Center for Psychiatric Neurosciences                                                                           Français

Unit for Research in Schizophrenia

Contact information :

Center for Psychiatric Neuroscience
Site de Cery
CH – 1008 Prilly-Lausanne       location plan
Tel. ++41 (0)21 643 65 60 / 65
Fax ++41 (0)21 643 65 62
Email : Kim.Do@chuv.ch

Head :

Dr Kim Q. Do Cuénod, Dr. Sci. Nat., Associate Professor

Collaborators :

• Prof. Michel Cuénod, MD : consultant
• Dr Jan-Harry Cabungcal, Dr Margot Fournier, Dr Pascal Steullet : post-doctoral students
• Dr Philippe Baumann, Dr Sara Crespi : psychiatrists
• Carina Ferrari, Tanja Teichmann : psychologists
• Daniella Dwir, Anita Frank, Aline Monin, Pierre Progin : doctoral students (PhD, MD)
• Emel Duran : Master student
• Adeline Cottier, Hélène Moser : laboratory technicians

Profile :

The Unit for Research in Schizophrenia (URS) was set up in 1999 at the Center for Psychiatric Neurosciences. It works towards identifying neurobiological factors which are likely to expose an individual to the risk of being affected by schizophrenia. The main goal is to discover biological vulnerability factors in patients – such as genes and/or abnormal enzymes – in order to develop new and more efficient treatments, and ultimately preventive measures. Its integration to the psychiatric hospital of Cery facilitates close collaboration with psychiatrists (Service of General Psychiatry, Section "Eugène Minkowski"), in particular with Dr Philippe Conus, head of the TIPP program (Treatment and Intervention in the early Phase of Psychosis).

The URS works towards bridging basic neuroscience with problems of clinical psychiatry. It favors an interdisciplinary and translational approach, in which scientific specialists (neurobiology, biology, biochemistry, chemistry, genetics, physiology, physics) cooperate with clinicians, radiologists and pharmacologists. The collaboration between researchers and clinicians is essential to achieve progress, and to encourage the decisive participation of patients and their families in the research process.

Research projects :

Clinical research, in patients, is aimed at a better understanding of the causes and mechanisms leading to schizophrenia phenotypes, and includes following analyses:

• Psychopathology
• Neuropsychology
• Genetic, transcriptomic, proteomic and metabolomic analyses
• EEG analysis (electroencephalogram)
• Non invasive measure of cerebral glutathione and of the neurochemical profile by magnetic resonance spectroscopy (MRS)
• Measure of the cerebral connectivity (DSI)
• Clinical trials with substances which potentially modify the glutathione / redox system

Experimental research focuses on the consequences of a low glutathione level; the pharmacological lowering of glutathione synthesis in neuron cultures and brain tissue, as well as the use of transgenic animals.  allow to set up models meant to determine whether a decreased glutathione level, in particular during brain development, causes anomalies analogous to those observed in patients. These preclinical animal models also represent valuable tools to monitor the efficacy of new drugs. Experimental research includes following observations :

• Morphology: changes in the anatomy and biochemical characteristics of neurons
• Physiology
• Behavior: changes in cognitive functions

Schizophrenia and Glutathione

In this project, which is aimed at a better understanding of pathophysiological mechanisms in schizophrenia, we propose a hypothesis based on the observation of a glutathione (GSH) deficit. In a study of the cerebrospinal fluid of drug-naïve patients with schizophrenia, we observed a significant decrease in the concentration of GSH and of its metabolite -glutamylglutamine – reflecting a decrease in medial prefrontal cortex GSH as detected by in vivo magnetic resonance spectroscopy (MRS).

Converging evidence suggests that schizophrenia is a developmental syndrome involving faulty connectivity deriving from multiple genetic and environmental factors that set off a cascade of events extending into adulthood. Anatomical findings point to a highly distributed underlying neuropathology. It is necessary to identify “hubs” or “final common pathways” leading to various phenotypes.

