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Clozapine, a drug used for patients with schizophrenia who do not respond to standard treatments, 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 drug is given.
The study was led by Professor Kim Eui-tae, a neuropsychiatrist at Seoul National University Bundang Hospital (SNUBH). The research team included Moon Sun-young of the hospital’s neuropsychiatry department and Jo Won-ik 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 disordered thinking for more than six months. It can make it difficult for patients to maintain relationships, study, or work. But early diagnosis and steady treatment can help many patients return to daily life.
Most patients are treated with antipsychotic drugs, which help regulate brain chemicals such as dopamine. But about 30 percent of patients do not respond after trying at least two standard antipsychotics. They are classified as having treatment-resistant schizophrenia.
For these patients, clozapine is often the final treatment option. In the paper, the researchers called it the “gold-standard treatment” for treatment-resistant schizophrenia, but said, “its mechanism of action remains unclear.”
That has left doctors with a difficult problem: clozapine can work when other drugs fail, but there has been no clear way to know in advance who will benefit. The drug still fails to improve symptoms in 40 percent to 70 percent of patients with treatment-resistant schizophrenia, the researchers wrote.
From left, Seoul National University Bundang Hospital (SNUBH) psychiatry professor Kim Eui-tae, psychiatry professor Moon Sun-young, and Seoul National University brain and cognitive sciences researcher Jo Won-ik (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 work.
“This study could help predict in advance which patients are likely to respond to clozapine, reduce unnecessary drug prescriptions, and bring forward the start of appropriate treatment,” Kim said.
The SNUBH team sought to answer that question by examining 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 smaller changes inside brain tissue.
The researchers instead used texture analysis, a method that studies brightness patterns in MRI images. The authors wrote that the technique may detect subtle tissue changes 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 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 fine structure 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 structure 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 more complex microstructure showed less 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.
Kim Ji-hye
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