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Treating and preventing mental illness from a molecular perspective

Creating a treatment for depression by focusing on glia

Currently, antidepressants used to treat depression are effective for many patients, but approximately 30% of patients still suffer from "treatment-resistant depression," for which the drugs are ineffective. To address this issue, we are focusing on "glial cells" in the brain. Glial cells are "cells that support nerves," which have not received much attention until now, but they may actually be deeply involved in the onset and treatment of psychiatric disorders.

From the perspective of "learning from the past to create something new," we have once again focused on tricyclic antidepressants (TCAs), which were discovered by chance in the 1950s. TCAs are known to be highly effective in severe cases where currently mainstream SSRIs and other medications are ineffective, but their detailed mechanism of action remained unknown for many years.

As a result of our research, we discovered that TCAs target lysophosphatidic acid receptor 1 (LPAR1), which is highly expressed in glial cells, suggesting an entirely new therapeutic mechanism via glial cells.

We are currently applying this knowledge to "drug repositioning research" to identify new antidepressant drug candidates from the approximately 1,600 existing drugs. We have narrowed down promising drugs that can reach the central nervous system and act on LPAR1, and are verifying their effects in animal models.

Clarifying the mechanisms of neuromodulation therapy and spreading it to society

Among mental illnesses such as depression, there are severe, intractable cases that require urgent treatment and are difficult to treat with medication. In such cases, neuromodulation therapy, which directly stimulates the brain, is considered effective. Typical treatments include modified electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), and their effectiveness has been scientifically proven. However, there are only a limited number of facilities where these treatments can be received, and they are not yet sufficiently known among the general public. There are also many misunderstandings and concerns about using electricity and magnets.

We are conducting research to clarify how these treatments affect the brain and produce their effects from multiple perspectives, including glia, lipid metabolism, inflammation, and immunity, and to "visualize" changes within the brain.

We also contribute to the dissemination of treatments and the social implementation of new technologies through the activities of neuromodulation committees of the Japanese Society of Psychiatry and Neurology, the Japanese Society of Mood Disorders, the Japanese Society of General Hospital Psychiatry, and the Clinical TMS Study Group.

Searching for clues (biomarkers) for mental illness and creating new treatments

Psychiatric disorders such as depression and schizophrenia are thought to involve various biological processes mediated by glial cells, such as inflammation in the brain, abnormalities in lipid metabolism, and changes in neurotrophic factors. However, the overall picture has not yet been fully elucidated.

We analyze blood and cerebrospinal fluid (CSF) to search for molecular biomarkers (molecules that provide clues to the disease) related to psychiatric disorders. We have particularly focused on matrix metalloproteinases (MMPs), lysophosphatidic acid (LPA) and its synthesizing enzyme autotaxin (ATX), and glial cell line-derived neurotrophic factor (GDNF), a neurotrophic factor. Our research has revealed that patients with depression have elevated MMPs and decreased LPA/ATX and GDNF levels, and these levels are significantly associated with the severity of depressive symptoms and treatment response. We are particularly focused on decreased ATX and docosahexaenoic acid-LPA (DHA-LPA) levels in blood and CSF, and are currently conducting preclinical research with a company on a new approach to treating depression by supplementing LPA (LPA replacement therapy).

Looking after elderly people in the community over the long term and exploring ways to prevent dementia and depression

As the population ages, the number of elderly people suffering from dementia and depression is increasing year by year. Early detection and prevention of these diseases is a major challenge for society.

In collaboration with the Department of Neuropsychiatry at Kumamoto University, we are conducting a large-scale cohort study (a study in which the same people are observed over a long period of time) of approximately 1,500 elderly people living in Arao City, Kumamoto Prefecture. This study aims to track long-term changes in brain structure and lifestyle habits associated with aging and to identify early signs (risk factors and biomarkers) of conditions such as dementia and depression.

Currently, we are conducting joint research with a company to analyze the stored blood samples, with the aim of using this information in the future to assess the risk of dementia and to develop new diagnostic and preventive markers.