Glycine reuptake inhibition as a new therapeutic approach in schizophrenia: focus on the glycine transporter 1 (GlyT1).

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.