Leeds researchers 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.
The faculty's Dr Steve Clapcote, 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, 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 new drugs that are specific for individual bipolar patients."
The research was a collaboration with scientists at the University of Toronto, and was funded by the Canadian Institutes of Health Research and the Medical Research Council.
Ioannis Delis, Physiological Society (Jul 2018), £10,000
Scott Bowen, Physiological Society (Jul 2018), £10,000
Steve Clapcote, Jamie Johnston, The Dunhill Medical Trust (Jun 2018), £254,874
Adrian Goldman, MRC (Jun 2018), £98,627
Darren Tomlinson, Michelle Peckham, Megan Wright, BBSRC (Jun 2018), £150,443
Simon Walker, Royal Society (Jun 2018), £337,601
Tom Thirkell, N8 Agrifood (Jun 2018), £14,870
Stephen Muench with Glaxo SmithKline & UCB Celltech, BBSRC Industrial Partnership Award (Apr 2018), £480,225
Steve Clapcote, BBSRC (Apr 2018), £443,072
Helen Miller, Innovate UK (Apr 2018), £999,960
Elisabetta Groppelli, David Rowlands & Stanley Lemon (University of North Carolina), Medical Research Foundation Fellowship (Apr 2018), £293,494
Nikesh Patel, Medical Research Foundation fellowship (Apr 2018), £290,976
Graham Askew with colleagues in Hull and Liverpool, BBSRC (Apr 2018), £150,498
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Nikita Gamper, BBSRC (Feb 2018), £30,000
Lars Jeuken, BBSRC (Feb 2018), £30,000
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Alex O'Neill, Oxford Drug Design (Jan 2018), £86,098
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Alison Dunn, NERC (Dec 2017), £18,000
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Ralf Richter, Royal Society (Dec 2017), £6,000
Christine Foyer, British Council Newton Fund (Dec 2017), £49,840
Adrian Whitehouse and colleagues in School of Chemistry and University of Liverpool, MRC (Nov 2017), £622,319
Michelle Peckham, Neil Ransom, MRC (Nov 2017), £495,159
Dave Lewis, British Council India (Nov 2017), £22,540
Elton Zeqiraj, Royal Society (Nov 2017), £15,000
Hannah Dugdale, Royal Society (Nov 2017), £15,000
Shaunna Burke, Cancer Research UK Innovation Grant (Nov 2017), £20,000
Alex O'Neill and colleagues in Chemistry, BBSRC (Nov 2017), £431,865
Jessica Kwok, Wings for Life (Nov 2017), £87,365
Tom Bennett, BBSRC (Oct 2017), £523,679
Neil Ranson, Darren Tomlinson, BBSRC (Oct 2017), £494,318
Nikita Gamper, BBSRC (Oct 2017), £490,426
Amanda Bretman and colleagues from UEA, NERC (Oct 2017), £430,886
Juan Fontana, Rosetrees Trust consumables grant (Oct 2017), £22,500
Helen Miller, DSM Nutritional Products AG (Sep 2017), £69,988
Neil Ranson, Juan Fontana, Mark Harris, Michelle Peckham, Ralf Richter, Peter Stockley, Patricija Van Oosten-Hawle and colleagues in Engineering, FMH and MAPS, Wellcome Trust Equipment Call (Sep 2017), £418,000
Jamie Johnston, Physiological Society (Sep 2017), £10,000
Frank Sobott, Adrian Goldman, Mark Harris, Andrew Macdonald, Stephen Muench, Sheena Radford and colleagues in FMH and MAPS, Wellcome Trust Equipment Call (Aug 2017), £415,000