Schizophrenia Clinical Trial
Official title:
Effect of Sarcosine on Symptomatology, Quality of Life, Cognitive and Sexual Functioning, Blood Levels of Sarcosine, Glycine, BDNF and MMP-9, Oculomotor, Brain Metabolism and Oxidative Stress Parameters in Schizophrenia.
The purpose of study is to determine whether dietary supplement sarcosine is effective in treatment of schizophrenia. The investigators will assess impact of sarcosine on quality of life and sexual functioning. In this project the investigators will also measure glycine, sarcosine, BDNF, MMP-9 levels and oxydative stress parameters in blood, brain glutamatergic metabolism parameters in magnetic resonance spectroscopy and oculomotoric changes in electrooculography.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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