt, Gloria Roberts, Peter P. Zandi, Martin Alda, Michael Bauer, Francis J. McMahon, Philip B. Mitchell, Thomas G. Schulze, Marcella Rietschel, and Bernhard T. Baune

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

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
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6. Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Author

Michael Bauer, Tasha Glenn, Eric D. Achtyes, Martin Alda, Esen Agaoglu, Kürşat Altınbaş, Ole A. Andreassen, Elias Angelopoulos, Raffaella Ardau, Edgar Arrua Vares, Memduha Aydin, Yavuz Ayhan, Christopher Baethge, Rita Bauer, Bernhard T. Baune, Ceylan Balaban, Claudia Becerra-Palars, Aniruddh P. Behere, Prakash B. Behere, Habte Belete, Tilahun Belete, Gabriel Okawa Belizario, Frank Bellivier, Robert H. Belmaker, Francesco Benedetti, Michael Berk, Yuly Bersudsky, Şule Bicakci, Harriet Birabwa-Oketcho, Thomas D. Bjella, Conan Brady, Jorge Cabrera, Marco Cappucciati, Angela Marianne Paredes Castro, Wei-Ling Chen, Eric Y. Wo Cheung, Silvia Chiesa, Marie Crowe, Alessandro Cuomo, Sara Dallaspezia, Maria Del Zompo, Pratikkumar Desai, Seetal Dodd, Markus Donix, Bruno Etain, Andrea Fagiolini, Frederike T. Fellendorf, Ewa Ferensztajn-Rochowiak, Jess G. Fiedorowicz, Kostas N. Fountoulakis, Mark A. Frye, Pierre A. Geoffroy, Ana Gonzalez-Pinto, John F. Gottlieb, Paul Grof, Bartholomeus C. M. Haarman, Hirohiko Harima, Mathias Hasse-Sousa, Chantal Henry, Lone Høffding, Josselin Houenou, Massimiliano Imbesi, Erkki T. Isometsä, Maja Ivkovic, Sven Janno, Simon Johnsen, Flávio Kapczinski, Gregory N. Karakatsoulis, Mathias Kardell, Lars Vedel Kessing, Seong Jae Kim, Barbara König, Timur L. Kot, Michael Koval, Mauricio Kunz, Beny Lafer, Mikael Landén, Erik R. Larsen, Melanie Lenger, Ute Lewitzka, Rasmus W. Licht, Carlos Lopez-Jaramillo, Alan MacKenzie, Helle Østergaard Madsen, Simone Alberte Kongstad A. Madsen, Jayant Mahadevan, Agustine Mahardika, Mirko Manchia, Wendy Marsh, Monica Martinez-Cengotitabengoa, Klaus Martiny, Yuki Mashima, Declan M. McLoughlin, Ybe Meesters, Ingrid Melle, Fátima Meza-Urzúa, Mok Yee Ming, Scott Monteith, Muthukumaran Moorthy, Gunnar Morken, Enrica Mosca, Anton A. Mozzhegorov, Rodrigo Munoz, Starlin V. Mythri, Fethi Nacef, Ravi K. Nadella, Takako Nakanotani, René Ernst Nielsen, Claire O‘Donovan, Adel Omrani, Yamima Osher, Uta Ouali, Maja Pantovic-Stefanovic, Pornjira Pariwatcharakul, Joanne Petite, Andrea Pfennig, Yolanda Pica Ruiz, Maximilian Pilhatsch, Marco Pinna, Maurizio Pompili, Richard Porter, Danilo Quiroz, Francisco Diego Rabelo-da-Ponte, Raj Ramesar, Natalie Rasgon, Woraphat Ratta-apha, Michaela Ratzenhofer, Maria Redahan, M. S. Reddy, Andreas Reif, Eva Z. Reininghaus, Jenny Gringer Richards, Philipp Ritter, Janusz K. Rybakowski, Leela Sathyaputri, Ângela M. Scippa, Christian Simhandl, Emanuel Severus, Daniel Smith, José Smith, Paul W. Stackhouse, Dan J. Stein, Kellen Stilwell, Sergio Strejilevich, Kuan-Pin Su, Mythily Subramaniam, Ahmad Hatim Sulaiman, Kirsi Suominen, Andi J. Tanra, Yoshitaka Tatebayashi, Wen Lin Teh, Leonardo Tondo, Carla Torrent, Daniel Tuinstra, Takahito Uchida, Arne E. Vaaler, Julia Veeh, Eduard Vieta, Biju Viswanath, Maria Yoldi-Negrete, Oguz Kaan Yalcinkaya, Allan H. Young, Yosra Zgueb, and Peter C. Whybrow

Subjects
Bipolar disorder, Suicide, Sunlight, Solar insolation, Psychiatry, Circadian, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p

Published
2021
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7. HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Author

Sigrid Le Clerc, Laura Lombardi, Bernhard T. Baune, Azmeraw T. Amare, Klaus Oliver Schubert, Liping Hou, Scott R. Clark, Sergi Papiol, Micah Cearns, Urs Heilbronner, Franziska Degenhardt, Fasil Tekola-Ayele, Yi-Hsiang Hsu, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Clara Brichant-Petitjean, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Stephane Jamain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John R. Kelsoe, Sarah Kittel-Schneider, Ewa Ferensztajn-Rochowiak, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Susan G. Leckband, Alfonso Tortorella, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Francesc Colom, Vincent Millischer, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O’Donovan, Norio Ozaki, Urban Ösby, Andrea Pfennig, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Claudia Pisanu, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Mario Maj, Gustavo Turecki, Eduard Vieta, Julia Veeh, Stephanie H. Witt, Adam Wright, Peter P. Zandi, Philip B. Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Jean-Louis Spadoni, Wahid Boukouaci, Jean-Romain Richard, Philippe Le Corvoisier, Caroline Barrau, Jean-François Zagury, Marion Leboyer, and Ryad Tamouza

Subjects
Medicine, Science
Abstract

Abstract Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p

Published
2021
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8. Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

Author

Abraham Nunes, William Stone, Raffaella Ardau, Anne Berghöfer, Alberto Bocchetta, Caterina Chillotti, Valeria Deiana, Franziska Degenhardt, Andreas J. Forstner, Julie S. Garnham, Eva Grof, Tomas Hajek, Mirko Manchia, Manuel Mattheisen, Francis McMahon, Bruno Müller-Oerlinghausen, Markus M. Nöthen, Marco Pinna, Claudia Pisanu, Claire O’Donovan, Marcella D. C. Rietschel, Guy Rouleau, Thomas Schulze, Giovanni Severino, Claire M. Slaney, Alessio Squassina, Aleksandra Suwalska, Gustavo Turecki, Rudolf Uher, Petr Zvolsky, Pablo Cervantes, Maria del Zompo, Paul Grof, Janusz Rybakowski, Leonardo Tondo, Thomas Trappenberg, and Martin Alda

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

Published
2021
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9. Prediction of lithium response using genomic data

Author

William Stone, Abraham Nunes, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, Jean-Michel Aubry, Lena Backlund, Michael Bauer, Frank Bellivier, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Cristiana Cruceanu, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Liping Hou, Esther Jiménez, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Po-Hsiu Kuo, Ichiro Kusumi, Catharina Lavebratt, Mirko Manchia, Lina Martinsson, Manuel Mattheisen, Francis J. McMahon, Vincent Millischer, Philip B. Mitchell, Markus M. Nöthen, Claire O’Donovan, Norio Ozaki, Claudia Pisanu, Andreas Reif, Marcella Rietschel, Guy Rouleau, Janusz Rybakowski, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Giovanni Severino, Alessio Squassina, Julia Veeh, Eduard Vieta, Thomas Trappenberg, and Martin Alda

Subjects
Medicine, Science
Abstract

Abstract Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen’s kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

Published
2021
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10. Correction: Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author

Klaus Oliver Schubert, Anbupalam Thalamuthu, Azmeraw T. Amare, Joseph Frank, Fabian Streit, Mazda Adl, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Cynthia Marie-Claire, Micah Cearns, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Liping Hou, Yi-Hsiang Hsu, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Ewa Ferensztajn-Rochowiak, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan McElroy, Francesc Colom, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O’Donovan, Norio Ozaki, Urban Ösby, Sergi Papiol, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fasil Tekola-Ayele, Alfonso Tortorella, Gustavo Turecki, Julia Veeh, Eduard Vieta, Stephanie H. Witt, Gloria Roberts, Peter P. Zandi, Martin Alda, Michael Bauer, Francis J. McMahon, Philip B. Mitchell, Thomas G. Schulze, Marcella Rietschel, and Bernhard T. Baune

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published
2022
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11. Internet use by older adults with bipolar disorder: international survey results

Author

Rita Bauer, Tasha Glenn, Sergio Strejilevich, Jörn Conell, Martin Alda, Raffaella Ardau, Bernhard T. Baune, Michael Berk, Yuly Bersudsky, Amy Bilderbeck, Alberto Bocchetta, Angela M. Paredes Castro, Eric Y. W. Cheung, Caterina Chillotti, Sabine Choppin, Alessandro Cuomo, Maria Del Zompo, Rodrigo Dias, Seetal Dodd, Anne Duffy, Bruno Etain, Andrea Fagiolini, Miryam Fernández Hernandez, Julie Garnham, John Geddes, Jonas Gildebro, Michael J. Gitlin, Ana Gonzalez-Pinto, Guy M. Goodwin, Paul Grof, Hirohiko Harima, Stefanie Hassel, Chantal Henry, Diego Hidalgo-Mazzei, Anne Hvenegaard Lund, Vaisnvy Kapur, Girish Kunigiri, Beny Lafer, Erik R. Larsen, Ute Lewitzka, Rasmus W. Licht, Blazej Misiak, Patryk Piotrowski, Ângela Miranda-Scippa, Scott Monteith, Rodrigo Munoz, Takako Nakanotani, René E. Nielsen, Claire O’Donovan, Yasushi Okamura, Yamima Osher, Andreas Reif, Philipp Ritter, Janusz K. Rybakowski, Kemal Sagduyu, Brett Sawchuk, Elon Schwartz, Claire Slaney, Ahmad H. Sulaiman, Kirsi Suominen, Aleksandra Suwalska, Peter Tam, Yoshitaka Tatebayashi, Leonardo Tondo, Julia Veeh, Eduard Vieta, Maj Vinberg, Biju Viswanath, Mark Zetin, Peter C. Whybrow, and Michael Bauer

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. Methods A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. Results Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. Conclusions Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Published
2018
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12. Circulating antithyroid antibodies contribute to the decrease of glomerular filtration rate in lithium-treated patients: a longitudinal study

Author

Alberto Bocchetta, Luca Ambrosiani, Gioia Baggiani, Claudia Pisanu, Caterina Chillotti, Raffaella Ardau, Fernanda Velluzzi, Doloretta Piras, Andrea Loviselli, and Antonello Pani

Subjects
Lithium, Renal insufficiency, Chronic, Glomerular filtration rate, Thyroid microsomal antibodies, Anti-thyroglobulin, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Concerns about the adverse effects of long-term treatment with lithium include reduced renal function. In the present study, we examined comorbidities which may be associated with chronic kidney disease in a cohort of patients treated with lithium for up to 41 years. Methods We studied 394 patients who were treated with lithium for ≥ 5 years. The potential role of comorbidities (diabetes, concurrent antihypertensive medication, treatment with l-thyroxine, and presence of antithyroid peroxidase/microsomes, anti-thyroglobulin, and/or anti-thyrotropin-receptor antibodies) was analysed. We focused on the categories of patients with an estimated glomerular filtration rate (eGFR) lower than 60 or 45 mL/min/1.73 m2 as calculated from serum creatinine according to the Modification of Diet in Renal Disease Study Group. We applied multivariate regression analysis and Cox survival analysis to study the effects exerted by sex, age, duration of lithium treatment, and comorbidities using eGFR categories as the dependent variable. Kaplan–Meier curves were generated to measure the time to decline to an eGFR lower than 45 mL/min/1.73 m2 in patients with positive or negative thyroid antibodies. Results Age was associated with a decline to an eGFR lower than 60 mL/min/1.73 m2 after controlling for sex, duration of lithium treatment, and comorbidities. Circulating thyroid antibodies were associated with a decline to an eGFR lower than 45 mL/min/1.73 m2. Conclusions The present study is the first to suggest a potential role of circulating thyroid antibodies in the severe decline of eGFR in lithium-treated patients.

