Investigation of potential biomarkers of treatment-resistant schizophrenia

Abstract

Approximately one third of all people with schizophrenia are diagnosed as having treatmentresistant schizophrenia (TRS) because they still suffer from persistent moderate-to-severe positive symptoms despite treatment with first line medications. Typically they also have poor-outcomes due to the length of time taken to reach this diagnosis which often takes many years. Clozapine remains the gold standard treatment for people with TRS where other antipsychotics have failed. Yet its use is limited by potentially fatal side effects and there is still a subset, approximately 50- 70% of patients treated with clozapine, who do not experience clinically significant improvements in their symptoms, they are then said to be clozapine-resistant or have ultra-treatment-resistant schizophrenia (UTRS). Several lines of evidence suggest that TRS may have a neurobiological basis distinct from schizophrenia that responds to different pharmacological intervention. The neurobiological basis of UTRS is yet to be investigated. Patients responsive to second generation antipsychotics (first-line responders) and those responsive to clozapine monotherapy (clozapine-responsive; TRS) were compared to each other, to those who do not respond to clozapine monotherapy (clozapine resistant; UTRS) and to a healthy control group. Two non-invasive magnetic resonance imaging (MRI) techniques were used to examine the structure and integrity of white matter pathways in the brain and potential alterations in the content of neurometabolites; diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (1H-MRS), respectively. Patients with TRS had widespread reductions in white matter (WM) integrity compared to controls. Perhaps surprisingly, responders to first-line antipsychotics and those with UTRS were indistinguishable from controls. Those with TRS had lower fractional anisotropy (FA) in the right superior longitudinal fasciculus than those with UTRS which could suggest that this region is “hyperconnected” in patients with UTRS. 1H-MRS revealed that people with TRS who are responsive to clozapine have increased glutamate + glutamine (Glx) content in the putamen compared to those with UTRS. Glx levels in the putamen may represent an important biomarker of response to clozapine treatment where levels are higher in those who are responsive and lower in those with UTRS. Reduced white matter integrity may also be a potential biomarker for individuals with TRS. Patients with UTRS are the most treatment resistant and yet WM integrity and neurometabolite content were no different to control subjects. This suggests that UTRS might have a distinct underlying pathophysiology to other forms of schizophrenia. Future research should be undertaken to investigate whether these changes are present before treatment with clozapine is initiated.