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1. Gender-specific shared genetic determinants between severe mental disorders and body mass index

Author: Pisanu, C., primary, Meloni, A., additional, Congiu, D., additional, Severino, G., additional, Ardau, R., additional, Chillotti, C., additional, Del Zompo, M., additional, and Squassina, A., additional
Published: 2023
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2. Influence of birth cohort on age of onset cluster analysis in bipolar I disorder

Author: Bauer, M., Glenn, T., Alda, M., Andreassen, O.A., Angelopoulos, E., Ardau, R., Baethge, C., Bauer, R., Bellivier, F., Belmaker, R.H., Berk, M., Bjella, T.D., Bossini, L., Bersudsky, Y., Cheung, E.Y.W., Conell, J., Del Zompo, M., Dodd, S., Etain, B., Fagiolini, A., Frye, M.A., Fountoulakis, K.N., Garneau-Fournier, J., Gonzalez-Pinto, A., Harima, H., Hassel, S., Henry, C., Iacovides, A., Isometsä, E.T., Kapczinski, F., Kliwicki, S., König, B., Krogh, R., Kunz, M., Lafer, B., Larsen, E.R., Lewitzka, U., Lopez-Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Melle, I., Monteith, S., Morken, G., Munoz, R., Nery, F.G., O’Donovan, C., Osher, Y., Pfennig, A., Quiroz, D., Ramesar, R., Rasgon, N., Reif, A., Ritter, P., Rybakowski, J.K., Sagduyu, K., Scippa, A.M., Severus, E., Simhandl, C., Stein, D.J., Strejilevich, S., Hatim Sulaiman, A., Suominen, K., Tagata, H., Tatebayashi, Y., Torrent, C., Vieta, E., Viswanath, B., Wanchoo, M.J., Zetin, M., and Whybrow, P.C.
Published: 2015
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3. Solar insolation in springtime influences age of onset of bipolar I disorder

Author: Bauer, M., Glenn, T., Alda, M., Aleksandrovich, M. A., Andreassen, O. A., Angelopoulos, E., Ardau, R., Ayhan, Y., Baethge, C., Bharathram, S. R., Bauer, R., Baune, B. T., Becerra‐Palars, C., Bellivier, F., Belmaker, R. H., Berk, M., Bersudsky, Y., Bicakci, Ş., Birabwa‐Oketcho, H., Bjella, T. D., Bossini, L., Cabrera, J., Cheung, E. Y. W., Del Zompo, M., Dodd, S., Donix, M., Etain, B., Fagiolini, A., Fountoulakis, K. N., Frye, M. A., Gonzalez‐Pinto, A., Gottlieb, J. F., Grof, P., Harima, H., Henry, C., Isometsä, E. T., Janno, S., Kapczinski, F., Kardell, M., Khaldi, S., Kliwicki, S., König, B., Kot, T. L., Krogh, R., Kunz, M., Lafer, B., Landén, M., Larsen, E. R., Lewitzka, U., Licht, R. W., Lopez‐Jaramillo, C., MacQueen, G., Manchia, M., Marsh, W., Martinez‐Cengotitabengoa, M., Melle, I., Meza‐Urzúa, F., Yee Ming, M., Monteith, S., Morken, G., Mosca, E., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nery, F. G., Nielsen, R. E., OʼDonovan, C., Omrani, A., Osher, Y., Østermark Sørensen, H., Ouali, U., Pica Ruiz, Y., Pilhatsch, M., Pinna, M., da Ponte, F. D. R., Quiroz, D., Ramesar, R., Rasgon, N., Reddy, M. S., Reif, A., Ritter, P., Rybakowski, J. K., Sagduyu, K., Scippa, Â. M., Severus, E., Simhandl, C., Stein, D. J., Strejilevich, S., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tagata, H., Tatebayashi, Y., Tondo, L., Torrent, C., Vaaler, A. E., Veeh, J., Vieta, E., Viswanath, B., Yoldi‐Negrete, M., Zetin, M., Zgueb, Y., and Whybrow, P. C.
Published: 2017
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4. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients (vol 12, 278, 2022)

Author: Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, 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, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nothen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, Baune, BT, Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, 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, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nothen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, and Baune, BT
Published: 2022

5. An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes

Author: Scott, J., Etain, B., Manchia, M., Brichant-Petitjean, C., Geoffroy, P. A., Schulze, T., Alda, M., Bellivier, F., Amare, A., Ardau, R., Backlund, L., Baune, B., Barboza, A., Benabarre, A., Chaumette, B., Chen, H., Chillotti, C., Clark, S., Colom, F., Del Zompo, M., Dalkner, N., Dantas, C., Ferentinos, P., Garnham, J., Jamain, S., Jimenez, E., Khan, J. -P., Kuo, P., Lavebratt, C., Maj, M., Millischer, V., Monteleone, P., Pisanu, C., Potash, J., Reif, A., Reininghaus, E., Schalling, M., Schofield, P., Schubert, K., Severino, G., Slaney, C., Smith, D., Squassina, A., Tondo, L., Vieta, E., and Witt, S.
Subjects: Male, psychometrics, Bipolar Disorder, Scale (ratio), Computer science, media_common.quotation_subject, Sample (statistics), Lithium, Machine learning, computer.software_genre, clinimetrics, 03 medical and health sciences, 0302 clinical medicine, Multidimensional index, Humans, genetics, Quality (business), clinical phenotypes, Biological Psychiatry, Reliability (statistics), Retrospective Studies, media_common, Interpretability, business.industry, Confounding, Reproducibility of Results, Alda scale, 030227 psychiatry, Psychiatry and Mental health, Phenotype, lithium response, Lithium Compounds, Female, Artificial intelligence, Construct (philosophy), business, computer, 030217 neurology & neurosurgery
Abstract: Objectives The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. Methods We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. Results The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. Conclusions This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies.
Published: 2019
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6. Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Author: Bauer, M. Glenn, T. Achtyes, E.D. Alda, M. Agaoglu, E. Altınbaş, K. Andreassen, O.A. Angelopoulos, E. Ardau, R. Vares, E.A. Aydin, M. Ayhan, Y. Baethge, C. Bauer, R. Baune, B.T. Balaban, C. Becerra-Palars, C. Behere, A.P. Behere, P.B. Belete, H. Belete, T. Belizario, G.O. Bellivier, F. Belmaker, R.H. Benedetti, F. Berk, M. Bersudsky, Y. Bicakci, Ş. Birabwa-Oketcho, H. Bjella, T.D. Brady, C. Cabrera, J. Cappucciati, M. Castro, A.M.P. Chen, W.-L. Cheung, E.Y.W. Chiesa, S. Crowe, M. Cuomo, A. Dallaspezia, S. Del Zompo, M. Desai, P. Dodd, S. Donix, M. Etain, B. Fagiolini, A. Fellendorf, F.T. Ferensztajn-Rochowiak, E. Fiedorowicz, J.G. Fountoulakis, K.N. Frye, M.A. Geoffroy, P.A. Gonzalez-Pinto, A. Gottlieb, J.F. Grof, P. Haarman, B.C.M. Harima, H. Hasse-Sousa, M. Henry, C. Høffding, L. Houenou, J. Imbesi, M. Isometsä, E.T. Ivkovic, M. Janno, S. Johnsen, S. Kapczinski, F. Karakatsoulis, G.N. Kardell, M. Kessing, L.V. Kim, S.J. König, B. Kot, T.L. Koval, M. Kunz, M. Lafer, B. Landén, M. Larsen, E.R. Lenger, M. Lewitzka, U. Licht, R.W. Lopez-Jaramillo, C. MacKenzie, A. Madsen, H.Ø. Madsen, S.A.K.A. Mahadevan, J. Mahardika, A. Manchia, M. Marsh, W. Martinez-Cengotitabengoa, M. Martiny, K. Mashima, Y. McLoughlin, D.M. Meesters, Y. Melle, I. Meza-Urzúa, F. Ming, M.Y. Monteith, S. Moorthy, M. Morken, G. Mosca, E. Mozzhegorov, A.A. Munoz, R. Mythri, S.V. Nacef, F. Nadella, R.K. Nakanotani, T. Nielsen, R.E. O‘Donovan, C. Omrani, A. Osher, Y. Ouali, U. Pantovic-Stefanovic, M. Pariwatcharakul, P. Petite, J. Pfennig, A. Ruiz, Y.P. Pilhatsch, M. Pinna, M. Pompili, M. Porter, R. Quiroz, D. Rabelo-da-Ponte, F.D. Ramesar, R. Rasgon, N. Ratta-apha, W. Ratzenhofer, M. Redahan, M. Reddy, M.S. Reif, A. Reininghaus, E.Z. Richards, J.G. Ritter, P. Rybakowski, J.K. Sathyaputri, L. Scippa, Â.M. Simhandl, C. Severus, E. Smith, D. Smith, J. Stackhouse, P.W., Jr. Stein, D.J. Stilwell, K. Strejilevich, S. Su, K.-P. Subramaniam, M. Sulaiman, A.H. Suominen, K. Tanra, A.J. Tatebayashi, Y. Teh, W.L. Tondo, L. Torrent, C. Tuinstra, D. Uchida, T. Vaaler, A.E. Veeh, J. Vieta, E. Viswanath, B. Yoldi-Negrete, M. Yalcinkaya, O.K. Young, A.H. Zgueb, Y. Whybrow, P.C.
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 < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed. © 2021, The Author(s).
Published: 2021

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

Author: Le Clerc, S, Lombardi, L, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Pisanu, C, Squassina, A, Le Clerc, S, Lombardi, L, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Pisanu, C, and Squassina, A
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 < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Published: 2021

8. Prediction of lithium response using genomic data

Author: Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, Alda, M, Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, and Alda, M
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

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

Author: Bauer, M, Glenn, T, Achtyes, ED, Alda, M, Agaoglu, E, Altınbaş, K, Andreassen, OA, Angelopoulos, E, Ardau, R, Vares, EA, Aydin, M, Ayhan, Y, Baethge, C, Bauer, R, Baune, BT, Balaban, C, Becerra-Palars, C, Behere, AP, Behere, PB, Belete, H, Belete, T, Belizario, GO, Bellivier, F, Belmaker, RH, Benedetti, F, Berk, Michael, Bersudsky, Y, Bicakci, Ş, Birabwa-Oketcho, H, Bjella, TD, Brady, C, Cabrera, J, Cappucciati, M, Castro, AMP, Chen, WL, Cheung, EYW, Chiesa, S, Crowe, M, Cuomo, A, Dallaspezia, S, Del Zompo, M, Desai, P, Dodd, Seetal, Donix, M, Etain, B, Fagiolini, A, Fellendorf, FT, Ferensztajn-Rochowiak, E, Fiedorowicz, JG, Fountoulakis, KN, Frye, MA, Geoffroy, PA, Gonzalez-Pinto, A, Gottlieb, JF, Grof, P, Haarman, BCM, Harima, H, Hasse-Sousa, M, Henry, C, Høffding, L, Houenou, J, Imbesi, M, Isometsä, ET, Ivkovic, M, Janno, S, Johnsen, S, Kapczinski, F, Karakatsoulis, GN, Kardell, M, Kessing, LV, Kim, SJ, König, B, Kot, TL, Koval, M, Kunz, M, Lafer, B, Landén, M, Larsen, ER, Lenger, M, Lewitzka, U, Licht, RW, Lopez-Jaramillo, C, MacKenzie, A, Madsen, HØ, Madsen, SAKA, Mahadevan, J, Mahardika, A, Manchia, M, Marsh, W, Martinez-Cengotitabengoa, M, Martiny, K, Mashima, Y, McLoughlin, DM, Meesters, Y, Melle, I, Meza-Urzúa, F, Ming, MY, Monteith, S, Moorthy, M, Morken, G, Bauer, M, Glenn, T, Achtyes, ED, Alda, M, Agaoglu, E, Altınbaş, K, Andreassen, OA, Angelopoulos, E, Ardau, R, Vares, EA, Aydin, M, Ayhan, Y, Baethge, C, Bauer, R, Baune, BT, Balaban, C, Becerra-Palars, C, Behere, AP, Behere, PB, Belete, H, Belete, T, Belizario, GO, Bellivier, F, Belmaker, RH, Benedetti, F, Berk, Michael, Bersudsky, Y, Bicakci, Ş, Birabwa-Oketcho, H, Bjella, TD, Brady, C, Cabrera, J, Cappucciati, M, Castro, AMP, Chen, WL, Cheung, EYW, Chiesa, S, Crowe, M, Cuomo, A, Dallaspezia, S, Del Zompo, M, Desai, P, Dodd, Seetal, Donix, M, Etain, B, Fagiolini, A, Fellendorf, FT, Ferensztajn-Rochowiak, E, Fiedorowicz, JG, Fountoulakis, KN, Frye, MA, Geoffroy, PA, Gonzalez-Pinto, A, Gottlieb, JF, Grof, P, Haarman, BCM, Harima, H, Hasse-Sousa, M, Henry, C, Høffding, L, Houenou, J, Imbesi, M, Isometsä, ET, Ivkovic, M, Janno, S, Johnsen, S, Kapczinski, F, Karakatsoulis, GN, Kardell, M, Kessing, LV, Kim, SJ, König, B, Kot, TL, Koval, M, Kunz, M, Lafer, B, Landén, M, Larsen, ER, Lenger, M, Lewitzka, U, Licht, RW, Lopez-Jaramillo, C, MacKenzie, A, Madsen, HØ, Madsen, SAKA, Mahadevan, J, Mahardika, A, Manchia, M, Marsh, W, Martinez-Cengotitabengoa, M, Martiny, K, Mashima, Y, McLoughlin, DM, Meesters, Y, Melle, I, Meza-Urzúa, F, Ming, MY, Monteith, S, Moorthy, M, and Morken, G
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, a
Published: 2021

10. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Author: Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, Y-H, Shekhtman, T, AdIi, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, K, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Etain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Vieta, E, Veeh, J, Witt, SH, Wright, A, Zandi, PP, Mitchell, PB, Bauer, M, Alda, M, Rietschel, M, McMahon, FJ, Schulze, TG, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, Y-H, Shekhtman, T, AdIi, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, K, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Etain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Vieta, E, Veeh, J, Witt, SH, Wright, A, Zandi, PP, Mitchell, PB, Bauer, M, Alda, M, Rietschel, M, McMahon, FJ, Schulze, TG, and Baune, BT
Abstract: Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findin
Published: 2021

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

Author: Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, 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, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Oesby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, Baune, BT, Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, 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, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Oesby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, and Baune, BT
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

12. P.305 Convergent sequencing and microarray data analyses suggest the involvement of miRNAs and target mRNAs in lithium response in bipolar disorder

Author: Squassina, A., primary, Pisanu, C., additional, Papadima, E. Merkouri, additional, Melis, C., additional, Calza, S., additional, Congiu, D., additional, Loizedda, A., additional, Orrù, N., additional, Severino, G., additional, Ardau, R., additional, Chillotti, C., additional, Orrù, S., additional, Carcassi, C., additional, and Del Zompo, M., additional
Published: 2019
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13. EVIDENCE OF A SUSCEPTIBILITY LOCUS FOR BIPOLAR DISORDER ON CHROMOSOME 1p IN THE SARDINIAN POPULATION

Author: Del Zompo, M., Piccardi, M., Severino, G., Ardau, R., Chillotti, C., Saba, G., Dib, C., Ricard, S., Thomas, G., Soubigou, S., Poirier, M., Fournel, R., Deleuze, J., Meloni, R., Biguet, N. Faucon, and Mallet, J.
Published: 2009

14. The diacylglycerol kinase eta gene and bipolar disorder: a replication study in a Sardinian sample

Author: Squassina, A, Manchia, M, Congiu, D, Severino, G, Chillotti, C, Ardau, R, Piccardi, M, and Del Zompo, M
Published: 2009

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

Author: Bauer, M. Glenn, T. Alda, M. Andreassen, O.A. Angelopoulos, E. Ardau, R. Ayhan, Y. Baethge, C. Bauer, R. Baune, B.T. Becerra-Palars, C. Bellivier, F. Belmaker, R.H. Berk, M. Bersudsky, Y. Bicakci, Ş. Birabwa-Oketcho, H. Bjella, T.D. Cabrera, J. Wo Cheung, E.Y. Del Zompo, M. Dodd, S. Donix, M. Etain, B. Fagiolini, A. Fountoulakis, K.N. Frye, M.A. Gonzalez-Pinto, A. Gottlieb, J.F. Grof, P. Harima, H. Henry, C. Isometsä, E.T. Janno, S. Kapczinski, F. Kardell, M. Khaldi, S. Kliwicki, S. König, B. Kot, T.L. Krogh, R. Kunz, M. Lafer, B. Landén, M. Larsen, E.R. Lewitzka, U. Licht, R.W. Lopez-Jaramillo, C. MacQueen, G. Manchia, M. Marsh, W. Martinez-Cengotitabengoa, M. Melle, I. Meza-Urzúa, F. Ming, M.Y. Monteith, S. Morken, G. Mosca, E. Mozzhegorov, A.A. Munoz, R. Mythri, S.V. Nacef, F. Nadella, R.K. Nery, F.G. Nielsen, R.E. O'Donovan, C. Omrani, A. Osher, Y. Sørensen, H.Ø. Ouali, U. Ruiz, Y.P. Pilhatsch, M. Pinna, M. da Ponte, F.D.R. Quiroz, D. Ramesar, R. Rasgon, N. Reddy, M.S. Reif, A. Ritter, P. Rybakowski, J.K. Sagduyu, K. Raghuraman, B.S. Scippa, Â.M. Severus, E. Simhandl, C. Stackhouse, P.W., Jr. Stein, D.J. Strejilevich, S. Subramaniam, M. Sulaiman, A.H. Suominen, K. Tagata, H. Tatebayashi, Y. Tondo, L. Torrent, C. Vaaler, A.E. Vares, E. Veeh, J. Vieta, E. Viswanath, B. Yoldi-Negrete, M. Zetin, M. Zgueb, Y. Whybrow, P.C.
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 < 0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed. © 2019 Elsevier Ltd
Published: 2019

16. EVIDENCE OF A SUSCEPTIBILITY LOCUS FOR BIPOLAR DISORDER ON CHROMOSOME 1p IN THE SARDINIAN POPULATION

Author: Del Zompo, M., Piccardi, M., Severino, G., Ardau, R., Chillotti, C., Saba, G., Dib, C., Ricard, S., Thomas, G., Soubigou, S., Poirier, M., Fournel, R., Deleuze, J., Meloni, R., Biguet, N. Faucon, and Mallet, J.
Published: 2005

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

Author: Kalman, JL, Papiol, S, Forstner, AJ, Heilbronner, U, Degenhardt, F, Strohmaier, J, Adli, M, Adorjan, K, Akula, N, Alda, M, Anderson-Schmidt, H, Andlauer, TFM, Anghelescu, IG, Ardau, R, Arias, B, Arolt, V, Aubry, JM, Backlund, L, Bartholdi, K, Bauer, M, Baune, BT, Becker, T, Bellivier, F, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Budde, M, Cervantes, P, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Comes, AL, Cruceanu, C, Czerski, PM, Dannlowski, U, Dayer, A, Del Zompo, M, DePaulo, JR, Dietrich, DE, Étain, B, Ethofer, T, Falkai, P, Fallgatter, A, Figge, C, Flatau, L, Folkerts, H, Frisen, L, Frye, MA, Fullerton, JM, Gade, K, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Gryaznova, A, Hake, M, Hauser, J, Herms, S, Hoffmann, P, Hou, L, Jäger, M, Jamain, S, Jiménez, E, Juckel, G, Kahn, JP, Kassem, L, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, Klohn-Sagatholislam, F, Koller, M, König, B, Konrad, C, Lackner, N, Laje, G, Landén, M, Lang, FU, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McMahon, FJ, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Nieratschker, V, Nievergelt, CM, Novák, T, Ösby, U, Pfennig, A, Potash, JB, Kalman, JL, Papiol, S, Forstner, AJ, Heilbronner, U, Degenhardt, F, Strohmaier, J, Adli, M, Adorjan, K, Akula, N, Alda, M, Anderson-Schmidt, H, Andlauer, TFM, Anghelescu, IG, Ardau, R, Arias, B, Arolt, V, Aubry, JM, Backlund, L, Bartholdi, K, Bauer, M, Baune, BT, Becker, T, Bellivier, F, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Budde, M, Cervantes, P, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Comes, AL, Cruceanu, C, Czerski, PM, Dannlowski, U, Dayer, A, Del Zompo, M, DePaulo, JR, Dietrich, DE, Étain, B, Ethofer, T, Falkai, P, Fallgatter, A, Figge, C, Flatau, L, Folkerts, H, Frisen, L, Frye, MA, Fullerton, JM, Gade, K, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Gryaznova, A, Hake, M, Hauser, J, Herms, S, Hoffmann, P, Hou, L, Jäger, M, Jamain, S, Jiménez, E, Juckel, G, Kahn, JP, Kassem, L, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, Klohn-Sagatholislam, F, Koller, M, König, B, Konrad, C, Lackner, N, Laje, G, Landén, M, Lang, FU, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McMahon, FJ, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Nieratschker, V, Nievergelt, CM, Novák, T, Ösby, U, Pfennig, A, and Potash, JB
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.
Published: 2019

18. Prediction of lithium response using clinical data

Author: Nunes, A., primary, Ardau, R., additional, Berghöfer, A., additional, Bocchetta, A., additional, Chillotti, C., additional, Deiana, V., additional, Garnham, J., additional, Grof, E., additional, Hajek, T., additional, Manchia, M., additional, Müller‐Oerlinghausen, B., additional, Pinna, M., additional, Pisanu, C., additional, O’Donovan, C., additional, Severino, G., additional, Slaney, C., additional, Suwalska, A., additional, Zvolsky, P., additional, Cervantes, P., additional, Zompo, M., additional, Grof, P., additional, Rybakowski, J., additional, Tondo, L., additional, Trappenberg, T., additional, and Alda, M., additional
Published: 2019
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19. Analysis of the influence of microRNAs in lithium response in bipolar disorder

Author: Reinbold, CS, Forstner, AJ, Hecker, J, Fullerton, JM, Hoffmann, P, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Marie-Claire, C, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dayer, A, Étain, B, Falkai, P, Frisén, L, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, MacQueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, TJ, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, SH, Wright, AJ, Trevor Young, L, Zandi, PP, Potash, JB, DePaulo, JR, Bauer, M, Reininghaus, E, Novák, T, Aubry, JM, Reinbold, CS, Forstner, AJ, Hecker, J, Fullerton, JM, Hoffmann, P, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Marie-Claire, C, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dayer, A, Étain, B, Falkai, P, Frisén, L, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, MacQueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, TJ, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, SH, Wright, AJ, Trevor Young, L, Zandi, PP, Potash, JB, DePaulo, JR, Bauer, M, Reininghaus, E, Novák, T, and Aubry, JM
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
Published: 2018

20. 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: Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O'Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O'Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, and Turecki, G
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%
Published: 2018

21. Internet use by older adults with bipolar disorder: international survey results

Author: Bauer, R, Glenn, T, Strejilevich, S, Conell, J, Alda, M, Ardau, R, Baune, BT, Berk, M, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Castro, AMP, Cheung, EYW, Chillotti, C, Choppin, S, Cuomo, A, Del Zompo, M, Dias, R, Dodd, S, Duffy, A, Etain, B, Fagiolini, A, Fernandez Hernandez, M, Garnham, J, Geddes, J, Gildebro, J, Gitlin, MJ, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Lund, AH, Kapur, V, Kunigiri, G, Lafer, B, Larsen, ER, Lewitzka, U, Licht, RW, Misiak, B, Piotrowski, P, Miranda-Scippa, A, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Veeh, J, Vieta, E, Vinberg, M, Viswanath, B, Zetin, M, Whybrow, PC, Bauer, M, Bauer, R, Glenn, T, Strejilevich, S, Conell, J, Alda, M, Ardau, R, Baune, BT, Berk, M, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Castro, AMP, Cheung, EYW, Chillotti, C, Choppin, S, Cuomo, A, Del Zompo, M, Dias, R, Dodd, S, Duffy, A, Etain, B, Fagiolini, A, Fernandez Hernandez, M, Garnham, J, Geddes, J, Gildebro, J, Gitlin, MJ, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Lund, AH, Kapur, V, Kunigiri, G, Lafer, B, Larsen, ER, Lewitzka, U, Licht, RW, Misiak, B, Piotrowski, P, Miranda-Scippa, A, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Veeh, J, Vieta, E, Vinberg, M, Viswanath, B, Zetin, M, Whybrow, PC, and Bauer, M
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

