Understanding the Biology and Genetics of Bipolar Disorder

Bipolar disorder (BD) is a leading cause of global disability, with well-defined symptoms characterized largely by persistent mood instability. The classic presentation of the disease includes episodes of extreme elation and severe depression, with periods of relatively stable mood in between. Manic swings may include not only significant elevation in mood, but also related changes in behavior. For many patients, the depressive episodes are more prolonged, and of patients with BD, 10-15% die by suicide. This, coupled with an increased risk of mortality resulting from reckless behaviors, shortens average life expectancy by about fifteen years.

Despite our familiarity with its symptoms and ability to diagnose bipolar disorder, little is known about its biological or genetic basis. Because of this, medication options have remained fairly stagnant over time – we can’t effectively treat what we don’t understand. Current medications (lithium salts and antiepileptic drugs) help, but have undesirable side effects and are not effective in all patients. Understanding the biological causes of bipolar disorder is a crucial step in developing safe and effective therapies to help patients living with this disorder.

Advances in Genetics Increase Understanding

Although scientists do not fully understand the biological causes of bipolar disorder, new technologies are beginning to provide information about the genetics behind the disease. Studies have shown that the disorder is highly heritable – a child of an affected parent has about a ten-fold increased risk of developing BD – suggesting a genetic linkage. It is highly likely that several genes contribute to causing BD, and while we currently have found no strong evidence for BD-specific genes, analysis of almost 20,000 BD cases described several genetic risk areas. Identification of any genes associated with increased susceptibility to bipolar disorder will have a major impact on our understanding of the disease. New data will provide important opportunities to investigate the interaction between genetic and environmental factors involved in the development of BD. This is likely to lead to major improvements in treatment and patient care.

Targeting Specific Genes

Genetic sequencing technologies have already helped us identify susceptibility loci. These are specific areas on chromosomes where we have located genes that serve as indicators that a person may be more prone to developing the disease. We’ve also made progress towards narrowing down genes that are directly involved with causing some of the symptoms of bipolar disorder.

In particular, interest lately has focused on two genes based on what we know about their function. When combined with large-scale studies of people living with bipolar disorder, evidence shows:

  • The CACNA1C gene regulates the entrance of calcium into our brain cells
  • The ANK3 gene regulates the entrance of sodium into our brain cells

This is important because both calcium and sodium play an essential role in the propagation of an action potential in a neuron. In other words, these two ions help our brain cells fire. The possible involvement of calcium ions in BD has long been under investigation, with evidence suggesting elevated levels of calcium in the brains of people with bipolar disorder. Small changes in the sequence of CACNA1C cause it to malfunction, resulting in a calcium imbalance. This imbalance appears to contribute to the severe mood swings that people living with BD experience.

Advances in Medication

The good news is that there are several drugs that target the action of calcium in the brain, and the more we learn, the more hope we have for new developments. CACNA1C is also associated with schizophrenia and major depression. Therefore, understanding changes in this gene could help scientists develop pharmaceutical treatments for these diseases.

Complementing the progress in genetics are new developments using other methods that could further expand our understanding of BD. These include using modern technology like cell phones to help patients track and report symptoms. Right now we depend largely on personal accounts of what patients and those around them perceive as BD-associated symptoms. We rely on memory and personal recount of mood swings and other episodes. This approach carries inherent bias and unreliability: we’re only human and our memory is not perfect.

However, several approaches may improve the validity of personal assessments, including the use of wearable devices. Some of these platforms already exist. They allow patients to submit (via text, email, web, or app) their ratings of depression, mania, and other symptoms. Smartphones and other devices can also allow patients to record measures such as heart rate, activity, and speech. All this data can lead to a more complete and linear biological portfolio. Which, in turn, may contribute to a more objective and personalized diagnosis.

Future Directions

Overall, our understanding of bipolar disorder is still surprisingly limited. It continues to be largely a descriptive syndrome since we lack diagnosable genetic markers or other basics for biological diagnosis. However, the discovery of risk genes is promising. Identifying these genes may elucidate biochemical pathways involved in the development of BD and facilitate development of more effective, better-targeted treatments. Knowledge of these genes also offers opportunities for improving the validity of psychiatric diagnosis and classification. Additionally, the use of novel digital technologies is already starting to allow a more quantitative approach to diagnosis. Our goal is to work toward a more scientifically-informed approach to classifying, measuring, and ultimately treating bipolar disorder.