Glycine Reuptake Inhibition as a New Therapeutic Approach in Schizophrenia: Focus on the Glycine Transporter 1 (GlyT1)
Bibliographic record
Abstract
Primary negative symptoms (affective flattening or blunting, alogia, avolition) are prominent in approximately 20% of individuals suffering from schizophrenia. These symptoms are particularly associated with impaired functional outcome and poor prognosis. This is in part due to the lack of specific and effective treatments despite the development and use of the second generation antipsychotics. There is increasing evidence that suggests that combined dysfunction of the dopamine and glutamate neurotransmitter systems may underlie some of the key clinical and pathophysiological features of schizophrenia. Specifically, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) at critical circuits within the brain appears to be an important mechanism. Thus, it would be anticipated that modulation of NMDAR function by increasing the availability of the glutamate co-agonist, glycine, within the synaptic cleft may provide a new therapeutic strategy for the management of schizophrenia. However, the direct glycine receptor agonists such as glycine and D-cycloserine (d-4-amino-3-isoxazolidinone) have demonstrated limited efficacy in studies to date. One of the most promising approaches for enhancing NMDAR function involves modification of the activity of the high affinity glycine transporter 1 (GlyT1). Numerous compounds have been synthesized, with the early compounds being substituted glycine derivatives such as sarcosine (N-methylglycine) and Org 24598. More recent developments have focused on the non-amino acid derivatives Org 25935 (cis-N-methyl-N-(6-methoxy-1- phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)amino-methylcarboxylic acid hydrochloride) and bitopertin (RG 1678). Of the molecules being investigated currently, a proof-of-concept, double-blind study of bitopertin has yielded encouraging findings, with a significant decrease in negative symptoms and no major tolerability or toxicity issues. Further studies are needed to confirm these findings and to explore the potential application of these therapies in different clinical situations in order to achieve greatest effect on negative symptoms. In addition, there is still much to be learned about this class of agents in terms of other potential domains of efficacy such as positive symptoms or cognition as well as long-term safety.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".