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

Author: Bauer, M. Glenn, T. Alda, M. Aleksandrovich, M.A. Andreassen, O.A. Angelopoulos, E. Ardau, R. Ayhan, Y. Baethge, C. Bharathram, S.R. Bauer, R. Baune, B.T. Becerra-Palars, C. Bellivier, F. Belmaker, R.H. Berk, M. Bersudsky, Y. Bicakci, Ş. Birabwa-Oketcho, H. Bjella, T.D. Bossini, L. Cabrera, J. Cheung, E.Y.W. Del Zompo, M. Dodd, S. Donix, M. Etain, B. Fagiolini, A. Fountoulakis, K.N. Frye, M.A. Gonzalez-Pinto, A. Gottlieb, J.F. Grof, P. Harima, H. Henry, C. Isometsä, E.T. Janno, S. Kapczinski, F. Kardell, M. Khaldi, S. Kliwicki, S. König, B. Kot, T.L. Krogh, R. Kunz, M. Lafer, B. Landén, M. Larsen, E.R. Lewitzka, U. Licht, R.W. Lopez-Jaramillo, C. MacQueen, G. Manchia, M. Marsh, W. Martinez-Cengotitabengoa, M. Melle, I. Meza-Urzúa, F. Yee Ming, M. Monteith, S. Morken, G. Mosca, E. Munoz, R. Mythri, S.V. Nacef, F. Nadella, R.K. Nery, F.G. Nielsen, R.E. O'Donovan, C. Omrani, A. Osher, Y. Østermark Sørensen, H. Ouali, U. Pica Ruiz, Y. Pilhatsch, M. Pinna, M. da Ponte, F.D.R. Quiroz, D. Ramesar, R. Rasgon, N. Reddy, M.S. Reif, A. Ritter, P. Rybakowski, J.K. Sagduyu, K. Scippa, Â.M. Severus, E. Simhandl, C. Stein, D.J. Strejilevich, S. Subramaniam, M. Sulaiman, A.H. Suominen, K. Tagata, H. Tatebayashi, Y. Tondo, L. Torrent, C. Vaaler, A.E. Veeh, J. Vieta, E. Viswanath, B. Yoldi-Negrete, M. Zetin, M. Zgueb, Y. Whybrow, P.C.
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. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Published: 2017

23. An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes.

Author: Scott, Jan, Etain, Bruno, Manchia, Mirko, Brichant‐Petitjean, Clara, Geoffroy, Pierre A., Schulze, Thomas, Alda, Martin, Bellivier, Frank, Amare, A, Ardau, R, Backlund, L, Baune, B, Barboza, A, Benabarre, A, Chaumette, B, Chen, H, Chillotti, C, Clark, S, Colom, F, and Del Zompo, M
Subjects: THERAPEUTIC use of lithium, SIGNAL-to-noise ratio, MEASUREMENT errors, PHENOTYPES
Abstract: Objectives: The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. Methods: We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. Results: The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. Conclusions: This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies. [ABSTRACT FROM AUTHOR]
Published: 2020
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24. Prediction of lithium response using clinical data.

Author: Nunes, A., Ardau, R., Berghöfer, A., Bocchetta, A., Chillotti, C., Deiana, V., Garnham, J., Grof, E., Hajek, T., Manchia, M., Müller‐Oerlinghausen, B., Pinna, M., Pisanu, C., O'Donovan, C., Severino, G., Slaney, C., Suwalska, A., Zvolsky, P., Cervantes, P., and Zompo, M.
Subjects: *MACHINE learning, *RECEIVER operating characteristic curves, *THERAPEUTIC use of lithium, *BIOMARKERS
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. [ABSTRACT FROM AUTHOR]
Published: 2020
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25. Erratum to: online information seeking by patients with bipolar disorder: results from an international multisite survey

Author: Conell, J, Bauer, R, Glenn, T, Alda, M, Ardau, R, Baune, BT, Berk, Michael, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Bossini, L, Paredes Castro, AM, Cheung, EYW, Chillotti, C, Choppin, S, Del Zompo, M, Dias, R, Dodd, Seetal, Duffy, A, Etain, B, Fagiolini, A, Garnham, J, Geddes, J, Gildebro, J, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Kapur, V, Kunigiri, G, Lafer, B, Lam, C, Larsen, ER, Lewitzka, U, Licht, RW, Lund, AH, Misiak, B, Piotrowski, P, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Scippa, Â, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Vieta, E, Vinberg, M, Viswanath, B, Volkert, J, Zetin, M, Zorrilla, I, Whybrow, PC, Bauer, M, Conell, J, Bauer, R, Glenn, T, Alda, M, Ardau, R, Baune, BT, Berk, Michael, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Bossini, L, Paredes Castro, AM, Cheung, EYW, Chillotti, C, Choppin, S, Del Zompo, M, Dias, R, Dodd, Seetal, Duffy, A, Etain, B, Fagiolini, A, Garnham, J, Geddes, J, Gildebro, J, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Kapur, V, Kunigiri, G, Lafer, B, Lam, C, Larsen, ER, Lewitzka, U, Licht, RW, Lund, AH, Misiak, B, Piotrowski, P, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Scippa, Â, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Vieta, E, Vinberg, M, Viswanath, B, Volkert, J, Zetin, M, Zorrilla, I, Whybrow, PC, and Bauer, M
Published: 2017

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

Author: Bauer, M, Glenn, T, Alda, M, Aleksandrovich, MA, Andreassen, OA, Angelopoulos, E, Ardau, R, Ayhan, Y, Baethge, C, Bharathram, SR, Bauer, R, Baune, BT, Becerra-Palars, C, Bellivier, F, Belmaker, RH, Berk, M, Bersudsky, Y, Bicakci, S, Birabwa-Oketcho, H, Bjella, TD, Bossini, L, Cabrera, J, Cheung, EYW, Del Zompo, M, Dodd, S, Donix, M, Etain, B, Fagiolini, A, Fountoulakis, KN, Frye, MA, Gonzalez-Pinto, A, Gottlieb, JF, Grof, P, Harima, H, Henry, C, Isometsae, ET, Janno, S, Kapczinski, F, Kardell, M, Khaldi, S, Kliwicki, S, Koenig, B, Kot, TL, Krogh, R, Kunz, M, Lafer, B, Landen, M, Larsen, ER, Lewitzka, U, Licht, RW, Lopez-Jaramillo, C, MacQueen, G, Manchia, M, Marsh, W, Martinez-Cengotitabengoa, M, Melle, I, Meza-Urzua, F, Yee Ming, M, Monteith, S, Morken, G, Mosca, E, Munoz, R, Mythri, SV, Nacef, F, Nadella, RK, Nery, FG, Nielsen, RE, O'Donovan, C, Omrani, A, Osher, Y, Ostermark Sorensen, H, Ouali, U, Pica Ruiz, Y, Pilhatsch, M, Pinna, M, da Ponte, FDR, Quiroz, D, Ramesar, R, Rasgon, N, Reddy, MS, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Scippa, AM, Severus, E, Simhandl, C, Stein, DJ, Strejilevich, S, Subramaniam, M, Sulaiman, AH, Suominen, K, Tagata, H, Tatebayashi, Y, Tondo, L, Torrent, C, Vaaler, AE, Veeh, J, Vieta, E, Viswanath, B, Yoldi-Negrete, M, Zetin, M, Zgueb, Y, Whybrow, PC, Bauer, M, Glenn, T, Alda, M, Aleksandrovich, MA, Andreassen, OA, Angelopoulos, E, Ardau, R, Ayhan, Y, Baethge, C, Bharathram, SR, Bauer, R, Baune, BT, Becerra-Palars, C, Bellivier, F, Belmaker, RH, Berk, M, Bersudsky, Y, Bicakci, S, Birabwa-Oketcho, H, Bjella, TD, Bossini, L, Cabrera, J, Cheung, EYW, Del Zompo, M, Dodd, S, Donix, M, Etain, B, Fagiolini, A, Fountoulakis, KN, Frye, MA, Gonzalez-Pinto, A, Gottlieb, JF, Grof, P, Harima, H, Henry, C, Isometsae, ET, Janno, S, Kapczinski, F, Kardell, M, Khaldi, S, Kliwicki, S, Koenig, B, Kot, TL, Krogh, R, Kunz, M, Lafer, B, Landen, M, Larsen, ER, Lewitzka, U, Licht, RW, Lopez-Jaramillo, C, MacQueen, G, Manchia, M, Marsh, W, Martinez-Cengotitabengoa, M, Melle, I, Meza-Urzua, F, Yee Ming, M, Monteith, S, Morken, G, Mosca, E, Munoz, R, Mythri, SV, Nacef, F, Nadella, RK, Nery, FG, Nielsen, RE, O'Donovan, C, Omrani, A, Osher, Y, Ostermark Sorensen, H, Ouali, U, Pica Ruiz, Y, Pilhatsch, M, Pinna, M, da Ponte, FDR, Quiroz, D, Ramesar, R, Rasgon, N, Reddy, MS, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Scippa, AM, Severus, E, Simhandl, C, Stein, DJ, Strejilevich, S, Subramaniam, M, Sulaiman, AH, Suominen, K, Tagata, H, Tatebayashi, Y, Tondo, L, Torrent, C, Vaaler, AE, Veeh, J, Vieta, E, Viswanath, B, Yoldi-Negrete, M, Zetin, M, Zgueb, Y, and Whybrow, PC
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

27. Online information seeking by patients with bipolar disorder: results from an international multisite survey (vol 4, pg 1, 2016)

Author: Conell, J, Bauer, R, Glenn, T, Alda, M, Ardau, R, Baune, BT, Berk, M, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Bossini, L, Castro, AMP, Cheung, EYW, Chillotti, C, Choppin, S, Del Zompo, M, Dias, R, Dodd, S, Duffy, A, Etain, B, Fagiolini, A, Garnham, J, Geddes, J, Gildebro, J, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Kapur, V, Kunigiri, G, Lafer, B, Lam, C, Larsen, ER, Lewitzka, U, Licht, R, Lund, AH, Misiak, B, Piotrowski, P, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Scippa, AM, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Vieta, E, Vinberg, M, Viswanath, B, Volkert, J, Zetin, M, Zorrilla, I, Whybrow, PC, Bauer, M, Conell, J, Bauer, R, Glenn, T, Alda, M, Ardau, R, Baune, BT, Berk, M, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Bossini, L, Castro, AMP, Cheung, EYW, Chillotti, C, Choppin, S, Del Zompo, M, Dias, R, Dodd, S, Duffy, A, Etain, B, Fagiolini, A, Garnham, J, Geddes, J, Gildebro, J, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Kapur, V, Kunigiri, G, Lafer, B, Lam, C, Larsen, ER, Lewitzka, U, Licht, R, Lund, AH, Misiak, B, Piotrowski, P, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Scippa, AM, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Vieta, E, Vinberg, M, Viswanath, B, Volkert, J, Zetin, M, Zorrilla, I, Whybrow, PC, and Bauer, M
Published: 2017

28. Impact of sunlight on the age of onset of bipolar disorder

Author: Bauer, M., Glenn, T., Alda, M., Andreassen, O., Ardau, R., Bellivier, F., Berk, M., Bjella, T. D., Bossini, L., Del Zompo, M., Dodd, S., Fagiolini, Andrea, Frye, M. A., Gonzalez Pinto, A., Henry, C., Kapczinski, F., Kliwicki, S., König, B., Kunz, M., Lafer, B., Lopez Jaramillo, C., Manchia, M., Marsh, W., Martinez Cengotitabengoa, M., Melle, I., Morken, G., Munoz, R., Nery, F. G., O'Donovan, C., Pfennig, A., Quiroz, D., Rasgon, N., Reif, A., Rybakowski, J., Sagduyu, K., Simhandl, C., Torrent, C., Vieta, E., Zetin, M., Whybrow, P. C., Farmacologie en Toxicologie, and RS: CARIM School for Cardiovascular Diseases
Subjects: Adult, Aged, 80 and over, Male, bipolar disorder, Adolescent, Photoperiod, Middle Aged, Age of onset, Bipolar disorder, Solar insolation, Sunlight, Article, solar insolation, age of onset, Solar Energy, Humans, Female, Seasons, sunlight, Geography, Medical, Aged, Retrospective Studies
Abstract: Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= -4.724, 95% CI: -8.124 to -1.323, p=0.006), controlling for each country's median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.? 2012 John Wiley and Sons A/S.
Published: 2012
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29. Exploring Lithium Impact on Glomerular Function in Bipolar Patients Through Pharmacogenomics

Author: Tsermpini, E.E., primary, Zhang, Y., additional, Niola, P., additional, Chillotti, C., additional, Ardau, R., additional, Severino, G., additional, Bocchetta, A., additional, Patrinos, G.P., additional, Lee, M.T.M., additional, and Squassina, A., additional
Published: 2017
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30. Influence of birth cohort on age of onset cluster analysis in bipolar I disorder

