High dose D-serine in the treatment of schizophrenia

Abstract

Background D-serine is an allosteric modulator of the brain N-methyl-D-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (~2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of D-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day). Methods 42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses ≥30 mg/kg was also evaluated. Results Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses ≥60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function. Discussion These findings support double-blind investigation of D-serine at doses ≥60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

Role of astrocytes in alterations of glutamatergic neurotransmission in schizophrenia

“…Считают, что особенно оправданно использование D-серина, который обладает высоким сродством к глицино-вому сайту NMDA-рецепторов и легко проникает через ге-матоэнцефалический барьер. По данным некоторых иссле-дователей [86,87], добавление D-серина к обычной нейро-лептической терапии существенно повышает ее эффектив-ность, особенно в отношении негативных симптомов.…”

D-Serine in Neuropsychiatric Disorders: New Advances

“…A number of clinical studies [62,65,[88][89][90] have demonstrated that adjuvant DSR (30-120 mg/kg/day) added to ongoing treatment with non-clozapine antipsychotics results in significant symptom improvements in chronic schizophrenia patients. The most significant changes were registered in the negative symptom cluster ( Figure 2).…”

“…Two schizophrenia treatment issues stemming from these findings are the potential use of DSR for improving cognition and as stand-alone pharmacotherapy in this disorder. In a preliminary four week open-label study [65], it was shown that high dose DSR (≥60 mg/kg/day) improves neurocognitive functions as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. An additional controlled pilot investigation [93] compared the effectiveness of DSR (3 g/day) versus high-dose olanzapine (30 mg/day) as antipsychotic monotherapy in 18 treatment-resistant schizophrenia patients.…”

Cognitive Remediation for Schizophrenia

“…102) Because glycine modulates NMDA receptor function, the glycine agonist D-serine is under investigation and has shown positive preliminary results, while, inhibitors of glycine reuptake are also being studied. 105) Studies of GABAergic agents, such as MK-0777-a GABA (A) α2/α3 partial agonist have produced conflicting results thus far. 106) Modafinil and d-amphetamine have promising pro-cognitive effects, though their clinical use for this purpose in schizophrenia patients remains to be established.…”