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.
Keywords
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Article info
Publication history
Published online: January 27, 2023
Accepted:
January 13,
2023
Received in revised form:
January 11,
2023
Received:
August 10,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Society of Biological Psychiatry.
