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 (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.

Rodent Mismatch Negativity/theta Neuro-Oscillatory Response as a Translational Neurophysiological Biomarker for N-Methyl-D-Aspartate Receptor-Based New Treatment Development in Schizophrenia

“…Deficits in γ-generation in schizophrenia, in general, are thought to represent long-term adaptation to NMDAR blockade, mediated through downregulation of GAD67 and PV levels, rather than NMDAR dysfunction itself (Jadi et al, 2016;Rotaru et al, 2012). Nevertheless, the present study suggests a late phase of γ-band activity that may be NMDAR-sensitive, and may represent an additional target for new treatment development (Javitt et al, 2008;Light et al, 2017).…”

Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia

“…Examination of possible changes in the underlying neural substrates resulting in cortical source redistribution are of particular interest given counterintuitive decreases in MMN response [37]. Likewise, other ERP [56] or oscillatory measures [57][58][59][60] may also hold promise for predicting/monitoring response to TCT and other procognitive interventions. Although the durability of cognitive improvement several months following completion of the full course of TCT is well characterized [19], more detailed longitudinal studies examining the stability of neurophysiologic changes would be beneficial, especially in this "treatment refractory" population.…”

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

“…It is unclear how cognitive rating scales used in the other studies would translate to changes in the MCCB. The MCCB also has limitations – important cognitive measures such as sensory gating, mismatch negativity (MMN) [74, 75], and cortical oscillatory response dynamics/gamma oscillations [76] are not captured by the scale.…”