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Bipolar disorder is characterized by dramatic changes in mood, energy and activity levels that impact a person’s ability to carry out everyday tasks. The exact cause of the condition is unknown. But now, researchers are one step closer to finding out with the discovery of two new genetic regions that are connected to the disease.

The international research team, led by investigators from Germany and Switzerland, recently published their findings in the journal Nature Communications.

Although the cause of bipolar disorder is unclear, researchers do know that genetic factors play a large part.

“There is no one gene that has a significant effect on the development of bipolar disorder,” says Dr. Markus M. Nöthen, of the University of Bonn Hospital in Germany.

“Many different genes are evidently involved and these genes work together with environmental factors in a complex way.”

For their study, the researchers obtained genetic data from 2,226 patients with bipolar disorder and 5,028 individuals without the condition. This data was merged with existing data sets and analyzed.

This led to the comparison of genetic material from 9,747 bipolar patients with that of 14,728 healthy individuals – the largest investigation of the genetic foundations of bipolar disorder to date, according to the researchers.

The team says that the search for genes involved in bipolar disorder is like “looking for a needle in a haystack.” Dr. Sven Cichon, of the University of Basel Hospital in Switzerland, explains that individual genes make contributions to the disease that are so small, it is difficult to identify them.

However, comparing the DNA of large numbers of bipolar patients with the DNA of large numbers of healthy individuals makes this process easier, as differences between the two groups can be confirmed statistically.

Five risk regions found, two newly discovered

Using their large data collection, the investigators analyzed around 2.3 million different genetic regions, first in the bipolar patients, then in the healthy controls.

Fast facts about bipolar disorder

•Biopolar disorder affects around 5.7 million adults in the US every year.
•Onset of the disorder usually occurs in late teens or early adult years.
•Children who have a parent or sibling with bipolar disorder are much more likely to develop the illness.

Subsequent evaluation of these regions revealed five risk regions on DNA that are associated with bipolar disorder.

Three of these regions – ANK3, ODZ4 and TRANK1 – have been described in previous studies, although the researchers note that they were statistically better confirmed in this study.

But the other two risk regions – ADCY2 on chromosome five and so-called MIR2113-POU3F2 on chromosome six – were newly discovered.

The research team says the ADCY2 region is of particular interest, as it codes an enzyme that plays a part in sending signals to nerve cells.

“This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,” explains Dr. Nöthen.

The research team concludes that their findings – particularly the discovery of the ADCY2 risk region – provide new insight into the biological mechanisms involved in the development of bipolar disorder.

Dr. Nöthen adds:

“Only when we know the biological foundations of this disease can we also identify starting points for new therapies.”

Last year, Medical News Today reported on a study detailing new brain scans that measure blood flow, which could diagnose bipolar disorder in its early stages and differentiate it from depression.

Written by Honor Whiteman

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First on top of the world and then in the depths of despair – this is what the extreme mood changes for people with bipolar disorder are like. Under the direction of scientists from the University of Bonn Hospital, the Central Institute of Mental Health of Mannheim and the University of Basel Hospital, an international collaboration of researchers discovered two new gene regions which are connected with the prevalent disease. In addition, they were able to confirm three additional suspect genes. In this unparalleled worldwide study, the scientists are utilizing unprecedented numbers of patients. The results are now being published in the renowned journal “Nature Communications”.

Throughout the course of their lives, about one percent of the population suffers from bipolar disorder, also known as manic-depressive disorder. The patients undergo a veritable rollercoaster of emotions: During extreme shifts, they experience manic phases with delusions of grandeur, increased drive and a decreased need for sleep as well as depressive episodes with a severely depressed mood to the point of suicidal thoughts. The causes of the disease are not yet fully understood, however in addition to psychosocial triggers, genetic factors play a large role. “There is no one gene that has a significant effect on the development of bipolar disorder,” says Prof. Dr. Markus M. Nöthen, Director of the Institute of Human Genetics of the University of Bonn Hospital. “Many different genes are evidently involved and these genes work together with environmental factors in a complex way.”

Scale of the investigation is unparalleled worldwide

In recent years, scientists at the Institute of Human Genetics were already involved in decoding several genes associated with bipolar disorder. The researchers working with Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health of Mannheim, Prof. Dr. Markus M. Nöthen from the University of Bonn Hospital and Prof. Dr. Sven Cichon from the University of Basel Hospital are now using unprecedented numbers of patients in an international research collaboration: New genetic data from 2266 patients with manic-depressive disorder and 5028 control persons were obtained, merged with existing data sets and analyzed together. In total, data on the genetic material of 9747 patients were compared with data from 14,278 healthy persons. “The investigation of the genetic foundations of bipolar disorder on this scale is unique worldwide to date,” says Prof. Rietschel from the Central Institute of Mental Health of Mannheim.

