# US 10,309,967 B2 · Methods of diagnosing bipolar disorders and screening for therapeutic compounds

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- Number: US 10,309,967 B2
- Document ID: US10309967B2
- Status: Granted
- Kind: B2
- Application number: 15/156,352
- Filed: 2016-05-17
- Published: 2016-11-24
- Granted: 2019-06-04
- Earliest claimed: 2015-05-18
- Assignees: National University Corporation Chiba University
- Applicants: National University Corporation Chiba University
- Inventors: Kenji Hashimoto; Takashi Futamura; Noriko Yoshimi; Takeo Yoshikawa; Yoshimi Iwayama; Mikael Landen
- Web page: https://patentgrep.com/patent/US10309967B2

## CPC

- G01N 33/6812: {Assays for specific amino acids}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- G01N 2500/00: Screening for compounds of potential therapeutic value
- G01N 2570/00: Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
- G01N 2800/304: Mood disorders, e.g. bipolar, depression
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

Methods of diagnosing, confirming a diagnosis of, and determining a predisposition for a bipolar disorder in a subject are provided. An amount of at least one of biomarker from the cerebrospinal fluid and/or serum of a subject is measured, for example, isocitric acid. The amount of the at least one biomarker can be compared with a control amount of the at least one biomarker in a corresponding sample collected from a subject without the bipolar disorder. An increase or decrease in the amount of the particular biomarker or biomarkers measured can be indicative that the subject has the bipolar disorder or a predisposition for the bipolar disorder. Methods of identifying a compound for preventing and/or treating a bipolar disorder are also provided based on the expression level of an isocitric acid dehydrogenase 3 alpha and/or beta-subunit gene, and/or based on one or more metabolite biomarker.

## Claims

### Claim 1

A method of treating a bipolar disorder in a subject, the method comprising:
collecting, from the subject, a cerebrospinal fluid sample or both a cerebrospinal fluid sample and a serum sample, wherein the cerebrospinal fluid sample comprises at least one biomarker comprising isocitric acid, or at least two biomarkers comprising isocitric acid and cis-aconitic acid and wherein the serum sample comprises at least one biomarker selected from the group consisting of N-acetylglutamic acid, 2-oxoglutaric acid, and serine;
measuring an amount of the at least one biomarker in the cerebrospinal fluid sample or both of the cerebrospinal fluid sample and the serum sample collected from the subject;
comparing the amount of the at least one biomarker in the cerebrospinal fluid sample or both of the cerebrospinal fluid sample and the serum sample collected from the subject with a control amount of the at least one biomarker in a corresponding sample collected from a subject without the bipolar disorder, wherein an increase in the amount of isocitric acid, an increase in the amount of cis-aconitic acid, an increase in the amount of N-acetylglutamic acid, an increase in the amount of 2-oxoglutaric acid, and a decrease in the amount of serine, in comparison to the control amount of the at least one biomarker are indicative that the subject has the bipolar disorder or a predisposition for the bipolar disorder; and
administering at least one bipolar medication selected from the group consisting of lithium, valproic acid, carbamazepine, oxcarbazepine, lamotrigine, lurasidone, divalproex, and a salt of lurasidone to the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the serum sample is collected from the subject and the at least one biomarker further comprises serine.

### Claim 3 (depends on 1)

The method of claim 1, wherein the cerebrospinal fluid sample and the serum sample are both collected from the subject and each sample comprises at least one of the biomarkers.

### Claim 4 (depends on 1)

The method of claim 1, wherein the cerebrospinal fluid sample, or both the cerebrospinal fluid sample and the serum sample are collected from the subject, and wherein at least two of the biomarkers are measured in combination.

### Claim 5 (depends on 1)

The method of claim 1, wherein both the cerebrospinal fluid sample and the serum sample are collected from the subject, and wherein five of the biomarkers are measured in combination.

### Claim 6 (depends on 1)

The method of claim 1, wherein the collecting is performed when the subject is euthymic.

### Claim 7 (depends on 1)

The method of claim 1, wherein the subject has had at least one bipolar episode, at least one manic episode, at least one hypomanic episode, at least one depressive episode, or any combination thereof.

### Claim 8 (depends on 1)

The method of claim 1, further comprising performing a second diagnostic test for the bipolar disorder, wherein the second diagnostic test is not based on a biomarker.

### Claim 9 (depends on 1)

The method of claim 1, wherein the bipolar disorder is a bipolar I disorder, a bipolar II disorder, rapid-cycling bipolar disorder, bipolar disorder not otherwise specified, cyclothymia, or any combination thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the administering of the at least one bipolar medication is carried out before the measuring and comparing, after the measuring and comparing, or both.

### Claim 11

A method of treating a bipolar disorder in a subject, the method comprising:
collecting, from the subject, a cerebrospinal fluid sample, a serum sample, or both a cerebrospinal fluid sample and a serum sample, wherein the cerebrospinal fluid sample comprises at least one biomarker selected from the group consisting of isocitric acid and cis-aconitic acid, and wherein the serum sample comprises at least one biomarker selected from the group consisting of N-acetylglutamic acid, 2-oxoglutaric acid, and serine;
measuring an amount of the at least one biomarker in one or both of the cerebrospinal fluid sample and the serum sample collected from the subject;
comparing the amount of the at least one biomarker in one or both of the cerebrospinal fluid sample and the serum sample collected from the subject with a control amount of the at least one biomarker in a corresponding sample collected from a subject without the bipolar disorder, wherein an increase in the amount of isocitric acid, an increase in the amount of cis-aconitic acid, an increase in the amount of N-acetylglutamic acid, an increase in the amount of 2-oxoglutaric acid, and a decrease in the amount of serine, in comparison to the control amount of the at least one biomarker are indicative that the subject has the bipolar disorder or a predisposition for the bipolar disorder; and
administering at least one bipolar medication selected from the group consisting of lithium, valproic acid, carbamazepine, oxcarbazepine, lamotrigine, lurasidone, divalproex, and a salt of lurasidone to the subject, and
wherein:
the at least one biomarker of the serum sample further comprises at least one further biomarker selected from the group consisting of pyruvic acid, β-alanine, arginine, uric acid, and citric acid, and
wherein the method further comprises:
measuring an amount of at least one further biomarker in the serum sample collected from the subject; and
comparing the amount of the at least one further biomarker with a control amount of the at least one further biomarker in a corresponding sample collected from a subject without the bipolar disorder,
wherein an increase in the amount of pyruvic acid, a decrease in the amount of β-alanine, a decrease in the amount of arginine, an increase in the amount of uric acid, and a decrease in the amount of citric acid, in comparison to the control amount of the at least one biomarker are indicative that the subject has the bipolar disorder or a predisposition for the bipolar disorder and wherein a) both the cerebrospinal fluid sample and the serum sample are collected from the subject, and wherein the following biomarkers are measured in combination:
isocitric acid;
cis-aconitic acid;
serine;
uric acid; and
citric acid;
or b) wherein the serum sample is collected from the subject, and wherein the following biomarkers are measured in combination:
pyruvic acid;
N-acetylglutamic acid;
2-oxoglutaric acid;
β-alanine;
arginine; and
serine.