Author: Bauer, M. Glenn, T. Alda, M. Andreassen, O. A. and Angelopoulos, E. Ardau, R. Baethge, C. Bauer, R. and Bellivier, F. Belmaker, R. H. Berk, M. Bjella, T. D. and Bossini, L. Bersudsky, Y. Cheung, E. Y. W. Conell, J. and Del Zompo, M. Dodd, S. Etain, B. Fagiolini, A. Frye, M. A. Fountoulakis, K. N. Garneau-Fournier, J. Gonzalez-Pinto, A. Harima, H. Hassel, S. Henry, C. Iacovides, A. and Isometsa, E. T. Kapczinski, F. Kliwicki, S. Koenig, B. and Krogh, R. Kunz, M. Lafer, B. Larsen, E. R. Lewitzka, U. and Lopez-Jaramillo, C. MacQueen, G. Manchia, M. Marsh, W. and Martinez-Cengotitabengoa, M. Melle, I. Monteith, S. and Morken, G. Munoz, R. Nery, F. G. O'Donovan, C. Osher, Y. and Pfennig, A. Quiroz, D. Ramesar, R. Rasgon, N. Reif, A. Ritter, P. Rybakowski, J. K. Sagduyu, K. Scippa, A. M. Severus, E. Simhandl, C. Stein, D. J. Strejilevich, S. Sulaiman, A. Hatim Suominen, K. Tagata, H. and Tatebayashi, Y. Torrent, C. Vieta, E. Viswanath, B. and Wanchoo, M. J. Zetin, M. Whybrow, P. C.
Abstract: Purpose: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. Methods: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. Results: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. Conclusion: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research. (C) 2014 Elsevier Masson SAS. All rights reserved.
Published: 2015

31. Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study

Author: Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Banzato, CEM, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Bui, ET, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dantas, CR, Dayer, A, Étain, B, Falkai, P, Forstner, AJ, Frisén, L, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, Macqueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, S, Wright, A, Young, LT, Zandi, PP, Potash, JB, Depaulo, JR, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Banzato, CEM, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Bui, ET, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dantas, CR, Dayer, A, Étain, B, Falkai, P, Forstner, AJ, Frisén, L, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, Macqueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, S, Wright, A, Young, LT, Zandi, PP, Potash, JB, and Depaulo, JR
Abstract: Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10-8; rs78015114, p=1·31×10-8; rs74795342, p=3·31×10-9; and rs75222709, p=3·50×10-9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Hea
Published: 2016

32. Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Author: Hou, L, Bergen, SE, Akula, N, Song, J, Hultman, CM, Landén, M, Adli, M, Alda, M, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Badner, JA, Barrett, TB, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Bhattacharjee, AK, Biernacka, JM, Birner, A, Bloss, CS, Brichant-Petitjean, C, Bui, ET, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Colom, F, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Davis, T, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Edenberg, HJ, Étain, B, Falkai, P, Foroud, T, Forstner, AJ, Frisén, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Gershon, ES, Goes, FS, Greenwood, TA, Grigoroiu-Serbanescu, M, Hauser, J, Heilbronner, U, Heilmann-Heimbach, S, Herms, S, Hipolito, M, Hitturlingappa, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koller, DL, König, B, Lackner, N, Laje, G, Lang, M, Lavebratt, C, Lawson, WB, Leboyer, M, Leckband, SG, Liu, C, Maaser, A, Mahon, PB, Maier, W, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McInnis, MG, McKinney, R, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Mühleisen, TW, Nievergelt, CM, Nöthen, MM, Novák, T, Nurnberger, JI, Nwulia, EA, Ösby, U, Hou, L, Bergen, SE, Akula, N, Song, J, Hultman, CM, Landén, M, Adli, M, Alda, M, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Badner, JA, Barrett, TB, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Bhattacharjee, AK, Biernacka, JM, Birner, A, Bloss, CS, Brichant-Petitjean, C, Bui, ET, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Colom, F, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Davis, T, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Edenberg, HJ, Étain, B, Falkai, P, Foroud, T, Forstner, AJ, Frisén, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Gershon, ES, Goes, FS, Greenwood, TA, Grigoroiu-Serbanescu, M, Hauser, J, Heilbronner, U, Heilmann-Heimbach, S, Herms, S, Hipolito, M, Hitturlingappa, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koller, DL, König, B, Lackner, N, Laje, G, Lang, M, Lavebratt, C, Lawson, WB, Leboyer, M, Leckband, SG, Liu, C, Maaser, A, Mahon, PB, Maier, W, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McInnis, MG, McKinney, R, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Mühleisen, TW, Nievergelt, CM, Nöthen, MM, Novák, T, Nurnberger, JI, Nwulia, EA, and Ösby, U
Abstract: Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of > 9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P= 5.87×10-9; odds ratio (OR)=1.12) and markers within ERBB2 (rs2517959, P= 4.53×10-9; OR=1.13). No significant X-chromosome associations were detected and Xlinked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Published: 2016

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

Author: Conell, J, Bauer, R, Glenn, T, Alda, M, Ardau, R, Baune, BT, Berk, M, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Bossini, L, Castro, AMP, Cheung, EYW, Chillotti, C, Choppin, S, Del Zompo, M, Dias, R, Dodd, S, Duffy, A, Etain, B, Fagiolini, A, Garnham, J, Geddes, J, Gildebro, J, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Kapur, V, Kunigiri, G, Lafer, B, Lam, C, Larsen, ER, Lewitzka, U, Licht, R, Lund, AH, Misiak, B, Piotrowski, P, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Scippa, AM, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Vieta, E, Vinberg, M, Viswanath, B, Volkert, J, Zetin, M, Zorrilla, I, Whybrow, PC, Bauer, M, Conell, J, Bauer, R, Glenn, T, Alda, M, Ardau, R, Baune, BT, Berk, M, Bersudsky, Y, Bilderbeck, A, Bocchetta, A, Bossini, L, Castro, AMP, Cheung, EYW, Chillotti, C, Choppin, S, Del Zompo, M, Dias, R, Dodd, S, Duffy, A, Etain, B, Fagiolini, A, Garnham, J, Geddes, J, Gildebro, J, Gonzalez-Pinto, A, Goodwin, GM, Grof, P, Harima, H, Hassel, S, Henry, C, Hidalgo-Mazzei, D, Kapur, V, Kunigiri, G, Lafer, B, Lam, C, Larsen, ER, Lewitzka, U, Licht, R, Lund, AH, Misiak, B, Piotrowski, P, Monteith, S, Munoz, R, Nakanotani, T, Nielsen, RE, O'Donovan, C, Okamura, Y, Osher, Y, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Sawchuk, B, Schwartz, E, Scippa, AM, Slaney, C, Sulaiman, AH, Suominen, K, Suwalska, A, Tam, P, Tatebayashi, Y, Tondo, L, Vieta, E, Vinberg, M, Viswanath, B, Volkert, J, Zetin, M, Zorrilla, I, Whybrow, PC, and Bauer, M
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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: 2016

34. Relationship between sunlight and the age of onset of bipolar disorder: An international multisite study

Author: Bauer, M, Glenn, T, Alda, M, Andreassen, OA, Angelopoulos, E, Ardau, R, Baethge, C, Bauer, R, Bellivier, F, Belmaker, RH, Berk, M, Bjella, TD, Bossini, L, Bersudsky, Y, Cheung, EYW, Conell, J, Del Zompo, M, Dodd, S, Etain, B, Fagiolini, A, Frye, MA, Fountoulakis, KN, Garneau-Fournier, J, Gonzalez-Pinto, A, Harima, H, Hassel, S, Henry, C, Iacovides, A, Isometsa, ET, Kapczinski, F, Kliwicki, S, Koenig, B, Krogh, R, Kunz, M, Lafer, B, Larsen, ER, Lewitzka, U, Lopez-Jaramillo, C, MacQueen, G, Manchia, M, Marsh, W, Martinez-Cengotitabengoa, M, Melle, I, Monteith, S, Morken, G, Munoz, R, Nery, FG, O'Donovan, C, Osher, Y, Pfennig, A, Quiroz, D, Ramesar, R, Rasgon, N, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Scippa, AM, Severus, E, Simhandl, C, Stein, DJ, Strejilevich, S, Sulaiman, AH, Suominen, K, Tagata, H, Tatebayashi, Y, Torrent, C, Vieta, E, Viswanath, B, Wanchoo, MJ, Zetin, M, Whybrow, PC, Bauer, M, Glenn, T, Alda, M, Andreassen, OA, Angelopoulos, E, Ardau, R, Baethge, C, Bauer, R, Bellivier, F, Belmaker, RH, Berk, M, Bjella, TD, Bossini, L, Bersudsky, Y, Cheung, EYW, Conell, J, Del Zompo, M, Dodd, S, Etain, B, Fagiolini, A, Frye, MA, Fountoulakis, KN, Garneau-Fournier, J, Gonzalez-Pinto, A, Harima, H, Hassel, S, Henry, C, Iacovides, A, Isometsa, ET, Kapczinski, F, Kliwicki, S, Koenig, B, Krogh, R, Kunz, M, Lafer, B, Larsen, ER, Lewitzka, U, Lopez-Jaramillo, C, MacQueen, G, Manchia, M, Marsh, W, Martinez-Cengotitabengoa, M, Melle, I, Monteith, S, Morken, G, Munoz, R, Nery, FG, O'Donovan, C, Osher, Y, Pfennig, A, Quiroz, D, Ramesar, R, Rasgon, N, Reif, A, Ritter, P, Rybakowski, JK, Sagduyu, K, Scippa, AM, Severus, E, Simhandl, C, Stein, DJ, Strejilevich, S, Sulaiman, AH, Suominen, K, Tagata, H, Tatebayashi, Y, Torrent, C, Vieta, E, Viswanath, B, Wanchoo, MJ, Zetin, M, and Whybrow, PC
Abstract: BACKGROUND: The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. METHODS: Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. RESULTS: There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California. LIMITATIONS: Recall bias for onset and family history data. CONCLUSIONS: A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.
Published: 2014

35. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study

Author: Sacchetti, E., Galluzzo, A., Valsecchi, P., Romeo, F., Gorini, B., Warrington, L., Study Group Regini C, M. O. Z. A. R. T., Aguglia, E, Lang, A, Pascolo, E, Antonini, A, D'Amario, A, Croce, F, Matteucci, M, Bilone, F, Bogetto, Filippo, Rocca, Paola, Cirla, M, Rivoira, E, Castrogiovanni, P, Ciappi, F, Attala, T, Perazzi, A, Corradini, P, Piras, A, Boi, R, Carcangiu, E, Del Zompo, M, Ardau, R, Mulas, S, Ducci, G, Cotugno, A, Accorrà, A, Fazzari, G, Garonna, F, Malara, G, Salvatori, F, Maggini, C, Meduri, M, Di Rosa, A, Cardia, R, Parisi, S, Di Rosa, E, Muscettola, G, Casiello, M, Nardini, M, Di Sciascio, G, Sciota, D, Nivoli, G, Nivoli, A, Lorettu, L, Paladin, C, Petralia, A, Fuda, P, Placidi, G, Rossi, M, Raja, M, Amadori, Siracusano, A, Zanasi, M, and Niolu, C.
Subjects: Male, medicine.medical_treatment, Treatment resistance, Piperazines, law.invention, Randomized controlled trial, law, Adult, Analysis of Variance, Antipsychotic Agents, Body Weight, Clozapine, Disease Progression, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glucose, Humans, Italy, Lipids, Middle Aged, Patient Compliance, Psychiatric Status Rating Scales, Quality of Life, Schizophrenia, Schizophrenic Psychology, Thiazoles, Young, Tolerability, Ziprasidone, Psychiatry and Mental health, Drug Therapy, Combination, Psychology, medicine.drug, medicine.medical_specialty, medicine.drug_class, Young Adult, Dose-Response Relationship, Drug, ziprasidone, Atypical antipsychotic, Internal medicine, medicine, Antipsychotic, Settore MED/25 - Psichiatria, Biological Psychiatry, medicine.disease, Endocrinology, Liver function
Abstract: This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS scoreor= 80, and CGI-S scoreor= 4. Patients were randomized to ziprasidone (80-160 mg/day, n = 73) or clozapine (250-600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (- 25.0 +/- 22.0, 95% CI - 30.2 to - 19.8) and clozapine (- 24.5 +/- 22.5, 95% CI - 29.7 to - 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.
Published: 2009

