Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine

Abstract

Background: Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination.

Methods: Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary).

Results: There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo.

Conclusions: Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.

Trial registration: ClinicalTrials.gov NCT03711500.

Keywords: Auditory learning; Clinical trial; Mismatch negativity; NMDA receptor; Schizophrenia; Target engagement.

Figure 1:

Bar graph for plasticity improvement, defined as change in pitch threshold [(pitch test tone – reference tone)/reference tone] from initial plateau (mean trials 20–30 of Treatment session 1) at end of treatment visit(s) after treatment 1 (A) and after treatments 2 and 3 (B). A. Includes 60 mg/kg data from Treatment visit 1 from Kantrowitz 2016. Scatter plot for Plasticity Improvement after Treatment visit 1 vs. auditory cognition (MCCB Verbal memory domain) (C) and MCCB Working Memory Domain (D).

Figure 2:

Top: Grand Average waveform for pitch mismatch negativity (MMN) by treatment group, with box showing the analyzed latency window. Bottom Left: Bar graph of mean ± standard error for pitch MMN. *p < 0.05, Bottom Right: topographical plots (headmaps) for peak MMN (200 ms).