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.

Pejman Sehatpour, Dan V Iosifescu, Heloise M De Baun, Constance Shope, Megan R Mayer, James Gangwisch, Elisa Dias, Tarek Sobeih, Tse-Hwei Choo, Melanie M Wall, Alice Medalia, Alice M Saperstein, Lawrence S Kegeles, Ragy R Girgis, Marlene Carlson, Joshua T Kantrowitz

Journal: Biological psychiatry 2023;94(2):164-173

PMID: 36958998

Free Full Text on PubMed Central View on PubMed

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.

Address: Area Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York; Nathan Kline Institute, Orangeburg, New York.; Nathan Kline Institute, Orangeburg, New York; Psychiatry, New York University Grossman School of Medicine, New York, New York.; Area Psychosis, New York State Psychiatric Institute, New York, New York.; Nathan Kline Institute, Orangeburg, New York.; Area Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.; Area Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York; Nathan Kline Institute, Orangeburg, New York. Electronic address: [email protected].

DOI: 10.1016/j.biopsych.2023.01.015

Link outs

Free resources

Full Text Sources:

https://pmc.ncbi.nlm.nih.gov/articles/pmid/3695899...

Medical:

Subscription / membership required

Full Text Sources:

MeSH Terms: Humans, Schizophrenia, Serine, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Excitatory Amino Acid Agonists, Glutamic Acid, Double-Blind Method, Neuronal Plasticity, Antipsychotic Agents