36. Age at onset in bipolar disorder: Investigation of the role of TaqIA polymorphism of DRD2 gene in a Sardinian sample

Author: Squassina, A., Manchia, M., Costa, M., Chillotti, C., Ardau, R., Del Zompo, M., and Severino, G.
Published: 2011
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37. Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Author: Manchia, M, Adli, M, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Banzato, CEM, Baune, BT, Bellivier, F, Bengesser, S, Biernacka, JM, Brichant-Petitjean, C, Bui, E, Calkin, CV, Cheng, ATA, Chillotti, C, Cichon, S, Clark, S, Czerski, PM, Dantas, C, Del Zompo, M, DePaulo, JR, Detera-Wadleigh, SD, Etain, B, Falkai, P, Frisén, L, Frye, MA, Fullerton, J, Gard, S, Garnham, J, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Heilbronner, U, Hoban, R, Hou, L, Jamain, S, Kahn, JP, Kassem, L, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Kuo, PH, Kusumi, I, Laje, G, Lavebratt, C, Leboyer, M, Leckband, SG, López Jaramillo, CA, Maj, M, Malafosse, A, Martinsson, L, Masui, T, Mitchell, PB, Mondimore, F, Monteleone, P, Nallet, A, Neuner, M, Novák, T, O'Donovan, C, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Potash, JB, Reich-Erkelenz, D, Reif, A, Reininghaus, E, Richardson, S, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schubert, OK, Schweizer, B, Seemüller, F, Grigoroiu-Serbanescu, M, Severino, G, Seymour, LR, Slaney, C, Smoller, JW, Squassina, A, Stamm, T, Steele, J, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Wray, NR, Wright, A, Zandi, PP, Zilles, D, Bauer, M, Rietschel, M, McMahon, FJ, Schulze, TG, Alda, M, Manchia, M, Adli, M, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Banzato, CEM, Baune, BT, Bellivier, F, Bengesser, S, Biernacka, JM, Brichant-Petitjean, C, Bui, E, Calkin, CV, Cheng, ATA, Chillotti, C, Cichon, S, Clark, S, Czerski, PM, Dantas, C, Del Zompo, M, DePaulo, JR, Detera-Wadleigh, SD, Etain, B, Falkai, P, Frisén, L, Frye, MA, Fullerton, J, Gard, S, Garnham, J, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Heilbronner, U, Hoban, R, Hou, L, Jamain, S, Kahn, JP, Kassem, L, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Kuo, PH, Kusumi, I, Laje, G, Lavebratt, C, Leboyer, M, Leckband, SG, López Jaramillo, CA, Maj, M, Malafosse, A, Martinsson, L, Masui, T, Mitchell, PB, Mondimore, F, Monteleone, P, Nallet, A, Neuner, M, Novák, T, O'Donovan, C, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Potash, JB, Reich-Erkelenz, D, Reif, A, Reininghaus, E, Richardson, S, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schubert, OK, Schweizer, B, Seemüller, F, Grigoroiu-Serbanescu, M, Severino, G, Seymour, LR, Slaney, C, Smoller, JW, Squassina, A, Stamm, T, Steele, J, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Wray, NR, Wright, A, Zandi, PP, Zilles, D, Bauer, M, Rietschel, M, McMahon, FJ, Schulze, TG, and Alda, M
Abstract: Objective: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.Materials and Methods: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.Results: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).Conclusions: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

38. P.1.020 Follow-up of bipolar patients who responded to lithium-carbamazepine combination

Author: Bocchetta, A., primary, Ardau, R., additional, Chillotti, C., additional, Quesada, G., additional, and Del Zompo, M., additional
Published: 1997
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39. Lithium prevents suicide in a high risk group of patients with affective disorder

Author: Bocchetta, A., primary, Ardau, R., additional, Burral, C., additional, Chillotti, C., additional, and Del Zompo, M., additional
Published: 1997
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40. Familial rates of major affective illness in Sardinia

