Abstract
BACKGROUND: Abnormalities in brain regions involved in the pathophysiology of schizophrenia (SCZ) may present insight into individual clinical symptoms. Specifically, functional connectivity irregularities may provide potential biomarkers for treatment response or treatment resistance, as such changes can occur before any structural changes are visible. We reviewed resting-state functional magnetic resonance imaging (rs-fMRI) findings from the last decade to provide an overview of the current knowledge on brain functional connectivity abnormalities and their associations to symptoms in treatment-resistant schizophrenia (TRS) and ultra-treatment-resistant schizophrenia (UTRS) and to look for support for the dysconnection hypothesis. METHODS: PubMed database was searched for articles published in the last 10 years applying rs-fMRI in TRS patients, i.e., who had not responded to at least two adequate treatment trials with different antipsychotic drugs. RESULTS: Eighteen articles were selected for this review involving 648 participants (TRS and control cohorts). The studies showed frontal hypoconnectivity before the initiation of treatment with CLZ or riluzole, an increase in frontal connectivity after riluzole treatment, fronto-temporal hypoconnectivity that may be specific for non-responders, widespread abnormal connectivity during mixed treatments, and ECT-induced effects on the limbic system. CONCLUSION: Probably due to the heterogeneity in the patient cohorts concerning antipsychotic treatment and other clinical variables (e.g., treatment response, lifetime antipsychotic drug exposure, duration of illness, treatment adherence), widespread abnormalities in connectivity were noted. However, irregularities in frontal brain regions, especially in the prefrontal cortex, were noted which are consistent with previous SCZ literature and the dysconnectivity hypothesis. There were major limitations, as most studies did not differentiate between TRS and UTRS (i.e., CLZ-resistant schizophrenia) and investigated heterogeneous cohorts treated with mixed treatments (with or without CLZ). This is critical as in different subtypes of the disorder an interplay between dopaminergic and glutamatergic pathways involving frontal, striatal, and hippocampal brain regions in separate ways is likely. Better definitions of TRS and UTRS are necessary in future longitudinal studies to correctly differentiate brain regions underlying the pathophysiology of SCZ, which could serve as potential functional biomarkers for treatment resistance.