The search for genes involved in manic-depressive disorder is like looking for a needle in a haystack. “The contributions of individual genes are so minor that they normally cannot be identified in the ‘background noise’ of genetic differences,” explains Prof. Cichon from the University of Basel Hospital. Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically. Such suspect regions which indicate a disease are known by scientists as candidate genes.

Two new gene regions discovered and three known gene regions confirmed

Using automated analysis methods, the researchers recorded about 2.3 million different regions in the genetic material of patients and comparators, respectively. The subsequent evaluation using biostatistical methods revealed a total of five risk regions on the DNA associated with bipolar disorder. Two of these regions were newly discovered: The gene “ADCY2” on chromosome five and the so-called “MIR2113-POU3F2” region on chromosome six. The risk regions “ANK3”, “ODZ4” and “TRANK1” have already been described in prior studies. “These gene regions were, however, statistically better confirmed in our current investigation – the connection with bipolar disorder has now become even clearer,” says Prof. Nöthen.

The researchers are particularly interested in the newly discovered gene region “ADCY2”. It codes an enzyme which is involved in the conduction of signals into nerve cells. “This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,” explains the human geneticist of the University of Bonn Hospital. With their search for genetic regions, the scientists are gradually clarifying the causes of manic-depressive disorder. “Only when we know the biological foundations of this disease can be also identify starting points for new therapies,” says Prof. Nöthen.

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Lithium, one of the oldest and most widely used drugs to treat neuropsychiatric illnesses, such as bipolar disorder, has a serious drawback – toxicity. In a continued effort to find a safer form of lithium, researchers at the University of South Florida (USF) have discovered that lithium salicylate, an alternative salt form, might be the answer.

The researchers found that oral lithium salicylate produced steady lithium levels up to 48 hours in rats without the toxic spike associated with the rapid absorption of current FDA-approved lithium carbonate. They concluded that lithium salicylate could be more effective than lithium carbonate, yet without accompanying risks of toxicity, a potentially important development in the next generation of lithium therapeutics.

Their study results appeared in a recent issue of RSC Advances, the journal of the Royal Society of Chemistry.

While lithium carbonate has been very effective for the treatment of mania in bipolar disorder, and credited for reducing suicides in depressive phases of the disease, patients who take lithium carbonate are often noncompliant because of adverse effects, including hand tremor, diarrhea, vomiting, weight gain and decreased thyroid function. New drugs that are as effective as lithium carbonate, but without toxicity, have not been forthcoming.

“Despite its narrow therapeutic window and the emergence of proprietary alternatives, U.S. FDA-approved lithium therapeutics are still regarded as the ‘gold standard’ for the treatment of the manic phase of bipolar disorder,” said study lead author Adam J. Smith, PhD, a neuroscientist at the Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, at USF Health.

“Our previous research suggested that re-engineering lithium therapeutics by crystal engineering might produce better performance with reduced toxicities.”

Crystal engineering is the design and synthesis of molecular solid crystal structures with desired properties using intermolecular interactions, Smith said.

For their latest study published in RSC Advances, the researchers tested two previously untested salts of lithium – salicylate and lactate – both of which are structurally different from lithium carbonate. In laboratory rats, they found that lithium salicylate and lithium lactate exhibited “profoundly different pharmacokinetics” when compared to the FDA-approved and widely used lithium carbonate. Pharmacokinetics is the way the body absorbs, distributes and gets rid of a drug.

“To our knowledge, this is the first pharmacokinetic study of lithium salicylate and lithium lactate in laboratory animals,” Smith said.

The findings support earlier suggestions that an ideal lithium preparation would be one that would both “flatten” high blood level peaks and also slow declining blood concentrations, the researchers report.

“This is exactly the pharmacokinetic profile produced by lithium salicylate in our study,” said senior author Doug Shytle, PhD, also of the Center of Excellence for Aging and Brain Repair at USF Health. “Remarkably, lithium salicylate produced elevated levels of lithium in the blood and brain 48 hours after the dose, but without the sharp peaks that contribute to the toxicity problems of lithium in the currently used form.”

That 48-hour window, the researchers said, represents a critical difference between lithium salicylate and current FDA-approved lithium therapeutics. If these preclinical results hold true in humans, this would allow for a less frequent dosing regimen and possibly fewer troublesome side effects that plague conventional lithium therapy.

“Psychiatry has long struggled with the fact that, while lithium is highly effective for treating bipolar disorder, the narrow therapeutic window and side effect profile often makes lithium both difficult and sometimes dangerous to work with clinically,” said Todd Gould, MD, of the Department of Psychiatry at the University of Maryland, an expert in the mechanisms of lithium and the neurobiology of bipolar disorder.