Published
2018
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13. An observational study of 110 elderly lithium-treated patients followed up for 6 years with particular reference to renal function

Author

Alberto Bocchetta, Francesca Cabras, Martina Pinna, Antonio Poddighe, Claudia Sardu, Raffaella Ardau, Caterina Chillotti, and Maria Del Zompo

Subjects
Mood disorders, Bipolar disorders, Depression, Lithium, Elderly, Creatinine, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Recent observational studies have focused on lithium treatment in the elderly, with particular reference to safety in terms of thyroid and renal functions. The purpose of this study was to compare the clinical characteristics of patients starting lithium treatment before (N = 79) or after (N = 31) the age of 65 years. Patients were followed up for 6 years with focus on renal function and prescription of levothyroxine and methimazole. Results At baseline, median lithium serum concentration was 0.55 mmol/l. The estimated glomerular filtration rate was lower than 60 ml/min/1.73 m2 in 43 (39%) patients. In a multiple regression analysis controlling for age and gender, we found a significant effect of duration of lithium treatment on estimated glomerular filtration rate (−0.85 ml/min/1.73 m2 per year of prior exposure). The annual decline during follow-up was 2.3 ml/min/1.73 m2. Two patients were prescribed levothyroxine, and two were prescribed methimazole for the first time during follow-up. Conclusions Median lithium serum concentration in this cohort of elderly patients with mainly bipolar disorders was lower than the therapeutic range indicated for younger adults. The decline in glomerular filtration rate may be accelerated by long-term lithium use. Thyroid and renal functions continue to require close monitoring throughout the course of lithium treatment. Trial registration NP/2013/3836. Registered 24 June 2013

Published
2017
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14. Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder

Author

Céline S. Reinbold, Andreas J. Forstner, Julian Hecker, Janice M. Fullerton, Per Hoffmann, Liping Hou, Urs Heilbronner, Franziska Degenhardt, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, Bárbara Arias, Lena Backlund, Antonio Benabarre, Susanne Bengesser, Abesh K. Bhattacharjee, Joanna M. Biernacka, Armin Birner, Cynthia Marie-Claire, Pablo Cervantes, Guo-Bo Chen, Hsi-Chung Chen, Caterina Chillotti, Scott R. Clark, Francesc Colom, David A. Cousins, Cristiana Cruceanu, Piotr M. Czerski, Alexandre Dayer, Bruno Étain, Peter Falkai, Louise Frisén, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Stéphane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Sarah Kittel-Schneider, Sebastian Kliwicki, Barbara König, Ichiro Kusumi, Nina Lackner, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A. López Jaramillo, Glenda MacQueen, Mirko Manchia, Lina Martinsson, Manuel Mattheisen, Michael J. McCarthy, Susan L. McElroy, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Urban Ösby, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, Daniela Reich-Erkelenz, Guy A. Rouleau, Peter R. Schofield, K. Oliver Schubert, Barbara W. Schweizer, Florian Seemüller, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Kazutaka Shimoda, Christian Simhandl, Claire M. Slaney, Jordan W. Smoller, Alessio Squassina, Thomas J. Stamm, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Julia Volkert, Stephanie H. Witt, Adam J. Wright, L. Trevor Young, Peter P. Zandi, James B. Potash, J. Raymond DePaulo, Michael Bauer, Eva Reininghaus, Tomáš Novák, Jean-Michel Aubry, Mario Maj, Bernhard T. Baune, Philip B. Mitchell, Eduard Vieta, Mark A. Frye, Janusz K. Rybakowski, Po-Hsiu Kuo, Tadafumi Kato, Maria Grigoroiu-Serbanescu, Andreas Reif, Maria Del Zompo, Frank Bellivier, Martin Schalling, Naomi R. Wray, John R. Kelsoe, Martin Alda, Francis J. McMahon, Thomas G. Schulze, Marcella Rietschel, Markus M. Nöthen, and Sven Cichon

Subjects
bipolar disorder, lithium response, microRNA, common variants, genome-wide association study, Psychiatry, RC435-571
Abstract

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Published
2018
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15. Erratum to: Online information seeking by patients with bipolar disorder: results from an international multisite survey

Author

Jörn Conell, Rita Bauer, Tasha Glenn, Martin Alda, Raffaella Ardau, Bernhard T. Baune, Michael Berk, Yuly Bersudsky, Amy Bilderbeck, Alberto Bocchetta, Letizia Bossini, Angela Marianne Paredes Castro, Eric Yat Wo Cheung, Caterina Chillotti, Sabine Choppin, Maria Del Zompo, Rodrigo Dias, Seetal Dodd, Anne Duffy, Bruno Etain, Andrea Fagiolini, Julie Garnham, John Geddes, Jonas Gildebro, Ana Gonzalez-Pinto, Guy M. Goodwin, Paul Grof, Hirohiko Harima, Stefanie Hassel, Chantal Henry, Diego Hidalgo-Mazzei, Vaisnvy Kapur, Girish Kunigiri, Beny Lafer, Chun Lam, Erik Roj Larsen, Ute Lewitzka, Rasmus W. Licht, Anne Hvenegaard Lund, Blazej Misiak, Patryk Piotrowski, Scott Monteith, Rodrigo Munoz, Takako Nakanotani, René E. Nielsen, Claire O’Donovan, Yasushi Okamura, Yamima Osher, Andreas Reif, Philipp Ritter, Janusz K. Rybakowski, Kemal Sagduyu, Brett Sawchuk, Elon Schwartz, Ângela Miranda Scippa, Claire Slaney, Ahmad Hatim Sulaiman, Kirsi Suominen, Aleksandra Suwalska, Peter Tam, Yoshitaka Tatebayashi, Leonardo Tondo, Eduard Vieta, Maj Vinberg, Biju Viswanath, Julia Volkert, Mark Zetin, Iñaki Zorrilla, Peter C. Whybrow, and Michael Bauer

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Published
2017
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16. Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report.

Author

Mirko Manchia, Mazda Adli, Nirmala Akula, Raffaella Ardau, Jean-Michel Aubry, Lena Backlund, Claudio Em Banzato, Bernhard T Baune, Frank Bellivier, Susanne Bengesser, Joanna M Biernacka, Clara Brichant-Petitjean, Elise Bui, Cynthia V Calkin, Andrew Tai Ann Cheng, Caterina Chillotti, Sven Cichon, Scott Clark, Piotr M Czerski, Clarissa Dantas, Maria Del Zompo, J Raymond Depaulo, Sevilla D Detera-Wadleigh, Bruno Etain, Peter Falkai, Louise Frisén, Mark A Frye, Jan Fullerton, Sébastien Gard, Julie Garnham, Fernando S Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Rebecca Hoban, Liping Hou, Stéphane Jamain, Jean-Pierre Kahn, Layla Kassem, Tadafumi Kato, John R Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Po-Hsiu Kuo, Ichiro Kusumi, Gonzalo Laje, Catharina Lavebratt, Marion Leboyer, Susan G Leckband, Carlos A López Jaramillo, Mario Maj, Alain Malafosse, Lina Martinsson, Takuya Masui, Philip B Mitchell, Frank Mondimore, Palmiero Monteleone, Audrey Nallet, Maria Neuner, Tomás Novák, Claire O'Donovan, Urban Osby, Norio Ozaki, Roy H Perlis, Andrea Pfennig, James B Potash, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Sara Richardson, Guy A Rouleau, Janusz K Rybakowski, Martin Schalling, Peter R Schofield, Oliver K Schubert, Barbara Schweizer, Florian Seemüller, Maria Grigoroiu-Serbanescu, Giovanni Severino, Lisa R Seymour, Claire Slaney, Jordan W Smoller, Alessio Squassina, Thomas Stamm, Jo Steele, Pavla Stopkova, Sarah K Tighe, Alfonso Tortorella, Gustavo Turecki, Naomi R Wray, Adam Wright, Peter P Zandi, David Zilles, Michael Bauer, Marcella Rietschel, Francis J McMahon, Thomas G Schulze, and Martin Alda

Subjects
Medicine, Science
Abstract

The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Published
2013
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17. Microcytic Anaemia as Susceptibility Factors in Bipolar Spectrum Disorders: Review of the Literature, Replication Survey, and Co-Segregation within Families

Author

Maria Carla Sollaino, Alberto Bocchetta, Caterina Chillotti, and Raffaella Ardau

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Epidemiology, Anemia, Alpha-thalassemia, Beta-thalassemia, Article, Hemoglobin A2, hemic and lymphatic diseases, medicine, Mean corpuscular volume, Blood cell count, medicine.diagnostic_test, business.industry, Erythrocyte indices, Beta thalassemia, medicine.disease, Thalassaemias, Psychiatry and Mental health, Mood, Mood disorders, business
Abstract

Background: Potential interactions between mood disorders and microcytic anaemias have been suggested by case reports, surveys of haematological parameters in psychiatric populations, and surveys of psychiatric morbidity in thalassaemic carriers. Objectives: a) To review published studies. b) To study the prevalence of microcytic anaemia in a sample of Sardinian outpatients with recurrent mood disorders. c) To check whether mood disorders and microcytic anaemia co-segregate within families. Methods: We extracted data on blood count and serum iron concentrations from the records of patients admitted between January 1st, 2001 and December 31st, 2016, to our clinic for mood disorders. Moreover, we studied siblings of subjects with both major mood disorders (according to Research Diagnostic Criteria) and heterozygous thalassaemia (according to Mean Corpuscular Volume, serum iron, and haemoglobin A2 concentrations). Siblings affected with a major mood disorder were examined for haematological concordance with the proband (reduced MCV and/or increased HbA2 in case of heterozygous β-thalassaemia, or presence of gene deletions in case of α-thalassaemia). Results: Microcytic anaemia was highly prevalent (81/337 = 24.0%) among outpatients with mood disorders. Starting from 30 probands with heterozygous ß-thalassaemia, concordance for reduced MCV and/or increased HbA2 was found in 78% (35/45) of affected siblings. Starting from 3 probands with heterozygous α-thalassaemia, only one of the 5 affected siblings carried four α-globin functional genes. Conclusion: Based on the review of the literature, the high prevalence of microcytic anaemia in outpatients, and the concordance between affected siblings, we can conclude that a role of heterozygous thalassaemias is highly probable. Future studies are required to establish the relevance of heterozygous thalassaemias and evaluate the magnitude of the effect, possibly using a molecular diagnosis also in the case of heterozygous β-thalassaemia.

Published
2021

19. Association between polarity of first episode and solar insolation in bipolar I disorder

Author

Michael Bauer, Tasha Glenn, Eric D. Achtyes, Martin Alda, Esen Agaoglu, Kürşat Altınbaş, Ole A. Andreassen, Elias Angelopoulos, Raffaella Ardau, Memduha Aydin, Yavuz Ayhan, Christopher Baethge, Rita Bauer, Bernhard T. Baune, Ceylan Balaban, Claudia Becerra-Palars, Aniruddh P. Behere, Prakash B. Behere, Habte Belete, Tilahun Belete, Gabriel Okawa Belizario, Frank Bellivier, Robert H. Belmaker, Francesco Benedetti, Michael Berk, Yuly Bersudsky, Şule Bicakci, Harriet Birabwa-Oketcho, Thomas D. Bjella, Conan Brady, Jorge Cabrera, Marco Cappucciati, Angela Marianne Paredes Castro, Wei-Ling Chen, Eric Y.W. Cheung, Silvia Chiesa, Marie Crowe, Alessandro Cuomo, Sara Dallaspezia, Maria Del Zompo, Pratikkumar Desai, Seetal Dodd, Bruno Etain, Andrea Fagiolini, Frederike T. Fellendorf, Ewa Ferensztajn-Rochowiak, Jess G. Fiedorowicz, Kostas N. Fountoulakis, Mark A. Frye, Pierre A. Geoffroy, Ana Gonzalez-Pinto, John F. Gottlieb, Paul Grof, Bartholomeus C.M. Haarman, Hirohiko Harima, Mathias Hasse-Sousa, Chantal Henry, Lone Høffding, Josselin Houenou, Massimiliano Imbesi, Erkki T. Isometsä, Maja Ivkovic, Sven Janno, Simon Johnsen, Flávio Kapczinski, Gregory N. Karakatsoulis, Mathias Kardell, Lars Vedel Kessing, Seong Jae Kim, Barbara König, Timur L. Kot, Michael Koval, Mauricio Kunz, Beny Lafer, Mikael Landén, Erik R. Larsen, Melanie Lenger, Ute Lewitzka, Rasmus W. Licht, Carlos Lopez-Jaramillo, Alan MacKenzie, Helle Østergaard Madsen, Simone Alberte Kongstad A. Madsen, Jayant Mahadevan, Agustine Mahardika, Mirko Manchia, Wendy Marsh, Monica Martinez-Cengotitabengoa, Klaus Martiny, Yuki Mashima, Declan M. McLoughlin, Ybe Meesters, Ingrid Melle, Fátima Meza-Urzúa, Yee Ming Mok, Scott Monteith, Muthukumaran Moorthy, Gunnar Morken, Enrica Mosca, Anton A. Mozzhegorov, Rodrigo Munoz, Starlin V. Mythri, Fethi Nacef, Ravi K. Nadella, Takako Nakanotani, René Ernst Nielsen, Claire O'Donovan, Adel Omrani, Yamima Osher, Uta Ouali, Maja Pantovic-Stefanovic, Pornjira Pariwatcharakul, Joanne Petite, Andrea Pfennig, Yolanda Pica Ruiz, Marco Pinna, Maurizio Pompili, Richard Porter, Danilo Quiroz, Francisco Diego Rabelo-da-Ponte, Raj Ramesar, Natalie Rasgon, Woraphat Ratta-apha, Michaela Ratzenhofer, Maria Redahan, M.S. Reddy, Andreas Reif, Eva Z. Reininghaus, Jenny Gringer Richards, Philipp Ritter, Janusz K. Rybakowski, Leela Sathyaputri, Ângela M. Scippa, Christian Simhandl, Daniel Smith, José Smith, Paul W. Stackhouse, Dan J. Stein, Kellen Stilwell, Sergio Strejilevich, Kuan-Pin Su, Mythily Subramaniam, Ahmad Hatim Sulaiman, Kirsi Suominen, Andi J. Tanra, Yoshitaka Tatebayashi, Wen Lin Teh, Leonardo Tondo, Carla Torrent, Daniel Tuinstra, Takahito Uchida, Arne E. Vaaler, Eduard Vieta, Biju Viswanath, Maria Yoldi-Negrete, Oguz Kaan Yalcinkaya, Allan H. Young, Yosra Zgueb, Peter C. Whybrow, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Bauer, Michael, Glenn, Tasha, Achtyes, Eric D, Alda, Martin, Agaoglu, Esen, Altınbaş, Kürşat, Andreassen, Ole A, Angelopoulos, Elia, Ardau, Raffaella, Aydin, Memduha, Ayhan, Yavuz, Baethge, Christopher, Bauer, Rita, Baune, Bernhard T, Balaban, Ceylan, Becerra-Palars, Claudia, Behere, Aniruddh P, Behere, Prakash B, Belete, Habte, Belete, Tilahun, Belizario, Gabriel Okawa, Bellivier, Frank, Belmaker, Robert H, Benedetti, Francesco, Berk, Michael, Bersudsky, Yuly, Bicakci, Şule, Birabwa-Oketcho, Harriet, Bjella, Thomas D, Brady, Conan, Cabrera, Jorge, Cappucciati, Marco, Castro, Angela Marianne Parede, Chen, Wei-Ling, Cheung, Eric Y W, Chiesa, Silvia, Crowe, Marie, Cuomo, Alessandro, Dallaspezia, Sara, Del Zompo, Maria, Desai, Pratikkumar, Dodd, Seetal, Etain, Bruno, Fagiolini, Andrea, Fellendorf, Frederike T, Ferensztajn-Rochowiak, Ewa, Fiedorowicz, Jess G, Fountoulakis, Kostas N, Frye, Mark A, Geoffroy, Pierre A, Gonzalez-Pinto, Ana, Gottlieb, John F, Grof, Paul, Haarman, Bartholomeus C M, Harima, Hirohiko, Hasse-Sousa, Mathia, Henry, Chantal, Høffding, Lone, Houenou, Josselin, Imbesi, Massimiliano, Isometsä, Erkki T, Ivkovic, Maja, Janno, Sven, Johnsen, Simon, Kapczinski, Flávio, Karakatsoulis, Gregory N, Kardell, Mathia, Kessing, Lars Vedel, Kim, Seong Jae, König, Barbara, Kot, Timur L, Koval, Michael, Kunz, Mauricio, Lafer, Beny, Landén, Mikael, Larsen, Erik R, Lenger, Melanie, Lewitzka, Ute, Licht, Rasmus W, Lopez-Jaramillo, Carlo, Mackenzie, Alan, Madsen, Helle Østergaard, Madsen, Simone Alberte Kongstad A, Mahadevan, Jayant, Mahardika, Agustine, Manchia, Mirko, Marsh, Wendy, Martinez-Cengotitabengoa, Monica, Martiny, Klau, Mashima, Yuki, Mcloughlin, Declan M, Meesters, Ybe, Melle, Ingrid, Meza-Urzúa, Fátima, Mok, Yee Ming, Monteith, Scott, Moorthy, Muthukumaran, Morken, Gunnar, Mosca, Enrica, Mozzhegorov, Anton A, Munoz, Rodrigo, Mythri, Starlin V, Nacef, Fethi, Nadella, Ravi K, Nakanotani, Takako, Nielsen, René Ernst, O'Donovan, Claire, Omrani, Adel, Osher, Yamima, Ouali, Uta, Pantovic-Stefanovic, Maja, Pariwatcharakul, Pornjira, Petite, Joanne, Pfennig, Andrea, Ruiz, Yolanda Pica, Pinna, Marco, Pompili, Maurizio, Porter, Richard, Quiroz, Danilo, Rabelo-da-Ponte, Francisco Diego, Ramesar, Raj, Rasgon, Natalie, Ratta-Apha, Woraphat, Ratzenhofer, Michaela, Redahan, Maria, Reddy, M S, Reif, Andrea, Reininghaus, Eva Z, Richards, Jenny Gringer, Ritter, Philipp, Rybakowski, Janusz K, Sathyaputri, Leela, Scippa, Ângela M, Simhandl, Christian, Smith, Daniel, Smith, José, Stackhouse, Paul W, Stein, Dan J, Stilwell, Kellen, Strejilevich, Sergio, Su, Kuan-Pin, Subramaniam, Mythily, Sulaiman, Ahmad Hatim, Suominen, Kirsi, Tanra, Andi J, Tatebayashi, Yoshitaka, Teh, Wen Lin, Tondo, Leonardo, Torrent, Carla, Tuinstra, Daniel, Uchida, Takahito, Vaaler, Arne E, Vieta, Eduard, Viswanath, Biju, Yoldi-Negrete, Maria, Yalcinkaya, Oguz Kaan, Young, Allan H, Zgueb, Yosra, and Whybrow, Peter C

