Effect of Sarcosine on Symptomatology, Quality of Life, Oxidative Stress and Glutamatergic Parameters in Schizophrenia (PULSAR)

Glutamic acid is the largest excitatory neurotransmitter in the central nervous system, the population of glutamatergic neurones represents approximately 50% of all neurones in the brain. Being closely dependent on the inhibitory GABA system, the glutamate system is responsible for the transmission and modulation of the majority of brain signals and connected with dopaminergic and serotonergic systems. The glutamate system plays an important role in the pathogenesis of schizophrenia. NMDA receptor antagonists, including phencyclidine, ketamine and MK-801, cause symptoms similar to those found in schizophrenia, as well as deterioration of mental state in patients with schizophrenia. What is important from a theoretical point of view NMDA agonists also cause negative symptoms which are not observed after amphetamine or other drugs intoxications. Based on these observations, it was assumed that normalization of glutamatergic transmission may result in an improvement in schizophrenia symptomatology.

According to the assumptions of this hypothesis, attempts were made to stimulate transmission within this system. Due to the high risk of excitotoxic effects induction therapy with glutamic acid is not administered (hyperactivity of glutamatergic system, leading to nerve cell damage was observed in neurodegenerative diseases). Along with glutamic acid and voltage changes dependent on another glutamatergic receptor - AMPA, presence of glycine is necessary to stimulate the NMDA receptor. This widely distributed amino acid, an important element of protein chains, is present in a daily diet (average consumption amounts to 2g/day). In addition to building properties, it is of paramount importance in the central nervous system. As a primary transmitter in glycinergic neurones it belongs to the class I of neurotransmitters. Moreover, it also plays a role as a co-agonist and a modulator, for example in the glutamatergic system. Glutamic acid is released from nerve endings into the synaptic cleft, where it is re-uptaken and dispersed, which, in consequence, results in a rapid decline in its concentration in the vicinity of NMDA receptors. As a result, the time of receptor binding is short. Intrasynaptic glycine turnover is different - it resides inside the synapses permanently, depending on the concentration and, to a greater or lesser extent, binds to a modulatory site. Glial cells, with identified glycine transport system (GlyT-1) are responsible for maintaining a stable level of glycine in neuronal junctions. New research on inhibitors of this transport system (GTI) eg. sarcosine, which may have similar or better effects to glycine administration, have begun. Glycine does not bind to all the modulatory sites on NMDA receptor in vivo, and augmentation of this saturation intensifies glutamatergic transmission. This phenomenon is particularly observed in individuals with relatively low (not sufficient for maximum saturation of the receptor site) levels of synaptic glycine.

We hypothesize that supplementation of sarcosine helps achieve betterment in symptomatology, general quality of life and also cognitive functioning and other prefrontal derivatives, eg. oculomotor functions.

To extend research we planned assessing blood levels of glycine, sarcosine but also other parameters involved in glutamatergic transmission such as BDNF and metalproteinase MMP-9. Knowing excitotoxic properties of glutamate TBARS (thiobarbituric acid reactive substances) - oxidative stress related will be assessed.

Methodology of the study. We plan to enroll 60-70 patients in stable mental state meeting criteria for schizophrenia according to ICD-10 with predominant negative symptoms (minimum of 21 points and severity of each negative symptom at least 3 points in PANSS-Negative subscale).

Main study part will be continued for 26 weeks (T0-T26) and 10 visits (W1-W10). The preceding 12-week period (W0-W1) will be used for evaluation of stability of mental state and pharmacotherapy.

Patients on visit T0 will be randomized to two comparable groups of 30 patients (sarcosine and control group). Researchers and patients will not have information on the administered treatment.

During the study patients will receive previous antipsychotic treatment (at least 3-month without dosage change). Mental stability will be assessed during the preceding period (W1 and W0 visit - 12 weeks before W1). Sarcosine (or placebo) will be augmented between visits W1 and W9, the subsequent period (between W9 and W10), will be used to evaluate the consequences of withdrawal sarcosine (and placebo).

Information on the history of the disease, and current mental status will be obtained during the psychiatric examination, in part, standardized by the use of commonly accepted psychiatric scales (PANSS, Calgary Depression Scale, CGI, SAS and quality of life and sexual activity scales). Assessment of the use of psychiatric scales will be used on each of the visits.

As the basic tools used to study cognitive functioning test Wisconsin Card Sorting (WCST), Trail Making Test (TMT) and Stroop Test will be used. Psychological testing will be performed by a psychologist on visits W1, W6 and W9.

Assessment of metabolism of glycine and glutamic acid in brain tissue in the frontal cortex and hippocampus using magnetic resonance spectroscopy, electrooculography, parameter of oxidative stress - T-BARS and blood assessments (glycine, sarcosine, BDNF and MMP-9) will be performed on visits W1 and W9.