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More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression, indicating that the disease has a genetic component. Studies seeking to identify the genetic basis of bipolar disorder indicate that susceptibility stems from multiple genes. Scientists are continuing their search for these genes using advanced genetic analytic methods and large samples of families affected by the illness. The researchers are hopeful that identification of susceptibility genes for bipolar disorder, and the brain proteins they code for, will make it possible to develop better treatments and preventive interventions targeted at the underlying illness process.TO BE
Researchers at NIMH have found a correlation between DGKH (diacylglycerol kinase eta) and bipolar disorder. The portion of the genome that encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway .[1] A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. The DGKH enzyme is related to the reactions of medications used in lithium therapy. The actual mechanism(s) and chemical effects of lithium in the brain with respect to mental illnesses it still not completely known. Researchers are developing better medications by looking at molecular compounds acting on the DGKH enzyme to control the rate at which it is produced. These therapies have the potential to control the rate and volume of enzyme production, potentially beneficial to sufferers of bipolar disorder or other related mental illnesses. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk.
Bipolar disorder may be a polygenic disease.
Bipolar disorder is considered to be a result of complex interactions between genes and environment. The monozygotic concordance rate for the disorder is 70%. This means that if a person has the disorder, an identical twin has a 70% likelihood of having the disorder as well. Dizygotic twins have a 23% concordance rate. These concordance rates are not universally replicated in the literature, recent studies have shown rates of around 40% for monozygotic and <10% for dizygotic twins (see Kieseppa, 2004 [2] and Cardno, 1999 [3]).
In 2003, a group of American and Canadian researchers published a paper that used gene linkage techniques to identify a mutation in the GRK3 gene as a possible cause of up to 10% of cases of bipolar disorder. This gene is associated with a kinase enzyme called G protein receptor kinase 3, which appears to be involved in dopamine metabolism, and may provide a possible target for new drugs for bipolar disorder.[4] Inhibitors of the enzyme GSK-3β may mimic the therapeutic action of mood stabilizers like lithium.[5]
Johns Hopkins and NIMH researchers [6] created a database for bipolar disorder and the database is comparable to large-scale genetics efforts, e.g. HapMap, Human Genome Project and the Genetic Analysis Information Network. The database offers the power to define novel clinical subtypes of bipolar disorder, test for familial aggregation, and carry out genetic linkage and association studies that use specific clinical features as co-variates or as primary phenotypes. Blood samples were collected in five sub-projects with various instruments over a 20-year period and that information has been added to the database. The information from a series of interviews was validated. After data cleansing and analysis, the result is combined with the Bipolar Disorder Phenome Database. It consists of 5,721 subjects (3,186 affected) in 1,177 families, 197 variables, and 1,127,037 data points. There are various possibilities for new research with this database, but it should be remembered that this is only a phenomenological database. Users of the Bipolar Disorder Phenome Database must have a legitimate scientific aim and researchers need to apply for user rights.
Researchers are using advanced brain imaging techniques to examine brain function and structure in people with bipolar disorder, particularly using the functional MRI and positron emission tomography. An important area of neuroimaging research focuses on identifying and characterizing networks of interconnected nerve cells in the brain, interactions among which form the basis for normal and abnormal behaviors. Researchers hypothesize that abnormalities in the structure and/or function of certain brain circuits could underlie bipolar and other mood disorders and studies have found anatomical differences in areas such as the prefrontal cortex[7] and hippocampus. A meta-analysis of 98 MRI or CT neuroimaging studies reported that patients with bipolar disorder had lateral ventricles which were 17% larger than controls and patients were 2.5 times more likely to have deep white matter hyperintensities.[8] Better understanding of the neural circuits involved in regulating mood states, and genetic factors such as the cadherin gene FAT linked to bipolar disorder,[9] may influence the development of new and better treatments and may ultimately aid in early diagnosis and even a cure.
Further research from the Section of Section of Neurobiology of Psychosis, at the Institute of Psychiatry Institute of Psychiatry, King's College London has highlighted the role of key susceptibility genes for brain structure and function in Bipolar Disorder patients and their relatives. Specifically allelic variation at the CACNA1C gene affects brain structure in patients (click here for details) while the COMT gene seem to affect emotional processing (click here for details).
An evolving literature exists concerning the nature of personality and temperament in bipolar disorder patients, compared to major depressive disorder (unipolar) patients and non-sufferers. Such differences may be diagnostically relevant. Using MBTI continuum scores, bipolar patients were significantly more extroverted, intuitive and perceiving, and less introverted, sensing, and judging than were unipolar patients. This suggests that there might be a correlation between the Jungian extraverted intuiting process and bipolar disorder. There are limitations to this study in that many bipolar individuals, particularly poets, writers, scientists and artists tend to be introverted.
In late 2003, researchers at McLean Hospital found tentative evidence of improvements in mood during echo-planar magnetic resonance spectroscopic imaging (EP-MRSI), and attempts are being made to develop this into a form which can be evaluated as a possible treatment.[10],[11]
From 1998 to 2007, NIMH initiated a large-scale study at twenty sites across the U.S. to determine the most effective treatment strategies for people with bipolar disorder. This study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), followed patients and documented their treatment outcome for 5 to 8 years. For more information, visit the STEP-BD Clinical Trials page of the NIMH Web site [3].
Transcranial magnetic stimulation is another fairly new technique being studied.
Pharmaceutical research is extensive and ongoing, as seen at clinicaltrials.gov.
Gene therapy and nanotechnology are two more areas of future development.