Scientists uncover genetic causes of bipolar disorder

October 24, 2011
In an unfamiliar open arena, NKA mutant mice showed greater exploration, similar to the increased exploration exhibited by manic humans in an unfamiliar environment.

Researchers at the University of Leeds investigating the genetic causes of bipolar disorder have identified two new drugs – one of which has already been found safe in clinical trials – that may be effective in treating the disorder.

Bipolar disorder is characterised by mood swings between mania and depression. Like autism, it is thought to be a spectrum of disorders and, although its causes are not well understood, it seems to run in families and is thought to be caused by both genetic and environmental factors.

Dr Steve Clapcote, of the Institute of Membrane and Systems Biology at the University of Leeds, who led the study, says: "We suspected from published studies of bipolar patients that levels of enzymes known as NKA or sodium pumps may be abnormal in , but so far the evidence has not been convincing enough to warrant detailed clinical investigations."

The research, published today in the US journal Proceedings of the National Academy of Sciences (PNAS), used a strain of genetically modified that exhibit symptoms very similar to humans in the manic phase of the disorder.

The mice were bred with a particular mutation that prevents the NKA enzyme from functioning normally. When tested, the mice showed characteristics closely associated with bipolar disorder, such as increased tendency to take risks, hyperactivity, and disturbed sleep patterns. They also exhibited reduced mania when treated with anti-manic drugs.

Current drugs available to treat bipolar disorders, although usually successful, are limited to either Lithium or Valproate. They can't be matched to specific types of bipolar disorder, and can sometimes cause unpleasant side effects. There is therefore a need for treatments which can be better targeted, and which are more effective and better tolerated by patients.

The Leeds researchers found that the mice showed decreased activity of the NKA enzyme, as well as increased activity of a protein called ERK. Drugs known to have an effect on these two elements were administered to the mice, including Rostafuroxin and SL327, and both reduced their mania-like behaviour.

"Rostafuroxin has been found to be safe in clinical trials for treating high blood pressure," explained Dr Clapcote. "No one has previously looked at this drug's effects on the brain, but our mouse studies show there's a possibility that it might also be suitable for people with mania. Similarly, SL327, which is known to inhibit ERK activity, was also found to reduce manic behaviour in the mice."

"We think there is enough evidence now to start screening people with bipolar disorder to look for genetic mutations in the same NKA enzyme as that affected in our mice," says Dr Clapcote. "This will help us identify whether there is a group of bipolar patients that may be responsive to the novel treatments we have tested in the mice."

He added, "We also want to do some further studies of these drugs on the mice, such as test different doses to see whether there are any side effects, and determine what biochemical changes occur in the drug-treated mice to find out how the drugs work. This will help us determine whether they might be suitable for people."

Dr Tariq Mahmood, a consultant psychiatrist with Leeds Partnerships NHS Foundation Trust, who runs a bipolar disorders clinic, said: "Bipolar disorder is a serious condition that can affect one in 100 people. Like most psychiatric conditions, its biological basis is not well understood, which has hindered our efforts to develop diagnostic tests and specific treatments. This research is exciting and will, hopefully, lead to development of tests that will enable us to diagnose this condition early, and discovery of that are specific for individual bipolar patients."

More information: "Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+- ATPase α3 sodium pump" is published in PNAS online Early Edition today.

Related Stories

Recommended for you

Gene variant activity is surprisingly variable between tissues

August 21, 2017
Every gene in almost every cell of the body is present in two variants called alleles—one from the mother, the other one from the father. In most cases, both alleles are active and transcribed by the cells into RNA. However, ...

Genome analysis with near-complete privacy possible, say researchers

August 17, 2017
It is now possible to scour complete human genomes for the presence of disease-associated genes without revealing any genetic information not directly associated with the inquiry, say Stanford University researchers.

Science Says: DNA test results may not change health habits

August 17, 2017
If you learned your DNA made you more susceptible to getting a disease, wouldn't you work to stay healthy?

Genetic variants found to play key role in human immune system

August 16, 2017
It is widely recognized that people respond differently to infections. This can partially be explained by genetics, shows a new study published today in Nature Communications by an international collaboration of researchers ...

Active non-coding DNA might help pinpoint genetic risk for psychiatric disorders

August 16, 2017
Northwestern Medicine scientists have demonstrated a new method of analyzing non-coding regions of DNA in neurons, which may help to pinpoint which genetic variants are most important to the development of schizophrenia and ...

Phenotype varies for presumed pathogenic variants in KCNB1

August 16, 2017
(HealthDay)—De novo KCNB1 missense and loss-of-function variants are associated with neurodevelopmental disorders, with or without seizures, according to a study published online Aug. 14 in JAMA Neurology.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

jllitvay
not rated yet Nov 03, 2011
I have two relatives with comprooved bipolar disorder (mother and daughter). If we could help the research, please contact, or forward to the researcher.
Thanks

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.