The cortical silent period in schizophrenia: A systematic review and meta-analysis focusing on disease stage and antipsychotic medication

Abstract

Background: Although numerous studies reported some changes of cortical silent period (CSP), an indicator of gamma-aminobutyric acid (GABA) function in central nervous system, in schizophrenia patients, it has been unknown how the disease stage and antipsychotic medication affect CSP values. Methods: The present study conducted a systematic review of previous literature comparing CSP between schizophrenia patients and healthy subjects, and then performed meta-analysis on the effects of (1) the disease stage and (2) antipsychotics on CSP. Results: (1) In the comparison of the disease stage comprising a total of 17 reports, there was no significant difference in CSP between patients under drug-naïve first-episode psychoses and healthy controls, or between patients with antipsychotic medication and healthy controls. (2) In the comparison of the antipsychotic class, patients treated with clozapine were longer in CSP compared to healthy controls. Patients treated with olanzapine/quetiapine or with other type of antipsychotics were not different from healthy controls. Regarding other type of antipsychotics, the iteration analysis after leaving out one literature showed that patients were shorter in CSP than healthy controls. Conclusion: The results showed that clozapine seems to surely prolong CSP, indicating the enhancement of GABA transmission via GABAB receptors, suggesting the possible relationship between the CSP prolongation by clozapine and its high efficacy in psychopathology. The finding of shorter CSP in patients with other type of antipsychotics was distinct from clozapine/olanzapine/quetiapine, but was difficult to interpret since this group included a variety of transcranial magnetic stimulation (TMS) methodologies and patients’ background.

Neuroimaging in schizophrenia: A review article

“…Keedy et al (2009) also found an increase in bilateral supplementary eye fields, left frontal eye fields, and bilateral cerebellum functional activity during visual attention and sensorimotor tasks and a decrease activity in other distributed brain regions in patients treated with risperidone, ziprasidone, or haloperidol. Miyazawa et al (2022) noted that that clozapine prolongs cortical silent period (the interruption of voluntary muscle contraction following a motor-evoked potential triggered by transcranial magnetic stimulation over the primary motor cortex) due to increase GABA transmission with GABA B receptors. Sarpal et al (2015) examined the association between antipsychotic treatment (e.g., aripiprazole or risperidone) and activity changes in striatal areas of the brain in patient with schizophrenia via resting-state fMRI.…”

“… Miyazawa et al (2022) noted that that clozapine prolongs cortical silent period (the interruption of voluntary muscle contraction following a motor-evoked potential triggered by transcranial magnetic stimulation over the primary motor cortex) due to increase GABA transmission with GABA B receptors.…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…An impaired ability to filter external auditory sensory information mediated by altered GABA B receptor firing has been associated with schizophrenia [ 117 , 118 ]. Specifically, an increase in the cortical silent period directly correlated with GABA function was observed in clozapine-treated patients compared to other antipsychotics [ 119 , 120 ], suggesting clozapine’s ability to improve signal-to-noise discrimination [ 121 ], potentially through the potentiation of GABA B -mediated inhibitory transmission [ 119 , 122 ]. Through X-ray crystal structure analysis, a recent study demonstrated that clozapine binds directly to the GABA B similarly to baclofen, a GABA B receptor agonist proposed as a non-canonical antipsychotic [ 122 ].…”

Effects of Clozapine on Cortical Inhibition

“…The effect of clozapine on preexistent excitation-inhibition imbalance in schizophrenia has been studied only in a few TMS studies, and the results are inconsistent. Cross-sectional studies demonstrated shorter CSP durations in unmedicated or non-clozapine antipsychotic users compared with clozapine users 18,37,38 . Short-interval intracortical inhibition was not different between healthy controls, unmedicated patients, and clozapine users in one study 18 .…”