Like diabetes, bipolar disorder was described by Areteus of Cappadocia in the first century ad. But for bipolar disorder, no equivalent of insulin has emerged. How close are we to identifying the mechanisms of bipolar disorder? Selected for clinical implications, here are some highlights from the recent acceleration in understanding of those mechanisms. Findings range from genetics and neuroplasticity (plasticity-specific genes, epigenetics, neurotrophic factors) to brain imaging, brain networks, and broader processes (inflammation, clockworks).
Unlike Huntington disease, in which the number of nucleotide repeats in a single gene determine outcome, bipolar disorder appears to be influenced by several hundred genes: 266 in a recent meta-analysis.1 Some genes are more central to the development of bipolar disorder than others, suggesting that there are several main pathways to the development of this illness, not 266 different routes. For example, one of the most consistently identified genes is CACNA1C.2 This gene codes for a calcium channel subunit that affects amygdala processing of emotional events, which itself has been shown to be one of the central differences in brain function in bipolar disorder.3
The search for genes associated with bipolar disorder is complicated because many of the same genes, such as CACNA1C, are also associated with major depression and schizophrenia.4 This should not be surprising: given the large number of genes involved, the range of potential variations of mood and thought is vast. Just 2 variations at each of 266 genes allows 35,000 different permutations, and many of these genes have more than 2 variants. Although not all these variations would necessarily look different clinically, they are better mapped in continua rather than categories, as noted by Dr Ellen Leibenluft, Chief of the NIMH’s Section on Bipolar Spectrum Disorders. She commented that DSM categories “will remain somewhat arbitrary [italics added] because they will be imposed on fully continuous, smooth distributions.”5
The search for genes associated with bipolar disorder is further complicated by the overlap between genes that confer bipolar risk and genes that confer “plasticity.” The latter refers to genes that allow individuals to respond more directly to environmental experience, to mold themselves to their environment and potential future environments based on past experience.
Plasticity-specific genes. Multiple genes appear to confer an increased capacity to mold to or respond to one’s environment (particularly childhood environment). These genes include the serotonin transporter gene (SERT) and the brain-derived neurotrophic factor (BDNF) gene, among others.
Differences in the SERT gene length have been extensively investigated in relation to mood and anxiety disorders. The short version of the SERT gene is associated with an increased risk of depression in the face of life stresses, but only in the context of adverse childhood experiences. Benign childhoods appear to completely mask the gene length difference effects, as originally shown in the seminal work by Caspi and colleagues.6 These findings were recently replicated in bipolar disorder.7 Not all previous studies have found an association between bipolar disorder and the short SERT allele, however.8
The frequency of the short allele itself is highly variable across ethnic groups; none were found in one Chinese population.9 Overall, the findings originally shown by Caspi and colleagues have been consistent, particularly if age of adverse events is factored in (early childhood events have more impact, which to clinicians is of course no surprise).10,11
Similarly, a substantial literature associates the BDNF gene with mood disorders and bipolar disorder in particular. A base pair difference in the gene (single nucleotide polymorphism) leads to insertion of a methionine in the BDNF protein instead of a valine. The methionine variant is associated with increased susceptibility to Alzheimer disease, Parkinson disease, depression, eating disorders—and bipolar disorder.12 In bipolar disorder, carriers of the methionine-yielding allele have significantly higher suicide attempt rates.13
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