Subjects
Bipolar Disorder/complications, Male, Polarity, Bipolar disorder, Circadian rhythm, Depression, Psychiatry and Mental health, Clinical Psychology, Solar insolation, Sunlight, Humans, Female, Seasons
Abstract

OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth.METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer.RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001).CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

Published
2022

20. Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach - CORRIGENDUM

Author

Micah, Cearns, Azmeraw T, Amare, Klaus Oliver, Schubert, Anbupalam, Thalamuthu, Joseph, Frank, Fabian, Streit, Mazda, Adli, Nirmala, Akula, Kazufumi, Akiyama, Raffaella, Ardau, Bárbara, Arias, JeanMichel, Aubry, Lena, Backlund, Abesh Kumar, Bhattacharjee, Frank, Bellivier, Antonio, Benabarre, Susanne, Bengesser, Joanna M, Biernacka, Armin, Birner, Clara, Brichant-Petitjean, Pablo, Cervantes, HsiChung, Chen, Caterina, Chillotti, Sven, Cichon, Cristiana, Cruceanu, Piotr M, Czerski, Nina, Dalkner, Alexandre, Dayer, Franziska, Degenhardt, Maria Del, Zompo, J Raymond, DePaulo, Bruno, Étain, Peter, Falkai, Andreas J, Forstner, Louise, Frisen, Mark A, Frye, Janice M, Fullerton, Sébastien, Gard, Julie S, Garnham, Fernando S, Goes, Maria, Grigoroiu-Serbanescu, Paul, Grof, Ryota, Hashimoto, Joanna, Hauser, Urs, Heilbronner, Stefan, Herms, Per, Hoffmann, Andrea, Hofmann, Liping, Hou, Yi-Hsiang, Hsu, Stephane, Jamain, Esther, Jiménez, Jean-Pierre, Kahn, Layla, Kassem, Po-Hsiu, Kuo, Tadafumi, Kato, John, Kelsoe, Sarah, Kittel-Schneider, Sebastian, Kliwicki, Barbara, König, Ichiro, Kusumi, Gonzalo, Laje, Mikael, Landén, Catharina, Lavebratt, Marion, Leboyer, Susan G, Leckband, Mario, Maj, Mirko, Manchia, Lina, Martinsson, Michael J, McCarthy, Susan, McElroy, Francesc, Colom, Marina, Mitjans, Francis M, Mondimore, Palmiero, Monteleone, Caroline M, Nievergelt, Markus M, Nöthen, Tomas, Novák, Claire, O'Donovan, Norio, Ozaki, Vincent, Millischer, Sergi, Papiol, Andrea, Pfennig, Claudia, Pisanu, James B, Potash, Andreas, Reif, Eva, Reininghaus, Guy A, Rouleau, Janusz K, Rybakowski, Martin, Schalling, Peter R, Schofield, Barbara W, Schweizer, Giovanni, Severino, Tatyana, Shekhtman, Paul D, Shilling, Katzutaka, Shimoda, Christian, Simhandl, Claire M, Slaney, Alessio, Squassina, Thomas, Stamm, Pavla, Stopkova, Fasil, TekolaAyele, Alfonso, Tortorella, Gustavo, Turecki, Julia, Veeh, Eduard, Vieta, Stephanie H, Witt, Gloria, Roberts, Peter P, Zandi, Martin, Alda, Michael, Bauer, Francis J, McMahon, Philip B, Mitchell, Thomas G, Schulze, Marcella, Rietschel, Scott R, Clark, and Bernhard T, Baune

Subjects
Machine Learning, Psychiatry and Mental health, Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant, Bipolar Disorder, Humans, Lithium
Published
2022

21. MicroRNA expression profiling of lymphoblasts from bipolar disorder patients who died by suicide, pathway analysis and integration with postmortem brain findings

Author

Claudia Pisanu, Alessio Squassina, Paola Niola, Donatella Congiu, Cristiana Cruceanu, Martin Alda, Maria Del Zompo, Raffaella Ardau, Giovanni Severino, Juan Pablo Lopez, Gustavo Turecki, and Caterina Chillotti

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Bipolar Disorder, Lithium (medication), 03 medical and health sciences, 0302 clinical medicine, Internal medicine, microRNA, medicine, Humans, Gene Regulatory Networks, Pharmacology (medical), Lymphocytes, Bipolar disorder, Biological Psychiatry, Pharmacology, Postmortem brain, business.industry, Gene Expression Profiling, Lymphoblast, Brain, Middle Aged, Pathway analysis, medicine.disease, 030227 psychiatry, Gene expression profiling, MicroRNAs, Suicide, Psychiatry and Mental health, Inhibitory Postsynaptic Potentials, Neurology, Cell culture, Female, Autopsy, Neurology (clinical), business, Biomarkers, 030217 neurology & neurosurgery, medicine.drug
Abstract

Post-mortem brain studies suggest that miRNAs may be involved in suicide, but their role as peripheral biomarkers or targets of preventive pharmacological treatments in suicide has yet to be elucidated. We used nCounter miRNA Expression assay to measure miRNAs expression in lymphoblastoid cell lines (LCLs) from patients with Bipolar Disorder (BD) who died by suicide (SC, n = 7) and with low risk of suicide (LR, n = 11). Five miRNAs were differentially expressed in SC compared to LR (false discovery rate p0.05). The two most significant miRNAs were measured with RT-qPCR in the same sample and in 12 healthy controls (HC): miR-4286 was increased while miR-186-5p was decreased in SC compared to LR and HC (ANOVA F = 14.92, p = 0.000043 and F = 3.95, p = 0.032 respectively). miR-4286 was also decreased in postmortem brains from 12 patients with BD who died by suicide compared to 13 controls, even though it did not reach statistical significance (FC=0.51, p = 0.07). Treatment with lithium of human neural progenitor cells reduced the expression of miR-4286 (FC=0.30, p = 0.038). Pathway analysis on predicted miR-4286 targets showed that "insulin resistance" was significantly enriched after correction for multiple testing. This pathway comprised 17 genes involved in lipid and glucose metabolism, several of which were also dysregulated in postmortem brains from patients with BD who died by suicide from the Stanley-foundation array collection. In conclusion, our study suggests that miR-4286 could be a biomarker of suicide but further studies are warranted to investigate its targeted genes and how these could be involved in the neurobiology of suicide.

Published
2020

22. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author

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.

Subjects
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

23. Investigating the Role of Leukocyte Telomere Length in Treatment-Resistant Depression and in Response to Electroconvulsive Therapy

Author

Donatella Congiu, Caterina Chillotti, Massimo Gennarelli, Claudia Pisanu, Giovanni Severino, Alessio Squassina, Luigi Trabucchi, Erika Vitali, Raffaella Ardau, Marco Bortolomasi, Anna Meloni, and Alessandra Minelli

Subjects
Oncology, Senescence, medicine.medical_specialty, senescence, medicine.medical_treatment, Medicine (miscellaneous), Genome-wide association study, Article, Electroconvulsive therapy, Internal medicine, medicine, accelerated aging, GWAS, Bipolar disorder, Depression (differential diagnoses), treatment-resistance, bipolar disorder, telomere, major depressive disorder, business.industry, ECT, Accelerated aging, Major depressive disorder, Mental disorders, Psychiatric disorders, Telomere, Treatment-resistance, medicine.disease, mental disorders, psychiatric disorders, Medicine, business, Treatment-resistant depression
Abstract

Psychiatric disorders seem to be characterized by premature cell senescence. However, controversial results have also been reported. In addition, the relationship between accelerated aging and treatment-resistance has scarcely been investigated. In the current study, we measured leukocyte telomere length (LTL) in 148 patients with treatment-resistant depression (TRD, 125 with major depressive disorder, MDD, and 23 with bipolar disorder, BD) treated with electroconvulsive therapy (ECT) and analyzed whether LTL was associated with different response profiles. We also compared LTL between patients with TRD and 335 non-psychiatric controls. For 107 patients for which genome-wide association data were available, we evaluated whether a significant overlap among genetic variants or genes associated with LTL and with response to ECT could be observed. LTL was negatively correlated with age (Spearman’s correlation coefficient = −0.25, p &lt, 0.0001) and significantly shorter in patients with treatment-resistant MDD (Quade’s F = 35.18, p &lt, 0.0001) or BD (Quade’s F = 20.84, p &lt, 0.0001) compared to controls. Conversely, baseline LTL was not associated with response to ECT or remission. We did not detect any significant overlap between genetic variants or genes associated with LTL and response to ECT. Our results support previous findings suggesting premature cell senescence in patients with severe psychiatric disorders and suggest that LTL could not be a predictive biomarker of response to ECT.

Published
2021

24. Prediction of lithium response using clinical data

Author

Janusz K. Rybakowski, Paul Grof, Giovanni Severino, Alberto Bocchetta, Alexandra Suwalska, Claire O'Donovan, Claudia Pisanu, Caterina Chillotti, Thomas Trappenberg, Anne Berghöfer, Tomas Hajek, Marco Pinna, P. Zvolsky, Martin Alda, Leonardo Tondo, Abraham Nunes, E. Grof, Raffaella Ardau, Julie Garnham, Bruno Müller-Oerlinghausen, Pablo Cervantes, Claire Slaney, Valeria Deiana, M. Del Zompo, and Mirko Manchia

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Bipolar Disorder, Sample (statistics), Machine Learning, 03 medical and health sciences, 0302 clinical medicine, Cohen's kappa, Maintenance therapy, Antimanic Agents, Risk Factors, Clinical Decision Rules, Sleep Initiation and Maintenance Disorders, Internal medicine, medicine, Humans, Bipolar disorder, Age of Onset, Receiver operating characteristic, business.industry, Clinical course, Middle Aged, medicine.disease, 030227 psychiatry, 3. Good health, Random forest, Psychiatry and Mental health, Treatment Outcome, ROC Curve, Feature (computer vision), Area Under Curve, Disease Progression, Lithium Compounds, Female, business, 030217 neurology & neurosurgery
Abstract

Objective Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. Method Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. Results Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. Conclusion Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

