Clozapine, an antipsychotic medication used for patients with schizophrenia who do not respond to standard treatments (treatment-resistant schizophrenia, TRS), appears to change the brain’s microstructure, researchers in Korea have found.
The findings, published in Translational Psychiatry, suggest that MRI texture analysis could one day help doctors predict which patients with treatment-resistant schizophrenia are more likely to respond to clozapine before the treatment initiation.
The study was led by Kim Euitae, a Professor at the Department of Neuropsychiatry in Seoul National University Bundang Hospital (SNUBH). The research team included Moon Sun Young(Assistant Professor, Department of Neuropsychiatry, SNUBH) and Jo Wonik of Seoul National University’s Department of Brain and Cognitive Sciences, who were co-first authors.
Schizophrenia is a severe mental illness that can cause delusions, hallucinations, and disorganized thoughts or behavior. Diagnosis can be made when such symptoms persist for more than six months. The symptoms of schizophrenia can make it difficult for patients to maintain their studies, occupation, or social relationships. But early diagnosis and sustained treatment can help patients relieve their symptoms and help them return to daily life.
Most patients are treated with antipsychotic drugs, which help regulate brain neurotransmitters such as dopamine or serotonin. But about 30 percent of patients do not respond adequately even after two or more trials of standard antipsychotic medications. They are classified as having treatment-resistant schizophrenia, posing a significantly increased disease burden.
For these patients, clozapine is the only FDA-approved treatment option. However, its mechanism of action has remained unclear.
That has left psychiatrists with a difficult problem: clozapine may exert its effects when other antipsychotics fail, but there has been no clear method to predict who will benefit from this treatment. Unfortunately, clozapine still fails to improve symptoms in 40 percent to 70 percent of patients with treatment-resistant schizophrenia, the researchers wrote.
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From left, Seoul National University Bundang Hospital (SNUBH), Professor at the Department of Neuropsychiatry, Kim Euitae; also at the SNUBH, Assistant Professor at the Department of Neuropsychiatry, Moon Sun Young, and M.Sc. at the Seoul National University Brain and Cognitive Sciences, Jo Wonik (Courtesy of SNUBH)
Kim said in a hospital statement that many patients receive clozapine only after trying at least two first-line drugs without success, delaying the start of treatment that may be effective even earlier in the disease process, which may improve longer-term prognoses of these patients.
“This study could help predict in advance which patients are likely to respond to clozapine, reduce unnecessary prolonged treatment with less effective antipsychotic medications, and serve as an evidence that may bring forward the earlier initiation of clozapine treatment,” Kim said.
The SNUBH team sought to answer that question by examining microstructural brain changes that conventional MRI analysis often misses.
Standard MRI analysis usually measures larger structural features, such as brain volume or thickness. It is less useful for detecting microstructural changes occuring at the brain tissue level.
The researchers instead used texture analysis, a method that studies brightness patterns in MRI images at a very minuscule level. The authors wrote that the technique may detect subtle, microstructural tissue changes sensitiviely before larger structural changes become visible.
The study included 33 patients with treatment-resistant schizophrenia and 31 patients whose schizophrenia responded to standard treatment. The treatment-resistant group received clozapine for 18 weeks. The treatment-responsive group received standard antipsychotics for the same period.
All patients had brain MRI scans before and after treatment.
After 18 weeks, patients treated with clozapine showed significant texture changes in the left caudate nucleus, a deep brain region linked to dopamine circuits in schizophrenia. The change was observed regardless of whether the patients responded clinically to the drug.
In the paper, the researchers said the changes suggested a “shared neural reorganization” potentially linked to clozapine treatment. Put more simply, the drug appeared to alter the microstructure of the caudate nucleus even in patients whose symptoms did not improve enough to count as a treatment response.
Patients treated with standard antipsychotics did not show the same significant change.
The result suggests clozapine itself may alter brain microstructure, especially in the caudate nucleus, the team said.
The study also found a difference between patients who responded to clozapine and those who did not. Both groups showed similar brain changes after treatment. But their brain microstructure, as reflected by texture feature, was different before treatment began.
Before receiving clozapine, the 15 patients who later responded to the drug had a less complex microstructure in the left caudate nucleus than the 18 patients who did not respond.
Among the responders, patients with less complex microstructure at baseline showed greater improvement in positive symptoms such as delusions and hallucinations, according to the paper. In the non-responder group, however, greater baseline complexity was linked to greater improvement in general and total symptom scores.
Source: https://www.koreabiomed.com/news/articleView.html?idxno=31603
