Unit for Research in Schizophrenia (URS)

PROF. DR. KIM Q. DO

Research interests

The Unit for Research in Schizophrenia (URS) was set up in 1999 at the Center for Psychiatric Neuroscience. The activities of the URS are focused on identifying neurobiological factors of vulnerability, which are likely to further the risk of being affected by schizophrenia. Its main objective is directed at a better understanding of the causes and mechanisms leading to schizophrenia in order to be able to make an early diagnosis of the disease, develop new treatments and ultimately preventive measures. The same objective applies to the fields of autism and bipolar disorders, which are being progressively included in the URS research program since there is evidence that the three diseases have certain mechanisms in common.

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, etc.) 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.

Translational approach to the identification of neurobiological markers in the early phase of psychosis

Psychotic disorders evolve through various stages, from prodromes to full blown disorder, but the boundaries of these stages are defined essentially on the basis of rather imprecise clinical characteristics. Early detection of psychotic disorders has become an essential focus for research, leading to the emergence of a preventive approach to major psychiatric disorders. There is an important need for basic neurobiological research in this domain. We have therefore developed a translational research program, bridging basic research to crucial clinical issues (see Figure1).

This program includes :  

1. Clinical research – in close collaboration with psychiatrists (Service of General Psychiatry, Section "Eugène Minkowski"), in particular with Prof. Philippe Conus, founder of the TIPP program (Treatment and Intervention in the early Phase of Psychosis) :  

Cross sectional and longitudinal multimodal assessment of patients (clinical and neurobiological assessment, brain imaging, EEG) in the various stages of the disorder (ultra high-risk, first episode, early relapse and chronic phase, see Figure 2), aimed at identifying stage specific biomarker profiles in order to assess illness progression, allow early detection, and monitoring of the efficacy of new drugs.   

Clinical research includes following investigations :

2. Basic research with experimental models, aimed at clarifying pathophysiological mechanisms and discovering potential new treatments as well as preventive targets. Current basic research focuses on the consequences of oxidative stress induced by decreasing glutathione (GSH) levels, the main cellular antioxidant and redox regulator. The establishments of such models in neuronal cultures, brain slices and/or animals allow reproducing certain morphological, physiological and behavioral characteristics of the disease. Such models should also allow developing a therapeutic strategy based on the etiology.  

Basic research includes investigations at various levels (see Figure 1) :

  • Transcriptome and metabolome
  • Morphology
  • Neurophysiology
  • Cognitive, emotional and social behavior  

3. Bi-directional translation between human and animal models with experiments leading to similar endpoint assessments being conducted in both models.  

4. Clinical trials for innovative treatment and, in the long term, for prevention.  

The close link between preclinical and clinical components, which are both based on a precise hypothesis, ensures effective translation from bench to bedside and vice versa.

A core neurobiological mechanism impacting local microcircuits and long range connections

Based on converging evidence pointing at a redox imbalance and oxidative stress in the blood, fibroblasts, cerebro-spinal fluid and brain of patients suffering from schizophrenia (including association with the disease of common variants and copy number variations (CNV) in genes involved in GSH metabolism), we proposed that redox dysregulation represents a hub on which various causal genetic and environmental risk factors converge during neurodevelopment, leading to structural and functional connectivity impairments (see Figure 3).

The genetic vulnerability factors involve either redox regulation genes directly affecting GSH metabolism, or genes which indirectly lead to oxidative stress, including DISC1, PROD, G72, NRG, DTNBP1. Environmental factors known to favor major psychiatric disorders generate Reactive Oxygen Species (ROS) as well, which, if the redox regulation is impaired, could perturb the developing nervous system in a time and region specific manner. As a consequence, two key systems, essential for cognitive and affective functioning, will be particularly affected: local microcircuits and long range connections or macrocircuits. The critical role of oxidative stress has been validated in a GSH deficit animal model (GCLM-KO mouse model) reproducing numerous schizophrenia phenotypes including NMDA receptor hypofunction, impaired parvalbumin fast-spiking GABA interneurons, neural synchronization, and related behavioral anomalies. Indeed, GSH-KO rodents display deficient multisensory integration, emotion and related social impairments.

Contact

Unit for Research in Schizophrenia
Centre de neurosciences psychiatriques
Site de Cery
CH -1008 Prilly-Lausanne
Tél. +41 21 314 3652
Fax +41 21 643 6562
Secretariat
Mrs Viveka Sari
Tél. +41 21 314 3652
 Last updated on 17/07/2019 at 10:10