Brain hypometabolism and disorganization domain as putative neuronal correlates in schizophrenia: a comparative head-to-head treatment-resistant vs. treatment-responsive schizophrenia PET study

Background: About a third of schizophrenia patients are refractory to antipsychotics, a condition characterized by poor clinical and functional outcomes known as treatment-resistant schizophrenia (TRS). The disorganization domain may represent the leading factor in categorizing a schizophrenia patient as affected by TRS, with different putative neuroimaging correlates compared to treatment-responsive schizophrenia (nTRS) patients. Aims & Objectives: The brain metabolic pattern of antipsychotics’ clinical response in schizophrenia was tackled using 18(F)Fluorodeoxyglucose Positron Emission Tomography (FDG PET) to identify significant differences in the brain metabolism of patients with TRS compared to nTRS and their correlation with the Positive and Negative Syndrome Scale (PANSS) 5-factor model domains. Method: The study enrolled 41 patients (31 M, 10 F, age 37 ± 10, disease duration 15,5 ± 8,6, chlorpromazine equivalents 465,6 ± 368,8): 21 TRS and 20 nTRS patients. The images were acquired with 18(F)FDG PET and analyzed with the voxel-per-voxel methodology using SPM12. The clinical features were evaluated using the PANSS 5-factor model. T-test for PANSS scores was performed using SPSS (P < .01). Results: PANSS Total and Disorganization factor scores were significantly higher in TRS compared to nTRS patients. Higher PANSS Total score was negatively correlated in TRS patients to hypometabolism in the Parietal Cortex bilaterally, including the Right Inferior Parietal Lobe (BA40) and the Left Angular Gyrus (BA39). Higher Disorganization factor score was negatively correlated in TRS patients to hypometabolism in the Left Angular Gyrus and the Left Middle Frontal Gyrus (P < .001 voxel level uncorrected, P < .05 cluster level FWE-corrected). Discussion & Conclusions: Hypometabolism of the parietal cortex correlates with worse clinical outcomes in patients with TRS but not nTRS. The results demonstrate how Parietal Lobe dysfunction might be involved in the neurobiology of TRS, suggesting that the brain metabolic pattern of TRS might putatively originate from a generalized disconnection of neural circuits. Moreover, the results indicate that based on the PANSS Total score, the Disorganization factor, which is poorly influenced by antipsychotics, might be a crucial domain in categorizing schizophrenia patients as suffering from TRS. In conclusion, these data suggest that the altered metabolism in TRS patients involving discrete brain regions potentially indicates a more severe disrupted functional brain network associated with disorganization symptoms. Future studies should explore the relationship between brain metabolism and specific cognitive functions to predict the pharmacological response in schizophrenia based on cognitive and brain metabolic alterations.