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 bipolar disorder, 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 mice 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 (see structure right), and both
reduced their mania-like behaviour.
"Rostafuroxin (see structure left) 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."....