Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial (2015)

Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised, double-blind, placebo-controlled trial.

Objectives Hypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, a d-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients. Methods This study compared add-on sarcosine (2 g/day) plus benzoate (1 g/day) vs. sarcosine (2 g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12. Results Adjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved. Conclusions This finding suggests N-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms

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Supplementation of antipsychotic treatment with sarcosine-G1yT1 inhibitor-causes changes of glutamatergic 1NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia. (2015)

Supplementation of antipsychotic treatment with sarcosine-G1yT1 inhibitor-causes changes of glutamatergic 1NMR spectroscopy parameters in the left hippocampus in patients with stable schizophrenia.

Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission. The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance (1H NMR) spectroscopy (1.5T). Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n=25) or placebo (n=25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS). In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups. This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.

“Sarcosine – an exogenous amino acid – is serving in the brain as a glycine transporter type 1 (GlyT-1) inhibitor and as a source of glycine (natural coagonist of the NMDA receptor, metabolized from sarcosine by sarcosine dehydrogenase). It was reported to be effective in treating negative and cognitive symptoms .

Supplementation of sarcosine at a 2 grams daily dose is supposed to increase glycine concentration and normalize hypofunction of the NMDA receptors, which are present in high density in the the prefrontal cortex and hippocampus – areas associated with development of cognitive and negative symptomatology”

table 3
Study results

“We conclude that augmentation of the antypsychotic treatment with sarcosine may reverse the increase in glutamatergic transmission in the left hippocampus in schizophrenia along with improvement of mental state, assessed with the PANSS. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus.”

See more:

Sarcosine Therapy – A New Complementary Direction for Schizophrenia Treatment?

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study. (2015)

Glycinergic, NMDA and AMPA augmentation – a review

GlyT1 inhibitors

Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex.

GlyT1 inhibitors

GlyT1 inhibitors may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects [1]. Similarly, GlyT1 inhibition is a potential therapeutic strategy in addressing the symptom domains of autism spectrum conditions [2].

Based on an animal model (reduced Sp4 expression in mice), GlyT1 inhibition may have promise in treating attentional deficits in neuropsychiatric patients but not learning or motivational deficits [3]:

“…by using this model relevant to schizophrenia, we demonstrated that GlyT-1 inhibition (Org 24598) significantly reversed the attentional but not learning or motivational deficits of these mice. Interestingly, GlyT-1 inhibition impaired the attention of WT littermate mice without affecting their learning or motivation. These data support GlyT-1 inhibition as a potential treatment for attentional but not positive valence deficiencies (negative symptoms) related to schizophrenia as well as a U-shape dose response of optimal synaptic glycine levels for attentional performance.”

That said:

“…the inability of GlyT1-inhibition to remediate behaviors relevant to negative symptoms is surprising given that: (1) lower plasma and cerebrospinal fluid glycine level of patients with schizophrenia is linked to negative symptoms (Hashimoto et al, 2003); and (2) glycine treatment (although chronic) modestly lowers negative symptom ratings (Heresco-Levy et al, 1999; Javitt et al, 1994). However, such positive findings have not always been reproduced (Buchanan et al, 2007). In fact, Roche recently stopped trials testing a GlyT-1 inhibitor for the improvement of negative symptoms in schizophrenia, perhaps due in part to the sole reliance on clinical rating scales rather than objective translational laboratory tests as primary outcome measures. Testing negative symptoms using laboratory-based measures with relevance to those presented here may provide more relevant cross-species findings (Barnes et al, 2014; Der-Avakian et al, 2013; Young et al, 2013b) and greater sensitivity to the effects of GlyT-1 inhibitors. Constitutively reducing Sp4 expression in mice resulted in impaired attention that was remediated by GlyT-1 inhibition. The finding that this treatment did not remediate motivational deficits suggests that the attentional deficits of Sp4 mice are unlikely a result of altered motivation or learning. The lack of effect on motivation could be because of a requirement of longer treatment duration, although it improved attention acutely. Alternatively, more direct NMDAR1 activation may be required. Furthermore, the mechanism(s) underlying impaired motivation and learning resulting from reduced Sp4 expression have yet to be delineated. As SP4 regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B (Priya et al, 2014; Priya et al, 2013), further investigation of other mechanisms using these mice is warranted.

