New Breakthrough: The new Treatment strategies for Bipolar Disorder and Epilepsy

Summary: A new study looks at how a gene associated with bipolar disorder affects the balance between inhibition and excitation; revealing a link with epilepsy.

People with bipolar disorder suffer from excessive emotional highs and lows that can cycle uncontrollably, severely distorting their awareness of self and others, impairing social and work ability and causing high risk of suicide. Current treatments are only partly effective. Researchers at Baylor College of Medicine have used mouse models and advanced molecular mapping studies in both mouse and human to learn how a gene associated with bipolar disorder controls the balance between brain excitation and inhibition and shown for the first time that it also is linked to epilepsy.

The findings, appearing recently in the early online edition of Molecular Psychiatry, open new treatment strategies for both bipolar disorder and epilepsy.

“We became very interested in a gene called ‘ankyrin 3’, or ANK3, a decade ago when we discovered it coded for a partner of two other genes that are mutated in some people with epilepsy. Soon afterward, ANK3 was connected with bipolar disorder by genetic testing of thousands of psychiatric patient volunteers around the world,” said Dr. Edward C. Cooper, associate professor of neurology, molecular and human genetics, and neuroscience at Baylor. “Although there are important differences, we noted similarities between bipolar disorder and epilepsy: both cycle, both are risk factors for the other, and both are currently treated using many of the same drugs. Reasons behind these overlaps were mysterious, and the specific parts of the ANK3 gene linked with bipolar had no known function. We decided to take a much closer look at the human brain and mice with bipolar-like behavior. In our study we found that reduced expression of one type of ANK3 removes a brake on the output of brain neurons, leading to excesses in firing in circuits for emotions, memory and epilepsy.”



Proteins coded by ANK3. Blue: output cells. Yellow: nerve impulse trigger zones of output cells. White: Inhibitory neurons that hold back output. Red: trigger zones with a different type of ANK3 protein, lost in bipolar disorder and epilepsy. NeuroscienceNews.com image is credited to the researchers.

Within each ANK3 gene are bits of DNA containing information coding for several different proteins. The research team found that, in both mice and human, different ANK3-coded proteins were expressed on brain cells responsible for increasing output (excitation) and holding back output (inhibition). Working with Cooper, Baylor genetics graduate student Angel Lopez discovered that an ANK3 type found in lower amounts in bipolar disorder patients was selectively lost by inhibitory neurons, lowering their output. Activity of neighboring excitatory cells proved unaffected. So, what scientists call “excitation/inhibition” balance, was shifted in the direction of excessive excitation.

When Lopez and colleagues engineered mice to lose this inhibitory form of ANK3, they found that the imbalance caused both frequent epileptic seizures and an increased risk of sudden death across the lifespan.

“This showed us that imbalance in ANK3 function can result not only in excessive circuit sensitivity and output leading to bipolar
disorder, but also severe epilepsy,” Cooper said.

Although diagnosis and care for bipolar disorder and epilepsy often are viewed as distinctly psychiatric and neurological issues, respectively, the study highlights an example of common genetic and biological underpinnings at a frontier between medical disciplines. The results open the door to additional lab and clinical research and could lead to new treatment options for both conditions by targeting ANK3 and its molecular partners in the brain.



“Our work also provides an example of how conducting and participating in unbiased human genetic studies, such as those that implicated ANK3 in bipolar disorder, can illuminate unforeseen connections between disease categories and the benefits of research that crosses disciplinary borders” said Cooper.
Source: Neuroscience News, Baylor College of Medicine

YOUR INPUT IS MUCH APPRECIATED! LEAVE YOUR COMMENT BELOW.

Depression: Are the symptoms correctly explained?

The standard rating scales used by healthcare professionals and researchers to diagnose this disease often differ in the symptoms they list, perhaps explaining why a one-size-fits-all treatment has to date been so ineffective, new research suggests.

Depression is generally considered to be a specific and consistent disorder characterized by a fixed set of symptoms and often treated with a combination of psychotherapy and medication. However, the standard rating scales used by healthcare professionals and researchers to diagnose this disease often differ in the symptoms they list, perhaps explaining why a one-size-fits-all treatment has to date been so ineffective. This is the finding of research conducted by psychologist Eiko Fried from the University of Amsterdam (AU). His results are published in the latest edition of the Journal of Affective Disorders.

Depression is often viewed as a common medical disorder like measles -- one either has it or one doesn't. As a result, diagnosis is generally followed by assigning specific treatment options. But unlike physical disorders where blood tests or other objective tests enable a reliable diagnosis, there are no such measures to determine whether someone is depressed. Instead, researchers and clinicians query patients about symptoms that are indicative of depression, such as sadness, suicidal ideation and sleep problems. If a person has many depression symptoms, she is considered depressed.



Heterogeneity
In his study, Fried used a content analysis to investigate the symptom overlap of 7 rating scales of symptoms that are commonly used in depression research. One of the scales is the Hamilton Rating Scale of Depression, which contains 17 predominantly physical depression symptoms like paralysis, weight loss and psychomotor retardation. Another is the Beck Depression Inventory, which includes 21 mostly cognitive-affective symptoms such as feelings like worthlessness, guilt, crying and self-dislike.

What he found was that these and other rating scales show surprisingly little symptom overlap. Moreover, together they feature a total of 52 different depression symptoms ranging from sadness, lack of interest and suicidal ideation to genital problems, irritability and anxiety.

These findings underline the striking heterogeneity of depression, a disorder mostly viewed as one consistent syndrome, says Fried. 'Patients diagnosed with depression are often thought to have similar kinds of problems and therefore receive very similar treatment. However, the fact that 7 common rating scales of depression contain over 50 different symptoms shows how strikingly different depressed patients can be in terms of the problems they experience. This seems to indicate the need for more personalized treatment and might explain why current "one-size-fits-all" solutions like antidepressants show so little efficacy.'



Predetermined outcome
Fried believes his findings could also pose a major problem for depression research because the type of scale used by researchers might determine the outcome of a scientific study. Fried: 'For example, imagine you are a researcher and want to study the brain structure of depressed patients. This is usually done by giving a large group of people one specific depression scale, and if these people have a certain number of symptoms they are enrolled into the study as depressed.

According to Fried, his findings suggest that the type of scale a researcher uses might dictate the kind of people who are enrolled in the study. 'For instance, if a researcher uses Hamilton's scale, which is focused on physical symptoms, the kinds of participants she examines in her brain study will differ dramatically from those who would be enrolled if she were to use Beck's cognitive-affective scale. And these different groups of people will likely differ in their brain structures.

As this and prior studies show, depressed people differ considerably in the problems they experience and symptoms they exhibit. This likely explains why so many different depression studies come to very different conclusions.'
Source: Material provided by Universiteit van Amsterdam (UVA).

Journal Reference: Eiko I. Fried. The 52 symptoms of major depression: lack of content overlap among seven common depression scales. Journal of Affective Disorders, 2016;

YOUR INPUT IS MUCH APPRECIATED! LEAVE YOUR COMMENT BELOW.