Published
2019

25. Characterization of Age and Polarity at Onset in Bipolar Disorder

Author

Aiden Corvin, Maria Grigoroiu-Serbanescu, Mark Hyman Rapaport, Frederike T. Fellendorf, Urs Heilbronner, Mariam M. Al Eissa, John J Nurnberger, Claire O'Donovan, Claire Slaney, Mark A. Frye, Niamh L. O'Brien, Roland Hasler, Michael John Owen, Michael Conlon O'Donovan, Farah Klöhn-Saghatolislam, Markus M. Nöthen, Scott R. Clark, Mikael Landén, Lina Jonsson, Peter Falkai, Qingqin S. Li, Alessio Squassina, Simon Schmitt, Gustavo Turecki, Heike Anderson-Schmidt, Jonathan Repple, Sofie R. Aminoff, Eduard Vieta, Katherine Gordon-Smith, Stéphane Jamain, William Byerley, Hélène Richard-Lepouriel, Fermín Mayoral, Francis J. McMahon, Marin Veldic, Ingrid Melle, Andrew McQuillin, Nicholas Bass, Gloria Roberts, Douglas M. Ruderfer, John B. Vincent, Nelson B. Freimer, Kirov George, Wei Xu, Susan L. McElroy, Ceylan Balaban, Marco P. Boks, Franziska Degenhardt, Paul E. Croarkin, Wade H. Berrettini, Piotr M. Czerski, Fernando S. Goes, Peter P. Zandi, Sabrina K. Schaupp, Barbara W. Schweizer, Andrew M. McIntosh, Marcella Rietschel, Helena Pelin, Evelyn J. Bromet, Marion Leboyer, Ole A. Andreassen, Georgia Panagiotaropoulou, Alessia Fiorentino, Sally I. Sharp, Torbjørn Elvsåshagen, Kristina Adorjan, Monika Budde, Lisa Jones, Thomas G. Schulze, Vihra Milanova, Janos Kalman, Tim B. Bigdeli, Esther Jiménez, Abigail Ortiz, Dolores Malaspina, Kevin S. O’Connell, Sergi Papiol, Mario Maj, Tim Hahn, Frederike Stein, Jordan W. Smoller, Tomas Novak, Katrin Gade, J. Raymond DePaulo, Sarah Kittel-Schneider, Julia-Katharina Pfarr, Martin Alda, James A. Knowles, Sven Cichon, David Craig, Eli A. Stahl, William A. Scheftner, Bruno Etain, Annabel Vreeker, Guy A. Rouleau, Stephan Ripke, Clement C. Zai, Frank Bellivier, Giovanni Severino, Palmiero Monteleone, Ian Jones, Bertram Müller-Myhsok, Mark Adams, John Strauss, Philip B. Mitchell, Andreas Reif, Fabian Streit, Roel A. Ophoff, James L. Kennedy, Nils Opel, Raffaella Ardau, Paul Grof, Peter R. Schofield, Susanne Bengesser, Maria Hake, Loes M. Olde Loohuis, Joanna Pawlak, Daniela Reich-Erkelenz, Ingrid Agartz, Maria Del Zompo, Antonio Benabarre, Bernhard T. Baune, Arianna Di Florio, Ashley L. Comes, Michael Gill, Cristiana Cruceanu, Susanne Meinert, William Coryell, Alessio Maria Monteleone, Fanny Senner, Trine Vik Lagerberg, Jose Guzman-Parra, Erik Pålsson, Elliot S. Gershon, Melvin G. McInnis, Pavla Stopkova, Nikolaos Koutsouleris, René S. Kahn, Janice M. Fullerton, Howard J. Edenberg, Tilo Kircher, Nina Dalkner, Udo Dannlowski, Rolf Adolfsson, Alfonso Tortorella, Jean-Michel Aubry, James B. Potash, Catina Chillotti, Eva Z. Reininghaus, Janet L. Sobell, Thorsten M. Kranz, Tina Meller, Ayman H. Fanous, Kai Ringwald, K Oliver Schubert, Andreas J. Forstner, Till F. M. Andlauer, Helena Medeiros, Mirko Manchia, Joanna M. Biernacka, Katharina Brosch, Julie Garnham, Olav B. Smeland, Eva C. Schulte, Carlos N. Pato, Nicholas John Craddock, Srdjan Djurovic, Pablo Cervantes, Michele T. Pato, John R. Kelsoe, Claudia Pisanu, Joanna Twarowska-Hauser, and William Lawson

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, Genome-wide association study, Disease, Heritability, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Schizophrenia, Internal medicine, medicine, Bipolar disorder, business, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

BackgroundStudying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with BD disease characteristics.MethodsGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication sample (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of BD severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses.RELEVANCE STATEMENTIn the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.

Published
2021

26. Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Author

Eduard Vieta, Liping Hou, Markus M. Nöthen, Martin Schalling, Thomas Stamm, Thomas G. Schulze, Norio Ozaki, Claire O'Donovan, Azmeraw T. Amare, Alessio Squassina, Alfonso Tortorella, Kazufumi Akiyama, Urs Heilbronner, Caroline M. Nievergelt, Frank Bellivier, Palmiero Monteleone, Mirko Manchia, Tadafumi Kato, Per Hoffmann, Jean-Michel Aubry, Claudia Pisanu, Pavla Stopkova, Lena Backlund, Anthony Batzler, James B. Potash, Susan L. McElroy, Jean-Pierre Kahn, Guy A. Rouleau, Bernhard T. Baune, Francis M. Mondimore, Beth Larrabee, Peter P. Zandi, Christian Simhandl, Susan G. Leckband, Andrea Pfennig, Maria Del Zompo, Francis J. McMahon, Tatyana Shekhtman, Giovanni Severino, Tomas Novak, Andreas J. Forstner, Marcella Rietschel, Paul Grof, Maria Grigoroiu-Serbanescu, Ryota Hashimoto, Nirmala Akula, Sarah Kittel-Schneider, John R. Kelsoe, Andreas Reif, Joanna M. Biernacka, Barbara W. Schweizer, Janice M. Fullerton, Sébastien Gard, Julie Garnham, Barbara König, Mark A. Frye, Michael Bauer, Po-Hsiu Kuo, Janusz K. Rybakowski, Joanna Hauser, Pablo Cervantes, Gonzalo Laje, Urban Ösby, Nina Dalkner, Ewa Ferensztajn-Rochowiak, Mikael Landén, Hsi-Chung Chen, Claire Slaney, Eva Z. Reininghaus, Katzutaka Shimoda, Esther Jiménez, Cristiana Cruceanu, Francesc Colom, Catharina Lavebratt, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Stephanie H. Witt, Sven Cichon, Bruno Etain, Layla Kassem, Caterina Chillotti, Fernando S. Goes, Franziska Degenhardt, J. Raymond DePaulo, Martin Alda, Ichiro Kusumi, Peter Falkai, Antoni Benabarre, Stéphane Jamain, Philip B. Mitchell, Raffaella Ardau, Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Mario Maj, Paul D. Shilling, Mazda Adli, Louise Frisén, Brandon J. Coombes, Gustavo Turecki, Scott R. Clark, Bárbara Arias, Vincent Millischer, Michael McCarthy, Marion Leboyer, Lina Martinsson, Piotr M. Czerski, Coombes, Brandon J, Millischer, Vincent, Batzler, Anthony, Larrabee, Beth, Hou, Liping, Papiol, Sergi, Heilbronner, Ur, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Amare, Azmeraw T, Ardau, Raffaella, Arias, Barbara, Aubry, Jean-Michel, Backlund, Lena, Bauer, Michael, Baune, Bernhard T, Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Cruceanu, Cristiana, Czerski, Piotr M, Dalkner, Nina, Degenhardt, Franziska, Del Zompo, Maria, Depaulo, J Raymond, Étain, Bruno, Falkai, Peter, Ferensztajn-Rochowiak, Ewa, Forstner, Andreas J, Frisen, Louise, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kato, Tadafumi, Kelsoe, John R, Kittel-Schneider, Sarah, König, Barbara, Kuo, Po-Hsiu, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J, Mcelroy, Susan L, Mitchell, Philip B, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nievergelt, Caroline M, Nöthen, Markus M, Novák, Toma, O'Donovan, Claire, Osby, Urban, Ozaki, Norio, Pfennig, Andrea, Pisanu, Claudia, Potash, James B, Reif, Andrea, Reininghaus, Eva, Rietschel, Marcella, Rouleau, Guy A, Rybakowski, Janusz K, Schalling, Martin, Schofield, Peter R, Schubert, Klaus Oliver, Schweizer, Barbara W, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M, Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Witt, Stephanie H, Zandi, Peter P, Fullerton, Janice M, Alda, Martin, Frye, Mark A, Schulze, Thomas G, Mcmahon, Francis J, and Biernacka, Joanna M

Subjects
medicine.medical_specialty, Lithium (medication), business.industry, Bipolar disorder, General Medicine, medicine.disease, Polygenic risk scores, Attention-deficit/hyperactivity disorder, Lithium response, Adherence, medicine, Attention deficit hyperactivity disorder, Association (psychology), Psychiatry, business, Depression (differential diagnoses), 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, Research Article, medicine.drug
Abstract

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Published
2021

27. Prediction of lithium response using genomic data

Author

Martin Schalling, Martin Alda, Alexandre Dayer, Michael Bauer, Guy A. Rouleau, Sarah Kittel-Schneider, Alessio Squassina, Julia Veeh, Claire O'Donovan, Ryota Hashimoto, Eduard Vieta, Marcella Rietschel, Hsi-Chung Chen, Liping Hou, Franziska Degenhardt, Ichiro Kusumi, Francis J. McMahon, Claudia Pisanu, Cristiana Cruceanu, Frank Bellivier, Will Stone, Markus M. Nöthen, Andreas Reif, Manuel Mattheisen, Mark A. Frye, Giovanni Severino, John R. Kelsoe, Caterina Chillotti, Maria Grigoroiu-Serbanescu, Thomas Trappenberg, Janusz K. Rybakowski, Catharina Lavebratt, Thomas G. Schulze, Norio Ozaki, Paul Grof, Lina Martinsson, Mirko Manchia, Philip B. Mitchell, Maria Del Zompo, Raffaella Ardau, Peter R. Schofield, Andreas J. Forstner, Vincent Millischer, Po-Hsiu Kuo, Esther Jiménez, Lena Backlund, Pablo Cervantes, Abraham Nunes, Jean-Michel Aubry, Nirmala Akula, Janice M. Fullerton, Kazufumi Akiyama, and Tadafumi Kato

Subjects
Adult, Male, 0301 basic medicine, Bipolar Disorder, Adolescent, Genomic data, Science, Medizin, chemistry.chemical_element, Single-nucleotide polymorphism, Computational biology, Lithium, Biology, Polymorphism, Single Nucleotide, Article, Machine Learning, Young Adult, 03 medical and health sciences, Medical research, 0302 clinical medicine, Genetics, Humans, Multidisciplinary, Models, Genetic, Genomics, Prognosis, Liti, Confidence interval, Cell membranes, Postsynaptic membrane, Treatment Outcome, 030104 developmental biology, chemistry, Medicine, Female, Membranes cel·lulars, 030217 neurology & neurosurgery, Kappa
Abstract

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen’s kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

Published
2021

29. Exemplar Scoring Identifies Genetically Separable Phenotypes of Lithium Responsive Bipolar Disorder

Author

J. S. Menzies, M. Del Zompo, Alessio Squassina, Markus M. Nöthen, Paul Grof, Claire O'Donovan, Abraham Nunes, Martin Alda, Francis J. McMahon, A. Berghoefer, M. Rietschel, Franziska Degenhardt, Thomas Trappenberg, Raffaella Ardau, Pablo Cervantes, Giovanni Severino, Alberto Bocchetta, Claudia Pisanu, Thomas G. Schulze, Tomas Hajek, Gustavo Turecki, E. Grof, Guy A. Rouleau, Bruno Müller-Oerlinghausen, Alexandra Suwalska, Caterina Chillotti, Marco Pinna, Valeria Deiana, P. Zvolsky, Janusz K. Rybakowski, Leonardo Tondo, Will Stone, Claire Slaney, Andreas J. Forstner, and Mirko Manchia

Subjects
Psychosis, Lithium (medication), Receiver operating characteristic, Genetic heterogeneity, Computational biology, Biology, medicine.disease, Phenotype, 3. Good health, 030227 psychiatry, 03 medical and health sciences, 0302 clinical medicine, Mood, Genotype, medicine, Bipolar disorder, 030217 neurology & neurosurgery, medicine.drug
Abstract

Predicting lithium response (LiR) in bipolar disorder (BD) could expedite effective pharmacotherapy, but phenotypic heterogeneity of bipolar disorder has complicated the search for genomic markers. We thus sought to determine whether patients with "exemplary phenotypes"---those whose clinical features are reliably predictive of LiR and non-response (LiNR)---are more genetically separable than those with less exemplary phenotypes. We applied machine learning methods to clinical data collected from people with BD (n=1266 across 7 international centres; 34.7% responders) to compute an "exemplar score", which identified a subset of subjects whose clinical phenotypes were most robustly predictive of LiR/LiNR. For subjects whose genotypes were available (n=321), we evaluated whether responders/non-responders with exemplary phenotypes could be more accurately classified based on genetic data than those with non-exemplary phenotypes. We showed that the best LiR exemplars had later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p=0.0032) among the poor exemplars. Variants in the Alzheimer's amyloid secretase pathway, along with G-protein coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were particularly informative predictors. In sum, the most reliably predictive clinical features of LiR and LiNR patients correspond to previously well-characterized phenotypic spectra whose genomic profiles are relatively distinct. Future work must enlarge the sample for genomic classification and include prediction of response to other mood stabilizers.

Published
2020
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30. Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications

Author

Maria Antonietta Montis, Alessio Squassina, Valeria Sogos, Cristina Cocco, Andrea Mura, Anna Meloni, Roberta Vanni, Caterina Chillotti, Donatella Congiu, Renato Robledo, Giovanni Severino, Alberto Bocchetta, Raffaella Ardau, Maria Del Zompo, E. Cossu, Pasquale Paribello, Mario Garzilli, Barbara Noli, Gian-Luca Ferri, Tinuccia Dettori, Daniela Virginia Frau, Claudia Pisanu, Bernardo Carpiniello, Elias Manca, Paola Caria, Mirko Manchia, Federica Pinna, Carlo Arzedi, and Mariella Nieddu

Subjects
medicine.medical_specialty, Bipolar Disorder, Population, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Bipolar disorder, education, Psychiatry, In Situ Hybridization, Fluorescence, Pharmacology, education.field_of_study, Depressive Disorder, Major, biology, business.industry, C-reactive protein, Telomere, medicine.disease, Comorbidity, 030227 psychiatry, Psychiatry and Mental health, Mood disorders, Schizophrenia, Case-Control Studies, Cohort, biology.protein, Major depressive disorder, business, 030217 neurology & neurosurgery
Abstract

Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F(6, 137) = 20.128, p = 8.73 × 10(−17), effect of diagnosis, F(3) = 31.870; p = 1.08 × 10(−15)). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = −0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.

