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Glutathion/redox dysregulation in early psychosis: towards a biomarker profile for early intervention

Applicant Conus Philippe
Number 122419
Funding scheme Project funding (Div. I-III)
Research institution DUP CHUV Clinique de Cery Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Neurology, Psychiatry
Start/End 01.10.2008 - 30.09.2011
Approved amount 375'000.00
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Keywords (8)

psychosis; early intervention; schizophrenia; biomarker; glutathione; redox; oxidative stress; N-acetyl-cystein

Lay Summary (English)

Lead
Lay summary
Intervention in early psychosis (EP) has become a major domain of clinical development and research, but the benefits of these new treatment strategies are still hampered by a lack of evidence based knowledge regarding neurobiological mechanisms involved in the illness process. Identification of biomarkers for psychosis or for its various forms and identifications of new and more specific targets for medication are therefore important issues to be resolved. Once these problem overcome, important new developments may become possible. Research conducted in our laboratory and clinical program, have led to the development of the hypothesis that a genetically mediated glutathione/redox antioxidant dys-regulation is a vulnerability factor, contributing to the development of schizophrenia. However, most of this research has been conducted in samples of patients presenting with chronic schizophrenia and suffer therefore numerous biases (influence of treatment, relapses and duration of illness as well as selection of poor outcome patients).2.AIMS OF THE PROJECTIn this research, we aim at exploring if glutathione/redox dysregulation observed in chronic schizophrenia is also present in the early phase of schizophrenia and other psychoses and if a pharmacological intervention targeting this dysregulation may have beneficial effects in EP patients. The project is composed of two parts targeting these complementary issues: Project A aims at establishing a biomarker profile in EP and to explore its specificity for certain subtypes of psychotic disorders. Project B aims at studying a new pharmacological approach to the treatment of EP based on supplementation with N-Acetyl-Cysteine (NAC), a precursor of glutathione, in the frame of a randomized controlled trial.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia.
Gysin René, Kraftsik Rudolf, Boulat Olivier, Bovet Pierre, Conus Philippe, Comte-Krieger Emily, Polari Andrea, Steullet Pascal, Preisig Martin, Teichmann Tanja, Cuénod Michel, Do Kim Q (2011), Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia., in Antioxidants & redox signaling, 15(7), 2003-10.
[The "SYNAPSY" project: where psychiatrists and neuroscientists meet].
Conus Philippe, Preisig Martin, Aubry Jean-Michel, Marquet Pierre, Malafosse Alain, Dayer Alexandre, Baumann Philipp (2011), [The "SYNAPSY" project: where psychiatrists and neuroscientists meet]., in Revue médicale suisse, 7(309).
Qualitative methods in early-phase drug trials: broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia.
Berk Michael, Munib Ahmed, Dean Olivia, Malhi Gin S, Kohlmann Kristy, Schapkaitz Ian, Jeavons Sue, Katz Fiona, Anderson-Hunt Murray, Conus Philippe, Hanna Barbara, Otmar Renée, Ng Felicity, Copolov David L, Bush Ashley I (2011), Qualitative methods in early-phase drug trials: broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia., in The Journal of clinical psychiatry, 72(7), 909-13.
OXIDATIVE STRESS AND SCHIZOPHRENIA: 1H-MRS AT 14.1 T IN DEVELOPING MICE WITH GLUTATHIONE DEFICIT
Do KQ, Duarte JM, Kulak A, Cuenod M, Gruetter R (2011), OXIDATIVE STRESS AND SCHIZOPHRENIA: 1H-MRS AT 14.1 T IN DEVELOPING MICE WITH GLUTATHIONE DEFICIT, in SCHIZOPHRENIA BULLETIN, 37, 123-123.
Interaction of GAG trinucleotide repeat and C-129T polymorphisms impairs expression of the glutamate-cysteine ligase catalytic subunit gene.
Butticaz Christophe, Gysin René, Cuénod Michel, Do Kim Q (2011), Interaction of GAG trinucleotide repeat and C-129T polymorphisms impairs expression of the glutamate-cysteine ligase catalytic subunit gene., in Free radical biology & medicine, 50(5), 617-23.
Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia.
Kulak Anita, Duarte João M N, Do Kim Q, Gruetter Rolf (2010), Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia., in Journal of neurochemistry, 115(6), 1466-77.
Redox dysregulation and oxidative stress in schizophrenia: nutrigenetics as a challenge in psychiatric disease prevention.
Do Kim Q, Conus Philippe, Cuenod Michel (2010), Redox dysregulation and oxidative stress in schizophrenia: nutrigenetics as a challenge in psychiatric disease prevention., in Journal of nutrigenetics and nutrigenomics, 3(4-6), 267-89.
Attenuated asymmetry of functional connectivity in schizophrenia: a high-resolution EEG study.
Jalili Mahdi, Meuli Reto, Do Kim Q, Hasler Martin, Crow Timothy J, Knyazeva Maria G (2010), Attenuated asymmetry of functional connectivity in schizophrenia: a high-resolution EEG study., in Psychophysiology, 47(4), 706-16.
Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors.
Steullet Pascal, Cabungcal Jan-Harry, Kulak Anita, Kraftsik Rudolf, Chen Ying, Dalton Timothy P, Cuenod Michel, Do Kim Q (2010), Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 30(7), 2547-58.
Redox dysregulation, neurodevelopment, and schizophrenia.
Do Kim Q, Cabungcal Jan H, Frank Anita, Steullet Pascal, Cuenod Michel (2009), Redox dysregulation, neurodevelopment, and schizophrenia., in Current opinion in neurobiology, 19(2), 220-30.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
8ème Symposium de la Société Suisse des Troubles Bipolaires (SSTB) 29.09.2011 Lausanne, Switzerland
15th World Congress of Psychiatry 18.09.2011 Buenos Aires, Argentinia
19th European Congress of Psychiatry 12.03.2011 Vienna, Austria
Montagskolloquium, UPK 07.03.2011 Basel, Switzerland
Die Subjective Seite des Schizophrenie; Bedürfnisorientierte Behandlung – Integration der Versorgung, XIII. Tagung 23.02.2011 Hamburg, Germany
7th International Conference on Early Psychosis 29.11.2010 Amsterdam, Netherlands
18th European Congress of Psychiatry 27.03.2010 Munich, Germany
Journées Internationales des Pathologies Emergentes de l’adolescent et du Jeune Adulte 23.03.2010 Paris, France
28èmes Journées de la Société de l’Information Psychiatrique 01.10.2009 Arcachon, France
Congrès de la Société Suisse de Psychiatrie Biologique 01.11.2008 Basel, Switzerland


