Why do people with bipolar disorder have high rates of early heart disease and other problems? The Centre for Youth Bipolar Disorder is searching for clues in proteins found in patients' blood
John remembers the onset of his bipolar disorder clearly. He began to lose interest in all of the sports and activities he once loved, including tennis and badminton, the summer he was 16 years old.
"It got to the point where I stayed in bed all day."
Following that were the manic episodes, like days-long road trips with friends during which "I would do a lot of things I wouldn't normally do, a lot of risky behaviour." When he returned, he would be unable to recall what had happened during the trips.
The highs and lows worsened until they culminated in December 2013 with a suicide attempt. John, then 18, was admitted to acute care at
Sunnybrook and was treated by Dr. Benjamin Goldstein, who diagnosed him with bipolar disorder. Dr. Goldstein, director of the Centre for Youth Bipolar Disorder at Sunnybrook and an award-winning researcher into the condition, has since enrolled John in a five-year study he is conducting to "learn whether specific markers in the blood can help us better understand, and predict, the course of symptoms among adolescents with
bipolar disorder." It may also guide future treatment of young people like John, he says.
Bipolar disorder (BD), which is characterized by repeated episodes of mania and depression, affects 2 to 5 per cent of teens and adults. While risk of suicide in patients is high, the leading cause of death is actually heart disease. The study, funded by the Canadian Institutes of Health Research, will also look at how the biomarkers in the blood and blood vessel functioning might be related to future heart disease in adolescents and adults with the condition.
"The fact is, people with bipolar [disorder] have high rates of heart disease. And they develop this extremely prematurely, 10 to 20 years earlier than expected," says Dr. Goldstein. "The question is, 'Why?' And my career is dedicated to answering that question."
Recent research has shown that those with the disorder experience upsurges or decreases in certain types of proteins in the blood, such as those related to inflammation during bipolar episodes. Dr. Goldstein and his team predict that the spikes or dips in these proteins, along with increased inflammation over many years, can lead to a host of diseases, such as heart disease, obesity and arthritis.
Mapping out the biology of people who are in phases of mania or depression will also allow doctors to predict the course of the illness, he says.
"Right now, we have to wait for fully manifested symptoms to evolve and present themselves. It's a little like saying we're going to figure out heart disease by waiting for you to walk in having a heart attack. We want to pre-empt that."
To conduct the study, currently in its third year, Dr. Goldstein and his team of researchers will recruit teenagers with bipolar disorder, as well as a comparison group of teenagers without major psychiatric disorders. The testing consists of blood draws and fingertip probe tests. The youth with bipolar disorder are required to return for tests at regular intervals, both during times of stable mood and times of bipolar episodes, over a period of two years. The blood draw is used to check for levels of specific proteins in the blood (see sidebar).
The fingertip probe test, also called peripheral arterial tonometry, meanwhile, is done via a non-invasive clip placed on the index fingers. It measures the pulse-to-pulse blood volume several minutes before and then after a blood pressure cuff is used to prevent blood flow for five minutes. Dr. Goldstein's team is looking at the extent to which the blood vessels dilate after blood flow is resumed with the cuff. Increased pulse volume in the fingertip reflects dilation, which, in turn, reflects blood vessel function.
"A sluggish or minimal increase in pulse volume is a marker of potential future cardiovascular risk. This blood vessel function is, in part, related to acute circumstances, including mood episodes," says Dr. Goldstein.
It makes sense to study the biology of otherwise healthy teens because as many as two-thirds of patients first develop the condition between the ages of 13 and 19, says Dr. Goldstein. If researchers were able to identify those who have biomarkers in their blood now, it would help physicians guide preventative treatment when the disease is less entrenched.
While the illness has been studied fairly extensively in adults via cross-
sectional studies, Dr. Goldstein notes, there are few studies that follow people over time, especially in teens. "There is a real dearth of information on this topic in youth."
Current treatments for teens with bipolar disorder are not preventative, but, rather, treat the symptoms of mania and depression. They include drugs, therapy and lifestyle changes. Drugs include mood stabilizers (such as lithium),
anti-convulsants and anti-psychotics, says psychiatrist Dr. Anthony Levitt, chief of the Hurvitz Brain Sciences Program at Sunnybrook.
But psychiatrists have to be extremely careful in selecting medication for those with bipolar disorder, the psychiatrist adds, because most can cause side effects, including weight gain. "If weight goes up significantly, now you are at risk for other kinds of metabolic disturbances, including diabetes, hypoglycemia and heart disease", he says.
Another key component is cognitive behavioural therapy, Dr. Levitt says. "In youth, if you have bipolar [disorder], you need help dealing with intense emotions."
This has been especially true for John. "It helps, definitely, when you are able to talk to the therapist. You can actually work out what is causing your mood, why you are feeling that way." He is also taking a mood stabilizer and an anti-psychotic, which have worked extremely well. John has been symptom-free for seven months.
Exercise, eating well and getting enough sleep are also crucial to successfully treating bipolar youths, says Dr. Levitt. John, for his part, is now vigilant about regular bedtimes. He does three workouts per week and he's back on the tennis courts.
"Exercise and healthy living are enhancing blood flow to the brains in those with bipolar illness, so we know that can be 'brain-protective' for young people with the disorder," says Dr. Levitt.
Moving forward, the big push is to identify risk factors for the development of the condition. He continues, "If we can accurately identify risk factors, we know who's going to develop it. [It would be helpful to] also recognize some of the vascular dangers of the disorder – we know they exist, but we need to recognize them early – so that people live longer, healthier lives."
Dr. Neal Westreich, who co-heads the hospital's Adolescent Inpatient Psychiatry department, says that, up to this point, doctors are unable to use a blood test to diagnose depression, bipolar disorder or other psychological disorders. He says that the study of biomarkers "could help us make, in a more scientific way, the diagnosis."
But he cautions that doctors likely won't simplify it to the point where "x" biological issue causes bipolar disorder. "I think it's going to be more complicated than that," says Dr. Westreich.
"In many ways, it is no different than any other biological illness. Take diabetes, for example. I would argue that it is a biological, social, psychological illness. It is dependent on lifestyle and compliance and stressors and, of course, biology."
For his part, John is optimistic about his future. He is taking hospitality management at George Brown College this fall and hopes to become a restaurant or hotel manager. He sees taking part in research, such as Dr. Goldstein's, as critically important – not only for his future, but also for all bipolar teens.
"It would be great for them to have that data that could treat other patients."
Dr. Westreich agrees. "The bottom line is, any research we have in terms of understanding what could prevent the illness, what causes the illness and how we can mitigate it with the least amount of side-effects is welcome, necessary and could change the quality of life of so many people in Canada."
John's name has been changed to protect confidentiality.
ON THE HUNT FOR BIOMARKERS
Dr. Goldstein's team at the Centre for Youth Bipolar Disorder at Sunnybrook will be studying the blood samples of teens with bipolar disorder and healthy teens.
They are looking to see, among other things, whether their blood contains several proteins, including:
• Brain-derived neurotrophic factor (decreases during acute depression or mania), which assists in the growth, maturation and maintenance of nerve cells. It's found in the brain and the blood.
• C-reactive protein (rises during episodes), which is a protein produced by the liver that indicates an increase in inflammation in the body. Higher levels of C-reactive protein can be a biomarker for future disease risk, including heart disease.
• Interleukin-6 (marker of increased inflammation), which is a protein found in blood plasma that is produced during inflammatory phases in the body. It is also released into the bloodstream after a muscle contracts.
• TNF (tumour necrosis factor)-alpha (marker of increased inflammation), which is a protein that appears during an acute phase of inflammation. •
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