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