The Relationship Between Cortical Inhibition, Antipsychotic Treatment, and the Symptoms of Schizophrenia

Background: Cortical inhibition (CI) deficits assessed by transcranial magnetic stimulation paradigms, short-interval cortical inhibition (SICI), and cortical silent period (CSP) have been demonstrated in schizophrenia (SCZ) patients. Antipsychotic treatments can modify CI and improve clinical symptoms, suggesting a neurophysiological link between the two. Previous studies have demonstrated that clozapine is associated with prolongation in CSP, a gamma-hydroxybutyric acid (GABA)e mediated phenomenon. Furthermore, SICI deficits were associated with psychotic symptom severity, suggesting alternation in GABA(A)-mediated neurotransmission. Such differential association patterns between clinical symptoms and CI deficits and their relationship to antipsychotic treatment thus might provide insights to the pathophysiology of schizophrenia. Methods: CI was assessed in 78 SCZ patients and 38 healthy subjects. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Subjects were grouped according to antipsychotic medication status: unmedicated (n = 7), clozapine (n = 19), olanzapine/quetiapine (n = 32), and risperidone/typical antipsychotics (n = 20). Results: Relative to control subjects, patients receiving clozapine had longer CSP and reduced SIG, whereas patients receiving other antipsychotics and unmedicated patients had shorter CSP. Across all subjects with SCZ, CSP was inversely associated with negative symptoms, and SICI was inversely associated with positive symptoms. Conclusions: These results confirm that unmedicated SCZ patients have CI deficits and that clozapine treatment is associated with potentiation of GABA(B)-inhibitory neurotransmission and reduced GABA(A) inhibitory neurotransmission. Also, the differential associations among SICI, CSP, and clinical symptom dimensions suggest that GABAA and GABA(B)-mediated CI might have different roles in the pathophysiology of symptoms of schizophrenia.