‘Fascinating’ and ‘provocative’ research examines genetic elements of bipolar, schizophrenia

Saturday, October 1, 2011

Last week, Nature Genetics carried twin studies into the genetics of bipolar disorder and schizophrenia. This special report examines the month’s research into the illnesses in detail, with Wikinews obtaining comment from experts based in Australia, the United States, and the United Kingdom ahead of the U.S. Mental Illness Awareness Week, which starts tomorrow.

Eleven genetic regions were identified; seven of these were for schizophrenia and five of those were hitherto undiscovered. The parallel studies, conducted separately, examined more than 50,000 people worldwide and identified two genetic loci associated with both diseases.

Little is known about the two illnesses, each of which affects around 1% of people and is treated with strong medication. Bipolar sufferers experience extremes of mood – depression and mania, hence the previous name “manic depression” for the illness. Schizophrenia is associated with hearing voices, chaotic thoughts, and paranoia. There is no known cure.

The latest research examined both the healthy and the afflicted, using computers to scan genomes. Inheritance was thought to be a factor from prior knowledge of the diseases as a familial trait, but the original desire had been to isolate a single faulty gene. Instead it has become apparent that the genetic factors are many; in the case of schizophrenia, at most around 30% of the genetic components are thought to have been identified.

The University of Chicago’s Pablo Gejman, a lead researcher on the schizophrenia study, explained to Wikinews in a telephone interview from Buenos Aires, Argentina that “One of the goals of genetic research is to find druggable targets” – to “find treatments at the root of the problem”.

Whilst noting that there is no guarantee the genetic code identified is druggable, Gejman named calcium-activated neurochemical channels in the brain as candidates for new drugs. The channels were linked to schizophrenia in the study.

Gejman explained that a genetic locus called mir137 “suggests an abnormality of gene regulation.” The diseases are so poorly understood that it is uncertain if they are in fact two components of a single spectrum, or even each comprised of multiple illnesses.

The new and “provocative data” gathered showed the significant loci identified were “not part of the pre-existent hypothesis.” Calling this “interesting”, Gejman added that the team found no evidence that dopamine receptors are involved; current drug treatments target dopamine receptors. The findings are “not related to anything we thought we knew [about schizophrenia],” he told our correspondent.

Quizzed about the possibility variations in the genetic factors involved in expressing the diseases explained the variation seen in symptoms, Gejman was uncertain. “We will have the answer, probably, only when we sequence the whole [human] genome.” He notes that the relationship between genotype and phenotype is unclear, and that “We know very little of the genetic architecture of schizophrenia and” other disorders.At the time the results were published, participating scientist Professor Rodney Scott from the University of Newcastle in Australia said “The strength of this research is in the numbers. The findings are robust and give us a lot of statistical power to identify the genetic determinants of schizophrenia.” Scott told Wikinews that “If any single centre tried to undertake such a study, it would require millions of pounds. Since it was a collection of data from across the world the costs were spread. In this era of financial difficulty it will become increasingly difficult to secure funding for this type of project even though the pay-offs will be significant.”

Gejman expressed similar sentiment. “The research budget is not growing, which makes [funding] difficult,” he said, though he felt the cost “is not prohibitive because of the benefits.” “I think that it was money well invested” and “very well spent for the future,” he said, adding that organisations in Europe and the US were aware of the importance of such research.

Gejman also agreed on reliability – the study is “Very reliable because of the sample size; that should provide robust results… [we] have worked with a much larger sample than before.” Scott told us it was “a highly reliable study” that has the potential to lead to new treatments “in the long run”.

Another point was the two genetic loci identified as common to both – how much support do they lend to the notion the diseases are linked? “Until more information is available it is really only suggestive,” says Scott. “Strong enough to say there may be potentially a common pathway that bifurcates to give rise to two diseases.”

“It is an excellent demonstration,” said Gejman “because you have the same chains that are common to both disorders, in fact not just the same chains but also the same alleles.” He stressed uncertainty in how strong the relationship was, however.

Scott said examining how the variation of genetic factors may translate into varied symptoms being expressed “certainly is a good target for future research”; “It is not known how many genetic factors contribute to either of these diseases but it is likely that not all are necessary to trigger disease.” “New questions will always arise from any major study,” he told our reporter. “Certainly, new questions about bipolar and schizophrenia are now able to be formulated on the basis of the results presented in the two reports.”

These weren’t the only studies to look at the two diseases together in September. The British Medical Journal carried research by a team from the University of Oxford and King’s College London that examined mortality rates in England for schizophrenia and bipolar sufferers. They found both groups continued to suffer higher mortality rates than the general population – whilst these included suicides, three quarters of deaths were down to ailments such a s heart conditions. General death rates dropped from 1999 to 2006, but sufferers below 65 saw their death rate remain stable – and the over-65 saw theirs increase.

“By 2006, the excess risk in these groups had risk to twice the rate of the general population, whereas prior to that it had only been 1.6 times the risk, so it increased by almost 40%,” said Dr Uy Hoang of Oxford. The study looked at every discharged inpatient with a diagnosis of either condition in England in the relevant time.

