Outline of the Protocols

An Integrated Approach to Treatment-Resistant Mood Disorders Focusing on the Dopaminergic System

The research group for Field F conducted a clinical study that demonstrated the efficacy of a dopamine D2 receptor agonist for treatment-resistant depression. Additionally, animal models were used for a basic study whose results provided important evidence that rats subjected to long-term methamphetamine administration manifest biological rhythm disturbances that resemble those of bipolar disorder. Based on these findings, the research team aims to study the neural etiology of treatment-resistant mood disorders, using an integrated approach that combines clinical studies and the corresponding basic studies.

Specifically, studies focusing on the dopaminergic system and biological rhythm will be conducted to search for biomarkers of differential diagnoses for major depression, bipolar disorder and cases for which dopamine agonists are effective, as well as to search for evidence of the identified biomarkers.

1. Clinical Studies for Finding Biomarkers Available for Differential Diagnoses

With regard to the five items described below, comparative studies will be conducted of individuals suffering from depression or bipolar disorder and of healthy individuals for the purpose of identifying biomarkers for differential diagnoses of depression and bipolar disorder.

Studies will also be conducted to determine which biomarkers indicate responders to dopamine reinforcement therapy and which biomarkers indicate non-responders to such therapy, with an aim of obtaining indexes of cases in which dopamine agonists are effective and to identify predictors and/or to evaluate factors of drug efficacy.

  1. Measuring reward-related brain activity in the ventral striatum with an fMRI device
  2. Measuring HVA levels in the blood, to analyze the relationship between HVA levels and various symptoms
  3. Analyzing the relationship between the dopamine system in the brain and symptoms of depression by using dopamine transporter (DAT) ligands for SPECT imaging
  4. Conducting tests for dexamethasone/corticotropin-releasing hormone (DEX/CRH) in order to determine how the HPA system works and to examine the relationship between its functions and various symptoms
  5. Conducting questionnaire research for the assessment of stress, biological rhythm disturbances and seasonal variations in symptoms in childhood and adulthood; measuring biological rhythms with Actiwatch toward analyzing the relationship between biological rhythms and depression/bipolar disorder
2. Analysis of Biomarkers Using Animal Models of Mood Disorders

It is necessary to verify the adequacy of the biomarkers that are identified in clinical studies for differential diagnoses of depression, bipolar disorder and cases for which dopamine agonists are effective. The pathophysiological significance of the biomarkers needs to be understood, too. In light of this, animal models of mood disorders will be developed toward examining whether the biomarkers obtained in the clinical studies are potentially applicable for diagnoses and for elucidating the pathophysiology of mood disorders.

aDThe Development of Animal Models and Verification of Their Adequacy
Animal models of depression will be created in the form of combined stress models of juvenile stress and adult stress. Animal models of bipolar disorder will be created in the form of combined stress models of animals with MAP administration or clock gene mutation and of animals with juvenile stress or adult stress. The adequacy of these animal models will be verified by the following tests and analyses: a behavioral test battery consisting of a sucrose preference test, a forced swim test and other tests; analysis of biological rhythms; analysis of gene and protein expression in the brain areas associated with dopaminergic function; and molecular anatomical analyses regarding the plasticity of dopaminergic synapses and alteration of the dopaminergic neural network.

The adequacy of the animal models will be additionally verified by examining the drug reactivity of each animal model in comparison with the symptoms and the drug's therapeutic effects in individuals suffering from depression or bipolar disorder.
bDAnalysis of Biomarkers
The adequacy and pathophysiological significance of the biomarkers identified in the studies described in #1 to #5 above will be verified with animal models.

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