Improving treatment of patients with schizophrenia - glutamatergic and GABAergic disturbances as possible markers of choice-of-treatment

Background: Insufficient treatment response to dopaminergic antipsychotics constitutes a major challenge in the treatment of patients with schizophrenia and seems to be related to persistently high levels of the neurotransmitter glutamate. Excess glutamate is neurotoxic and highly likely causes the progressive loss of brain tissue and functions seen in many patients. The neurotransmitter gamma-amino-butyric-acid, (GABA), regulates levels of glutamate, and hypofunctional GABAergic interneurons may cause the high levels of glutamate in patients with schizophrenia.
Objectives: To test the hypothesis that a subgroup of initially antipsychotic naïve patients with schizophrenia with poor treatment response is characterized by persistently high levels of glutamate in two interconnected brain areas termed the anterior cingulate cortex (ACC) and thalamus. Further, we wish to clarify the relationship between levels of glutamate and GABA and psychopathology as well as level of function.
Methods: The study is a prospective follow-up study of 60 antipsychotic naïve patients with schizophrenia and 60 matched healthy controls. Levels of glutamate and GABA are measured with proton magnetic resonance imaging (1H-MRS) before and after 6 weeks’ treatment with a partial dopamine agonist (aripiprazol) and treatment response by clinical rating scales measuring psychopathology and level of function. Patients are retested after 6 months and 2 years.
Results: Inclusion started on 1 January 2014. To date, 5 of the planned 60 patients have been included. Preliminary analyses based on the first included patients will be presented at the meeting.
Conclusion: Elucidation of glutamatergic and GABAergic disturbances in a presumed subgroup of patients is clinically crucial. The results can pave the way for development of new antipsychotic medication modulating glutamatergic and GABAergic disturbances and lead to better prevention strategies for the progressive loss of brain tissue and functions. Lastly, it is the hope that glutamatergic disturbances in the future can be used as a clinical marker for best choice of treatment in the clinical practice.