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1. A comparison of cardiovascular risk factors for ten antipsychotic drugs in clinical practice

Author

Bodén,Robert, Edman,Gunnar, Reutfors,Johan, Östenson,Claes-Göran, Ösby,Urban, Bodén,Robert, Edman,Gunnar, Reutfors,Johan, Östenson,Claes-Göran, and Ösby,Urban

Abstract

Robert Bodén,1,2 Gunnar Edman,3,4 Johan Reutfors,2 Claes-Göran Östenson,3 Urban Ösby3,4 1Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden; 2Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 4Department of Psychiatry, Tiohundra AB, Norrtälje, Sweden Abstract: It is well known that abdominal obesity, dyslipidemia, and insulin resistance are highly prevalent in patients receiving maintenance treatment with antipsychotics, but there is limited knowledge about the association between cardiovascular risk factors and treatment with antipsychotic drugs. In this naturalistic study we investigated a sample of 809 antipsychotic-treated patients from Swedish psychosis outpatient teams. Cardiovascular risk factors (eg, metabolic syndrome, homeostasis model assessment of insulin resistance, and low-density lipoprotein values) were measured, and their associations to current antipsychotic pharmacotherapy were studied. Ten antipsychotic drugs were compared in a stepwise logistic regression model. For the patients, the presence of the components of metabolic syndrome ranged from 35% for hyperglycemia to 64% for elevated waist circumference. Hypertriglyceridemia was associated with clozapine (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.08–3.04), reduced high-density lipoprotein with both clozapine and olanzapine (OR = 1.73, 95% CI 1.01–2.97; and OR = 2.03, 95% CI 1.32–3.13), hypertension with perphenazine (OR = 2.00, 95% CI 1.21–3.59), and hyperglycemia inversely with ziprasidone (OR = 0.21, 95% CI 0.05–0.89) and positively with haloperidol (OR = 2.02, 95% CI 1.18–3.48). There were no significant relationships between any of the antipsychotic drugs and increased waist circumference, homeostasis model

Published
2013

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

Author

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

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

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

Published
2018

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