Molecular Research Reveals New Pathways for Treating Psychiatric Disorders—Hiroki Shiwaku
Science Tokyo Faces vol. 002
Breaking Ground in Schizophrenia Treatment Research
Psychiatric disorders, despite their known link to genetic and environmental factors, continue to challenge scientists seeking to understand how they develop, even for extensively studied conditions like schizophrenia. Making significant strides in this field, Hiroki Shiwaku, a psychiatrist and associate professor in the Department of Psychiatry and Behavioral Sciences, leads research that examines schizophrenia’s pathogenesis at a molecular and cellular level. During 2022-2023, his research team identified novel autoantibodies in schizophrenia patients’ blood and cerebrospinal fluid that could be targeted in future treatment, and in 2025, uncovered relationships between the interactions of products of high-risk genes for schizophrenia.
Discovery of autoantibodies related to schizophrenia
Shiwaku’s team is focusing its research on the psychiatric disorder schizophrenia. Symptoms include auditory hallucinations and delusions, in addition to impaired willpower and cognitive functions. It largely occurs in adolescence, and it affects as many as 1 in 100 people. The standards for making a diagnosis are based on the symptoms, and patients who are diagnosed with schizophrenia can have a variety of pathogeneses.
Current drug therapies mostly involve modulating the signals of dopamine, a neurotransmitter, but many patients do not see their symptoms make sufficient improvements. Biomarkers (physiological markers) are needed for new treatments and accurate diagnosis, and the underlying pathogeneses are starting to be understood.
Shiwaku’s focus is on the relationship between schizophrenia and autoantibodies/autoimmunity. He describes the reason for setting this focus as “if there are antibodies against synapses that are neuronal junctions, they would likely have a negative effect on the brain.” Antibodies are the primary molecules of the immune system. They provide defense when viruses or other foreign objects invade the body, but autoantibodies that attack the body’s own cells or molecules can cause various diseases. Autoantibodies that attack the brain have been found in encephalitis patients, but Shiwaku’s team has been performing research with the hypothesis that there are unknown autoantibodies that specifically cause psychiatric symptoms in cases of schizophrenia.
The team successively found two autoantibodies—anti-NCAM1 antibody and anti-NRXN1 antibody—from the blood and cerebrospinal fluid provided by patients that help explain the pathogenesis of schizophrenia. When these autoantibodies were administered to the cerebrospinal fluid of mice, synapse reduction and behavioral changes indicative of schizophrenia were observed. If these antibodies are found in patients, treatment could involve the removal of these antibodies, and they could be used as markers to identify the type of schizophrenia.
Preparation of clinical tests for treatment
Based on these achievements, Shiwaku received the President’s Award in the 6th Japan Medical Research and Development Awards in 2023 from the Japan Agency for Medical Research and Development (AMED). He stated, “I’m very thankful that this was regarded as a clinically important discovery. I think we have an important mission to keep researching how to translate these findings into treatments and diagnostics. It also provided me a chance to gain more colleagues to advance the research.” Using an immunological approach, they plan to start clinical trials for an autoantibody removal treatment within the next few years. This could lead to a new treatment strategy for patients who do not respond well to current drug therapies.
Uncovering the pathogenesis of schizophrenia with gene variants
Autoantibodies are one factor in explaining part of schizophrenia, but there are also patients where the cause is something else, meaning that autoantibodies do not provide the full explanation.
For many patients, schizophrenia is thought to be caused by a combination of changes in relatively low-risk genes. Therefore, it has been considered difficult to replicate schizophrenia in model organisms using individual genetic mutations. However, ten genes that pose a high risk of schizophrenia were reported in the journal Nature in 2022. Genes are received with one part from each parent, but if one part of the pair does not function, the risk of schizophrenia increases by 10 to 40 times.
Animals with such genetic mutations are expected to be the focus of future schizophrenia research. In 2025, Shiwaku’s research team created mice with modifications to Xpo7, a high-risk gene, and they reported the pathogenesis caused by the high-risk gene products interacting. Shiwaku stated, “Autoantibodies should be a factor that can partially explain schizophrenia. This is important for treatment strategies, but an explanation is still required for the pathogenesis in cases where autoantibodies are not the cause. Therefore, our team decided to focus on uncovering the pathogenesis by examining gene mutations. Of course, we probably won’t be able to fully understand the pathogenesis for most patients by focusing solely on individual genes, so we are also pursuing an approach to address that issue.” The results of the research are eagerly anticipated.
Figure 2: Brain pathogenesis of Xpo7 haploinsufficiency mice
Advancing research with ideas from psychiatry
Shiwaku is also a psychiatrist who sees many patients, and not only those with schizophrenia. “I was interested in neuroscience at first, but it was a natural path toward becoming a psychiatrist because there are many unexplained aspects in the pathogeneses of psychiatric disorders. Clinical psychiatry generally has an image of counseling, but the development of logical and scientific treatments is the same as in the practices of other medical fields.”
He says that when he’s in clinical environments, he can really feel “what is lacking in current psychiatry.” Current psychiatry can support patients through its three pillars: biological treatment (drug therapy, etc.), psychological treatment, and social welfare. However, Shiwaku speaks passionately, saying, “In order to get past the current limits of treatment, we must aim for treatments that are more fundamental. The drive to apply the results that we achieve from understanding pathogenesis to clinical settings is my biggest motivation for research.”
Creating the future of psychiatry with the next generation
After entering the Faculty of Medicine at Tokyo Medical and Dental University in 2003, he selected the MD-PhD course, which is a course for training medical researchers from early on. After completing four years of his six-year program at the Faculty of Medicine, he took a temporary leave to join a three-year graduate program, where he obtained a PhD through research, before going back to the Faculty of Medicine. He looked back, saying: “The biggest advantage was being able to put all of my energy as a person in my early 20s into research, allowing me to get my research skills early on.” After researching the molecular pathogenesis of neurodegenerative diseases, he became a psychiatrist and researched psychiatric disorders with his team of students. He has been reaching out to others, stating, “In the field of current psychiatry, it is possible to take an approach that is significant in terms of molecular biology,” and he has found other psychiatrists, medical students, and international exchange students who share his interest in researching molecular pathogenesis. However, in order to move forward with advanced research, he thinks people with a broader background are necessary. “With this school becoming the Institute of Science Tokyo, I hope to create the future of psychiatry and psychiatric treatment by finding more colleagues to perform research in this field, including from the science and engineering fields.”
Profile
Hiroki Shiwaku
Associate Professor, Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences
- October 2024 to Present
- Associate Professor, Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo
- October 2022
- Associate Professor, Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
- April 2019
- Assistant Professor, Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
- April 2018
- Specially Appointed Assistant Professor, Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University
- April 2016
- Doctor, Psychiatry, Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University
- April 2014
- Doctor, Psychiatry, Tokyo Metropolitan Tama Medical Center
- April 2013
- Clinical Intern, Medical Hospital, Tokyo Medical and Dental University
- April 2012
- Clinical Intern, Yokohama City Minato Red Cross Hospital
- March 2010
- Completed doctoral studies at the Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
Obtained Medical Doctorate - March 2012
- Graduated from the School of Medicine, Faculty of Medicine, Tokyo Medical and Dental University
Interview Date: November 24, 2024 / 13th floor of Building 3, Yushima Campus
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“Faces“ is an article series introducing Science Tokyo researchers and their groundbreaking work. The series highlights their efforts to unravel the mysteries of our world and address the challenges facing our society.
