The quest within scientific research to identify new biomarkers for a wide spectrum of diseases and disorders is something that we at Medical News Today report on frequently.
In recent months we have looked at studies investigating biomarkers that can be used to test concussion severity, the relationship between Alzheimer's biomarkers and severity of symptoms, and biomarkers as a fast, non-invasive test for brain cancer.
But can biomarkers be used to diagnose or improve treatment for patients with psychiatric disorders?
Mental health problems are often perceived as being "ethereal" in origin, compared with more visible and quantifiable health problems.
Depression, for instance, is not considered to have a specific root cause but is believed to be influenced by a combination of stressful life events, genetic susceptibility, chemical changes in the brain or other underlying medical conditions.
Yet, in the past couple of years, there has been a drive in research to locate biomarkers for depression and to develop reliable tests that detect these biomarkers in depressed patients.
Only last week, it was announced that the world's biggest scanning project - UK Biobank - is currently analyzing the DNA of half a million participants in order to identify biomarkers for conditions including not just the likes of cancer, stroke and heart disease, but also depression.
What are biomarkers?
Biomarkers are "biological clues" that doctors can look for in patients to confirm the presence or risk of disease. These clues are usually found in changes in blood, urine or body tissue. Fasting glucose, for example, can be used to diagnose diabetes, and the presence of liver enzymes in the blood can indicate liver disease.
Biomarkers are a popular area of study. A 2012 article in Massachusetts General Hospital's Proto magazine calculated that out of 150,000 published papers announcing the discovery of thousands of new biomarkers for a range of conditions, only about 100 biomarkers are in routine use (resource no longer available at protomag.com).
The article added that even some of the most long-established of these - such as prostate-specific antigen screening for prostate cancer and the antigen-125 blood test for ovarian cancer - have recently been discredited.
Finding new ways to identify the presence of disease is desirable where there is a demand for faster, cheaper and less invasive testing - such as in cancer and other severe conditions. But the hunt for new biomarkers is sometimes described as circular.
Given that the process of establishing biomarkers for any condition is prone to yielding disappointments, why is there an impetus to locate biomarkers for depression? Especially given that this is a condition that does not involve costly or invasive testing to diagnose?
Medical News Today put this question to Eva E. Redei, PhD, of the Feinburg School of Medicine at Northwestern University, IL. In 2012, Dr. Redei's research into blood biomarkers for major depressive disorder (MDD) in teenagers aged 15-19 was listed by The New York Times as one of "32 innovations that will change your tomorrow." Despite this, her work faced criticism. "The current level of hype for this study is unwarranted," insisted one colleague.
"I believe that the only way to convince those who do not believe in the accuracy or usefulness of biomarkers is to show their accuracy and process the diagnostic test through [the Food and Drug Administration]," Dr. Redei told us.
"The need is another issue," she says. "Primary care physicians see a large proportion of depressed patients. According to studies involving large number of patients, they diagnose correctly less than half of them."
Early and correct diagnosis, Dr. Redei reminds, leads to better treatment response, which "helps to reduce the burden of depression on the patients, their family and the society as a whole. Blood-based simple laboratory tests could help tremendously."
Blood test to diagnose depression?
Dr. Redei's team identified a set of 11 genes that express proteins in the blood of teenagers with MDD, and a total of 26 biomarkers that they believed could differentiate between depressed teens, non-depressed teens and even teens with an anxiety disorder or other subtype of depression.
Blood-based simple laboratory tests could help remove depression's burden on patients, their families and society, Dr. Redei claims.
Currently, MDD is diagnosed by patients reporting their own symptoms, but Dr. Redei believes that her blood test would be more objective and have less bias than current diagnostic methods.
It could also provide comfort to adolescent patients who otherwise might not feel their condition is taken seriously by peers or family.
Not everyone was convinced, however. "From a public health point of view, you have to think, 'What value does this test have, and compared to what?,'" questioned Dr. Lloyd Sederer, medical director of the New York State Office of Mental Health.
"Standard clinical diagnosis is pretty good," Sederer wrote in The Huffington Post. "If you have essentially a low-tech, low-cost and relatively effective means of determining a condition, then all of those attributes have to be exceeded for something else to be more valuable.
"When something like this comes out and gets a lot of attention, it's a false promise to parents," he says of Redei's work. "And does it really shape, in any way, how effective your treatment is going to be now?"
Perhaps, though, there has been a shift in how tests for depression biomarkers are viewed - even within the 2 years since Dr. Redei's research was published in the journal Translational Psychiatry.
Measuring cortisol levels in teenage boys' saliva 'can predict adult clinical depression'
A recent study by researchers from Cambridge University in the UK, which proposed measuring levels of the stress hormone cortisol in adolescents' saliva as a diagnostic and prognostic marker for depression - alongside the traditional self-reported symptoms - seemed to generate more favorable commentary.
For example, Cynthia Joyce, chief executive of the charity MQ: Transforming Health, wrote in a blog for the Wellcome Trust:
"This finding is important because while any number of candidate biomarkers (genes, proteins, physical traits, symptoms) have been identified for depression, the associations have proven difficult to pin down and validate as bona fide markers.
