Researchers at the University of Michigan have discovered that antipsychotics may work, at least in part, by restoring normal gene function in people with bipolar disorder. (Chen, H., Wang, N., Zhao, X., Ross, C. A., O’Shea, K. S. and McInnis, M. G. (2013), “Gene expression alterations in bipolar disorder postmortem brains.” Bipolar Disorders, 15: 177–187. doi: 10.1111/bdi.12039)

The research team did post-mortem (after death) examinations on the brains of three groups of people:

• People with bipolar disorder who never took antipsychotics
• People with bipolar disorder who had taken antipsychotics
• People without bipolar disorder (the control group)
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October 15, 2012, researchers at Kings College in London published a study in the journal Biological Psychiatry, entitled “Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder” Biological Psychiatry. 2012 Oct 15;72(8):645-50. Vassos E, et al.) This study replicates earlier findings that connect changes at a particular gene region on chromosome 3p21.1 to bipolar disorder.

In the September issue of the American Journal of Psychiatry, researchers report a series of studies that suggest a strong association between one particular genetic variation and manic symptoms. (Studies in humans and mice implicate neurocan in the etiology of mania. Miró X, Meier S, Dreisow ML, Frank J, Strohmaier J, Breuer R, Schmäl C, Albayram O, Pardo-Olmedilla MT, Mühleisen TW, Degenhardt FA, Mattheisen M, Reinhard I, Bilkei-Gorzo A, Cichon S, Seidenbecher C, Rietschel M, Nöthen MM, Zimmer A. Am J Psychiatry, 2012 Sep 1;169(9):982-90.)

This month’s edition of Discovery’s Edge, Mayo Clinic’s Online Research Magazine, features an article entitled “The Genomics of Bipolar Disorder.” The article looks at biobanking – a practice in which research centers store a lot of information on thousands of people with certain disorders, in this case bipolar. Mayo Clinic, in conjunction with several other research centers, is collecting blood samples and clinical information from 2,000 patients. This information is stored anonymously, and researchers can use this high volume of data to look at specific questions about bipolar disorder.

The primary focus of this work is related to genomics – looking at genetic associations to bipolar disorder. The work is not just about which genes and genetic variations contribute to causing bipolar disorder, but also examines subtypes of bipolar disorder and patterns of medication response. Partly due to genetic differences, people experience different benefits and side effects to the same medications.

Given all the activity and advances in genetic research, you might expect researchers to have mapped the entire human genome by now and identified the gene or genes responsible for bipolar disorder and other diseases that appear to have a genetic component. Obviously, that hasn’t happened. The best that researchers seem to have come up with are associations of certain gene variations with bipolar – hardly the smoking gun we would hope for.

Even the researchers seem to be getting a little discouraged, as is evident in a two articles I have recently come across. The first, published in the April 2011 edition of the American Journal of Psychiatry is entitled “After GWAS: Searching for Genetic Risk for Schizophrenia and Bipolar Disorder,” (by Elliot S. Gershon, Ney Alliey-Rodriguez, and Chunyu Liu). In their abstract, the authors explain:

Ten years ago it was widely expected that the genetic basis of common disease would be resolved by genome-wide association studies (GWAS), large-scale studies in which the entire genome is covered by genetic markers. However, the bulk of heritable variance remains unexplained.

In a study published in the journal Molecular Psychiatry entitled “A genome-wide association study of attempted suicide,” a group of Johns Hopkins researchers (Willour, et al.) report the discovery of a “a small region on chromosome 2 that is associated with increased risk for attempted suicide.”

Willour and her colleagues studied DNA samples from nearly 2,700 adults with bipolar disorder, 1,201 of them with a history of suicide attempts and 1,497 without. They found that those with one copy of a genetic variant in the region of chromosome 2 where ACP1 is located were 1.4 times more likely to have attempted suicide, and those with two copies were almost three times as likely.

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Psych Central’s Senior News Editor Rick Nauert recently posted a piece entitled “Genetic Variant Heightens Risk for Bipolar Disorder.” In it, he calls attention to a recent study published in the American Journal of Human Genetics that’s “based on a relatively new technique for the study of the genetics of bipolar disorder” termed genome-wide association studies (GWAS).

We invite you to check out the post, especially if you’re interested in keeping up on the latest breakthroughs in identifying the genetic component of bipolar disorder. Although it may be years before these genetic studies translate into any sort of gene therapy, if that’s even possible, they deliver an immediate benefit in three important ways:

Researchers in Germany may have come closer to confirming one of the possible genetic components that contribute to a vulnerability to bipolar disorder. For some time, we have known two things about bipolar disorder:

• It’s a brain illness, a neurological disorder.
• It has a strong genetic component.

The unknown, until now, was the link between the genetic component and the actual neural abnormalities. Relatively recently, several studies have implicated a variant on chromosome 12, the CACNA1C gene, as increasing the risk for bipolar disorder. So researchers wanted to find out whether this gene variant could be traced to a particular region of the brain.

Researchers at Johns Hopkins University School of Medicine have published a study entitled “Chronic Corticosterone Exposure Increases Expression and Decreases Deoxyribonucleic Acid Methylation of Fkbp5 in Mice,” Endocrinology, September 2010, in which they claim to have identified a possible epigenetic cause of depression and other mood disorders, including bipolar disorder. For a more layman’s account of the study and its conclusions, I recommend the Johns Hopkins press release entitled “Chronic Stress May Cause Long-Lasting Epigenetic Changes.”

The prefix epi- means outside, above, over, or on top of. The term epigenetic refers to factors outside the fundamental gene structure that affect a gene’s expression. In this study, researchers examined the effects of a common stress hormone on a gene that has been linked to mood disorders and found that “… long-term exposure to a common stress hormone may leave a lasting mark on the genome and influence how genes that control mood and behavior are expressed.”

We often discuss the potential risks to a fetus when the mother is taking psychiatric medications, but we rarely if ever consider the potential risks of a prospective father taking psychiatric medications. One of our readers posted a question addressing this issue.

Heidi asks…

Hi there, my husband started taking Depakote for bipolar disorder several months ago. We are talking about having another baby and are wondering whether it’s safe for us to conceive while he is on Depakote? Any advice is helpful, thanks.