Journal Article

Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia

Bhakta, Savita, Light, Gregory A, Joshi, Yash B, Talledo, Jo A, Swerdlow, Neal R, Zhang, Wen

2017

Overview

Aberrant gamma-band (30-80 Hz) oscillations may underlie cognitive deficits in schizophrenia (SZ). Gamma oscillations and their regulation by NMDA receptors can be studied via their evoked power (γEP) and phase locking (γPL) in response to auditory steady-state stimulation; these auditory steady-state responses (ASSRs) may be biomarkers for target engagement and early therapeutic effects. We previously reported that memantine, an NMDA receptor antagonist, enhanced two biomarkers of early auditory information processing: prepulse inhibition and mismatch negativity (MMN) in SZ patients and healthy subjects (HS). Here, we describe memantine effects on γEP and γPL in those subjects. SZ patients (n=18) and HS (n=14) received memantine 20 mg (p.o.) and placebo over 2 test days in a double-blind, randomized, counterbalanced, cross-over design. The ASSR paradigm (1 ms, 85 dB clicks in 250-0.5 s trains at a frequency of 40 Hz; 0.5 s inter-train interval) was used to assess γEP and γPL. SZ patients had reduced γEP and γPL; memantine enhanced γEP and γPL (p<0.025 and 0.002, respectively) in both SZ and HS. In patients, significant correlations between age and memantine effects were detected for γEP and γPL: greater memantine sensitivity on γEP and γPL were present in younger SZ patients, similar to our reported findings with MMN. Memantine acutely normalized cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Ongoing studies will clarify whether these acute changes predict beneficial clinical, neurocognitive and functional outcomes. These data support the use of gamma-band ASSR as a translational end point in pro-cognitive drug discovery and early-phase clinical trials.

• Publisher: Nature Publishing Group
• Subject: Adult / Antipsychotic Agents - therapeutic use / Auditory Perception - drug effects / Auditory Perception - physiology / Biomarkers / Chronic Disease / Clinical trials / Cognition / Cognitive ability / Cortex / Cortical Synchronization - drug effects / Cortical Synchronization - physiology / Cross-Over Studies / Depressive Disorder - drug therapy / Depressive Disorder - physiopathology / Double-Blind Method / Drug discovery / Excitatory Amino Acid Antagonists - therapeutic use / Female / Frequency dependence / Gamma Rhythm - drug effects / Gamma Rhythm - physiology / Glutamic acid receptors (ionotropic) / Humans / Information processing / Male / Memantine / Memantine - therapeutic use / Mental disorders / Middle Aged / Mismatch negativity / N-Methyl-D-aspartic acid receptors / Original / Oscillations / Prepulse Inhibition - drug effects / Prepulse Inhibition - physiology / Psychotic Disorders - drug therapy / Psychotic Disorders - physiopathology / Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors / Receptors, N-Methyl-D-Aspartate - metabolism / Schizophrenia / Schizophrenia - drug therapy / Schizophrenia - physiopathology / Treatment Outcome / Young Adult