Author: Severino, G, primary, Bocchetta, A, additional, Bernardi, F, additional, Chillotti, C, additional, Ardau, R, additional, and Zompo, M Del, additional
Published: 1995
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41. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Author: Amare, Azmeraw T., Schubert, Klaus Oliver, Hou, Liping, Clark, Scott R., Papiol, Sergi, Cearns, Micah, Heilbronner, Urs, Degenhardt, Franziska, Tekola-Ayele, Fasil, Hsu, Yi Hsiang, Shekhtman, Tatyana, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, 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, Étain, Bruno, Jamain, Stephane, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Jiménez, Esther, Kahn, Jean Pierre, Kassem, Layla, Kuo, Po Hsiu, Kato, Tadafumi, Kelsoe, John R., Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Tortorella, Alfonso, Manchia, Mirko, Martinsson, Lina, McCarthy, Michael J., McElroy, Susan L., Colom, Francesc, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nöthen, Markus M., Novák, Tomas, O’Donovan, Claire, Ozaki, Norio, Ösby, Urban, Pfennig, Andrea, Potash, James B., Reif, Andreas, Wray, Naomi R., Ripke, Stephan, Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F.M., Bacanu, Silviu Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T.F., Bigdeli, Tim B., Binder, Elisabeth B., Blackwood, Douglas H.R., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane varregaard, Clarke, Toni Kim, Coleman, Jonathan R.I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Deary, Ian J., Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Kiadeh, Farnush Farhadi Hassan, Finucane, Hilary K., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Gordon, Scott D., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Hickie, Ian B., Homuth, Georg, Horn, Carsten, Hottenga, Jouke Jan, Hougaard, David M., Ising, Marcus, Jansen, Rick, Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Krogh, Jesper, Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O’Reilly, Paul F., Oskarsson, Hogni, Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Pettersson, Erik, Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C.B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Dannlowski, Udo, de Geus, E. J.C., Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A.F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O’Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Penninx, Brenda W.J.H., Perlis, Roy H., Porteous, David J., Preisig, Martin, Rietschel, Marcella, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., 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, Thomas, Stopkova, Pavla, Maj, Mario, Turecki, Gustavo, Vieta, Eduard, Veeh, Julia, Wright, Adam, Zandi, Peter P., Mitchell, Philip B., Bauer, Michael, Alda, Martin, McMahon, Francis J., APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, APH - Digital Health, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Complex Trait Genetics, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Jamain, Stéphane, University of Adelaide, South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), Mental Health Services [Adelaide, SA, Australia], National Institute of Mental Health (NIMH), Ludwig Maximilian University [Munich] (LMU), Georg-August-University = Georg-August-Universität Göttingen, Institut für Genetik - Universität Bonn / Institute of Genetics - University of Bonn, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Harvard Medical School [Boston] (HMS), Harvard School of Public Health, University of California [San Diego] (UC San Diego), University of California (UC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dokkyo Medical University, Università degli Studi di Cagliari = University of Cagliari (UniCa), Universitat Autònoma de Barcelona (UAB), Centro de Investigación Biomédica en Red de Salud Mental [Barcelona, Spain] (CIBERSAM), Hospital Sant Joan de Déu [Barcelona], Geneva University Hospital (HUG), Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Karl-Franzens-Universität Graz, Mayo Clinic [Rochester], McGill University Health Center [Montreal] (MUHC), National Taiwan University [Taiwan] (NTU), University Hospital Basel [Basel], Poznan University of Medical Sciences [Poland] (PUMS), Johns Hopkins University (JHU), 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), Fondation FondaMental [Créteil], IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Basel (Unibas), Neuroscience Research Australia [Sydney, NSW, Australia] (NRA), University of New South Wales [Sydney] (UNSW), Psychiatrie de l'enfant et de l'adolescent [CH C. Perrens, Bordeaux], SECOP - centre hospitalier Charles Perrens, Dalhousie University [Halifax], 'Prof. Dr. Alexandru Obregia' Clinical Hospital of Psychiatry [Bucharest, Romania], Mood Disorders Center of Ottawa (MDCO), University of Ottawa [Ottawa], Osaka University [Osaka], Graduate School of Medicine [Osaka], Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Psychiatrie et Psychologie Clinique de Liaison [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Psychothérapique de Nancy (CPN), National Institutes of Health [Bethesda] (NIH), Environmental Molecular Biology Laboratory (RIKEN), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Goethe-University Frankfurt am Main, Landesklinikum Neunkirchen (LK Neunkirchen), Hokkaido University Graduate School of Medicine [Sapporo, Japan], Sahlgrenska Academy at University of Gothenburg [Göteborg], Research Service VA San Diego Healthcare System, Università degli Studi di Perugia = University of Perugia (UNIPG), University of Cincinnati (UC), IMIM-Hospital del Mar, Generalitat de Catalunya, Max Planck Institute of Experimental Medicine [Göttingen] (MPI), Max-Planck-Gesellschaft, University of Salerno (UNISA), University of the Study of Campania Luigi Vanvitelli, National Institute of Mental Health [Klecany, Czech Republic] (NIMH), Nagoya University Graduate School of Medicine [Japon], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Medical University Graz, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Sigmund Freud University (SFU), Douglas Mental Health University Institute [Montréal], University of Heidelberg, Medical Faculty, Black Dog Institute [Sydney, Australia], Johns Hopkins Bloomberg School of Public Health [Baltimore], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, The Florey Institute of Neuroscience and Mental Health [Parkville, VIC, Australie], University of Melbourne, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium: Naomi R Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till F M Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T F Beekman, Tim B Bigdeli, Elisabeth B Binder, Douglas H R Blackwood, Julien Bryois, Henriette N Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Varregaard Christensen, Toni-Kim Clarke, Jonathan R I Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E Crawford, Gail Davies, Ian J Deary, Franziska Degenhardt, Eske M Derks, Nese Direk, Conor V Dolan, Erin C Dunn, Thalia C Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K Finucane, Andreas J Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Fernando S Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Marcus Ising, Rick Jansen, Eric Jorgenson, James A Knowles, Isaac S Kohane, Julia Kraft, Warren W Kretzschmar, Jesper Krogh, Zoltán Kutalik, Yihan Li, Penelope A Lind, Donald J MacIntyre, Dean F MacKinnon, Robert M Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E Medland, Divya Mehta, Christel M Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M Mondimore, Grant W Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G Nivard, Dale R Nyholt, Paul F O'Reilly, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A Quiroz, Per Qvist, John P Rice, Brien P Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C Schulte, Ling Shen, Jianxin Shi, Stanley I Shyn, Engilbert Sigurdsson, Grant C B Sinnamon, Johannes H Smit, Daniel J Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A Thomson, Thorgeir E Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M van Hemert, Alexander Viktorin, Peter M Visscher, Yunpeng Wang, Bradley T Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H Witt, Yang Wu, Hualin S Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T Baune, Klaus Berger, Dorret I Boomsma, Sven Cichon, Udo Dannlowski, E J C de Geus, J Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J Grabe, Steven P Hamilton, Caroline Hayward, Andrew C Heath, Kenneth S Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S Li, Susanne Lucae, Pamela A F Madden, Patrik K Magnusson, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M Nöthen, Michael C O'Donovan, Sara A Paciga, Nancy L Pedersen, Brenda W J H Penninx, Roy H Perlis, David J Porteous, James B Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G Schulze, Jordan W Smoller, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M Weissman, Thomas Werge, Cathryn M Lewis, Douglas F Levinson, Gerome Breen, Anders D Børglum, Patrick F Sullivan., Epidemiology, Internal Medicine, Child and Adolescent Psychiatry / Psychology, Georg-August-University [Göttingen], University of California, Universita degli Studi di Cagliari [Cagliari], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Graz, Università degli Studi di Perugia (UNIPG), University of Münster, Karl-Franzens-Universität [Graz, Autriche], Amare, A. T., Schubert, K. O., Hou, L., Clark, S. R., Papiol, S., Cearns, M., Heilbronner, U., Degenhardt, F., Tekola-Ayele, F., Hsu, Y. -H., Shekhtman, T., Adli, 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., Brichant-Petitjean, C., Cervantes, P., Chen, H. -C., Chillotti, C., Cichon, S., Cruceanu, C., Czerski, P. M., Dalkner, N., Dayer, A., Del Zompo, M., Depaulo, J. R., Etain, B., Jamain, S., 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., Herms, S., Hoffmann, P., Hofmann, A., Jimenez, E., Kahn, J. -P., Kassem, L., Kuo, P. -H., Kato, T., Kelsoe, J. R., Kittel-Schneider, S., Kliwicki, S., Konig, B., Kusumi, I., Laje, G., Landen, M., Lavebratt, C., Leboyer, M., Leckband, S. G., Tortorella, A., Manchia, M., Martinsson, L., Mccarthy, M. J., Mcelroy, S. L., Colom, F., Mitjans, M., Mondimore, F. M., Monteleone, P., Nievergelt, C. M., Nothen, M. M., Novak, T., O'Donovan, C., Ozaki, N., Osby, U., Pfennig, A., Potash, J. B., Reif, A., Wray, N. R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., Adams, M. J., Agerbo, E., Air, T. M., Andlauer, T. F. M., Bacanu, S. -A., Baekvad-Hansen, M., Beekman, A. T. F., Bigdeli, T. B., Binder, E. B., Blackwood, D. H. R., Bryois, J., Buttenschon, H. N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J., Clarke, T. -K., Coleman, J. R. I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G. E., Davies, G., Deary, I. J., Derks, E. M., Direk, N., Dolan, C. V., Dunn, E. C., Eley, T. C., Escott-Price, V., Kiadeh, F. F. H., Finucane, H. K., Frank, J., Gaspar, H. A., Gill, M., Gordon, S. D., Grove, J., Hall, L. S., Hansen, C. S., Hansen, T. F., Hickie, I. B., Homuth, G., Horn, C., Hottenga, J. -J., Hougaard, D. M., Ising, M., Jansen, R., Jorgenson, E., Knowles, J. A., Kohane, I. S., Kraft, J., Kretzschmar, W. W., Krogh, J., Kutalik, Z., Li, Y., Lind, P. A., Macintyre, D. J., Mackinnon, D. F., Maier, R. M., Maier, W., Marchini, J., Mbarek, H., Mcgrath, P., Mcguffin, P., Medland, S. E., Mehta, D., Middeldorp, C. M., Mihailov, E., Milaneschi, Y., Milani, L., Montgomery, G. W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M. G., Nyholt, D. R., O'Reilly, P. F., Oskarsson, H., Owen, M. J., Painter, J. N., Pedersen, C. B., Pedersen, M. G., Peterson, R. E., Pettersson, E., Peyrot, W. J., Pistis, G., Posthuma, D., Quiroz, J. A., Qvist, P., Rice, J. P., Riley, B. P., Rivera, M., Mirza, S. S., Schoevers, R., Schulte, E. C., Shen, L., Shi, J., Shyn, S. I., Sigurdsson, E., Sinnamon, G. C. B., Smit, J. H., Smith, D. J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K. E., Teismann, H., Teumer, A., Thompson, W., Thomson, P. A., Thorgeirsson, T. E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A. G., Umbricht, D., Van der Auwera, S., van Hemert, A. M., Viktorin, A., Visscher, P. M., Wang, Y., Webb, B. T., Weinsheimer, S. M., Wellmann, J., Willemsen, G., Witt, S. H., Wu, Y., Xi, H. S., Yang, J., Zhang, F., Arolt, V., Baune, B. T., Berger, K., Boomsma, D. I., Dannlowski, U., de Geus, E. J. C., Domenici, E., Domschke, K., Esko, T., Grabe, H. J., Hamilton, S. P., Hayward, C., Heath, A. C., Kendler, K. S., Kloiber, S., Lewis, G., Li, Q. S., Lucae, S., Madden, P. A. F., Magnusson, P. K., Martin, N. G., Mcintosh, A. M., Metspalu, A., Mors, O., Mortensen, P. B., Muller-Myhsok, B., Nordentoft, M., O'Donovan, M. C., Paciga, S. A., Pedersen, N. L., Penninx, B. W. J. H., Perlis, R. H., Porteous, D. J., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T. G., Smoller, J. W., Stefansson, K., Tiemeier, H., Uher, R., Volzke, H., Weissman, M. M., Werge, T., Lewis, C. M., Levinson, D. F., Breen, G., Borglum, A. D., Sullivan, P. F., Reininghaus, E., Rouleau, G. A., Rybakowski, J. K., Schalling, M., Schofield, P. R., Schweizer, B. W., Severino, G., Shilling, P. D., Shimoda, K., Simhandl, C., Slaney, C. M., Squassina, A., Stamm, T., Stopkova, P., Maj, M., Turecki, G., Vieta, E., Veeh, J., Wright, A., Zandi, P. P., Mitchell, P. B., Bauer, M., Alda, M., Mcmahon, F. J., and Adult Psychiatry
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Lithium (medication), [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Genome-wide association study, Logistic regression, THERAPY, ddc:616.89, 0302 clinical medicine, Medicine, Major depression, PREDICTORS, Depression (differential diagnoses), RISK, Depression, Psychiatry and Mental health, Quartile, Cohort, AUGMENTATION, medicine.drug, POLARITY, medicine.medical_specialty, GENETICS, Bipolar disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Lithium, PROPHYLACTIC LITHIUM, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Internal medicine, Humans, ddc:610, AGENTS, Molecular Biology, Genetic association, Depressive Disorder, Major, business.industry, medicine.disease, EFFICACY, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, PHARMACOLOGICAL-TREATMENTS, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
Published: 2021
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42. 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
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43. Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Author: Bauer, Michael, Glenn, Tasha, Achtyes, Eric, Alda, Martin, Agaoglu, Esen, Altınbaş, Kürşat, Andreassen, Ole, Angelopoulos, Elias, Ardau, Raffaella, Vares, Edgar Arrua, Aydin, Memduha, Ayhan, Yavuz, Baethge, Christopher, Bauer, Rita, Baune, Bernhard, Balaban, Ceylan, Becerra-Palars, Claudia, Behere, Aniruddh, Behere, Prakash, Belete, Habte, Belete, Tilahun, Belizario, Gabriel Okawa, Bellivier, Frank, Belmaker, Robert, Benedetti, Francesco, Berk, Michael, Bersudsky, Yuly, Bicakci, Şule, Birabwa-Oketcho, Harriet, Bjella, Thomas, Brady, Conan, Cabrera, Jorge, Cappucciati, Marco, Castro, Angela Marianne Paredes, Chen, Wei-Ling, Cheung, Eric, Chiesa, Silvia, Crowe, Marie, Cuomo, Alessandro, Dallaspezia, Sara, del Zompo, Maria, Desai, Pratikkumar, Dodd, Seetal, Donix, Markus, Etain, Bruno, Fagiolini, Andrea, Fellendorf, Frederike, Ferensztajn-Rochowiak, Ewa, Fiedorowicz, Jess, Fountoulakis, Kostas, Frye, Mark, Geoffroy, Pierre, Gonzalez-Pinto, Ana, Gottlieb, John, Grof, Paul, Haarman, Bartholomeus, Harima, Hirohiko, Hasse-Sousa, Mathias, Henry, Chantal, Høffding, Lone, Houenou, Josselin, Imbesi, Massimiliano, Isometsä, Erkki, Ivkovic, Maja, Janno, Sven, Johnsen, Simon, Kapczinski, Flávio, Karakatsoulis, Gregory, Kardell, Mathias, Kessing, Lars Vedel, Kim, Seong Jae, König, Barbara, Kot, Timur, Koval, Michael, Kunz, Mauricio, Lafer, Beny, Landén, Mikael, Larsen, Erik, Lenger, Melanie, Lewitzka, Ute, Licht, Rasmus, Lopez-Jaramillo, Carlos, Mackenzie, Alan, Madsen, Helle Østergaard, Madsen, Simone Alberte Kongstad A, Mahadevan, Jayant, Mahardika, Agustine, Manchia, Mirko, Marsh, Wendy, Martinez-Cengotitabengoa, Monica, Martiny, Klaus, Mashima, Yuki, Mcloughlin, Declan, Meesters, Ybe, Melle, Ingrid, Meza-Urzúa, Fátima, Ming, Mok Yee, Monteith, Scott, Moorthy, Muthukumaran, Morken, Gunnar, Mosca, Enrica, Mozzhegorov, Anton, Munoz, Rodrigo, Mythri, Starlin, Nacef, Fethi, Nadella, Ravi, 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, Pilhatsch, Maximilian, 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., Reif, Andreas, Reininghaus, Eva, Richards, Jenny Gringer, Ritter, Philipp, Rybakowski, Janusz, Sathyaputri, Leela, Scippa, Ângela, Simhandl, Christian, Severus, Emanuel, Smith, Daniel, Smith, José, Stackhouse, Paul, Stein, Dan, Stilwell, Kellen, Strejilevich, Sergio, Su, Kuan-Pin, Subramaniam, Mythily, Sulaiman, Ahmad Hatim, Suominen, Kirsi, Tanra, Andi, Tatebayashi, Yoshitaka, Teh, Wen Lin, Tondo, Leonardo, Torrent, Carla, Tuinstra, Daniel, Uchida, Takahito, Vaaler, Arne, Veeh, Julia, Vieta, Eduard, Viswanath, Biju, Yoldi-Negrete, Maria, Yalcinkaya, Oguz Kaan, Young, Allan, Zgueb, Yosra, Whybrow, Peter, Madsen, Simone Alberte Kongstad A., Bauer, M., Glenn, T., Achtyes, E. D., Alda, M., Agaoglu, E., Altinbas, K., Andreassen, O. A., Angelopoulos, E., Ardau, R., Vares, E. A., Aydin, M., Ayhan, Y., Baethge, C., Bauer, R., Baune, B. T., Balaban, C., Becerra-Palars, C., Behere, A. P., Behere, P. B., Belete, H., Belete, T., Belizario, G. O., Bellivier, F., Belmaker, R. H., Benedetti, F., Berk, M., Bersudsky, Y., Bicakci, S., Birabwa-Oketcho, H., Bjella, T. D., Brady, C., Cabrera, J., Cappucciati, M., Castro, A. M. P., Chen, W. -L., Cheung, E. Y. W., Chiesa, S., Crowe, M., Cuomo, A., Dallaspezia, S., Del Zompo, M., Desai, P., Dodd, S., Donix, M., Etain, B., Fagiolini, A., Fellendorf, F. T., Ferensztajn-Rochowiak, E., Fiedorowicz, J. G., Fountoulakis, K. N., Frye, M. A., Geoffroy, P. A., Gonzalez-Pinto, A., Gottlieb, J. F., Grof, P., Haarman, B. C. M., Harima, H., Hasse-Sousa, M., Henry, C., Hoffding, L., Houenou, J., Imbesi, M., Isometsa, E. T., Ivkovic, M., Janno, S., Johnsen, S., Kapczinski, F., Karakatsoulis, G. N., Kardell, M., Kessing, L. V., Kim, S. J., Konig, B., Kot, T. L., Koval, M., Kunz, M., Lafer, B., Landen, M., Larsen, E. R., Lenger, M., Lewitzka, U., Licht, R. W., Lopez-Jaramillo, C., Mackenzie, A., Madsen, H. O., Madsen, S. A. K. A., Mahadevan, J., Mahardika, A., Manchia, M., Marsh, W., Martinez-Cengotitabengoa, M., Martiny, K., Mashima, Y., Mcloughlin, D. M., Meesters, Y., Melle, I., Meza-Urzua, F., Ming, M. Y., Monteith, S., Moorthy, M., Morken, G., Mosca, E., Mozzhegorov, A. A., Munoz, R., Mythri, S. V., Nacef, F., Nadella, R. K., Nakanotani, T., Nielsen, R. E., O'Donovan, C., Omrani, A., Osher, Y., Ouali, U., Pantovic-Stefanovic, M., Pariwatcharakul, P., Petite, J., Pfennig, A., Ruiz, Y. P., Pilhatsch, M., Pinna, M., Pompili, M., Porter, R., Quiroz, D., Rabelo-da-Ponte, F. D., Ramesar, R., Rasgon, N., Ratta-apha, W., Ratzenhofer, M., Redahan, M., Reddy, M. S., Reif, A., Reininghaus, E. Z., Richards, J. G., Ritter, P., Rybakowski, J. K., Sathyaputri, L., Scippa, A. M., Simhandl, C., Severus, E., Smith, D., Smith, J., Stackhouse, P. W., Stein, D. J., Stilwell, K., Strejilevich, S., Su, K. -P., Subramaniam, M., Sulaiman, A. H., Suominen, K., Tanra, A. J., Tatebayashi, Y., Teh, W. L., Tondo, L., Torrent, C., Tuinstra, D., Uchida, T., Vaaler, A. E., Veeh, J., Vieta, E., Viswanath, B., Yoldi-Negrete, M., Yalcinkaya, O. K., Young, A. H., Zgueb, Y., Whybrow, P. C., Etain, Bruno, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), GHU Paris Psychiatrie et Neurosciences, 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), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation FondaMental [Créteil], Clinical Cognitive Neuropsychiatry Research Program (CCNP), Department of Pathology, and Faculty of Health Sciences
Subjects: Neurophysiology and neuropsychology, Psychiatry, Bipolar disorder, QP351-495, Research, Seasonal variation, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Circadian, Neurosciences. Biological psychiatry. Neuropsychiatry, Solar insolation, Suicide, Sunlight, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, RC321-571
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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44. Characterisation of age and polarity at onset in bipolar disorder

Author: Kalman, Janos, Olde Loohuis, Loes, Vreeker, Annabel, Mcquillin, Andrew, Stahl, Eli, Ruderfer, Douglas, Grigoroiu-Serbanescu, Maria, Panagiotaropoulou, Georgia, Ripke, Stephan, Bigdeli, Tim, Stein, Frederike, Meller, Tina, Meinert, Susanne, Pelin, Helena, Streit, Fabian, Papiol, Sergi, Adams, Mark, Adolfsson, Rolf, Adorjan, Kristina, Agartz, Ingrid, Aminoff, Sofie, Anderson-Schmidt, Heike, Andreassen, Ole, Ardau, Raffaella, Aubry, Jean-Michel, Balaban, Ceylan, Bass, Nicholas, Baune, Bernhard, Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Berrettini, Wade, Boks, Marco, Bromet, Evelyn, Brosch, Katharina, Budde, Monika, Byerley, William, Cervantes, Pablo, Chillotti, Catina, Cichon, Sven, Clark, Scott, Comes, Ashley, Corvin, Aiden, Coryell, William, Craddock, Nick, Craig, David, Croarkin, Paul, Cruceanu, Cristiana, Czerski, Piotr, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, del Zompo, Maria, Depaulo, J Raymond, Djurovic, Srdjan, Edenberg, Howard, Eissa, Mariam Al, Elvsåshagen, Torbjørn, Etain, Bruno, Fanous, Ayman, Fellendorf, Frederike, Fiorentino, Alessia, Forstner, Andreas, Frye, Mark, Fullerton, Janice, Gade, Katrin, Garnham, Julie, Gershon, Elliot, Gill, Michael, Goes, Fernando, Gordon-Smith, Katherine, Grof, Paul, Guzman-Parra, Jose, Hahn, Tim, Hasler, Roland, Heilbronner, Maria, Heilbronner, Urs, Jamain, Stephane, Jimenez, Esther, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene, Kelsoe, John, Kennedy, James, Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Klöhn-Saghatolislam, Farah, Knowles, James, Kranz, Thorsten, Lagerberg, Trine Vik, Landen, Mikael, Lawson, William, Leboyer, Marion, Li, Qingqin, Maj, Mario, Malaspina, Dolores, Manchia, Mirko, Mayoral, Fermin, Mcelroy, Susan, Mcinnis, Melvin, McIntosh, Andrew, Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Mitchell, Philip, Monteleone, Palmiero, Monteleone, Alessio Maria, Nöthen, Markus, Novak, Tomas, Nurnberger, John, O'Brien, Niamh, O'Connell, Kevin, O'Donovan, Claire, O'Donovan, Michael, Opel, Nils, Ortiz, Abigail, Owen, Michael, Pålsson, Erik, Pato, Carlos, Pato, Michele, Pawlak, Joanna, Pfarr, Julia-Katharina, Pisanu, Claudia, Potash, James, Rapaport, Mark, Reich-Erkelenz, Daniela, Reif, Andreas, Reininghaus, Eva, Repple, Jonathan, Richard-Lepouriel, Hélène, Rietschel, Marcella, Ringwald, Kai, Roberts, Gloria, Rouleau, Guy, Schaupp, Sabrina, Scheftner, William, Schmitt, Simon, Schofield, Peter, Schubert, K Oliver, Schulte, Eva, Schweizer, Barbara, Senner, Fanny, Severino, Giovanni, Sharp, Sally, Slaney, Claire, Smeland, Olav, Sobell, Janet, Squassina, Alessio, Stopkova, Pavla, Strauss, John, Tortorella, Alfonso, Turecki, Gustavo, Twarowska-Hauser, Joanna, Veldic, Marin, Vieta, Eduard, Vincent, John, Xu, Wei, Zai, Clement, Zandi, Peter, Di Florio, Arianna, Smoller, Jordan, Biernacka, Joanna, Mcmahon, Francis, Alda, Martin, Müller-Myhsok, Bertram, Koutsouleris, Nikolaos, Falkai, Peter, Freimer, Nelson, Andlauer, Till, Schulze, Thomas, Ophoff, Roel, Depaulo, J. Raymond, Schubert, K. Oliver, Andlauer, Till F.M., Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Etain, Bruno, Child and Adolescent Psychiatry / Psychology, Psychiatry, Kalman, J. L., Loohuis, L. M. O., Vreeker, A., Mcquillin, A., Stahl, E. A., Ruderfer, D., Grigoroiu-Serbanescu, M., Panagiotaropoulou, G., Ripke, S., Bigdeli, T. B., Stein, F., Meller, T., Meinert, S., Pelin, H., Streit, F., Papiol, S., Adams, M. J., Adolfsson, R., Adorjan, K., Agartz, I., Aminoff, S. R., Anderson-Schmidt, H., Andreassen, O. A., Ardau, R., Aubry, J. -M., Balaban, C., Bass, N., Baune, B. T., Bellivier, F., Benabarre, A., Bengesser, S., Berrettini, W. H., Boks, M. P., Bromet, E. J., Brosch, K., Budde, M., Byerley, W., Cervantes, P., Chillotti, C., Cichon, S., Clark, S. R., Comes, A. L., Corvin, A., Coryell, W., Craddock, N., Craig, D. W., Croarkin, P. E., Cruceanu, C., Czerski, P. M., Dalkner, N., Dannlowski, U., Degenhardt, F., Del Zompo, M., Depaulo, J. R., Djurovic, S., Edenberg, H. J., Al Eissa, M., Elvsashagen, T., Etain, B., Fanous, A. H., Fellendorf, F., Fiorentino, A., Forstner, A. J., Frye, M. A., Fullerton, J. M., Gade, K., Garnham, J., Gershon, E., Gill, M., Goes, F. S., Gordon-Smith, K., Grof, P., Guzman-Parra, J., Hahn, T., Hasler, R., Heilbronner, M., Heilbronner, U., Jamain, S., Jimenez, E., Jones, I., Jones, L., Jonsson, L., Kahn, R. S., Kelsoe, J. R., Kennedy, J. L., Kircher, T., Kirov, G., Kittel-Schneider, S., Klohn-Saghatolislam, F., Knowles, J. A., Kranz, T. M., Lagerberg, T. V., Landen, M., Lawson, W. B., Leboyer, M., Li, Q. S., Maj, M., Malaspina, D., Manchia, M., Mayoral, F., Mcelroy, S. L., Mcinnis, M. G., Mcintosh, A. M., Medeiros, H., Melle, I., Milanova, V., Mitchell, P. B., Monteleone, P., Monteleone, A. M., Nothen, M. M., Novak, T., Nurnberger, J. I., O'Brien, N., O'Connell, K. S., O'Donovan, C., O'Donovan, M. C., Opel, N., Ortiz, A., Owen, M. J., Palsson, E., Pato, C., Pato, M. T., Pawlak, J., Pfarr, J. -K., Pisanu, C., Potash, J. B., Rapaport, M. H., Reich-Erkelenz, D., Reif, A., Reininghaus, E., Repple, J., Richard-Lepouriel, H., Rietschel, M., Ringwald, K., Roberts, G., Rouleau, G., Schaupp, S., Scheftner, W. A., Schmitt, S., Schofield, P. R., Schubert, K. O., Schulte, E. C., Schweizer, B., Senner, F., Severino, G., Sharp, S., Slaney, C., Smeland, O. B., Sobell, J. L., Squassina, A., Stopkova, P., Strauss, J., Tortorella, A., Turecki, G., Twarowska-Hauser, J., Veldic, M., Vieta, E., Vincent, J. B., Xu, W., Zai, C. C., Zandi, P. P., Di Florio, A., Smoller, J. W., Biernacka, J. M., Mcmahon, F. J., Alda, M., Muller-Myhsok, B., Koutsouleris, N., Falkai, P., Freimer, N. B., Andlauer, T. F. M., Schulze, T. G., and Ophoff, R. A.
Subjects: Paper, Multifactorial Inheritance, medicine.medical_specialty, Autism Spectrum Disorder, Bipolar disorder, MESH: Age of Onset, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, GWAS, age at onset, polarity at onset, polygenic score, MESH: Depressive Disorder, Major, BF, Genome-wide association study, Disease, Psykiatri, SDG 3 - Good Health and Well-being, ddc:150, Polarity at onset, Internal medicine, MESH: Bipolar Disorder, Polygenic score, medicine, Humans, Academic Psychiatry, Age of Onset, Genetic association, Psychiatry, MESH: Autism Spectrum Disorder, Depressive Disorder, Major, MESH: Humans, business.industry, Age at onset, Heritability, medicine.disease, Genetic architecture, ddc, Psychiatry and Mental health, Schizophrenia, Autism spectrum disorder, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, RC0321, MESH: Multifactorial Inheritance, business, Genome-Wide Association Study
Abstract: BackgroundStudying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder 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 bipolar disorder disease characteristics.MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 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 a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 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 bipolar disorder 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.
Published: 2021
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45. Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Author: J. Raymond DePaulo, Martin Alda, Alfonso Tortorella, Susan G. Leckband, Jean-Michel Aubry, James B. Potash, Clara Brichant-Petitjean, Layla Kassem, Joanna Hauser, Tomas Novak, David Zilles, Claire O'Donovan, Rebecca Hoban, Sarah Kittel-Schneider, Claire Slaney, Lena Backlund, Peter Falkai, Andrew T. A. Cheng, John R. Kelsoe, Andrea Pfennig, Janice M. Fullerton, Marcella Rietschel, Caterina Chillotti, Stéphane Jamain, Elise Bui, Po-Hsiu Kuo, Alessio Squassina, Claudio E. M. Banzato, Joanna M. Biernacka, Lisa R. Seymour, Naomi R. Wray, Ichiro Kusumi, Thomas Stamm, Fernando S. Goes, Audrey Nallet, Sarah K. Tighe, Giovanni Severino, Jean-Pierre Kahn, Maria Neuner, Nirmala Akula, Norio Ozaki, Francis J. McMahon, Frank Bellivier, Andreas Reif, Ryota Hashimoto, Barbara W. Schweizer, Palmiero Monteleone, Florian Seemüller, Urs Heilbronner, Sevilla D. Detera-Wadleigh, Pavla Stopkova, Martin Schalling, Julie Garnham, Sébastien Gard, Mark A. Frye, Eva Z. Reininghaus, Lina Martinsson, Urban Ösby, Maria Grigoroiu-Serbanescu, Sara Richardson, Tadafumi Kato, Marion Leboyer, Catharina Lavebratt, Piotr M. Czerski, Scott R. Clark, Daniela Reich-Erkelenz, Sebastian Kliwicki, Guy A. Rouleau, Oliver Gruber, Gonzalo Laje, Adam Wright, Gustavo Turecki, Roy H. Perlis, Takuya Masui, Mirko Manchia, Bernhard T. Baune, Mazda Adli, Michael Bauer, Sven Cichon, Frank Mondimore, Bruno Etain, Philip B. Mitchell, Thomas G. Schulze, Peter P. Zandi, Raffaella Ardau, Peter R. Schofield, Susanne Bengesser, Liping Hou, Janusz K. Rybakowski, Mario Maj, Clarissa de Rosalmeida Dantas, Louise Frisén, O. Schubert, Carlos Jaramillo, Maria Del Zompo, Paul Grof, Cynthia V. Calkin, Jo Steele, Jordan W. Smoller, Alain Malafosse, Manchia, M, Adli, M, Akula, N, Ardau, R, Aubry, Jm, Backlund, L, Banzato, Ce, Baune, Bt, Bellivier, F, Bengesser, S, Biernacka, Jm, Brichant Petitjean, C, Bui, E, Calkin, Cv, Cheng, At, Chillotti, C, Cichon, S, Clark, S, Czerski, Pm, Dantas, C, Zompo, Md, Depaulo, Jr, Detera Wadleigh, Sd, Etain, B, Falkai, P, Frisén, L, Frye, Ma, Fullerton, J, Gard, S, Garnham, J, Goes, F, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Heilbronner, U, Hoban, R, Hou, L, Jamain, S, Kahn, Jp, Kassem, L, Kato, T, Kelsoe, Jr, Kittel Schneider, S, Kliwicki, S, Kuo, Ph, Kusumi, I, Laje, G, Lavebratt, C, Leboyer, M, Leckband, Sg, López Jaramillo, Ca, Maj, Mario, Malafosse, A, Martinsson, L, Masui, T, Mitchell, Pb, Mondimore, F, Monteleone, P, Nallet, A, Neuner, M, Novák, T, O'Donovan, C, Osby, U, Ozaki, N, Perlis, Rh, Pfennig, A, Potash, Jb, Reich Erkelenz, D, Reif, A, Reininghaus, E, Richardson, S, Rouleau, Ga, Rybakowski, Jk, Schalling, M, Schofield, Pr, Schubert, Ok, Schweizer, B, Seemüller, F, Grigoroiu Serbanescu, M, Severino, G, Seymour, Lr, Slaney, C, Smoller, Jw, Squassina, A, Stamm, T, Steele, J, Stopkova, P, Tighe, Sk, Tortorella, Alfonso Antonio Vincenzo, Turecki, G, Wray, Nr, Wright, A, Zandi, Pp, Zilles, D, Bauer, M, Rietschel, M, Mcmahon, Fj, Schulze, Tg, Alda, M., Department of Psychiatry, Dalhousie University [Halifax], Department of Psychiatry and Psychotherapy, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Unit of Clinical Pharmacology, University-Hospital of Cagliari, Department of Mental Health and Psychiatry, University Hospital of Geneva, Trinity College Dublin-St. James's Hospital, University of Campinas [Campinas] (UNICAMP), University of Adelaide, Pôle de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Medical University Graz, Mayo Clinic, Division of Epidemiology and Genetics, Academia Sinica-Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo (USP)-Universidade de São Paulo (USP), Department of Genomics, Life and Brain Center, University of Bonn, Psychiatric Genetic Unit, Poznan University of Medical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, University of Homburg, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Service de psychiatrie adulte, Université Bordeaux Segalen - Bordeaux 2-Hôpital Charles Perrens-Centre Expert Trouble Bipolaire, Mood Disorders Center of Ottawa (MDCO), University of Ottawa [Ottawa], University of Toronto, Georg-August-University [Göttingen], Osaka University Graduate School of Medicine, University of California [San Diego] (UC San Diego), University of California-University of California, Service de Psychiatrie et Psychologie Clinique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital Jeanne-d'Arc, Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science [Wako] (RIKEN CBS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Mental Health Sciences Unit, University College of London [London] (UCL), Department of Adult Psychiatry, Institute of Epidemiology and Preventive Medicine, National Taiwan University [Taiwan] (NTU), Hokkaido University Graduate School of Medicine, Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Center for Molecular Medicine, Karolinska University Hospital [Stockholm], Department of Pharmacy, Veterans Affairs San Diego Healthcare System, Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego], University of Antioquia, University of Napoli, School of Psychiatry, University of New South Wales [Sydney] (UNSW)-Black Dog Institute, Prague Psychiatric Center, University of Prague, Fujita Health University School of Medicine, Nagoya University Graduate School of Medicine, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Technische Universität Dresden = Dresden University of Technology (TU Dresden), University of Iowa [Iowa City], Center of Excellence in Neuroscience, CHU de Montréal, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, McGill Group for Suicide Studies, Douglas Mental Health University Institute, Queensland Brain Institute, University of Queensland [Brisbane], Department of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, The work on assessment of lithium response has been supported by a grant from Canadian Institutes of Health Research #64410 to MA. MG-S was supported by Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI), Bucharest, Romania (grant no. 89/2012). JMA and AN were supported by a grant from the Swiss National Foundation (#32003B_125469/1 to JM Aubry). ConLiGen is in part supported by funds from the Intramural Research Program of the National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH), Department of Health and Human Services, United States Government, Aubry, Jean-Michel, Universidade Estadual de Campinas = University of Campinas (UNICAMP), Universidade de São Paulo = University of São Paulo (USP)-Universidade de São Paulo = University of São Paulo (USP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Georg-August-University = Georg-August-Universität Göttingen, University of California (UC)-University of California (UC), Guellaen, Georges, Université Bordeaux Segalen - Bordeaux 2-Centre hospitalier Charles Perrens [Bordeaux]-Centre Expert Trouble Bipolaire, and Ikeda, Kazutaka
Subjects: Male, Bipolar Disorder, Lithium (medication), Psychometrics, Psychopharmacology, Epidemiology, International Cooperation, lcsh:Medicine, Lithium, Maintenance Treatment, ConLiGen, ddc:616.89, 0302 clinical medicine, Antimanic Agents, Psychology, lcsh:Science, Reliability (statistics), Psychiatry, Genetics, 0303 health sciences, Multidisciplinary, ASSOCIATION, Genomics, Pharmacoepidemiology, 3. Good health, Mental Health, Phenotype, Treatment Outcome, MAPPING SUSCEPTIBILITY GENES, Behavioral Pharmacology, RELIABILITY, Lithium Compounds, Medicine, Female, Research Article, medicine.drug, Drugs and Devices, MAPPING SUSCEPTIBILITY GENES, PROPHYLACTIC LITHIUM, OBSERVER AGREEMENT, MOOD DISORDERS, ONSET, ASSOCIATION, RELIABILITY, MORTALITY, ILLNESS, AGE, ILLNESS, PROPHYLACTIC LITHIUM, 03 medical and health sciences, AGE, Neuropharmacology, Genomic Medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genome-Wide Association Studies, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Bipolar disorder, ddc:610, Biology, 030304 developmental biology, Mood Disorders, business.industry, MORTALITY, lcsh:R, Computational Biology, Reproducibility of Results, Models, Theoretical, medicine.disease, OBSERVER AGREEMENT, Mood disorders, Pharmacogenetics, Therapies, ONSET, lcsh:Q, Pharmacogenomics, business, 030217 neurology & neurosurgery, Kappa
Abstract: Objective: 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. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] 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. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 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 (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: 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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46. Sex differences in shared genetic determinants between severe mental disorders and metabolic traits.

