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

ABSTRACT: 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 (?EP) and phase locking (?PL) 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 ?EP and ?PL 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 ?EP and ?PL. SZ patients had reduced ?EP and ?PL; memantine enhanced ?EP and ?PL (p<0.025 and 0.002, respectively) in both SZ and HS. In patients, significant correlations between age and memantine effects were detected for ?EP and ?PL: greater memantine sensitivity on ?EP and ?PL 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.

SUBMITTER: Light GA 

PROVIDER: S-EPMC5686499 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature