Neuroimaging findings in treatment-resistant schizophrenia: A systematic review

Abstract

Background Recent developments in neuroimaging have advanced understanding biological mechanisms underlying schizophrenia. However, neuroimaging correlates of treatment-resistant schizophrenia (TRS) and superior effects of clozapine on TRS remain unclear. Methods Systematic search was performed to identify neuroimaging characteristics unique to TRS and ultra-resistant schizophrenia (i.e. clozapine-resistant [URS]), and clozapine's efficacy in TRS using Embase, Medline, and PsychInfo. Search terms included (schizophreni*) and (resistan* OR refractory OR clozapine) and (ASL OR CT OR DTI OR FMRI OR MRI OR MRS OR NIRS OR PET OR SPECT). Results 25 neuroimaging studies have investigated TRS and effects of clozapine. Only 5 studies have compared TRS and non-TRS, collectively providing no replicated neuroimaging finding specific to TRS. Studies comparing TRS and healthy controls suggest hypometabolism in the prefrontal cortex, hypermetabolism in the basal ganglia, and structural anomalies in the corpus callosum contribute to TRS. Clozapine may increase prefrontal hypoactivation in TRS although this was not related to clinical improvement; in contrast, evidence has suggested a link between clozapine efficacy and decreased metabolism in the basal ganglia and thalamus. Conclusion Existing literature does not elucidate neuroimaging correlates specific to TRS or URS, which, if present, might also shed light on clozapine's efficacy in TRS. This said, leads from other lines of investigation, including the glutamatergic system can prove useful in guiding future neuroimaging studies focused on, in particular, the frontocortical-basal ganglia-thalamic circuits. Critical to the success of this work will be precise subtyping of study subjects based on treatment response/nonresponse and the use of multimodal neuroimaging.

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

“…These findings are consistent with the two other reviews of treatment-resistant vs treatment-responsive patients [48, 53] which identified studies demonstrating reduced grey matter; however again, the 2015 review is more cautious stating no consistent findings based on the two they discuss, while the 2016 review identifies seven studies and thus highlights reduced grey matter (particularly in frontal regions) as one of the features of treatment-resistance. The latter also suggest that these structural differences could be caused by high concentrations of glutamate, providing a plausible link between these findings within the neuroimaging literature.…”

“…One 2015 review [53] reported the Demjaha et al findings but concluded there were no consistent findings in the field, whereas the 2016 Mouchlianitis et al review [48] reported both papers included in the present review and highlighted both elevated glutamate in the ACC and elevated Glx in the putamen of clozapine responders as features of treatment-resistance.…”

Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia

“…More research is needed to better understand the potential "subtypes" of schizophrenia [103]. Such research will likely be guided by elucidating brain-specific biomarkers associated with clinical nonresponse to antipsychotics [104].…”

Resting-State Isolated Effective Connectivity of the Cingulate Cortex as a Neurophysiological Biomarker in Patients with Severe Treatment-Resistant Schizophrenia

“…As the quality of life in patients with TRS is remarkably disturbed through their lifespan, understanding the pathophysiology of TRS is a priority for mental health research. However, the neural basis of TRS, especially the difference from non-treatment resistant schizophrenia (nTRS), remains unclear [ 3 ].…”