Published
2020

31. Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment

Author

Valeria Sogos, Donatella Congiu, Alessio Squassina, Renato Robledo, Maria Del Zompo, Caterina Chillotti, Raffaella Ardau, Anna Meloni, Gian-Luca Ferri, Federica Pinna, Giovanni Severino, Alberto Bocchetta, Roberta Vanni, Claudia Pisanu, Bernardo Carpiniello, Daniela Virginia Frau, Tinuccia Dettori, Elias Manca, Paola Caria, Mirko Manchia, Mariella Nieddu, Cristina Cocco, and Barbara Noli

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Bipolar Disorder, Lithium (medication), 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Leukocytes, Humans, Bipolar disorder, Longitudinal Studies, Telomere Shortening, Pharmacology, business.industry, Mendelian Randomization Analysis, Middle Aged, Telomere, medicine.disease, Antidepressive Agents, 030227 psychiatry, Treatment Outcome, Lithium Compounds, Molecular Medicine, Female, business, 030217 neurology & neurosurgery, Pharmacogenetics, medicine.drug, Genome-Wide Association Study
Abstract

Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

Published
2020

32. Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

Author

Marco Pinna, Claire O'Donovan, Pablo Cervantes, Leonardo Tondo, Maria Del Zompo, Tomas Hajek, Paul Grof, Bruno Müller-Oerlinghausen, Alessio Squassina, Andreas J. Forstner, Julie Garnham, Giovanni Severino, Alberto Bocchetta, Mirko Manchia, Marcella Rietschel, Caterina Chillotti, Guy A. Rouleau, Francis J. McMahon, Martin Alda, Markus M. Nöthen, Anne Berghöfer, P. Zvolsky, Thomas G. Schulze, Will Stone, Manuel Mattheisen, Raffaella Ardau, Eva Grof, Rudolf Uher, Claudia Pisanu, Franziska Degenhardt, Valeria Deiana, Thomas Trappenberg, Claire Slaney, Aleksandra Suwalska, Janusz K. Rybakowski, Abraham Nunes, and Gustavo Turecki

Subjects
Oncology, Psychosis, medicine.medical_specialty, Bipolar Disorder, Lithium (medication), education, Lithium, Predictive markers, Article, lcsh:RC321-571, Cellular and Molecular Neuroscience, Text mining, Antimanic Agents, Internal medicine, medicine, Humans, Bipolar disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Receiver operating characteristic, Genetic heterogeneity, business.industry, medicine.disease, Phenotype, Personalized medicine, Psychiatry and Mental health, Mood, Lithium Compounds, business, medicine.drug
Abstract

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

Published
2020

33. Convergent analysis of genome-wide genotyping and transcriptomic data suggests association of zinc finger genes with lithium response in bipolar disorder

Author

Donatella Congiu, Caterina Chillotti, Giovanni Severino, Alessio Squassina, Andrea Angius, Claudia Pisanu, Francis J. McMahon, Urs Heilbronner, Raffaella Ardau, Thomas G. Schulze, Liping Hou, Maria Del Zompo, and Marta Costa

Subjects
Male, Bipolar Disorder, Genotype, Lithium (medication), Lithium, Biology, Article, Biomarkers, Pharmacological, Transcriptome, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Gene, Genotyping, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Retrospective Studies, Zinc finger, Gene Expression Profiling, Computational Biology, Zinc Fingers, Molecular biology, 030227 psychiatry, DNA-Binding Proteins, Psychiatry and Mental health, Treatment Outcome, chemistry, Pharmacogenomics, Lithium chloride, Biomarker (medicine), Female, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors, medicine.drug
Abstract

Lithium is the mainstay treatment in bipolar disorder (BD) for its effectiveness in the acute phases of illness and in prevention of recurrences. Lithium’s mechanism of action is complex, and while it modulates the function of hundreds of molecular targets, most of these effects could be unspecific and not relevant for its clinical efficacy. In this study, we applied an integrated analytical approach using genome-wide expression and genotyping data from BD patients characterized for lithium response to identify lithium-responsive genes that may serve as biomarkers of its efficacy. To this purpose, we tested the effect of treatment with LiCl 1mM on the transcriptome of lymphoblasts from 10 lithium responders (LR) and 10 non-responders (NR) patients and identified genes significantly influenced by the treatment exclusively in LR. These findings were integrated with gene-based analysis on genome-wide genotyping data from an extended sample of 205 BD patients characterized for lithium response. The expression of 29 genes was significantly changed by lithium exclusively in LR. Gene-based analysis showed that two of these genes, zinc finger protein 429 (ZNF429) and zinc finger protein 493 (ZNF493), were also significantly associated with lithium response. Validation of transcriptomic data with quantitative real-time PCR confirmed the lithium-induced downregulation of ZNF493 in LR (p=0.036). Using convergent analyses of genome-wide expression and genotyping data, we identified ZNF493 as a potential lithium-responsive target that may be involved in modulating lithium efficacy in BD. To our knowledge, this is the first evidence supporting the involvement of zinc finger proteins in lithium response.

Published
2018

34. Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study

Author

Francis M. Mondimore, Farah Klohn-Sagatholislam, Jana Strohmaier, Jens Wiltfang, Jay Raymond DePaulo, Udo Dannlowski, Markus Jäger, Moritz E. Wigand, Ion Anghelescu, Michael Bauer, Louise Frisén, Ashley L. Comes, Carsten Spitzer, Claire Slaney, Janice M. Fullerton, Giovanni Severino, Janusz K. Rybakowski, Andreas J. Fallgatter, Maria Hake, Martin Alda, Peter R. Schofield, Susanne Bengesser, Nirmala Akula, Stefan Herms, Paul D. Shilling, Franziska Degenhardt, Mazda Adli, Armin Birner, Alexandre Dayer, Cristiana Cruceanu, Fanny Senner, Peter Falkai, Maria Del Zompo, Mark A. Frye, Christian Simhandl, Stéphane Jamain, Andrea Pfennig, Layla Kassem, Sébastien Gard, Heike Anderson-Schmidt, Marion Leboyer, Peter P. Zandi, Susan L. McElroy, Martin Schalling, Sebastian Stierl, Detlef E. Dietrich, Frank Bellivier, Palmiero Monteleone, Sybille Schulz, Caterina Chillotti, Volker Arolt, Michael McCarthy, Alfonso Tortorella, Andreas Thiel, Marcella Rietschel, Kristina Adorjan, Tatyana Shekhtman, Maria Grigoroiu-Serbanescu, Jean-Michel Aubry, Daniela Reich-Erkelenz, Laura Flatau, Markus Reitt, Harald Scherk, Here Folkerts, Julia Veeh, Joanna Hauser, Fernando S. Goes, Philip B. Mitchell, Gustavo Turecki, John R. Kelsoe, Thomas Stamm, Sophia Stegmaier, Georg Juckel, Markus M. Nöthen, Lina Martinsson, Bárbara Arias, Vanessa Nieratschker, Clara Brichant-Petitjean, Antonio Benabarre, Bernhard T. Baune, James B. Potash, Urs Heilbronner, Caroline M. Nievergelt, Raffaella Ardau, Mikael Landén, Pablo Cervantes, Pavla Stopkova, Adam Wright, Tomas Novak, Scott R. Clark, Manfred Koller, Gonzalo Laje, Katrin Gade, Andreas J. Forstner, Sarah Kittel-Schneider, Susan G. Leckband, Sebastian Kliwicki, Guy A. Rouleau, Kim Bartholdi, Martin von Hagen, Per Hoffmann, Eva C. Schulte, Alessio Squassina, Monika Budde, Thomas G. Schulze, Eduard Vieta, Liping Hou, Jörg Zimmermann, Barbara König, Stephan Ripke, Sarah K. Tighe, Jean-Pierre Kahn, Julie Garnham, Piotr M. Czerski, Janos Kalman, Anna Gryaznova, Francis J. McMahon, Mario Maj, Thomas Becker, Thomas Ethofer, Andreas Reif, Carsten Konrad, Mirko Manchia, Lena Backlund, Jens Reimer, Urban Ösby, Esther Jiménez, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Stephanie H. Witt, Sven Cichon, Bruno Etain, Till F. M. Andlauer, Joanna M. Biernacka, Max Schmauß, Christian Figge, Fabian U. Lang, N. Lackner, Eva Z. Reininghaus, Francesc Colom, Catharina Lavebratt, K Oliver Schubert, Kalman, Janos L, Papiol, Sergi, Forstner, Andreas J, Heilbronner, Ur, Degenhardt, Franziska, Strohmaier, Jana, Adli, Mazda, Adorjan, Kristina, Akula, Nirmala, Alda, Martin, Anderson-Schmidt, Heike, Andlauer, Till Fm, Anghelescu, Ion-George, Ardau, Raffaella, Arias, Bárbara, Arolt, Volker, Aubry, Jean-Michel, Backlund, Lena, Bartholdi, Kim, Bauer, Michael, Baune, Bernhard T, Becker, Thoma, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M, Birner, Armin, Brichant-Petitjean, Clara, Budde, Monika, Cervantes, Pablo, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Comes, Ashley L, Cruceanu, Cristiana, Czerski, Piotr M, Dannlowski, Udo, Dayer, Alexandre, Del Zompo, Maria, Depaulo, Jay Raymond, Dietrich, Detlef E, Étain, Bruno, Ethofer, Thoma, Falkai, Peter, Fallgatter, Andrea, Figge, Christian, Flatau, Laura, Folkerts, Here, Frisen, Louise, Frye, Mark A, Fullerton, Janice M, Gade, Katrin, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grigoroiu-Serbanescu, Maria, Gryaznova, Anna, Hake, Maria, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hou, Liping, Jäger, Marku, Jamain, Stephane, Jiménez, Esther, Juckel, Georg, Kahn, Jean-Pierre, Kassem, Layla, Kelsoe, John, Kittel-Schneider, Sarah, Kliwicki, Sebastian, Klohn-Sagatholislam, Farah, Koller, Manfred, König, Barbara, Konrad, Carsten, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lang, Fabian U, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Maj, Mario, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J, Mcelroy, Susan L, Mcmahon, Francis J, Mitchell, Philip B, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nieratschker, Vanessa, Nievergelt, Caroline M, Novák, Toma, Ösby, Urban, Pfennig, Andrea, Potash, James B, Reich-Erkelenz, Daniela, Reif, Andrea, Reimer, Jen, Reininghaus, Eva, Reitt, Marku, Ripke, Stephan, Rouleau, Guy A, Rybakowski, Janusz K, Schalling, Martin, Scherk, Harald, Schmauß, Max, Schofield, Peter R, Schubert, K Oliver, Schulte, Eva C, Schulz, Sybille, Senner, Fanny, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Simhandl, Christian, Slaney, Claire M, Spitzer, Carsten, Squassina, Alessio, Stamm, Thoma, Stegmaier, Sophia, Stierl, Sebastian, Stopkova, Pavla, Thiel, Andrea, Tighe, Sarah K, Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Veeh, Julia, von Hagen, Martin, Wigand, Moritz E, Wiltfang, Jen, Witt, Stephanie, Wright, Adam, Zandi, Peter P, Zimmermann, Jörg, Nöthen, Marku, Rietschel, Marcella, and Schulze, Thomas G

Subjects
Adult, Male, Oncology, Multifactorial Inheritance, medicine.medical_specialty, Schizophrenia/genetics, Disease onset, Adolescent, early onset, Late onset, ddc:616.89, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Bipolar disorder, Child, Research Articles, Biological Psychiatry, bipolar disorder, Trastorn bipolar, business.industry, Bipolar Disorder/genetics, age at onset, polygenic risk score, schizophrenia, Age Factors, Bipolar Disorder, Female, Middle Aged, Phenotype, Schizophrenia, Original Articles, medicine.disease, Genetic architecture, 030227 psychiatry, Psychiatry and Mental health, Institutional repository, Clinical research, Esquizofrènia, Original Article, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. peerReviewed

Published
2018

35. Evidence towards RNA Binding Motif (RNP1, RRM) Protein 3 (RBM3) as a Potential Biomarker of Lithium Response in Bipolar Disorder Patients

Author

Caterina Chillotti, Alessio Squassina, Maria Del Zompo, Carla Melis, Paola Niola, Gustavo Turecki, Donatella Congiu, Eleni Merkouri Papadima, Claudia Pisanu, Cristiana Cruceanu, Raffaella Ardau, Juan Pablo Lopez, and Giovanni Severino

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Bipolar Disorder, Adolescent, Lithium (medication), Microarray, Biology, Transcriptome, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cell Line, Tumor, Internal medicine, Gene expression, medicine, Humans, Gene, Cells, Cultured, Binding Sites, RNA-Binding Proteins, General Medicine, Middle Aged, Antidepressive Agents, In vitro, Reverse transcription polymerase chain reaction, 030104 developmental biology, Endocrinology, Case-Control Studies, Lithium Compounds, Cancer research, RNA, Biomarker (medicine), Female, Biomarkers, 030217 neurology & neurosurgery, Protein Binding, medicine.drug
Abstract

Lithium has been used for more than six decades for the management of bipolar disorder (BD). In a previous transcriptomic study, we showed that patients affected by either BD or cluster headache, both disorders characterized by circadian disturbances and response to lithium in a subgroup of patients, have higher expression of the RNA binding motif (RNP1, RRM) protein 3 (RBM3) gene compared to controls. To investigate whether RBM3 could represent a biomarker of lithium response, we screened raw microarray expression data from lymphoblastoid cell lines (LCLs) derived from 20 BD patients, responders or non-responders to lithium. RBM3 was the most significantly differentially expressed gene in the list, being overexpressed in responders compared to non-responders (fold change = 2.0; p = 1.5 × 10−16). We therefore sought to validate the microarray finding by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and explore whether RBM3 expression was modulated by lithium treatment in vitro in LCLs as well as in human-derived neural progenitor cells (NPCs). Our findings confirmed the higher expression of RBM3 in responders compared to non-responders (fold change = 3.78; p = 0.0002). Lithium did not change RBM3 expression in LCLs in any of the groups, but it increased its expression in NPCs. While preliminary, our data suggest that higher levels of RBM3 might be required for better lithium response and that the expression of this gene could be modulated by lithium in a tissue-specific manner.

