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?
advancingschizophreniatherapeutics 