Lithium has been established for more than 50 years as one of the most effective treatments for bipolar mood disorder.

However, scientists have never been entirely sure exactly how it operates in the human brain.

Now, new research from Cardiff University scientists suggests a mechanism for how Lithium works, opening the door for potentially more effective treatments.

Laboratory tests on cells have shown that Lithium affects a molecule called PIP3 that is important in controlling brain cell signalling. Lithium suppresses the production of inositol, a simple sugar from which PIP3 is made.

Lithium inhibits inositol monophosphatase (IMPase) an enzyme required for making inositol. Importantly, this research shows that increasing the amount of IMPase causes higher levels of PIP3. This can then be reduced by lithium treatment.

High levels of IMPA2, a gene for a variant of IMPase, has previously been linked to bipolar mood disorder. This new result suggests that Lithium could counteract the changes in IMPA2.

Professor Adrian Harwood of Cardiff School of Biosciences, who led the research, said: “We still cannot say definitively how Lithium can help stabilise bipolar disorder. However, our research does suggest a possible pathway for its operation. By better understanding Lithium, we can learn about the genetics of bipolar disorder and develop more potent and selective drugs.

“Further, altered PIP3 signalling is linked to other disorders, including epilepsy and autism, so this well established drug could be used to treat other conditions. Research into Lithium could become very important over the next few years.”

Lithium is currently under clinical trial for the treatment of neurogenerative disorder amyotrophic lateral sclerosis (ALS)

The research, funded by the Wellcome Trust, is published in the journal Disease Models and Mechanisms.

Source:
Professor Adrian Harwood
Cardiff University

• FADS2 gene expression elevated in bipolar patients]]>

Psychiatrists in London are a step closer to personalising treatment and prevention for manic depressive illness - also known as bipolar disorder. Their research has shown why some people are more at risk and why others are more resilient to genetic and environmental factors underlying bipolar disorder.

Bipolar disorder occurs when the brain cannot regulate mood effectively leading to mood swings. Around 300,000 people in the UK have the disorder. Coping with bipolar disorder can be very testing for patients and their families and may lead to difficulties and setbacks in relationships, work and education. Relatives of people with bipolar disorder are at higher risk for a range of mood disorders but about 60% of remain well.

Speaking at a meeting of the Biochemical Society in London, Dr Sophia Frangou said, “We know a lot about what makes people vulnerable to bipolar disorder, but most people who are at risk remain well,” she said. “We wanted to find out what keeps them well.”

Dr Frangou and her team from the Institute of Psychiatry in London examined how genetic risk factors translate into changes in the brain’s networks using a series of brain imaging studies involving 227 relatives from 53 families where one member had bipolar illness. The participants were in the scanner for one hour and they also took part in cognitive tests designed to engage brain networks involved in emotional processing, decision-making, working memory and attention.

“We found that genetic risk to bipolar disorder was associated with overactivity within brain regions that process emotion, such as the amygdala. However, we also found that it was the function of another brain region, called the prefrontal cortex that seemed to differentiate those who became unwell compared to those who did not. In people who remained well, despite their genetic risk for bipolar disorder, the function of the prefrontal cortex also remained intact while this was compromised in those who developed the illness”.

Further analysis of the complexities of what makes a person at risk or resilient to bipolar disorder is required but this research suggest that it may soon be possible to advise people with a family history of bipolar disorder about their individual risk or resilience .

“Being a risk of bipolar disorder does not mean that developing the illness is inescapable,” said Dr Frangou. “We are closer now to identifying risk so that people can be better informed about life choices. Our research will help us personalise prevention and treatment strategies.”

Note

The Biochemical Society http://www.biochemsoc.org.uk exists to advance molecular biosciences. It has around 7000 members.

Sophia Frangou is reader in psychiatry and Head of the Section of Neurobiology of Psychosis at the Institute of Psychiatry, King’s College, London.

Source
The Biochemical Society

• Communication Within The Brain Impaired By Genetic Variant With Possible Consequences Schizophrenia Or Manic Depression
• Patients With Bipolar Disorder Have Higher Specialty Care Costs Than Patients With Diabetes And Other Chronic Diseases
• Cephalon Announces Positive Results From A Phase Two Study Of NUVIGIL In Bipolar Depression

Decision Resources, one of the world’s leading research and advisory firms for pharmaceutical and healthcare issues, finds that surveyed psychiatrists identify a therapy’s effect on decrease in severity of depressive symptoms as the attribute that most influences their prescribing decisions in bipolar depression. Clinical data and the opinions of interviewed thought leaders indicate that current and emerging therapies have no advantage in this attribute over AstraZeneca’s Seroquel, the sales-leading agent in the market.

The new report entitled Bipolar Depression: Despite Negative Results, Physicians Still Hopeful About Aripiprazole also finds that an oral therapy that carries a lower risk of weight gain than Seroquel would earn a 21 percent patient share in bipolar depression in the United States and a 30 percent patient share in Europe, according to surveyed U.S. and European psychiatrists. The report also finds that, despite the failure of Bristol-Myers Squibb/Otsuka Pharmaceutical’s Abilify (aripiprazole) in bipolar depression clinical trials, most interviewed thought leaders believe that Abilify is still an efficacious therapy for bipolar depression.

In 2008, Decision Resources’ proprietary clinical gold standard for bipolar depression was lamotrigine (GlaxoSmithKline’s Lamictal, generics). Based on available data and expert opinion, lamotrigine will retain gold standard status through 2017. While some therapies in development for bipolar depression hold promise, most have efficacy, safety and tolerability, and/or delivery features that are inferior when compared with lamotrigine.

“Owing to its efficacy and tolerability advantages, lamotrigine edged out Seroquel, its closest competitor, to become the clinical gold standard,” said Decision Resources Analyst Sandra Chow, M.Sc. “Despite its slow onset of action, interviewed thought leaders were particularly impressed with lamotrigine’s side-effect profile and better evidence of efficacy as a long term mood stabilizer.”

About the Report

Bipolar Depression: Despite Negative Results, Physicians Still Hopeful About Aripiprazole is a DecisionBase 2009 report. DecisionBase 2009 is a decision-support tool that provides in-depth analysis of unmet need, physician expectations of new therapies and commercial dynamics to help pharmaceutical companies optimize their investments in drug development.

The report can be purchased by contacting Decision Resources. Members of the media may request an interview with an analyst.

Source: Decision Resources