Projects listed below are likely to result in concrete solutions for the treatment and prevention of schizophrenia and other psychiatric disorders. The Alamaya Foundation aims to raise private funds needed for the implementation of these projects by the team of the Unit for Research in Schizophrenia (URS).
 

Study in young patients during first psychotic episodes

The study of the URS focusing on adult chronic patients revealed that low glutathione (agent that protects cells against toxic substances in the human body) is a key risk factor. More recently, a study aimed at young patients during their first psychotic episode allowed to corroborate the results obtained in chronic patients: biochemical anomalies concerning glutathione are not only present in young patients but much more pronounced. It is crucial to continue the study in young people at risk and extend research to a larger number of patients in order to achieve a final result - the objective being to make an early diagnosis in young psychotics and set up a treatment before the disease causes irreversible damages. 

This study allows the collection of clinical, psychopathological and neuropsychological data on one hand - as well as genetic, biochemical and imaging data on the other hand, which represent a unique source of information concerning each patient, and contribute to a better understanding of the disease. It demonstrated so far that the large majority of patients show anomalies of the "redox" balance (balance between oxidations and reductions in nerve cells), which the genetic factors previously identified by the URS can only partly explain. Thus it seems that problems of the "redox" system from various origins generally affect patients suffering from schizophrenia. These findings appear to confirm the hypothesis proposed by the URS, i.e. that the "redox" imbalance constitutes a "hub" where a large variety of chain reactions come together, which all end up by generating an "oxidative stress" (resulting from the disturbed "redox" balance). This oxidative stress, in combination with other pathogenic factors, is likely to cause anomalies of the nervous system leading to the disease.   
 

New medication

The study of a new drug, proceeding from the URS research program, led to very interesting results. The drug, a substance called N-acetyl-cysteine (NAC), provides the keycomponent for glutathione synthesis and thus helps to avoid oxidative stress. It was tested in chronic patients and produced an amelioration of their symptoms, in particular of those which are not influenced by classic medication. No negative side effects were observed.  

Knowing that the defect in glutathione synthesis is already present during the early phases of the disease, and given the results achieved with NAC in chronic patients, this drug needs to be tested in young patients during their first psychotic episode with a view to protect them against the harm occasioned by the disease in the long term. A clinical trial is presently under way (see Objectives).

Glutathione in other psychiatric disorders

Several indications suggest that the deficiencies of the glutathione metabolism observed in patients suffering from schizophrenia could also be present in bipolar disorders, major depression and autism. 

In 2008, the URS reported the discovery, in schizophrenic patients, of an anomaly in the gene of the glutathione synthesizing enzyme. This finding has since then been confirmed in a larger number of patients and was extended to other psychiatric disorders; the same anomaly is also present in patients suffering from bipolar disorders. Such a genetic "overlapping" between schizophrenic and bipolar disorders is not surprising since it has been observed for other genetic anomalies common to both affections, as well as for several cerebral anomalies. Medication that is effective in one of the diseases is often also helpful in the other.  
 

Gene constellations involved in schizophrenia

The URS has identified various genes linked to glutathione in patients. It's generally admitted that the genetic component of schizophrenia involves several genes. Some have been identified by other researchers. It would be very important to determine whether specific constellations of affected genes can be monitored in patients.  
 

Biochemistry of a key enzyme 

The URS has detected genetic anomalies in patients concerning an enzyme that is essential to the synthesis of glutathione. In order to develop a new drug, it is crucial to define the properties of this protein. This will allow to produce molecules likely to correct these deficiencies, and potentially to contribute to the treatment of patients.   
 

Experimental model

In collaboration with an American researcher, the URS was able to obtain mice whose gene responsible for glutathione synthesis was suppressed - i.e. the gene that was proved to be less efficient in patients. The development of such a mice colony requires considerable efforts and a lot of time. 

First results of the effect of low glutathione on the development of the brain have been achieved. They focus on a key structure regarding memory and affective reactions: the hippocampus. In mice whose key gene is inactivated, the ventral hippocampus shows increased oxidative stress and reduced neuronal synchronization . The animals also show behavioral deficiencies known to be dependant on the functioning of the ventral hippocampus, such as increased reactivity to stress, trouble with social behavior and the identification of objects. These observations confirm the hypothesis that a glutathione deficit during brain development occasions specific and lasting consequences similar to those reported in patients. They thus contribute to a better understanding of the underlying mechanisms of cognitive disorders that greatly handicap patients.

Another section of the brain involved in schizophrenia was also studied in the animal with a glutathione deficit: the anterior cingular cortex, in the medial part of the frontal lobe. The animal model showed that anomalies of certain neurons are also present in that particular section of the brain; these anomalies are worsened by the impact of an oxidative stress if it occurs before the animal reaches its adult age. A significant result was achieved through the administration of NAC during gestation and the young animal's life: NAC protects against the anomalies caused by oxidative stress.

In collaboration with Professor Rolf Gruetter, director of the Centre for Biomedical Imaging (CIBM) at the Federal School of Technology in Lausanne (EPFL), the URS studied - in the mouse with low glutathione - alterations of cerebral molecules which can be detected and measured by magnetic resonance spectroscopy (MRS) at very high resolution (14 Tesla). This highly sophisticated method has the advantage of being non-invasive and can be used repeatedly in the same subjects during their development; it is a prime metod in translational research since MRS investigations are also undertaken in patients.
In the young animal, certain changes are very similar to those observed in patients; in particular, the ratio between two important amino-acids (glutamine and glutamate) increases likewise in the model and in patients. Significantly, treatment with NAC during the animal's whole life, from gestation onwards, restores normal values.

The animal model described above is not only important for a better understanding of the disease but also essential to the development of new drugs, the effectiveness and innocuousness of which must be tested in animals before they can be studied in humans.