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Longitudinal study on the neuroprotective and neurotrophic effects of lithium in bipolar disorder: identification of cellular and molecular targets clinically relevant

Grant number: 09/14891-9
Support type:Research Grants - Young Investigators Grants
Duration: September 01, 2010 - August 31, 2013
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Rodrigo Machado-Vieira
Grantee:Rodrigo Machado-Vieira
Home Institution: Instituto de Psiquiatria Doutor Antonio Carlos Pacheco e Silva (IPq). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Claudia da Costa Leite ; Geraldo Busatto Filho ; Leda Leme Talib ; Maria Concepción García Otaduy ; Wagner Farid Gattaz
Associated scholarship(s):11/13465-6 - A longitudinal study on the neuroprotective and neurotrophic effects of lithium in bipolar disorder: identification of cellular and molecular targets clinically relevant, BP.IC
10/16643-0 - A longitudinal study on the neuroprotective and neurotrophic effects of lithium in bipolar disorder: identification of cellular and molecular targets clinically relevant, BP.JP

Abstract

Mood disorders are the most prevalent psychiatric, presenting chronic course and high morbidity, affecting 10-15% of population. Diverse structural, functional and biochemical cerebral changes described in the pathophysiology of mood disorders, in special Bipolar Disorder (BPD), have been associated with impairments in neuroprotective mechanisms and cellular resilience leading to cellular stress and atrophy. Altered levels of markers associated with neuronal viability in functional imaging studies, as well as dysfunctions in the mitochondrial and endoplasmic reticulum activity and neurotrophins levels have been consistently associated with these deleterious cellular effects. However, the clinical relevance of these pathophysiological findings have been rarely addressed. Meanwhile, lithium has been considered the most used mood stabilizer worldwide, showing significant efficacy in the treatment of manic and depressive episodes, as well as in the prevention of suicide and maintenance. Several studies have demonstrated significant neuroprotective and neurotrophic effects induced by lithium treatment in diverse cellular and molecular targets, but again, few is known about the potential association between these cerebral effects and the its therapeutic clinical efficacy induced by this proof of concept agent. The present project aims to investigate brain levels of lithium using magnetic resonance spectroscopy (7Li-MRS) and its association with different markers of neuronal viability such as n-acetyl-aspartate (using 1H-MRS), as well as peripheral markers of mitochodrial, endoplasmic reticulum and neurotrophic factors activity, all highly implicated in the pathophysiology of BD. Thirty subjects with a DSM-ID-TR diagnosis of BPD during a depressive or hypomanic episode will be divided in two groups according to age and time of illness. All patients will receive lithium (flexible therapeutic dose) for 6 weeks and improvement will be evaluated weekly using depression and mania rating scales; this study also objectives to identify state/trait markers and predictors of response. The investigator has been working in this area in the last ten years, in which the last three and a half in the Lab of Molecular Pathophysiology and Experimental Therapeutics, NIMH, NIH. The candidate is looking forward to establish appropriate structure to develop a "Research Center for the Study of Neuroplasticity and Neuroprotection in Psychiatric Disorders" in the Institute of Psychiatry, University of Sao Paulo, Brazil. Overall, the study on the neuroplasticity-mediated pathophysiological basis of BPD implicated in the clinical presentation and outcome may shed light on the development of new, improved therapeutics for this and other devastating psychiatric disorders. (AU)

Scientific publications (14)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FAVRE, PAULINE; PAULING, MELISSA; STOUT, JACQUES; HOZER, FRANZ; SARRAZIN, SAMUEL; ABE, CHRISTOPH; ALDA, MARTIN; ALLOZA, CLARA; ALONSO-LANA, SILVIA; ANDREASSEN, OLE A.; BAUNE, BERNHARD T.; BENEDETTI, FRANCESCO; BUSATTO, GERALDO F.; CANALES-RODRIGUEZ, ERICK J.; CASERAS, XAVIER; CHAIM-AVANCINI, TIFFANY MOUKBEL; CHING, CHRISTOPHER R. K.; DANNLOWSKI, UDO; DEPPE, MICHAEL; EYLER, LISA T.; FATJO-VILAS, MAR; FOLEY, SONYA F.; GROTEGERD, DOMINIK; HAJEK, TOMAS; HAUKVIK, UNN K.; HOWELLS, FLEUR M.; JAHANSHAD, NEDA; KUGEL, HARALD; LAGERBERG, TRINE V.; LAWRIE, STEPHEN M.; LINKE, JULIA O.; MCINTOSH, ANDREW; MELLONI, ELISA M. T.; MITCHELL, PHILIP B.; POLOSAN, MIRCEA; POMAROL-CLOTET, EDITH; REPPLE, JONATHAN; ROBERTS, GLORIA; ROOS, ANNERINE; ROSA, PEDRO G. P.; SALVADOR, RAYMOND; SARRO, SALVADOR; SCHOFIELD, PETER R.; SERPA, MAURICIO H.; SIM, KANG; STEIN, DAN J.; SUSSMANN, JESS E.; TEMMINGH, HENK S.; THOMPSON, PAUL M.; VERDOLINI, NORMA; VIETA, EDUARD; WESSA, MICHELE; WHALLEY, HEATHER C.; ZANETTI, MARCUS V.; LEBOYER, MARION; MANGIN, JEAN-FRANCOIS; HENRY, CHANTAL; DUCHESNAY, EDOUARD; HOUENOU, JOSSELIN; WORKING, ENIGMA BIPOLAR DISORDER. Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals. NEUROPSYCHOPHARMACOLOGY, v. 44, n. 13, p. 2285-2293, DEC 2019. Web of Science Citations: 1.
HIBAR, D. P.; WESTLYE, L. T.; DOAN, N. T.; JAHANSHAD, N.; CHEUNG, J. W.; CHING, C. R. K.; VERSACE, A.; BILDERBECK, A. C.; UHLMANN, A.; MWANGI, B.; KRAEMER, B.; OVERS, B.; HARTBERG, C. B.; ABE, C.; DIMA, D.; GROTEGERD, D.; SPROOTEN, E.; BOEN, E.; JIMENEZ, E.; HOWELLS, F. M.; DELVECCHIO, G.; TEMMINGH, H.; STARKE, J.; ALMEIDA, J. R. C.; GOIKOLEA, J. M.; HOUENOU, J.; BEARD, L. M.; RAUER, L.; ABRAMOVIC, L.; BONNIN, M.; PONTEDURO, M. F.; KEIL, M.; RIVE, M. M.; YAO, N.; YALIN, N.; NAJT, P.; ROSA, P. G.; REDLICH, R.; TROST, S.; HAGENAARS, S.; FEARS, S. C.; ALONSO-LANA, S.; VAN ERP, T. G. M.; NICKSON, T.; CHAIM-AVANCINI, T. M.; MEIER, T. B.; ELVSASHAGEN, T.; HAUKVIK, U. K.; LEE, W. H.; SCHENE, A. H.; LLOYD, A. J.; YOUNG, A. H.; NUGENT, A.; DALE, A. M.; PFENNIG, A.; MCINTOSH, A. M.; LAFER, B.; BAUNE, B. T.; EKMAN, C. J.; ZARATE, C. A.; BEARDEN, C. E.; HENRY, C.; SIMHANDL, C.; MCDONALD, C.; BOURNE, C.; STEIN, D. J.; WOLF, D. H.; CANNON, D. M.; GLAHN, D. C.; VELTMAN, D. J.; POMAROL-CLOTET, E.; VIETA, E.; CANALES-RODRIGUEZ, E. J.; NERY, F. G.; DURAN, F. L. S.; BUSATTO, G. F.; ROBERTS, G.; PEARLSON, G. D.; GOODWIN, G. M.; KUGEL, H.; WHALLEY, H. C.; RUHE, H. G.; SOARES, J. C.; FULLERTON, J. M.; RYBAKOWSKI, J. K.; SAVITZ, J.; CHAIM, K. T.; FATJO-VILAS, M.; SOEIRO-DE-SOUZA, M. G.; BOKS, M. P.; ZANETTI, M. V.; OTADUY, M. C. G.; SCHAUFELBERGER, M. S.; ALDA, M.; INGVAR, M.; PHILLIPS, M. L.; KEMPTON, M. J.; BAUER, M.; LANDEN, M.; LAWRENCE, N. S.; VAN HAREN, N. E. M.; HORN, N. R.; FREIMER, N. B.; GRUBER, O.; SCHOFIELD, P. R.; MITCHELL, P. B.; KAHN, R. S.; LENROOT, R.; MACHADO-VIEIRA, R.; OPHOFF, R. A.; SARRO, S.; FRANGOU, S.; SATTERTHWAITE, T. D.; HAJEK, T.; DANNLOWSKI, U.; MALT, U. F.; AROLT, V.; GATTAZ, W. F.; DREVETS, W. C.; CASERAS, X.; AGARTZ, I.; THOMPSON, P. M.; ANDREASSEN, O. A.; WORKING, ENIGMA BIPOLAR DISORDER. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. MOLECULAR PSYCHIATRY, v. 23, n. 4, p. 932-942, APR 2018. Web of Science Citations: 85.
MACHADO-VIEIRA, RODRIGO; ZANETTI, MARCUS V.; OTADUY, MARIA C.; DE SOUSA, RAFAEL T.; SOEIRO-DE-SOUZA, MARCIO G.; COSTA, ALANA C.; CARVALHO, ANDRE F.; LEITE, CLAUDIA C.; BUSATTO, GERALDO F.; ZARATE, JR., CARLOS A.; GATTAZ, WAGNER F. Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder A 3-T H-1-MRS Study. Journal of Clinical Psychopharmacology, v. 37, n. 1, p. 40-45, FEB 2017. Web of Science Citations: 9.
MACHADO-VIEIRA, R.; OTADUY, M. C.; ZANETTI, M. V.; DE SOUSA, R. T.; DIAS, V. V.; LEITE, C. C.; FORLENZA, O. V.; BUSATTO, G. F.; SOARES, J. C.; GATTAZ, W. F. A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-Li-7 Magnetic Resonance Spectroscopy Study. ACTA PSYCHIATRICA SCANDINAVICA, v. 133, n. 3, p. 214-220, MAR 2016. Web of Science Citations: 8.
DE SOUSA, RAFAEL T.; STRECK, EMILIO L.; FORLENZA, ORESTES V.; BRUNONI, ANDRE R.; ZANETTI, MARCUS V.; FERREIRA, GABRIELA K.; DINIZ, BRENO S.; PORTELA, LUIS V.; CARVALHO, ANDRE F.; ZARATE, JR., CARLOS A.; GATTAZ, WAGNER F.; MACHADO-VIEIRA, RODRIGO. Regulation of leukocyte tricarboxylic acid cycle in drug-naive Bipolar Disorder. Neuroscience Letters, v. 605, p. 65-68, SEP 25 2015. Web of Science Citations: 4.
MACHADO-VIEIRA, RODRIGO; ZANETTI, MARCUS V.; TEIXEIRA, ANTONIO L.; UNO, MIYUKI; VALIENGO, LEANDRO L.; SOEIRO-DE-SOUZA, MARCIO G.; OBA-SHINJO, SUELI M.; DE SOUSA, RAFAEL T.; ZARATE, JR., CARLOS. A.; GATTAZ, WAGNER F.; MARIE, SUETY K. N. Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder. European Neuropsychopharmacology, v. 25, n. 4, p. 468-473, APR 2015. Web of Science Citations: 21.
ZANETTI, MARCUS V.; OTADUY, MARIA C.; DE SOUSA, RAFAEL T.; GATTAZ, WAGNER F.; BUSATTO, GERALDO F.; LEITE, CLAUDIA C.; MACHADO-VIEIRA, RODRIGO. Bimodal Effect of Lithium Plasma Levels on Hippocampal Glutamate Concentrations in Bipolar II Depression: A Pilot Study. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 18, n. 6 APR 2015. Web of Science Citations: 12.