Author: Pisanu C, Congiu D, Meloni A, Paribello P, Severino G, Ardau R, Chillotti C, Als TD, Børglum AD, Del Zompo M, Manchia M, and Squassina A
Abstract: High rates of metabolic risk factors contribute to premature mortality in patients with severe mental disorders, but the molecular underpinnings of this association are largely unknown. We performed the first analysis on shared genetic factors between severe mental disorders and metabolic traits considering the effect of sex. We applied an integrated analytical pipeline on the largest sex-stratified genome-wide association datasets available for bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SZ), and for body mass index (BMI) and waist-to-hip ratio (WHR) (all including participants of European origin). We observed extensive genetic overlap between all severe mental disorders and variants associated with BMI in women or men and identified several genetic loci shared between BD, or SZ and BMI in women (24 and 91, respectively) or men (13 and 208, respectively), with mixed directions of effect. A large part of the identified genetic variants showed sex differences in terms of location, genes modulated in adipose tissue and/or brain regions, and druggable targets. By providing a complete picture of disorder specific and cross-disorder shared genetic determinants, our results highlight potential sex differences in the genetic liability to metabolic comorbidities in patients with severe mental disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2024
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47. Phenotypic clustering of bipolar disorder supports stratification by lithium responsiveness over diagnostic subtypes.

Author: Scott K, O'Donovan C, Brancati GE, Cervantes P, Ardau R, Manchia M, Severino G, Rybakowski J, Tondo L, Grof P, Alda M, and Nunes A
Subjects: Humans, Male, Female, Adult, Middle Aged, Cluster Analysis, Antimanic Agents therapeutic use, Antimanic Agents pharmacology, Bipolar Disorder drug therapy, Bipolar Disorder classification, Bipolar Disorder diagnosis, Phenotype, Lithium Compounds pharmacology, Lithium Compounds therapeutic use
Abstract: Introduction: The aim of this study was to determine whether the clinical profiles of bipolar disorder (BD) patients could be differentiated more clearly using the existing classification by diagnostic subtype or by lithium treatment responsiveness., Methods: We included adult patients with BD-I or II (N = 477 across four sites) who were treated with lithium as their principal mood stabilizer for at least 1 year. Treatment responsiveness was defined using the dichotomized Alda score. We performed hierarchical clustering on phenotypes defined by 40 features, covering demographics, clinical course, family history, suicide behaviour, and comorbid conditions. We then measured the amount of information that inferred clusters carried about (A) BD subtype and (B) lithium responsiveness using adjusted mutual information (AMI) scores. Detailed phenotypic profiles across clusters were then evaluated with univariate comparisons., Results: Two clusters were identified (n = 56 and n = 421), which captured significantly more information about lithium responsiveness (AMI range: 0.033 to 0.133) than BD subtype (AMI: 0.004 to 0.011). The smaller cluster had disproportionately more lithium responders (n = 47 [83.8%]) when compared to the larger cluster (103 [24.4%]; p = 0.006)., Conclusions: Phenotypes derived from detailed clinical data may carry more information about lithium responsiveness than the current classification of diagnostic subtype. These findings support lithium responsiveness as a valid approach to stratification in clinical samples., (© 2024 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)
Published: 2024
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48. Exploring the genetics of lithium response in bipolar disorders.

Author: Herrera-Rivero M, Adli M, Akiyama K, Akula N, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O'Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Streit F, Tekola-Ayele F, Thalamuthu A, Tortorella A, Turecki G, Veeh J, Vieta E, Viswanath B, Witt SH, Zandi PP, Alda M, Bauer M, McMahon FJ, Mitchell PB, Rietschel M, Schulze TG, and Baune BT
Abstract: Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., (© 2024. The Author(s).)
Published: 2024
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49. Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets.

Author: Pisanu C, Congiu D, Meloni A, Paribello P, Patrinos GP, Severino G, Ardau R, Chillotti C, Manchia M, and Squassina A
Subjects: Humans, Bipolar Disorder genetics, Mental Disorders genetics, Schizophrenia genetics, DNA, Mitochondrial genetics, Genetic Predisposition to Disease genetics, DNA Copy Number Variations genetics, Cellular Senescence genetics, Genetic Pleiotropy, Depressive Disorder, Major genetics, Depressive Disorder, Major drug therapy
Abstract: Patients with severe mental disorders such as bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) show a substantial reduction in life expectancy, increased incidence of comorbid medical conditions commonly observed with advanced age and alterations of aging hallmarks. While severe mental disorders are heritable, the extent to which genetic predisposition might contribute to accelerated cellular aging is not known. We used bivariate causal mixture models to quantify the trait-specific and shared architecture of mental disorders and 2 aging hallmarks (leukocyte telomere length [LTL] and mitochondrial DNA copy number), and the conjunctional false discovery rate method to detect shared genetic loci. We integrated gene expression data from brain regions from GTEx and used different tools to functionally annotate identified loci and investigate their druggability. Aging hallmarks showed low polygenicity compared with severe mental disorders. We observed a significant negative global genetic correlation between MDD and LTL (r g = -0.14, p = 6.5E-10), and no significant results for other severe mental disorders or for mtDNA-cn. However, conditional QQ plots and bivariate causal mixture models pointed to significant pleiotropy among all severe mental disorders and aging hallmarks. We identified genetic variants significantly shared between LTL and BD (n = 17), SCZ (n = 55) or MDD (n = 19), or mtDNA-cn and BD (n = 4), SCZ (n = 12) or MDD (n = 1), with mixed direction of effects. The exonic rs7909129 variant in the SORCS3 gene, encoding a member of the retromer complex involved in protein trafficking and intracellular/intercellular signaling, was associated with shorter LTL and increased predisposition to all severe mental disorders. Genetic variants underlying risk of SCZ or MDD and shorter LTL modulate expression of several druggable genes in different brain regions. Genistein, a phytoestrogen with anti-inflammatory and antioxidant effects, was an upstream regulator of 2 genes modulated by variants associated with risk of MDD and shorter LTL. While our results suggest that shared heritability might play a limited role in contributing to accelerated cellular aging in severe mental disorders, we identified shared genetic determinants and prioritized different druggable targets and compounds., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
Published: 2024
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50. Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Author: Ou AH, Rosenthal SB, Adli M, Akiyama K, Akula N, Alda M, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bauer M, Baune BT, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dantas CR, Dayer A, Del Zompo M, Degenhardt F, DePaulo JR, Étain B, Falkai P, Fellendorf FT, Ferensztajn-Rochowiak E, Forstner AJ, Frisén L, Frye MA, Fullerton JM, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Gruber O, Hashimoto R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hofmann A, Hou L, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kittel-Schneider S, König B, Kuo PH, Kusumi I, Lackner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CAL, MacQueen G, Maj M, Manchia M, Marie-Claire C, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, McMahon FJ, Mitchell PB, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, Ösby U, Ozaki N, Papiol S, Perlis RH, Pisanu C, Potash JB, Pfennig A, Reich-Erkelenz D, Reif A, Reininghaus EZ, Rietschel M, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulze TG, Schweizer BW, Seemüller F, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Tighe SK, Tortorella A, Turecki G, Vieta E, Volkert J, Witt S, Wray NR, Wright A, Young LT, Zandi PP, and Kelsoe JR
Subjects: Humans, Proto-Oncogene Proteins c-akt genetics, Phosphatidylinositol 3-Kinases genetics, Genome-Wide Association Study, Multiomics, Focal Adhesions, Lithium pharmacology, Lithium therapeutic use, Bipolar Disorder drug therapy, Bipolar Disorder genetics
Abstract: Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)
Published: 2024
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