The URS has identified a developmental redox dysregulation which constitutes a "hub" on which converge genetic impairments of glutathione synthesis and environmental vulnerability factors generating oxidative stress. Genetic impairments may involve the glutathione metabolism or other systems, while environmental factors may be of various origins: inflammations, infections, obstetrical complications, brain trauma or psycho-social stresses. Their timing at critical periods of neurodevelopment plays a decisive role in inducing impairment of neural connectivity and synchronization as observed in schizophrenia. In experimental models, such redox dysregulation induces morphological, physiological and behavioral anomalies strikingly similar to those observed in patients. This is mediated by hypoactive NMDA receptors, impairment of fast-spiking parvalbumin GABA interneurons and neural synchronization and deficit in myelination (Do et al. Curr Opin Neurobiol, 19, 220-230, 2009).

These results were initially obtained in chronic patients and now in collaboration with Dr Philippe Conus (TIPP program), we have started a longitudinal study aimed at detecting potential anomalies of the glutathione metabolism in early psychosis patients. This will allow the development of a biomarker profile useful for early diagnosis.

A proof of concept has been provided by a clinical trial with the GSH precursor N-acetyl-cysteine (NAC). NAC, given as add-on treatment to antipsychotics, in a double-blind, placebo-controlled study, increased GSH plasma levels, improved negative symptoms and reduced side effects of antipsychotics (akathisia) in chronic patients. NAC, which is practically deprived of side effects, was also effective in improving mismatch negativity (MMN), an auditory related, NMDA-dependent evoked potential typically impaired in schizophrenia. This is encouraging since present antipsychotic treatments are rather ineffective against cognitive and negative symptoms and have no effect on MMN, a pre-attentional component which is proposed to gate some cognitive and functional modules.

A new clinical trial with NAC was started in 2009; it focuses on early psychosis patients, who joined the TIPP program headed by Dr Philippe Conus (Information Sheet, Informed Consent). The study is conducted in collaboration with other research centers, in particular Harvard Medical School.

up

Teaching :

• Privat-Docent course : Interactions entre les neurosciences et les maladies psychiatriques
• Course for medical doctors specializing in psychiatry and psychotherapy : Psychiatrie et Neurosciences : schizophrénie, troubles de l'humeur, troubles du développement
• Master in biology : Introduction to psychiatric neuroscience : Etiopathologie de la schizophrénie
• Bachelor in biology : Des fonctions cérébrales au comportement
• Bachelor in biology and Master in psychology (SSP) : Psychopharmacologie de la synapse aux activités mentales et à la réponse thérapeutique
• Bachelor in Lettres/SSP/Theology and religious sciences (Programme Sciences au carré) : Des activités mentales au comportement: le cerveau dans tous ses états
• Organisation of and participation in neuroscience doctoral modules
• Vocational training : Méthodologie de la recherche en psychiatrie et psychopathologie
• Training of doctoral and post-doctoral students in psychiatric neuroscience
• Training of laboratory technicians

Keywords :

schizophrenia, glutathione, free radicals, antioxidant, redox, oxidative stress, dopamine, GABA, NMDA

National and international collaborations :

• Dr Philippe Conus, TIPP Program, Department of Psychiatry, CHUV
• Prof. Pierre Bovet, Prof. Martin Preisig, Franziska Gamma, Department of Psychiatry, CHUV
• Prof. Pierre Magistretti, Prof. Beat Riederer, Prof. Françoise Schenk, Dr Jean-René Cardinaux, Center for Psychiatric Neuroscience, CHUV-UNIL
• Prof. Jean-Pierre Hornung, Dr Rudolf Kraftsig, Department of Cellular Biology and Morphology, UNIL
• Prof. Reto Meuli, Dr Patric Hagman, Dr Mario Knyazeva, Service of Radiology, CHUV
• Prof. Rolf Gruetter, Dr Micah Murray, Center for BioMedical Imaging, EPFL
• Prof. Jean-Philippe Thiran, Dr Leila Cammoun, Faculty of Engineer Sciences and Techniques, EPFL
• Dr Thierry Buclin, Division of Clinical Pharmacology and Toxicology, CHUV
• Dr Olivier Boulat, Central Laboratory of Clinical Chemistry, CHUV
• Prof. Takao Hensch, Prof. Larry Seidman, Harvard Medical School, Boston, USA
• Prof. Thomas Werge, University of Copenhagen, Denmark
• Prof. Håvard Bentsen, Prof. Helge Refsum, Dr Dag Solberg, Department of Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway
• Prof. Patricio O'Donnell, University of Maryland, Baltimore, USA
• Prof. Akira Sawa, Johns Hopkins University School of Medicine, Baltimore, USA
• Prof. Marco Romano-Silva, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil