Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia

Abstract

We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms. The aim of the present study was to determine if glycine, or its ratio to serine, a precursor of glycine, predicts change in negative symptoms in subjects with schizophrenia during treatment with clozapine, an atypical antipsychotic drug with multiple effects on glutamatergic activity. Plasma levels of glycine, serine, and their ratio, were measured in 44 patients with schizophrenia who were subsequently treated with clozapine. Baseline glycine levels or glycine/serine ratios predicted the Scale for the Assessment of Negative Symptoms - Sum of the Global Scales and Avolition-Apathy after 6 wk of clozapine treatment. These results indicate the association of these amino acid measures with response to clozapine in terms of negative symptoms in patients with schizophrenia.

Clozapine interacts with the glycine site of the NMDA receptor: Electrophysiological studies of dopamine neurons in the rat ventral tegmental area

“…L-701,324, prevent and even reverse the excitatory actions of clozapine on VTA DA neurons in rats (Schwieler and Erhardt, 2003;Schwieler et al, 2004). Notably, judging from receptor occupancy data measured by ex vivo autoradiography (Leysen et al, 1993) or in vivo receptor binding (Sumiyoshi et al, 2005) 1.25 mg/kg of clozapine corresponds with clinically therapeutic doses with regard to D 2 -receptor occupancy (Nordström et al, 1993a(Nordström et al, , 1993b; Depicting the effect on firing rate of intravenous administration of clozapine (0.078 + 0.078 + 0.153 + 0.312 + 0.625 + 1.25 + 2.5 + 5 mg/kg, injected at arrows) in a) control rats, b) rats pretreated with indomethacin (50 mg/kg, i.p., 1-3.5 h), and c) rats pretreated with parecoxib (25 mg/kg, i.v., 1-1.5 h). Schotte et al, 1996;Farde et al, 1997).…”

Neurobiological basis of motivational deficits in psychopathology

“…In patients with schizophrenia, treatment with conventional antipsychotic medication, which acts through D2 antagonism, has little positive effect on negative symptoms (Kirkpatrick et al, 2006;Leucht et al, 1999;Davis et al, 2014;Arango et al, 2014). However, clozapine may improve negative symptoms (Brar et al, 1997;Buchanan, 1995) and this has been attributed to its action on glutamate transmission (Lopez-Gil et al, 2007;Sumiyoshi et al, 2005;Tanahashi et al, 2012). The main evidence for the latter is indirect: in patients who are already taking an antipsychotic, adjunctive treatment with glycine or serine appears to have no effect when it is added to clozapine (Goff et al, 1999(Goff et al, , 1996.…”

Meta-Analysis of the Efficacy of Adjunctive NMDA Receptor Modulators in Chronic Schizophrenia

“…[32] Improvement in symptoms of schizophrenia positively correlates with elevation in D-serine levels, [33] and the severity of negative symptoms inversely correlates with circulating levels of glycine, [34,35] which rise with amelioration of negative symptoms. [36] In addition, there are reports of associations between schizophrenia and gene G72, and between G72 and DAAO, [37] the enzyme that is involved in the metabolism of D-serine. [38,39] Genetic impairment in redox regulation leading to a deficiency in GSH synthesis may also be a constituent factor in the precipitation of schizophrenia.…”