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 (approximately 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> or =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> or =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> or =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

Figure 1. Total and PANSS outcomes

Baseline (filled bars) and final (open bars) mean item scores for (a) total, (b) negative, (c) positive and (d) general symptoms on the PANSS. For the study as a whole, 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. *p<0.05, **p<0.01, ***p<0.001 paired t-test, baseline vs. final

Figure 2. MATRICS Outcomes

Baseline (filled bars) and final (open bars) normalized MATRICS domains and overall mean composite (mean T-score of six tested domains) for (a) 30, (b) 60, and (c) 120 mg/kg. d. Within group effect sizes for each dose. *p<0.05 in a paired t-test between baseline and final (a–c) or on a paired t-test for doses >60mg/kg (d). #Significant (p<0.05) dose by time interaction for 30 vs. ≥60 mg/kg.

Figure 3. D-serine Pharmacokinetics

a. 24-hour pharmacokinetics of an acute dose of D-serine on day 1 of treatment. b. 4-hour pharmacokinetics after 4 weeks of chronic dosing. c. Mean plasma level over 24 hours of acute and chronic D-serine during week 1 (filled bar) and week 4 (open bar) pharmacokinetics. The Week 4 pharmacokinetics session was not done in the 30 mg/kg phase.

Figure 4. D-serine Pharmacodynamics

Regression scatter plots of D-serine plasma level vs. behavioral outcome. Circles indicate an individual patient, diamonds and indicate final and baseline mean±SEM, respectively. a. Pretreatment D-serine level vs. pretreatment PANSS negative. As PANSS scores are reported as whole numbers, circles were vertically offset to avoid superimposing subjects. b and c. Peak D-serine level on Day 1 of treatment vs. improvement in (b) PANSS negative, (c) PANSS positive. d. Peak D-serine level on Day 1 of treatment vs. post-treatment MATRICS composite.