Published
2017

36. An observational study of 110 elderly lithium-treated patients followed up for 6 years with particular reference to renal function

Author

Claudia Sardu, Maria Del Zompo, Caterina Chillotti, Alberto Bocchetta, Francesca Cabras, Antonio Poddighe, Raffaella Ardau, and Martina Pinna

Subjects
medicine.medical_specialty, Lithium (medication), Urology, Levothyroxine, Renal function, Lithium, Kidney, Nephrotoxicity, lcsh:RC321-571, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Elderly, Internal medicine, medicine, Bipolar disorders, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Thyroid, Creatinine, business.industry, Depression, Research, lcsh:QP351-495, 030227 psychiatry, Psychiatry and Mental health, Endocrinology, medicine.anatomical_structure, lcsh:Neurophysiology and neuropsychology, chemistry, Cohort, Mood disorders, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background Recent observational studies have focused on lithium treatment in the elderly, with particular reference to safety in terms of thyroid and renal functions. The purpose of this study was to compare the clinical characteristics of patients starting lithium treatment before (N = 79) or after (N = 31) the age of 65 years. Patients were followed up for 6 years with focus on renal function and prescription of levothyroxine and methimazole. Results At baseline, median lithium serum concentration was 0.55 mmol/l. The estimated glomerular filtration rate was lower than 60 ml/min/1.73 m2 in 43 (39%) patients. In a multiple regression analysis controlling for age and gender, we found a significant effect of duration of lithium treatment on estimated glomerular filtration rate (−0.85 ml/min/1.73 m2 per year of prior exposure). The annual decline during follow-up was 2.3 ml/min/1.73 m2. Two patients were prescribed levothyroxine, and two were prescribed methimazole for the first time during follow-up. Conclusions Median lithium serum concentration in this cohort of elderly patients with mainly bipolar disorders was lower than the therapeutic range indicated for younger adults. The decline in glomerular filtration rate may be accelerated by long-term lithium use. Thyroid and renal functions continue to require close monitoring throughout the course of lithium treatment. Trial registration NP/2013/3836. Registered 24 June 2013

Published
2017

37. Pharmacogenetics of lithium effects on glomerular function in bipolar disorder patients under chronic lithium treatment: a pilot study

Author

Giovanni Severino, Alberto Bocchetta, Ming Ta Michael Lee, Yanfei Zhang, Maria Del Zompo, Evangelia-Eirini Tsermpini, Alessio Squassina, Paola Niola, Raffaella Ardau, Caterina Chillotti, and George P. Patrinos

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Bipolar Disorder, Genotype, Lithium (medication), Renal function, Pilot Projects, Single-nucleotide polymorphism, Genome-wide association study, Kidney, Polymorphism, Single Nucleotide, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Antimanic Agents, Internal medicine, medicine, Humans, Bipolar disorder, Aged, business.industry, General Neuroscience, Middle Aged, medicine.disease, Antidepressive Agents, Pharmacogenomic Testing, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Lithium Compounds, Female, medicine.symptom, business, Mania, 030217 neurology & neurosurgery, Pharmacogenetics, Glomerular Filtration Rate, medicine.drug
Abstract

Bipolar disorder (BD) is a psychiatric disease characterized by alternating episodes of mania and depression. Lithium (Li) represents the mainstay treatment for BD, although a significant proportion of patients shows insufficient or no response. Li is also associated with potentially severe side effects, including renal effects. Several studies reported that Li may induce reduction of glomerular filtration rate (GFR) in patients under long-term treatment. The biological systems and the genetic factors involved in susceptibility to Li-induced renal-side effects have been scarcely explored. The aim of our study was to test the contribution of putatively risk genetic variants in Li-induced reduction in estimated GFR (eGFR) in BD patients under long-term Li treatment. Tag SNPs, located in genes previously shown to be associated with kidney dysfunction or Li mechanism of action, were selected and genotyped in a sample of 70 BD patients of Sardinian origin. SNP rs378448, located in Acid Sensing Ion Channel Neurona-1 (ACCN1) gene, showed a significant interaction with duration of Li treatment on eGFR (F2=3.623, p=0.033). Our preliminary findings suggest that rs378448 could predispose BD subjects to a detrimental effect of chronic Li treatment on kidney functioning.

Published
2017

38. Association between solar insolation and a history of suicide attempts in bipolar I disorder

Author

Bharathram Sathur Raghuraman, Anton A. Mozzhegorov, Erkki Isometsä, Yosra Zgueb, Claire O'Donovan, Peter C. Whybrow, Rasmus Wentzer Licht, Eduard Vieta, Ingrid Melle, Sule Bicakci, Wendy K. Marsh, Julia Veeh, Rikke Krogh, Francisco Diego Rabelo da Ponte, John F. Gottlieb, Philipp Ritter, Fatima Meza-Urzua, Dan J. Stein, Mythily Subramaniam, Biju Viswanath, Ravi Kumar Nadella, Thomas Bjella, Marco Pinna, Kemal Sagduyu, Fabiano G. Nery, Kirsi Suominen, Hiromi Tagata, Mark A. Frye, Martin Alda, Mónica Martínez-Cengotitabengoa, Ole A. Andreassen, Mok Yee Ming, Chantal Henry, Michael Bauer, Scott Monteith, Elias Angelopoulos, Maurício Kunz, Ana González-Pinto, Erik Roj Larsen, Rodrigo A. Munoz, Frank Bellivier, Michael Berk, Mathias Kardell, Andrea Fagiolini, Mikael Landén, Janusz K. Rybakowski, Yavuz Ayhan, Ute Lewitzka, Sebastian Kliwicki, Starlin V. Mythri, Helle Østermark Sørensen, Robert H. Belmaker, Beny Lafer, Harriet Birabwa-Oketcho, Edgar Arrua Vares, Paul W. Stackhouse, Raffaella Ardau, Andreas Reif, René Ernst Nielsen, Jorge Cabrera, Sven Janno, Carlos López-Jaramillo, Ahmad Hatim Sulaiman, Fethi Nacef, Gunnar Morken, Kostas N. Fountoulakis, Arne E. Vaaler, Yoshitaka Tatebayashi, Tasha Glenn, Mirko Manchia, Barbara König, Rita Bauer, Raj Ramesar, Markus Donix, Bruno Etain, Mark Zetin, Danilo Quiroz, Yolanda Pica Ruiz, Slim Khaldi, Carla Torrent, Leonardo Tondo, Christopher Baethge, Sergio Strejilevich, Bernhard T. Baune, Enrica Mosca, Adel Omrani, Christian Simhandl, M. S. Reddy, Seetal Dodd, Maximilian Pilhatsch, Glenda MacQueen, Hirohiko Harima, Claudia Becerra-Palars, Flávio Kapczinski, Timur L. Kot, Paul Grof, Emanuel Severus, Yuly Bersudsky, Natalie L. Rasgon, Eric Yat Wo Cheung, Ângela Miranda Scippa, Maria Del Zompo, Yamima Osher, María Yoldi-Negrete, Uta Ouali, Department of Psychiatry, Clinicum, and HUS Psychiatry

Subjects
Male, Insolation, Internationality, Bipolar I disorder, RETINAL GANGLION-CELLS, MOOD DISORDERS, Substance-Related Disorders, Bipolar disorder, Climate, Seasonal variation, SEASONAL-VARIATION, Equator, Suicide, Attempted, 3124 Neurology and psychiatry, Latitude, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Risk Factors, medicine, Humans, Age of Onset, Solar insolation, Suicide, Sunlight, VITAMIN-D, SUBSTANCE USE, Biological Psychiatry, RISK, Suicide attempt, AGE-OF-ONSET, Age Factors, Middle Aged, Seasonality, medicine.disease, 030227 psychiatry, SHIFT WORK, Psychiatry and Mental health, Geography, Female, Seasons, CIRCADIAN-RHYTHMS, 030217 neurology & neurosurgery, BEHAVIOR, Demography
Abstract

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p

Published
2019

39. Involvement of microRNAs in Lithium Response in Patients With Bipolar Disorder and Related Phenotypes

Author

Caterina Chillotti, Annalisa Loizedda, Gustavo Turecki, Giovanni Severino, Alessio Squassina, Carlo Carcassi, Stefano Calza, N Orru, Sandro Orru, Maria Del Zompo, Raffaella Ardau, Juan Pablo Lopez, Paola Niola, Donatella Congiu, Cristiana Cruceanu, Eleni Merkouri Papadima, Claudia Pisanu, and Martin Alda

Subjects
Lithium (medication), business.industry, microRNA, medicine, Cancer research, In patient, Bipolar disorder, medicine.disease, business, Phenotype, Biological Psychiatry, medicine.drug
Published
2021

40. Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder

Author

Michael McCarthy, Alfonso Tortorella, Jean-Michel Aubry, James B. Potash, Hsi-Chung Chen, Eduard Vieta, Claire Slaney, Frank Bellivier, Claire O'Donovan, Palmiero Monteleone, Alexandre Dayer, Lena Backlund, Michael Bauer, Nina Dalkner, Christian Simhandl, Liping Hou, Katzutaka Shimoda, Cristiana Cruceanu, Janusz K. Rybakowski, Lina Martinsson, Gonzalo Laje, Susan G. Leckband, Andrea Hofmann, Micah Cearns, Eva Z. Reininghaus, Barbara W. Schweizer, Pablo Cervantes, Marcella Rietschel, Ryota Hashimoto, Paul Grof, Tomas Novak, Yi-Hsiang Hsu, Stephanie H. Witt, John R. Kelsoe, Julia Veeh, Thomas Stamm, Francesc Colom, Catharina Lavebratt, Adam Wright, Maria Grigoroiu-Serbanescu, Philip B. Mitchell, Ichiro Kusumi, Sarah Kittel-Schneider, Urs Heilbronner, Julie Garnham, Sven Cichon, Layla Kassem, Norio Ozaki, Piotr M. Czerski, Markus M. Nöthen, Peter Falkai, Bruno Etain, Mirko Manchia, Joanna Hauser, Urban Ösby, Caroline M. Nievergelt, Fasil Tekola-Ayele, Stéphane Jamain, Thomas G. Schulze, Clara Brichant-Petitjean, Antonio Benabarre, Bernhard T. Baune, Esther Jiménez, Joanna M. Biernacka, Paul D. Shilling, Caterina Chillotti, Barbara König, Abesh Kumar Bhattacharjee, Scott R. Clark, Andrea Pfennig, Mazda Adli, Raffaella Ardau, Marina Mitjans, Armin Birner, Andreas Reif, Sergi Papiol, Mario Maj, Giovanni Severino, Martin Schalling, Fernando S. Goes, Susan L. McElroy, Franziska Degenhardt, Louise Frisén, Pavla Stopkova, Peter P. Zandi, J. Raymond DePaulo, Martin Alda, Peter R. Schofield, Per Hoffmann, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Sebastian Kliwicki, Guy A. Rouleau, Andreas J. Forstner, Gustavo Turecki, Bárbara Arias, Azmeraw T. Amare, Marion Leboyer, Maria Del Zompo, Po-Hsiu Kuo, Nirmala Akula, Francis M. Mondimore, Sébastien Gard, Mark A. Frye, Mikael Landén, Alessio Squassina, Jean-Pierre Kahn, Francis J. McMahon, Kazufumi Akiyama, Tadafumi Kato, Tatyana Shekhtman, and Janice M. Fullerton

Subjects
Oncology, medicine.medical_specialty, Lithium (medication), business.industry, Genome-wide association study, Logistic regression, medicine.disease, 030227 psychiatry, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Quartile, Internal medicine, Medicine, Major depressive disorder, Bipolar disorder, business, 030217 neurology & neurosurgery, Depression (differential diagnoses), medicine.drug, Genetic association
Abstract

BackgroundLithium is a first-line medication for bipolar disorder (BD), but only ~30% of patients respond optimally to the drug. Since genetic factors are known to mediate lithium treatment response, we hypothesized whether polygenic susceptibility to the spectrum of depression traits is associated with treatment outcomes in patients with BD. In addition, we explored the potential molecular underpinnings of this relationship.MethodsWeighted polygenic scores (PGSs) were computed for major depressive disorder (MDD) and depressive symptoms (DS) in BD patients from the Consortium on Lithium Genetics (ConLi+Gen; n=2,586) who received lithium treatment. Lithium treatment outcome was assessed using the ALDA scale. Summary statistics from genome-wide association studies (GWAS) in MDD (130,664 cases and 330,470 controls) and DS (n=161,460) were used for PGS weighting. Associations between PGSs of depression traits and lithium treatment response were assessed by binary logistic regression. We also performed a cross-trait meta-GWAS, followed by Ingenuity® Pathway Analysis.OutcomesBD patients with a low polygenic load for depressive traits were more likely to respond well to lithium, compared to patients with high polygenic load (MDD: OR =1.64 [95%CI: 1.26-2.15], lowest vs highest PGS quartiles; DS: OR=1.53 [95%CI: 1.18-2.00]). Associations were significant for type 1, but not type 2 BD. Cross-trait GWAS and functional characterization implicated voltage-gated potassium channels, insulin-related pathways, mitogen-activated protein-kinase (MAPK) signaling, and miRNA expression.InterpretationGenetic loading to depression traits in BD patients lower their odds of responding optimally to lithium. Our findings support the emerging concept of a lithium-responsive biotype in BD.FundingSee attached details

Published
2018
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41. Circulating antithyroid antibodies contribute to the decrease of glomerular filtration rate in lithium-treated patients: a longitudinal study

Author

Doloretta Piras, Claudia Pisanu, Andrea Loviselli, Caterina Chillotti, Gioia Baggiani, Fernanda Velluzzi, Antonello Pani, Luca Ambrosiani, Raffaella Ardau, and Alberto Bocchetta

Subjects
medicine.medical_specialty, Lithium (medication), Renal function, 030209 endocrinology & metabolism, Lithium, Gastroenterology, lcsh:RC321-571, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Thyroid peroxidase, Internal medicine, Diabetes mellitus, medicine, 030212 general & internal medicine, Renal insufficiency, Chronic, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Survival analysis, Creatinine, biology, business.industry, Research, lcsh:QP351-495, medicine.disease, Anti-thyroglobulin, Anti-thyroid autoantibodies, Psychiatry and Mental health, lcsh:Neurophysiology and neuropsychology, Thyroid microsomal antibodies, chemistry, biology.protein, Glomerular filtration rate, business, medicine.drug, Kidney disease
Abstract

Background Concerns about the adverse effects of long-term treatment with lithium include reduced renal function. In the present study, we examined comorbidities which may be associated with chronic kidney disease in a cohort of patients treated with lithium for up to 41 years. Methods We studied 394 patients who were treated with lithium for ≥ 5 years. The potential role of comorbidities (diabetes, concurrent antihypertensive medication, treatment with l-thyroxine, and presence of antithyroid peroxidase/microsomes, anti-thyroglobulin, and/or anti-thyrotropin-receptor antibodies) was analysed. We focused on the categories of patients with an estimated glomerular filtration rate (eGFR) lower than 60 or 45 mL/min/1.73 m2 as calculated from serum creatinine according to the Modification of Diet in Renal Disease Study Group. We applied multivariate regression analysis and Cox survival analysis to study the effects exerted by sex, age, duration of lithium treatment, and comorbidities using eGFR categories as the dependent variable. Kaplan–Meier curves were generated to measure the time to decline to an eGFR lower than 45 mL/min/1.73 m2 in patients with positive or negative thyroid antibodies. Results Age was associated with a decline to an eGFR lower than 60 mL/min/1.73 m2 after controlling for sex, duration of lithium treatment, and comorbidities. Circulating thyroid antibodies were associated with a decline to an eGFR lower than 45 mL/min/1.73 m2. Conclusions The present study is the first to suggest a potential role of circulating thyroid antibodies in the severe decline of eGFR in lithium-treated patients.

