Quantitative electroencephalography parameters as neurophysiological biomarkers of schizophrenia-related deficits: A Phase II substudy of patients treated with iclepertin (BI 425809)

Abstract

Patients with schizophrenia experience cognitive impairment related to neural network dysfunction and deficits in sensory processing. These deficits are thought to be caused by N-methyl-D-aspartate receptor hypofunction and can be assessed in patient populations using electroencephalography (EEG). This substudy from a Phase II, randomized, double-blind, placebo-controlled, parallel-group study investigating the safety and efficacy of the novel glycine transporter-1 inhibitor, iclepertin (BI 425809), assessed the potential of EEG parameters as clinically relevant biomarkers of schizophrenia and response to iclepertin treatment. Eligible patients were randomized to once-daily add-on iclepertin (2, 5, 10, or 25 mg), or placebo (1:1:1:1:2 ratio) for 12 weeks. EEG data were recorded from a subgroup of patients (n = 79) at baseline and end of treatment (EoT). EEG parameters of interest were mismatch negativity (MMN), auditory steady-state response (ASSR), and resting state gamma power, and their correlations with clinical assessments. At baseline, MMN and ASSR exhibited consistent correlations with clinical assessments, indicating their potential value as neurophysiological biomarkers of schizophrenia-related deficits. ASSR measures were positively correlated to the MATRICS Consensus Cognitive Battery overall and neurocognitive composite scores; MMN amplitude was positively correlated with Positive and Negative Syndrome Scale scores. However, correlations between change from baseline (CfB) at EoT in clinical assessments, and baseline or CfB at EoT for EEG parameters were modest and inconsistent between dose groups, which might indicate low potential of these EEG parameters as predictive and treatment response biomarkers. Further methodological refinement is needed to establish EEG parameters as useful drug development tools for schizophrenia.

Trial registration: ClinicalTrials.gov NCT02832037.

Fig. 1. EEG parameters as neurophysiological biomarkers.

Spearman correlation of amplitude of MMN deviants, ASSR parameters, and gamma band power with all clinical assessments (A), MCCB overall composite T-score (B), and PANSS total score (C) at baseline. + Correlation coefficient ≥0.3 and p < 0.05; − correlation coefficient ≤ −0.3 and p < 0.05. ASSR auditory steady-state response, EEG electroencephalography, LNS letter-number span, MATRICS Measurement and Treatment Research to Improve Cognition in Schizophrenia, MCCB MATRICS Consensus Cognitive Battery, MMN mismatch negativity, NAB neuropsychological assessment battery, PANSS positive and negative syndrome scale, PLF phase-locking factor, TMTA Trail Making Test Part A, WMS-III SS Wechsler Memory Scale 3rd edition, Spatial Span.

Fig. 2. EEG parameters as treatment response biomarkers.

Spearman correlation of CfB in EEG parameters with CfB in clinical assessments in combined 10 + 25 mg dose groups (A) and placebo group (B). + Correlation coefficient ≥0.3 and p < 0.05; − correlation coefficient ≤ −0.7 and p < 0.05; − correlation coefficient ≤ −0.3 and p < 0.05. ASSR auditory steadystate response, CfB change from baseline, EEG electroencephalography, LNS letter-number span, MATRICS Measurement and Treatment Research to Improve Cognition in Schizophrenia, MCCB MATRICS Consensus Cognitive Battery, MMN mismatch negativity, NAB neuropsychological assessment battery, PANSS positive and negative syndrome scale, PLF phase-locking factor, TMTA Trail Making Test Part A, WMS-III SS Wechsler Memory Scale 3rd edition, Spatial Span.

Fig. 3. EEG parameters as predictive biomarkers.

Spearman correlation of EEG parameters at baseline with CfB in clinical assessments in the combined 10 + 25 mg dose groups (A) and placebo group (B). + Correlation coefficient ≥0.3 and p < 0.05; − correlation coefficient ≤ −0.3 and p < 0.05. ASSR auditory steady-state response, CfB change from baseline, EEG electroencephalography, LNS letter-number span, MATRICS Measurement and Treatment Research to Improve Cognition in Schizophrenia, MCCB MATRICS Consensus Cognitive Battery, MMN mismatch negativity, NAB neuropsychological assessment battery, PANSS positive and negative syndrome scale, PLF phase-locking factor, TMT-A Trail Making Test Part A, WMS-III SS Wechsler Memory Scale 3rd edition, spatial span.