DE SOUSA, RAFAEL T.; ZANETTI, MARCUS V.; TALIB, LEDA L.; SERPA, MAURICIO H.; CHAIM, TIFFANY M.; CARVALHO, ANDRE F.; BRUNONI, ANDRE R.; BUSATTO, GERALDO F.; GATTAZ, WAGNER E.; MACHADO-VIEIRA, RODRIGO. Lithium increases platelet serine-9 phosphorylated GSK-3 beta levels in drug-free bipolar disorder during depressive episodes. JOURNAL OF PSYCHIATRIC RESEARCH, v. 62, p. 78-83, MAR 2015. Web of Science Citations: 20.
LOCH, ALEXANDRE A.; ZANETTI, MARCUS V.; DE SOUSA, RAFAEL T.; CHAIM, TIFFANY M.; SERPA, MAURICIO H.; GATTAZ, WAGNER F.; TEIXEIRA, ANTONIO L.; MACHADO-VIEIRA, RODRIGO. Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 56, p. 243-246, JAN 2 2015. Web of Science Citations: 11.
TEIXEIRA, ANTONIO L.; DE SOUZA, RAFAEL T.; ZANETTI, MARCUS V.; BRUNONI, ANDRE R.; BUSATTO, GERALDO F.; ZARATE, JR., CARLOS A.; GATTAZ, WAGNER F.; MACHADO-VIEIRA, RODRIGO. Increased plasma levels of soluble TNF receptors 1 and 2 in bipolar depression and impact of lithium treatment. HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL, v. 30, n. 1, p. 52-56, JAN 2015. Web of Science Citations: 11.
MACHADO-VIEIRA, RODRIGO; ZANETTI, MARCUS V.; DE SOUSA, RAFAEL T.; SOEIRO-DE-SOUZA, MARCIO G.; MORENO, RICARDO A.; BUSATTO, GERALDO F.; GATTAZ, WAGNER F. Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study. EXPERIMENTAL AND THERAPEUTIC MEDICINE, v. 8, n. 4, p. 1205-1208, OCT 2014. Web of Science Citations: 5.
DE SOUSA, RAFAEL T.; ZANETTI, MARCUS V.; BUSATTO, GERALDO F.; MOURO, MARGARET G.; ZARATE, JR., CARLOS A.; GATTAZ, WAGNER F.; HIGA, ELISA M.; MACHADO-VIEIRA, RODRIGO. Lithium increases nitric oxide levels in subjects with bipolar disorder during depressive episodes. JOURNAL OF PSYCHIATRIC RESEARCH, v. 55, p. 96-100, AUG 2014. Web of Science Citations: 10.
SOEIRO-DE-SOUZA, MARCIO GERHARDT; GOLD, PHILIP W.; BRUNONI, ANDRE R.; DE SOUSA, RAFAEL T.; ZANETTI, MARCUS V.; CARVALHO, ANDRE F.; GATTAZ, WAGNER FARID; MACHADO-VIEIRA, RODRIGO; TEIXEIRA, ANTONIO LUCIO. Lithium Decreases Plasma Adiponectin Levels in Bipolar Depression. Neuroscience Letters, v. 564, p. 111-114, APR 3 2014. Web of Science Citations: 16.
VALIENGO, LEANDRO L.; SOEIRO-DE-SOUZA, MARCIO G.; MARQUES, ANDREA H.; MORENO, DORIS H.; JURUENA, MARIO F.; ANDREAZZA, ANA CRISTINA; GATTAZ, WAGNER F.; MACHADO-VIEIRA, RODRIGO. Plasma cortisol in first episode drug-naive mania: Differential levels in euphoric versus irritable mood. Journal of Affective Disorders, v. 138, n. 1-2, p. 149-152, APR 2012. Web of Science Citations: 16.

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