Modem psychiatry typically subdivides mood disorders into bipolar disorders (episodes of mania or both mania and depression) and unipolar depressive disorder (episodes of depression). Symptoms of mania include expansive, elevated or irritable mood, inflated self-esteem, grandiosity, decreased need for sleep, increased talkativeness, racing thoughts, distractibility, increased goal-directed activity, and excessive involvement in pleasurable activities with a high potential for painful consequences. Depressive symptoms include depressed mood, diminished interest or pleasure in activities, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness, excessive guilt, inability to concentrate or act decisively, and recurrent thoughts of death or suicide. Several mental disorders have been proposed as alternate expressions of a bipolar genotype, including variants of schizoaffective disorder, recurrent unipolar depression and hypomania (bipolar II disorder).
Neuropsychiatric disorders, such as schizophrenia, attention deficit disorders, schizoaffective disorders, bipolar disorders and unipolar disorders, differ from neurological disorders in that anatomical or biochemical pathologies are readily detectable for the latter but not the former. Largely as a result of this difference, drugs which have been used to treat individuals with neuropsychiatric disorders, including lithium salts, valproic acid and carbamazepine, have not been predictably effective in treatment regimens across a variety of patients. Treatment regimens are further complicated by the fact that clinical diagnosis currently relies on clinical observation and subjective reports. Identification of the anatomical or biochemical defects which result in neuropsychiatric disorders is needed in order to effectively distinguish between the disorders and to allow the design and administration of effective therapeutics for these disorders.
As described herein, it has been discovered that a polymorphism in the gene for brain-derived neurotrophic factor (BDNF) is negatively correlated with incidence of neuropsychiatric disorders (e.g., bipolar disorder). In particular, it has been discovered that one or more single nucleotide polymorphisms within the nucleotide sequence encoding the 132 amino acid prepro portion of the BDNF gene product is correlated with reduced incidence of bipolar disorder in a sample population assessed as described herein. In one embodiment, a single nucleotide polymorphism from G to A at nucleotide position 424, resulting in an amino acid change from valine to methionine at amino acid position xe2x88x9263 (relative to the start of the mature protein), is correlated with a reduced incidence of bipolar disorder in the sample population assessed as described herein. That is, it has been determined that there is a variation from random (i.e., that which would be expected by chance) in the transmission of the reference (G) and variant (A) alleles from a parent who is heterozygous for the BDNF alleles to an offspring diagnosed with bipolar disorder. The variant allele (A) is transmitted less frequently (34 of 98 times) to the bipolar offspring than would be expected by chance, while the reference allele (G) is transmitted more frequently (64 of 98 times) than would be expected by chance (p=0.004). Thus, it appears that the variant allele may contribute to protection or reduction in symptomology with respect to bipolar disorder. Alternatively, this particular polymorphism may be one of a group of two or more polymorphisms in the BDNF gene which contributes to the presence, absence or severity of the neuropsychiatric disorder, e.g., bipolar disorder.
Accordingly, the invention relates to methods for diagnosing and treating neuropsychiatric disorders, especially bipolar disorder, and to methods for identifying compounds for use in the diagnosis and treatment of neuropsychiatric disorders. The invention relates to novel compounds and pharmaceutical compositions for use in the diagnosis and treatment of neuropsychiatric disorders. The invention further relates to kits for use in diagnosing neuropsychiatric disorders. In a preferred embodiment, the neuropsychiatric disorder is bipolar disorder.
In one embodiment, the invention relates to a method for predicting the likelihood that an individual will have a neuropsychiatric disorder (or aiding in the diagnosis of a neuropsychiatric disorder), e.g., bipolar disorder, comprising the steps of obtaining a DNA sample from an individual to be assessed and determining the nucleotide present at nucleotide position 424 of the BDNF gene. The presence of an xe2x80x9cAxe2x80x9d (the variant nucleotide) at position 424 indicates that the individual has a lower likelihood of having a neuropsychiatric disorder than an individual having a xe2x80x9cGxe2x80x9d at that position, or a greater likelihood of having less severe symptomology. In a preferred embodiment, the neuropsychiatric disorder is bipolar disorder. In a particular embodiment, the individual is an individual at risk for development of bipolar disorder.