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Journées de la schizophrénie Western Switzerland 23.03.2011
Talks/events/exhibitions Journées portes ouvertes LUNEP-CNP Western Switzerland 08.06.2011

Associated projects

Number Title Start Funding scheme
130090 Imaging the connectome in the early phase of psychosis 01.01.2011 Project funding (Div. I-III)
135736 A reverse translational study of redox dysregulation in psychiatric disorders: role of oxidative stress in functional and structural dysconnectivity during neurodevelopment 01.06.2011 Project funding (Div. I-III)

Abstract

1.1 BackgroundIntervention in early psychosis (EP) has become a major domain of clinical development and research, but the benefits of these new treatment strategies are still hampered by a lack of evidence based knowledge regarding neurobiological mechanisms involved in the illness process. Identification of biomarkers for psychosis or for its various forms and identifications of new and more specific targets for medication are therefore important issues to be resolved. Once these problem overcome, important new developments may become possible. Research conducted in our laboratory and more recently in collaboration with our clinical program, have led to the development of the hypothesis that a genetically mediated glutathione/redox antioxidant dysregulation is a vulnerability factor, contributing to the development of schizophrenia. However, most of this research has been conducted in samples of patients presenting with chronic schizophrenia and suffer therefore numerous biases (influence of treatment, relapses, duration of illness, selection of poor outcome patients).1.2 Aims of the projectIn this research, we aim at exploring if glutathione/redox dysregulation observed in chronic schizophrenia is also present in the early phase of schizophrenia and other psychoses and if a pharmacological intervention targeting this dysregulation may have beneficial effects in EP patients. The project is composed of two parts targeting these complementary issues: Project A aims at establishing a biomarker profile in EP and to explore its specificity for certain subtypes of psychotic disorders. Project B aims at studying a new pharmacological approach to the treatment of EP based on supplementation with N-Acetyl-Cysteine (NAC), a precursor of glutathione.1.3 MethodsIn project A, we plan to recruit 60 EP patients and 60 healthy matched controls in order to study the presence of glutathione/redox dysregulation on the basis of genetic and biochemical assessment through blood and skin biopsy collection. Patients psychopathology and cognitive functioning will also be assessed in order to explore possible correlations between neurobiological characteristics and clinical manifestations of the illness or diagnostic subgroups. Additionally, the EP group will be compared to chronic schizophrenia patients that have already been recruited in a previous project.In project B, in collaboration with colleagues at Harvard, we plan to recruit 40 patients in each centre in a randomized controlled trial in order to explore the impact of 24 weeks NAC supplementation to standard treatment in EP. We will compare placebo and NAC group on psychopathology, functional level, cognitive functioning and neurophysiological characteristics.1.4 Expected value of the proposed projectThe identification of a biomarker profile for psychosis or for a subgroup of psychosis patients would be highly valuable for the improvement of early identification strategies. Development of new pharmacological treatments that are more specifically targeted at the mechanisms involved in the illness process and have less side effects would also be highly beneficial.
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