Published
2018

42. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

Author

Claire O'Donovan, Gustavo Turecki, Frank Bellivier, Palmiero Monteleone, Tatyana Shekhtman, Bárbara Arias, Paul Grof, Sébastien Gard, Tomas Novak, Maria Del Zompo, Martin Schalling, Sarah Kittel-Schneider, Hsi-Chung Chen, Eduard Vieta, Claire Slaney, Katzutaka Shimoda, J. Raymond DePaulo, Martin Alda, Liping Hou, Kazufumi Akiyama, Louise Frisén, Gonzalo Laje, Maria Grigoroiu-Serbanescu, Mikael Landén, Nirmala Akula, Cristiana Cruceanu, Tadafumi Kato, Marion Leboyer, Lina Martinsson, Alessio Squassina, Andrea Hofmann, James B. Potash, Barbara König, Markus M. Nöthen, Giovanni Severino, Michael McCarthy, Philip B. Mitchell, Mario Maj, Ichiro Kusumi, Caroline M. Nievergelt, Jean-Pierre Kahn, Ryota Hashimoto, Joanna M. Biernacka, Sebastian Kliwicki, Francis J. McMahon, Guy A. Rouleau, Thomas Stamm, Pablo Cervantes, Alexandre Dayer, Julia Volkert, Po-Hsiu Kuo, Urs Heilbronner, Per Hoffmann, Janice M. Fullerton, Raffaella Ardau, Julie Garnham, Scott R. Clark, Layla Kassem, Fasil Tekola-Ayele, Peter R. Schofield, Nina Dalkner, Caterina Chillotti, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Francis M. Mondimore, Alfonso Tortorella, Adam Wright, Joanna Hauser, Peter P. Zandi, Piotr M. Czerski, Eva Z. Reininghaus, Fernando S. Goes, Jean-Michel Aubry, Antonio Benabarre, Bernhard T. Baune, Thomas G. Schulze, Francesc Colom, Marcella Rietschel, Andrea Pfennig, Catharina Lavebratt, Andreas J. Forstner, Paul D. Shilling, Mazda Adli, Armin Birner, Andreas Reif, Mirko Manchia, Susan G. Leckband, Azmeraw T. Amare, Susan L. McElroy, Michael Bauer, Norio Ozaki, Urban Ösby, Janusz K. Rybakowski, Pavla Stopkova, Esther Jiménez, Christian Simhandl, Abesh Kumar Bhattacharjee, Yi-Hsiang Hsu, John R. Kelsoe, Marina Mitjans, Sergi Papiol, Clara Brichant-Petitjean, Mark A. Frye, Stephanie H. Witt, Franziska Degenhardt, Sven Cichon, Bruno Etain, Lena Backlund, Peter Falkai, Barbara W. Schweizer, Stéphane Jamain, Amare, Azmeraw T., Schubert, Klaus Oliver, Hou, Liping, Clark, Scott R., Papiol, Sergi, Heilbronner, Ur, Degenhardt, Franziska, Tekola-Ayele, Fasil, Hsu, Yi-Hsiang, Shekhtman, Tatyana, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bã¡rbara, Aubry, Jean-Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M., Birner, Armin, Brichant-Petitjean, Clara, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Dayer, Alexandre, Del Zompo, Maria, Depaulo, J. Raymond, à tain, Bruno, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sã©bastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Jamain, Stephane, Jimã©nez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Kliwicki, Sebastian, Kã¶nig, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landã©n, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Tortorella, Alfonso, Manchia, Mirko, Martinsson, Lina, Mccarthy, Michael J., Mcelroy, Susan, Colom, Francesc, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nã¶then, Markus M., Novã¡k, Toma, O'Donovan, Claire, Ozaki, Norio, à sby, Urban, Pfennig, Andrea, Potash, James B., Reif, Andrea, Reininghaus, Eva, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schweizer, Barbara W., Severino, Giovanni, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thoma, Stopkova, Pavla, Maj, Mario, Turecki, Gustavo, Vieta, Eduard, Volkert, Julia, Witt, Stephanie, Wright, Adam, Zandi, Peter P., Mitchell, Philip B., Bauer, Michael, Alda, Martin, Rietschel, Marcella, Mcmahon, Francis J., Schulze, Thomas G., and Baune, Bernhard T.

Subjects
Male, Oncology, Multifactorial Inheritance, Bipolar Disorder, Lithium (medication), Genome-wide association study, THERAPY, chemistry.chemical_compound, ddc:616.89, 0302 clinical medicine, HLA Antigens, Spectrum disorder, Original Investigation, RISK, Mood stabilizer, Middle Aged, GLYCOGEN-SYNTHASE KINASE-3, 3. Good health, PREVALENCE, Treatment Outcome, Schizophrenia, Psychiatry and Mental Health, Female, Schizophrenic Psychology, Genetic Load, GLYCOGEN-SYNTHASE KINASE-3, CYTOKINE PRODUCTION, PROPHYLACTIC LITHIUM, SPECTRUM DISORDER, RISK, PREVALENCE, METAANALYSIS, GENETICS, THERAPY, PROFILE, medicine.drug, Adult, medicine.medical_specialty, Genotype, GENETICS, medicine.drug_class, PROFILE, PROPHYLACTIC LITHIUM, 03 medical and health sciences, Lithium Carbonate, Internal medicine, mental disorders, medicine, Humans, Bipolar disorder, Psychiatry, METAANALYSIS, SPECTRUM DISORDER, Inflammation, business.industry, Lithium carbonate, Odds ratio, CYTOKINE PRODUCTION, medicine.disease, 030227 psychiatry, chemistry, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%CI, 1.42-8.41) at the first decile to 2.03 (95%CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

Published
2018

43. SU98CONVERGENT ANALYSIS OF SEQUENCING AND MICROARRAY DATA SUGGEST THE INVOLVEMENT OF MIRNAS AND THEIR TARGET MRNAS IN RESPONSE TO LITHIUM TREATMENT IN BIPOLAR DISORDER

Author

Caterina Chillotti, Donatella Congiu, Alessio Squassina, Carlo Carcassi, Maria Del Zompo, Stefano Calza, Sandro Orru, Annalisa Loizedda, Giovanni Severino, Claudia Pisanu, Carla Melis, N Orru, Eleni Merkouri Papadima, and Raffaella Ardau

Subjects
Pharmacology, Lithium (medication), Microarray analysis techniques, Computational biology, Biology, medicine.disease, Psychiatry and Mental health, Neurology, microRNA, medicine, Pharmacology (medical), Neurology (clinical), Bipolar disorder, Biological Psychiatry, medicine.drug
Published
2019

44. High genetic loading of schizophrenia predicts poor response to lithium in patients with bipolar disorder: A polygenic score and cross-trait genetic analysis

Author

Peter R. Schofield, Susanne Bengesser, Stefan Herms, Klaus Oliver Schubert, Susan G. Leckband, Maria Grigoroiu-Serbanescu, Scott R. Clark, Michael McCarthy, Thomas Stamm, Michael Bauer, Marion Leboyer, Layla Kassem, Fasil Tekola-Ayele, Caterina Chillotti, Andrea Hofmann, Fernando S. Goes, Urs Heilbronner, Tomas Novak, Francesc Colom, Philip B. Mitchell, Janusz K. Rybakowski, Alexandre Dayer, Piotr M. Czerski, Kazufumi Akiyama, Antonio Benabarre, Bernhard T. Baune, Sarah Kittel-Schneider, Nina Dalkner, Gustavo Turecki, Raffaella Ardau, Sébastien Gard, Gonzalo Laje, Mark A. Frye, Tadafumi Kato, Bárbara Arias, Norio Ozaki, Francis M. Mondimore, Per Hoffmann, Hsi-Chung Chen, Claire Slaney, Eva Z. Reininghaus, Andrea Pfennig, Susan L. McElroy, Katzutaka Shimoda, Louise Frisén, Peter P. Zandi, Maria Del Zompo, Nirmala Akula, Ryota Hashimoto, Catharina Lavebratt, Cristiana Cruceanu, Pavla Stopkova, Ichiro Kusumi, Paul Grof, Andreas J. Forstner, Janice M. Fullerton, Julie Garnham, Mikael Landén, Giovanni Severino, Paul D. Shilling, Mazda Adli, Armin Birner, Alessio Squassina, Frank Bellivier, Alfonso Tortorella, Lina Martinsson, Palmiero Monteleone, Jean-Michel Aubry, James B. Potash, Pablo Cervantes, Jean-Pierre Kahn, Francis J. McMahon, Po-Hsiu Kuo, Tatyana Shekhtman, Mirko Manchia, Joanna M. Biernacka, Barbara König, J. Raymond DePaulo, Martin Alda, Joanna Hauser, Christian Simhandl, Yi-Hsiang Hsu, John R. Kelsoe, Clara Brichant-Petitjean, Azmeraw T. Amare, Peter Falkai, Stéphane Jamain, Franziska Degenhardt, Marcella Rietschel, Stephanie H. Witt, Markus M. Nöthen, Caroline M. Nievergelt, Eduard Vieta, Liping Hou, Sven Cichon, Julia Volkert, Bruno Etain, Lena Backlund, Barbara W. Schweizer, Urban Ösby, Esther Jiménez, Abesh Kumar Bhattacharjee, Marina Mitjans, Sergi Papiol, Mario Maj, Adam Wright, Thomas G. Schulze, Martin Schalling, Sebastian Kliwicki, Guy A. Rouleau, Andreas Reif, and Claire O'Donovan

Subjects
Oncology, medicine.medical_specialty, Lithium (medication), business.industry, medicine.drug_class, Genome-wide association study, Mood stabilizer, Odds ratio, medicine.disease, 3. Good health, 030227 psychiatry, Treatment of bipolar disorder, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Internal medicine, Pharmacogenomics, mental disorders, medicine, Bipolar disorder, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

ImportanceLithium is a first-line mood stabilizer for the maintenance treatment of Bipolar Disorder (BPD). However, the efficacy of lithium varies widely, with a non-response rate of up to 30%. Biological response markers and predictors are lacking.ObjectiveGenetic factors are thought to mediate lithium treatment response, and the previously reported genetic overlap between BPD and schizophrenia (SCZ) led us to test whether a polygenic score (PGS) for SCZ could predict lithium treatment response in BPD. Further, we explored the potential molecular underpinnings of this association.DesignWeighted SCZ PGSs were computed at ten p-value thresholds (PT) using summary statistics from a genome-wide association study (GWAS) of 36,989 SCZ cases, and genotype data for BPD patients from the Consortium on Lithium Genetics (ConLi+Gen). For functional exploration, we performed a cross-trait meta-GWAS and pathway analysis, combining GWAS summary statistics on SCZ and lithium treatment response.SettingInternational multicenter GWAS.ParticipantsPatients with BPD who had undergone lithium treatment were genotyped and retrospectively assessed for long-term treatment response (n=2,586).Main outcome measuresClinical treatment response to lithium was defined on both the categorical and continuous scales using the ALDA score. The effect measures include odds ratios (ORs) and the proportion of variance explained (R2), and a significant association was determined at pResultsThe PGS for SCZ was inversely associated with lithium treatment response in the categorical outcome (p=8×10−5), at PT−2. Patients with BPD who had low polygenic load for SCZ responded better to lithium, with ORs for lithium response ranging from 3.46 [95%CI: 1.42-8.41 at 1stdecile] to 2.03 [95%CI: 0.86-4.81 at the 9th decile], compared to the patients in the 10thdecile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA complex and inflammatory cytokines (TNFα, IL-4, IFNγ) as molecular contributors to lithium treatment response in BPD.Conclusions and RelevanceThe study provides, for the first-time, evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.Key PointsQuestionDoes a polygenic score for Schizophrenia (SCZ) predict response to lithium in patients with Bipolar Disorder (BPD)? What are the molecular drivers of the association between SCZ and lithium treatment response?FindingsWe found an inverse association between genetic loading for SCZ risk variants and response to lithium in patients with BPD. Genetic variants in the HLA region on chromosome 6, the antigen presentation pathway and markers of inflammation (TNFα, IL-4, IFNγ) point to molecular underpinnings of lithium treatment response in BPD.MeaningIn patients with BPD, an assessment of a polygenic load for SCZ risk variants may assist in conjunction with clinical data to predict whether they would respond to lithium treatment.

Published
2017

45. International multi-site survey on the use of online support groups in bipolar disorder

Author

Mark Zetin, Jonas Gildebro, Sabine Choppin, Diego Hidalgo-Mazzei, Caterina Chillotti, Błażej Misiak, Alberto Bocchetta, Claire O'Donovan, Letizia Bossini, Yoshitaka Tatebayashi, René Ernst Nielsen, Guy M. Goodwin, Brett Sawchuk, Philipp Ritter, Jörn Conell, Amy C. Bilderbeck, Paul Grof, Scott Monteith, Vaisnvy Kapur, Hirohiko Harima, Chantal Henry, Martin Alda, Beny Lafer, Michael Bauer, Eric Yw Cheung, Ana González-Pinto, Julia Volkert, Maj Vinberg, Erik Roj Larsen, Michael Berk, Andrea Fagiolini, Patryk Piotrowski, Aleksandra Suwalska, Elon Schwartz, Rodrigo A. Munoz, Anne Duffy, Ângela Miranda Scippa, Maria Del Zompo, Angela Marianne Paredes Castro, Anne Hvenegaard Lund, Leonardo Tondo, Yamima Osher, Andreas Reif, Bernhard T. Baune, Peter Tam, Takako Nakanotani, Girish Kunigiri, Claire Slaney, Tasha Glenn, Rita Bauer, Eduard Vieta, Yuly Bersudsky, Biju Viswanath, Janusz K. Rybakowski, Julie Garnham, Miryam Fernández Hernandez, Rodrigo R. Dias, Raffaella Ardau, John R. Geddes, Ramus Licht, Ahmad Hatim Sulaiman, Peter C. Whybrow, Yasushi Okamura, Kemal Sagduyu, Kirsi Suominen, Stefanie Hassel, Ute Lewitzka, Seetal Dodd, and Bruno Etain

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, Internationality, Online support groups, Peer support, online support groups, Self-help, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Journal Article, medicine, Humans, survey, 030212 general & internal medicine, Bipolar disorder, self-help, Psychiatry, Generalized estimating equation, Internet, Descriptive statistics, business.industry, Information seeking, Psychiatry and Mental Health, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Self-Help Groups, The Internet, Female, business, Psychology, Clinical psychology
Abstract

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups.AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking.METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data.RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Published
2017

46. Involvement of core clock genes in lithium response

Author

Andrea Angius, Maria Del Zompo, Carla Melis, Caterina Chillotti, Alessio Squassina, Claudia Pisanu, Giovanni Severino, Donatella Congiu, and Raffaella Ardau

Subjects
0301 basic medicine, Bipolar Disorder, Lithium (medication), Gene Expression, Biology, Lithium, In vitro, Circadian Rhythm, CLOCK, 03 medical and health sciences, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, Lymphoblastoid cell, Gene expression, otorhinolaryngologic diseases, Cancer research, medicine, Humans, Circadian rhythm, Gene, 030217 neurology & neurosurgery, Biological Psychiatry, medicine.drug
Abstract

Dear editor,Geoffroy et al. (2017) reported an effect of in vitro lithium treatment (1 mM) on the expression of circadian genes in lymphoblastoid cell lines (LCL) derived from patients with bipolar...