In conclusion, reduced Sp4 expression in mice largely recreates the attentional deficits observed in patients with schizophrenia as measured by the 5C-CPT (Young et al, 2013a). These data support pairing attentional assessment with evidence of reduced SP4 levels in peripheral blood mononuclear cells, as seen in first-episode patients with schizophrenia (Fuste et al, 2013). Such an approach might provide a useful personalized biomarker for predicting whether GlyT-1 inhibition may remediate attentional deficits in individual patients. However, such treatment would unlikely treat impaired positive valence related to reward anticipation. SP4 rare copy number variations and reduced protein levels are linked to several psychiatric disorders that exhibit attentional deficits including schizophrenia, bipolar disorder, and major depressive disorder (Pinacho et al, 2011; Shi et al, 2011; Tam et al, 2010; Zhou et al, 2009). Hence, identifying the mechanism(s) of how reducing Sp4 levels negatively affect attention and the neurobiology underlying GlyT-1 inhibition-induced reversal of these effects will prove vital. Importantly though, the present work using this model organism provides opportunities for personalized medicine for the treatment of attentional deficits in neuropsychiatric patients having low SP4 levels (McMahon and Insel, 2012).”

Sarcosine, a simple GlyT-1 inhibitor, has demonstrated some promising potential [4, 5]. Some worsening of symptoms has been noted at doses in excess of 2000mg [6] and a case of hypomania has been reported [7]. Antidepressant effects have also been reported [8].

Regulation of GlyTs:

BDNF, acting on TrkB receptors, inhibits glycine uptake in astrocytes by promoting GlyT internalization through a Rho-GTPase activity dependent mechanism [9]. GSK3β is important for stabilising and/or controlling the expression of functional GlyTs on the neural cell surface [10].

A soon to be published article may be of interest:

Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there are no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation [link out]

See more:

Sarcosine Therapy – A New Complementary Direction for Schizophrenia Treatment?

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study. (2015)

Glycinergic, NMDA and AMPA augmentation – a review

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study. (2015)

A study expanding on previous research [see: Glycinergic, NMDA and AMPA augmentation – a review ] on the use of sarcosine in schizophrenia has recently been published:

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia – preliminary study.

BACKGROUND: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N-methylglycine an inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia.

METHODS: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients.

RESULTS: Significant improvement was observed after one week of treatment on PANSS sub-scale of ‘positive symptoms’ (Z= -2.68; P=0.007) and ‘general psychopathology’ (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively.

LIMITATIONS: This was a short period, open label pilot study with small sample size per dosage group.

CONCLUSIONS: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia.


From Examine.com:

“When looking at studies using sarcosine, 2,000mg sarcosine daily for six weeks in addition to antipsychotics noted improvements in symptoms in the range of 14-16% (BPRS and PANSS rating scales) reaching up to around 20% symptom reduction relative to control.

One study in persons on clozapine failed to find a benefit with sarcosine therapy at 2,000mg which is similar to null results seen with D-serine. Since clozapine is thought to be antipsychotic via D-serine signalling this signalling pathway may already be saturated in persons on clozapine.

This magnitude of response seen with sarcosine is somewhat comparable to D-Serine at a similar dose, Glycine at a higher dose (800mg/kg), and D-cycloserine. In direct comparative studies, however, sarcosine has been twice noted to outperform D-serine which may be due to the unreliability seen with D-serine supplementation.

It should be noted that some studies by the author Guochuan Tsai have potential conflicts of interest due to the aforementioned being the creator of sarcosine (US patent 6228875) alongside Joseph Coyle. These studies include the following, although publication bias does not seem likely as the authors have published negative results previously.”

Sarcosine at 2,000mg appears to be just as effective as D-serine for treating symptoms of schizophrenia when looking at the magnitude of benefit, but sarcosine seems to be more reliable and is thus currently seen as being a better therapeutic alternative