This proof-of-concept study represents a real advance for the study of depression. The combined 'bio-behavioural' marker will enable more comprehensive study of how depression evolves over time, and perhaps even how we might prevent it."
The Cambridge study found that teenage boys who have a combination of depression symptoms and elevated cortisol are up to 14 times more likely to develop clinical depression than boys with no symptoms and stable cortisol levels.
The researchers behind the study - which was published in the Proceedings of the National Academy of Sciences - think that their test will allow health care providers to strategically target preventions and interventions at patients, reducing their risk of serious depression in adult life.
However, the cortisol test is only effective in males because women naturally have higher levels of cortisol. The team has not yet found an equivalent indicator for predicting outcomes in females.
MQ believe that this combination of physiological biomarkers and self-reported symptoms as a tool to predict clinical depression has powerful implications. In the wake of the study's publication, the charity announced a funding call inviting biological and psychological scientists to work together for advancing care and understanding of depression.
Using biomarkers to personalize treatment for depression patients
Whereas the Redei study supplemented diagnosis of depression in teenagers, and the Cambridge study claimed to predict later depression, other studies into biomarkers of depression have focused instead on personalizing treatment for depression.
One study, funded in 2013 by the National Institute of Mental Health (NIMH) and published in JAMA Psychiatry, used a positron emission tomography (PET) scanner to analyze which brain regions are active at any given moment in patients with depression.
The researchers compared the brain activity of patients who successfully entered remission following treatment with those who did not. The treatments considered in the study were the talking therapy cognitive behavioral therapy (CBT) and the serotonin specific reuptake inhibitor (SSRI) antidepressant escitalopram.
They found that low activity in the insula of the brain before treatment predicted that the patient would respond well to CBT as a treatment, but that they would be less likely to achieve remission through use of escitalopram. Conversely, hyperactivity in the insula would predict remission through escitalopram but a poor response to CBT.
Trial and error currently determines whether a patient best responds to talking therapies or antidepressants, and the NIMH reports that only about 40% of patients achieve remission after initial treatment for depression.
"This is costly in terms of human suffering as well as health care spending," the organization claims, suggesting that the PET scan approach could be useful in guiding doctors toward more effective initial treatment decisions.
Watch the video below for more details on this study:
Study lead Dr. Helen S. Mayberg told Medical News Today that the next step is to further explore patients at different stages of the illness and to explore "mechanistically distinct" types of antidepressants. She says that this will allow the team to develop treatment selection algorithms for all scenarios throughout the progression of the illness.
We asked Dr. Mayberg how urgent the need is to identify biomarkers for depression, given that some critics have suggested it is a fallible and over-hyped science.
Pointing out that physicians do a variety of tests to determine the best course of action for illnesses such as cancer - including tests to exclude specific treatments - she responded:
"To expect that with a disorder as complex as depression we should use a single measure of any type (blood, questionnaire, brain scan) to distinguish among patients that require psychotherapy or medication, or are likely to be treatment-resistant and go on to need [electroconvulsive therapy] or more invasive interventions, would be to ignore many years of research demonstrating that understanding the biological heterogeneity of the disorder is key - as with any other medical illness."
Other recent studies have also looked at using cytokines or C-reactive protein to predict patients' SSRI response.
"All of these studies are very important and useful in their separate ways," Dr. Redei told Medical News Today. "They employ accumulated knowledge about the biology of depression and use the markers that were studied previously to identify differences in expression of RNA, proteins of steroids (and other means) between patients and controls."
"Our study was a discovery-based one," she clarifies, whereas "the transcripts that are on the potential diagnostic marker panel are novel. Some of them are completely unknown. Because of that, they may also open novel areas of research."
Asked which test she considers to have the greatest evidence base and most promising clinical applications, she replied: "Of course I believe in ours the most!"
Rethinking the physiological causes of depression?
The search for depression biomarkers is not an isolated fad, some scientists claim, but is part of a much larger rethink happening throughout science right now on the physiological causes of depression.
The search for depression biomarkers is part of a rethink on the physiological causes of depression.
This innovative thinking is opening up potential new treatments for depression that go beyond the standard antidepressant function of increasing or blocking the neurotransmitters implicated in depression.
Now molecular biomarkers, such as monoamine and neurogenesis regulators, and mediators of glutaminergic and GABAergic activity, are being investigated for their role in depression, as is the atrophy of nerve cells in the hippocampus as a result of chronic stress.
A recent study of depression biomarkers by researchers from Loyola University Health System in Illinois listed corticotropin-releasing hormone antagonists, ketamine, partial adrenalectomy, benzodiazepines, anesthetics, deep brain stimulation and transcranial magnetic stimulation as new or forthcoming depression treatments.
The new theories behind the development of these depression therapies "should not be viewed as separate entities because they are highly interconnected," the authors write. "Integrating them provides for a more expansive understanding of the pathophysiology of depression and biomarkers that are involved."
Explaining that it can take months to recover from depression, the researchers suggest that existing depression treatment programs averaging 6 weeks are not long enough for adequate recovery. They hope the new biomarker-led research will not only enhance treatment, but open doors for a new understanding of depression.