Effect of Sarcosine on Symptomatology, Quality of Life, Oxidative Stress and Glutamatergic Parameters in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Sarcosine
Intervention type(s): Dietary Supplement
Intervention description(s): Sarcosine group patients will receive 2 grams of sarcosine once a day in the morning for 6 months.
Placebo group patients will receive 2 grams of placebo once a day in the morning for 6 months.
Other intervention name(s): glycine transporter inhibitor; GlyT1 inhibitor
Intervention MeSH terms: Glycine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: glutamic acid; sarcosine; NMDA; schizophrenia