Published
2017

47. Erratum to:Online information seeking by patients with bipolar disorder: results from an international multisite survey

Author

Paul Grof, Claire Slaney, Martin Alda, Chantal Henry, Scott Monteith, Eric Yat Wo Cheung, Ana González-Pinto, Peter C. Whybrow, Guy M. Goodwin, Yamima Osher, Vaisnvy Kapur, Hirohiko Harima, Claire O'Donovan, Amy C. Bilderbeck, Anne Hvenegaard Lund, Yasushi Okamura, Kirsi Suominen, Ahmad Hatim Sulaiman, Rasmus Wentzer Licht, Biju Viswanath, Elon Schwartz, Julie Garnham, Brett Sawchuk, Jonas Gildebro, Sabine Choppin, Rodrigo A. Muñoz, Kemal Sagduyu, René Ernst Nielsen, Leonardo Tondo, Jörn Conell, Michael Bauer, Beny Lafer, Ângela Miranda Scippa, Michael Berk, Andrea Fagiolini, Janusz K. Rybakowski, Erik Roj Larsen, Takako Nakanotani, Rodrigo R. Dias, Andreas Reif, Ute Lewitzka, Maria Del Zompo, Seetal Dodd, Angela Marianne Paredes Castro, Maj Vinberg, Bernhard T. Baune, Aleksandra Suwalska, Chun Lam, Anne Duffy, Patryk Piotrowski, Stefanie Hassel, Bruno Etain, Yuly Bersudsky, John R. Geddes, Philipp Ritter, Peter Tam, Raffaella Ardau, Eduard Vieta, Mark Zetin, Iñaki Zorrilla, Girish Kunigiri, Tasha Glenn, Rita Bauer, Julia Volkert, Diego Hidalgo-Mazzei, Alberto Bocchetta, Caterina Chillotti, Błażej Misiak, Letizia Bossini, and Yoshitaka Tatebayashi

Subjects
medicine.medical_specialty, Published Erratum, Information seeking, lcsh:QP351-495, medicine.disease, lcsh:RC321-571, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, lcsh:Neurophysiology and neuropsychology, 0302 clinical medicine, medicine, Bipolar disorder, Erratum, Psychology, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 030217 neurology & neurosurgery, Biological Psychiatry, Clinical psychology
Abstract

Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information.A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data.976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor.Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Published
2017

48. Solar insolation in springtime influences age of onset of bipolar I disorder

Author

Christian Simhandl, Harriet Birabwa-Oketcho, Slim Khaldi, Claire O'Donovan, Ahmad Hatim Sulaiman, Janusz K. Rybakowski, Dan J. Stein, M. S. Reddy, Rasmus Wentzer Licht, Andreas Reif, Flávio Kapczinski, Y. Pica Ruiz, Ângela Miranda Scippa, Christopher Baethge, Julia Veeh, M. Yee Ming, Kemal Sagduyu, Hiromi Tagata, Biju Viswanath, F. D. R. da Ponte, Scott Monteith, Michael Bauer, Mark A. Frye, Yamima Osher, Raffaella Ardau, Ana González-Pinto, Yoshitaka Tatebayashi, Chantal Henry, Sven Janno, M. A. Aleksandrovich, Timur L. Kot, Beny Lafer, Paul Grof, Yavuz Ayhan, René Ernst Nielsen, Barbara König, Eduard Vieta, Emanuel Severus, Erik Roj Larsen, Kirsi Suominen, Sebastian Kliwicki, Eric Yat Wo Cheung, Peter C. Whybrow, H. Østermark Sørensen, John F. Gottlieb, Mikael Landén, Michael Berk, Andrea Fagiolini, M. Del Zompo, Juan Cabrera, Carlos López-Jaramillo, Mirko Manchia, Tasha Glenn, Ingrid Melle, Starlin V. Mythri, Sule Bicakci, Rita Bauer, Maximilian Pilhatsch, Rodrigo A. Munoz, Danilo Quiroz, Glenda MacQueen, Philipp Ritter, Hirohiko Harima, Ravi Kumar Nadella, Enrica Mosca, Yuly Bersudsky, Natalie L. Rasgon, Wendy K. Marsh, Konstantinos N. Fountoulakis, María Yoldi-Negrete, Adel Omrani, Mathias Kardell, Fatima Meza-Urzua, Letizia Bossini, Fethi Nacef, Franck Bellivier, Erkki Isometsä, Gunnar Morken, Elias Angelopoulos, Marco Pinna, Thomas Bjella, Fabiano G. Nery, Sergio Strejilevich, Markus Donix, Bernhard T. Baune, Ole A. Andreassen, Leonardo Tondo, Rajkumar Ramesar, Claudia Becerra-Palars, Arne E. Vaaler, Yosra Zgueb, Uta Ouali, Seetal Dodd, Rikke Krogh, Ute Lewitzka, Maurício Kunz, S. R. Bharathram, Bruno Etain, Carla Torrent, Mythily Subramaniam, Robert H. Belmaker, Martin Alda, Mónica Martínez-Cengotitabengoa, Mark Zetin, Ben Hassine, AbdelHakim, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), ChronoRecord Association Inc. [Fullerton, USA], Dalhousie University [Halifax], Soviet Psychoneurological Hospital [Urai, Russia], Norwegian Centre for Mental Disorders Research [Oslo] (NORMENT), University of Oslo (UiO)-Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB)-Oslo University Hospital [Oslo], University of Athens Medical School [Athens], Università degli Studi di Cagliari = University of Cagliari (UniCa), Faculty of Medicine [Hacettepe University], Hacettepe University = Hacettepe Üniversitesi, Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, National Institute of Mental Health and Neurosciences [Bangalore, Inde] (NIMHANS ), Adelaide Medical School [Australia], University of Adelaide, National Institute of Psychiatry Ramón de la Fuente Muñiz [Mexico City] (INPRF), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ben-Gurion University of the Negev (BGU), Deakin University [Burwood], University of Melbourne, Butabika Hospital [Kampala, Uganda], Università degli Studi di Siena = University of Siena (UNISI), Mood Disorders Clinic, Dr. Jose Horwitz Psychiatric Institute, Castle Peak Hospital [Hong Kong], Centre for Innovation in Mental and Physical Health and Clinical Treatment [Geelong Victoria, Australia] (IMPACT), Aristotle University of Thessaloniki, Mayo Clinic [Rochester], University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Northwestern University Feinberg School of Medicine, Mood Disorders Center of Ottawa (MDCO), University of Ottawa [Ottawa], Kobe University, Tokyo Metropolitan Matsuzawa Hospital [Tokyo, Japan], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), National Institute for Health and Welfare [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Tartu, Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Institute of Neuroscience and Physiology [Göteborg], Poznan University of Medical Sciences [Poland] (PUMS), BIPOLAR Zentrum Wiener Neustadt [Wiener Neustadt, Austria], Khanty-Mansiysk Clinical Psychoneurological Hospital [Khanty-Mansiysk, Russia], Aarhus University Hospital, Universidade de São Paulo Medical School (FMUSP), Karolinska Institutet [Stockholm], Aalborg University [Denmark] (AAU), Universidad de Antoquia, University of Calgary, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Institute of Mental Health [Singapore], Michigan State University [Traverse City], Michigan State University System, Department of Psychiatry [St. Olav's hospital, Trondheim], St. Olav's Hospital, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), University of California [San Diego] (UC San Diego), University of California (UC), Asha Bipolar Clinic [Hyderabad, Telangana, India] (ABC), Université de Tunis El Manar (UTM), Faculté de Médecine de Tunis, Hospital Ángeles del Pedregal [Mexico City, Mexico], Centro Lucio Bini [Cagliari, Italy], Universidad Diego Portales [Santiago] (UDP), Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Stanford University School of Medicine [CA, USA], Goethe-Universität Frankfurt am Main, University of Missouri [Kansas City] (UMKC), University of Missouri System, Universidade Federal da Bahia (UFBA), Institute of Neuroscience Foundation Favaloro, Favaloro Foundation, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), Tokyo Metropolitan Institute of Medical Science (TMIMS), McLean Hospital [Belmont, Ma.], University of Barcelona, Goethe-University Frankfurt am Main, Universitätsklinikum Frankfurt, Consejo Nacional de Ciencia y Tecnología [Mexico] (CONACYT), Chapman University, Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Michael Berk is supported by an NHMRC Senior Principal Research Fellowship (1059660). Ole A Andreassen, Thomas DBjella and Ingrid Melle are supported by Research Council of Norway (223273) and KG Jebsen Stiftelsen. Ravi Nadella has received funding from the Accelerator program for Discovery in Brain disorders using Stem cells (ADBS), jointly funded by the Department of Biotechnology, Government of India, and the Pratiksha trust. Biju Viswanath has received funding by Department of Science and Technology INSPIRE scheme, Government of India. Mikael Landén was supported by grants from the Swedish Research Council (K2014‐62X‐14647‐12‐51 and K2010‐61P‐21568‐01‐4), the Swedish foundation for Strategic Research (KF10‐0039), and the Swedish Federal Government under the LUA/ALF agreement (ALF 20130032, ALFGBG‐142041)., We thank Haydeh Olofsson for valuable data management support., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Tokyo Metropolitan Institute of Medical Science, Universita degli Studi di Cagliari [Cagliari], University of the Basque Country [Bizkaia] (UPV/EHU), University of Helsinki, University of California, University of Malaya [Kuala Lumpur, Malaisie], University of California-University of California, University of Cologne-University Hospital of Cologne [Cologne], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
Male, Internationality, Bipolar I disorder, Epidemiology, [SDV]Life Sciences [q-bio], 0302 clinical medicine, MESH: Asia/epidemiology, Age of Onset, Family history, First episode, MESH: Middle Aged, Circadian rhythm, Electromagnetic Radiation, MESH: Australia/epidemiology, Middle Aged, MESH: Seasons, 3. Good health, Europe, [SDV] Life Sciences [q-bio], MESH: Young Adult, Psychiatry and Mental Health, Solar insolation, Sunlight, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Seasons, Solar System, medicine.symptom, Mania, Adult, MESH: Sunlight, Asia, Adolescent, Bipolar disorder, MESH: Electromagnetic Radiation, MESH: Age of Onset, MESH: Solar System, MESH: Internationality, Young Adult, 03 medical and health sciences, MESH: Bipolar Disorder/epidemiology, MESH: South America/epidemiology, medicine, Journal Article, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Adolescent, MESH: Humans, business.industry, Australia, MESH: North America/epidemiology, MESH: Adult, South America, medicine.disease, MESH: Africa/epidemiology, MESH: Male, 030227 psychiatry, MESH: Europe/epidemiology, Mood disorders, 13. Climate action, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Africa, North America, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Age of onset, business, MESH: Female, 030217 neurology & neurosurgery, Demography
Abstract

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density.RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001).CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Published
2017

49. Continuation Versus Discontinuation of Lithium During Pregnancy

Author

Paolo Carta, Valeria Deiana, Alberto Bocchetta, Maria Del Zompo, Raffaella Ardau, Caterina Chillotti, and Mirko Manchia

Subjects
Adult, Pediatrics, medicine.medical_specialty, Bipolar Disorder, Lithium (medication), Young Adult, Continuation, Antimanic Agents, Pregnancy, medicine, Humans, Pharmacology (medical), Retrospective Studies, Series (stratigraphy), business.industry, Pregnancy Outcome, medicine.disease, Discontinuation, Pregnancy Complications, Psychiatry and Mental health, Lithium Compounds, Female, business, Follow-Up Studies, medicine.drug
Published
2014

50. Internet use by patients with bipolar disorder: Results from an international multisite survey

Author

Janusz K. Rybakowski, Julie Garnham, Mark Zetin, Peter C. Whybrow, Raffaella Ardau, Vaisnvy Kapur, Yasushi Okamura, Peter Tam, Claire O'Donovan, Rasmus Wentzer Licht, Hirohiko Harima, Chantal Henry, Girish Kunigiri, Jörn Conell, Bruno Etain, Anne Hvenegaard Lund, Tasha Glenn, Caterina Chillotti, Andreas Reif, Rita Bauer, Erik Roj Larsen, John R. Geddes, Ahmad Hatim Sulaiman, Miryam Fernández Hernandez, Leonardo Tondo, Scott Monteith, Błażej Misiak, Amy C. Bilderbeck, Seetal Dodd, Julia Volkert, Ana González-Pinto, Martin Alda, Eduard Vieta, Takako Nakanotani, René Ernst Nielsen, Letizia Bossini, Philipp Ritter, Elon Schwartz, Patryk Piotrowski, Brett Sawchuk, Angela Marianne Paredes Castro, Beny Lafer, Guy M. Goodwin, Jonas Gildebro, Sabine Choppin, Kemal Sagduyu, Rodrigo R. Dias, Yoshitaka Tatebayashi, Kirsi Suominen, Stefanie Hassel, Biju Viswanath, Maj Vinberg, Aleksandra Suwalska, Ute Lewitzka, Rodrigo A. Munoz, Anne Duffy, Diego Hidalgo-Mazzei, Michael Bauer, Michael Berk, Alberto Bocchetta, Andrea Fagiolini, Claire Slaney, Yamima Osher, Paul Grof, Eric Yat Wo Cheung, Ângela Miranda Scippa, Maria Del Zompo, Bernhard T. Baune, and Yuly Bersudsky

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, Internationality, Adolescent, media_common.quotation_subject, education, World wide web, Information source, Odds, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Surveys and Questionnaires, mental disorders, medicine, Humans, Bipolar disorder, Young adult, Psychiatry, Internet, Psychiatry and Mental Health, Biological Psychiatry, media_common, Internet use, business.industry, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Feeling, The Internet, Female, Self Report, Biological psychiatry, business, 030217 neurology & neurosurgery
Abstract

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Published
2016

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