Hoang said at the time of the research’s release that doctors should devote attention to predicting and preventing physical illness associated with mental disorders. His study comes at a time when the UK has launched a “no health without mental health” strategy which does attempt to screen for physical illnesses coinciding with mental illnesses. The government aims to reduce the death rate of those with mental disorders.

Rodney Scott described this research result to Wikinews as “Possibly” connected to genetic association with other hereditary ailments, such as cardiovascular disease; he told us another possibility is that “The continued raised mortality rates may be associated with the diseases themselves.”

“We believe the NHS [National Health Service] and Department of Health need to do more to support research and service development for people with bipolar disorder,” Wikinews was told by Suzanne Hudson, Chief Executive of London-based British charity MDF The Bipolar Organisation. “The provision of specialist services for bipolar is very limited in the UK and the demand for our services is unprecedented.”

“A genetic test for bipolar would be a useful tool but the science and ethics are very complex,” Hudson told us, referring to the Nature Genetics genetic study. “Just because someone has ‘bipolar genes’ does not mean they might go on to develop it. Family studies of bipolar show that this is a likely outcome of genetics research in this area. Even if it were possible to accurately predict bipolar in this way, questions about how you treat that person are difficult. For example do you start medication that is not necessary at that point in time?”

“Current treatment is not satisfactory” because it does not always work and has “side effects,” Gejman told us. Robert Whitaker, a US medical journalist and book author, told an audience in New Zealand at the end of August that evidence suggests antidepressant drugs may make children and teenagers worse – “You see many become worse and end up with a more severe diagnosis, like bipolar illness,” and the suicide risk may increase.

Whitaker blames commercial interests. “The adult market appeared saturated, and so they began eying children and teenagers. Prior to this, few children and youth were seen as suffering from major depression, and so few were prescribed anti-depressants.”

One possible alternative, raised by a connection between depressive illness and inflammation, is aspirin and similar compounds. “The link between inflammation and mood disorders has been known for sometime and the use of aspirin and other drugs in depression is now becoming more common in the literature,” Hudson says. “Any new treatments for bipolar, which is a very complex and co-morbid illness, has to be a good thing.”

Professor Dr. Michael Berk, chairman of psychiatry at Australia’s Deakin University, recently gave a talk to just this effect. Speaking at this year’s Congress of the European College of Neuropsychopharmacology, held this past month, he also highlighted statins as a treatment. Recognising the link to physical ailments, he told an interviewer “The brain does not exist in isolation, and we need to understand that pathways similar to those that underpin risks for cardiovascular disorders, stroke, and osteoporosis might also underpin the risk for psychiatric disorders, and that other treatments might be helpful.”

Berk also touched upon speed of diagnosis and treatment; “Early interventions can potentially improve the outcome” of bipolar sufferers, he told his audience. MDF The Bipolar Organisation claim an average of ten years is possible before a person is diagnosed. “This clearly is an issue, if we believe that earlier diagnosis and treatment facilitate better outcomes,” Berk told Wikinews. Though he questions the effectiveness of currently-used drugs on advanced bipolar cases, he does not go so far as to say drugs are actively harmful. He told us “it appears that our best treatments work best earlier in the illness course; and that seems to apply to psychotherapy and pharmacotherapy.”

Berk has already performed research using statins which suggests they can form a treatment. He now seeks funding for research involving aspirin. On funding, he tells Wikinews “psychiatric disorders comprise between 16% and 22% of the burden of disability (depending on who measures it), attracts^[sic] just over 6% of the clinical budget at least in Australia and 3% of the research budget. Research as a discretionary spending item is at great risk.”

Berk’s research, in the past, has been funded by companies including GlaxoSmithKline. Hudson told Wikinews this did not concern her charity; in fact, they welcomed it. “We believe it is important pharmaceutical companies continue to invest in the development of new medications for bipolar. This is how it works in all other health specialities and mental health should be no different.”

“There is a need for greater education for mental health professionals and GPs [general practitioners] about bipolar [in the UK],” she told us. “As the national bipolar charity we receive many, many calls and requests from GPs and other health professionals for our leaflets and information sheets which is fantastic. We very much welcome opportunities to work together for the benefit of individuals affected by bipolar.”

Wikinews contacted the UK’s National Institute for Clinical Excellence (NICE) to discuss issues raised in this article, including future treatments, genetic screening, and mortality rates. NICE did not respond.

Might statins and/or aspirin improve treatment – might they be cheaper, perhaps, or safer? “This is an area of research promise,” says Berk, “however it is too early to make any clinical treatment claims; [all] we can say is that this needs to be studied in properly designed trials capable of giving a more definitive answer.” And what of possible explanations for the increased mortality rate observed in England? Should researchers look at whether bipolar influences more than just the brain, or if it is linked to other genetic conditions?

“For sure,” he told us. “There is new evidence that similar pathways contribute to the risk for both medical and psychiatric illness, both in terms of lifestyle factors, and biomarkers of risk.”