“The pharmacokinetic data by Dr. Smith and colleagues suggests that lithium salts other than the commonly used lithium carbonate may have a broader therapeutic window and potentially fewer side effects. Studies in humans will be needed to confirm safety and demonstrate that the pharmacokinetic profile observed in rats is similarly observed in humans.”

USF researchers continue to pursue a safer, more effective lithium therapy, and expect to soon conduct the experiments required to support early clinical trials.

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New research suggests that a commonly used mood-stabilizing drug – valproic acid – could help reduce the risk of developing head and neck cancer.

The research team, led by Dr. Johann Christoph Brandes of the Atlanta Veterans Medical Center and Emory University in Atlanta, GA, recently published their findings in the journal Cancer.

Valproic acid (VPA) is a medication used to treat epilepsy and manic-depressive illness, such as bipolar disorder.

However, the medication is able to block histone acetyl transferases (HATs) – enzymes that control gene expression by altering DNA structure. This is a process that occurs in the early stages of many cancers, including lung, bladder, prostate, and head and neck cancers.

Therefore, the researchers investigated whether VPA has the potential to be used as an anticancer agent.

The team analyzed information from the National Veterans Affairs (VA) Medical SAS data set linked to the VA Central Cancer Registry. This involved 439,628 veterans, of which 26,911 were taking VPA for bipolar disorder, post-traumatic stress disorder, migraine and seizures.

‘VPA could prevent 16,000 new cases of head and neck cancer’

Results of the analysis revealed that individuals who had been using VPA for at least 1 year had a 34% lower risk of developing head and neck cancer, compared with those who did not use the medication.

Headache migraine
Researchers say VPA – a drug used to treat migraines, seizures and manic-depressive illness – may be effective in reducing the risk of head and neck cancer.

The researchers found that the risk reduction for head and neck cancer was most pronounced in individuals who took VPA for at least 3 years.

However, the team notes that they were not able to determine the optimal duration for which VPA should be taken because the number of patients in the study with longer exposure was limited.

Furthermore, the investigators found that higher doses of VPA were associated with a greater reduction in head and neck cancer risk. But again, the team was unable to determine the optimal dosage.

According to the National Cancer Institute, head and neck cancers account for approximately 3% of all cancers in the US and mainly occur in people aged over 50. At least 75% of all head and neck cancers are caused by tobacco and alcohol use.

Dr. Brandes says that a 34% risk reduction in head and neck cancer with VPA use equates to around 16,000 new cases and between 3,000 and 4,000 deaths being prevented in the US alone.

He says:

“Head and neck cancer is an important global health crisis, and low-cost and low-toxicity prevention strategies like VPA use have a high potential impact on pain, suffering, costs, and mortality associated with this disease.”

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It is unclear what causes bipolar disorder – a condition characterized by dramatic changes in mood. But researchers from the University of Michigan Medical School have created the first stem cell model for bipolar disorder, which they say could uncover the origins of the condition and open the door to new treatments.

The research team recently published their study in the journal Translational Psychiatry.

To reach their findings, the investigators obtained skin samples from people with bipolar disorder, alongside skin samples from individuals without the condition.

By exposing small samples of skin cells to carefully controlled conditions, the researchers turned them into induced pluripotent stem cells (iPSCs). These are stem cells that have the potential to be turned into any other type of cell. The team then turned the iPSCs into neurons.

They measured gene expression of the iPSCs and then re-evaluated gene expression once the stem cells became neurons.

From this, the team found significant differences between the stem cells taken from bipolar patients and those taken from individuals without the condition.

Bipolar patients ‘express more genes for calcium signaling’

Stem cell lines
The stem cell lines were made from the skin of bipolar patients.
Image credit: University of Michigan Medical School

The researchers found that the neurons from bipolar patients expressed more genes for membrane receptors and ion channels than the neurons from non-bipolar patients – particularly genes for receptors and channels involved in sending and receiving calcium signals between cells.

Since calcium signals play a significant role in neuron development and function, the investigators say their findings suggest that genetic differences in early brain development may contribute to the development of bipolar and other mental health conditions later in life.

When the researchers exposed the neurons to lithium – a chemical that bipolar patients often use to regulate their mood – signaling patterns changed.

The researchers explain that lithium changes how calcium signals are sent and received, so these new cell lines will allow them to determine the mechanisms behind this in cells specific to bipolar patients.

The team also found that the neurons from bipolar patients were “addressed” differently during development than those from non-bipolar patients, meaning signaling could be misdirected. They say this could affect brain development.

Furthermore, the researchers found differences in microRNA expression – small RNA fragments that play an important role in “reading” genes – in the cells of bipolar patients. The teams says this discovery supports the idea that bipolar disorder develops from a “combination of genetic vulnerabilities.”

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