In another embodiment, the invention relates to pharmaceutical compositions comprising a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. In one embodiment, the gene product is a peptide comprising amino acids xe2x88x921 through xe2x88x92132, or a functional portion thereof, of a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. The invention further relates to the use of compositions (i.e., agonists and antagonists) which enhance or increase or which reduce or decrease, respectively, the activity of a peptide comprising amino acids xe2x88x921 through xe2x88x92132, or a functional portion thereof, of a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. The invention also relates to the use of a nucleic acid molecule encoding a variant BDNF gene product for use in the treatment of neuropsychiatric disorders. In one embodiment, the gene product is a peptide comprising amino acids xe2x88x921 through xe2x88x92132, or a functional portion thereof, of a variant BDNF gene product. In a particular embodiment the neuropsychiatric disorder is bipolar disorder.
In another embodiment, the invention relates to a method for predicting the likelihood that an individual will have a neuropsychiatric disorder by determining the presence of prepro BDNF or fragment thereof containing the reference or variant amino acid at position xe2x88x9263. The method comprises obtaining a sample from an individual to be assessed, wherein the sample comprises prepro BDNF protein or fragment thereof, wherein said fragment includes amino acid xe2x88x9263 of prepro BDNF protein. The amino acid present at amino acid xe2x88x9263 of said prepro BDNF is determined, wherein the presence of an methionine at position xe2x88x9263 indicates that the individual has a lower likelihood of developing a neuropsychiatric disorder than an individual having a valine at that position. In one embodiment, the amino acid present at amino acid xe2x88x9263 is determined by contacting the sample with an antibody specific for prepro BDNF or fragment thereof containing the reference amino acid. In another embodiment, the amino acid present at amino acid xe2x88x9263 is determined by contacting the sample with an antibody specific for prepro BDNF or fragment thereof containing the variant amino acid.
In another embodiment, the invention is drawn to a method of predicting the likelihood that an individual will have reduced symptomology associated with a neuropsychiatric disorder, comprising determining the presence of prepro BDNF or fragment thereof containing the reference or variant amino acid as described above. The presence of an methionine at position xe2x88x9263 indicates that the individual has a greater likelihood of having reduced symptomology associated with a neuropsychiatric disorder than an individual having a valine at that position.
The invention is also drawn to kits for use the methods of the present invention. In one embodiment, the kit comprises a nucleic acid probe, wherein said probe allows the identification of the nucleotide at position 424 of the BDNF gene. The kit can also include control nucleic acid samples. The control nucleic acid samples can include, for example, the homozygous reference genotype, homozygous variant genotype and the heterozygous genotype at nucleotide position 424 of the BDNF gene. In one embodiment the kit comprises control nucleic acid samples representing the genotype of at least one of the group consisting of: an individual homozygous for a xe2x80x9cAxe2x80x9d at nucleotide position 424 of a BDNF gene, an individual homozygous for a xe2x80x9cGxe2x80x9d at nucleotide position 424 of a BDNF gene and an individual heterozygous for said position. In one embodiment, the kit comprises a probe that is an SBE-FRET primer. In more specific embodiment, the probe comprises SEQ ID NO: 11.
In another embodiment, the kit comprises at least one antibody, selected from the group consisting of: an antibody specific for a prepro portion of BDNF or fragment thereof, wherein said prepro portion of BDNF or fragment thereof comprises a methionine at amino acid position xe2x88x9263 and an antibody specific for a prepro portion or fragment thereof of BDNF, wherein said prepro portion or fragment there comprises a valine at amino acid position xe2x88x9263. The kit can also comprise control protein samples representing the genotype of at least one of the group consisting of: an individual homozygous for a nucleic acid sequence encoding a methionine at amino acid position xe2x88x9263 of prepro BDNF protein, an individual homozygous for a nucleic acid sequence encoding a valine at amino acid position xe2x88x9263 of prepro BDNF protein and an individual heterozygous for said position.