I scanned the table of contents of the British online journal BMC Medicine soon after it appeared in my email. A title caught my eye: "Depression Pathogenesis and Treatment: What Can We Learn From Blood mRNA Expression?" I thought about the many families that have asked me about biomarkers, especially for depression.
At a recent conference, a young woman came up to me, accompanied by her parents. She described how though she was in treatment for a major depression she had not, as yet, seen enough improvement to be able to regain good functioning at work. Her parents said they had read about blood tests that could better detect and inform the treatment of depression. They asked: Did they exist? Should they get them for their daughter?
So when I saw the journal article, I wondered if there was something new that could better explain how depression comes on in a person (called pathogenesis -- or how a disease process is born). Might there be new information about how to improve depression treatment?
Biomarkers are tests that uncover valuable information about a disease. Doctors, patients, and families all seek biomarkers that might help in the treatment of very common conditions that produce great suffering and burden, like depression.
Depression affects about 7 percent of adults in the U.S. annually, and about one-third of those people have severe symptoms that markedly decrease functioning. That's about 17 million people over 18 who suffer this condition, about 6 million severely, every year. We all know someone who has depression, and one in 10 Americans are on antidepressants. Controversy continues to brew, as well, about whether this disorder is over-diagnosed and whether antidepressants are effective. Might there be biomarkers to better resolve who needs and can benefit from which treatment(s) for this condition?
The article described people they studied with major (clinical) depression who demonstrated "... an altered pattern of expression in several genes ... compared with healthy controls." What was especially intriguing about this study was that it focused on how our genes express themselves, not simply the actual genes.
Humans have 22 chromosomes plus a sex chromosome (X or Y). On these chromosomes are about 3 million DNA "base pairs" -- the small molecules wound into the iconic double helix structure that pass genetic information from one generation to the next. But the information on the DNA must be sent out in message form to operate the way the cells in our body operate. That is the work of RNA (ribonucleic acid), especially messenger RNA (mRNA), miraculous compounds that decode and guide the expression of the genetic lineage that our DNA supplies. While DNA has the blueprint for human life, RNA is required to orchestrate the protein synthesis that will tell individual cells throughout the brain and body how to function, including moving muscles, digesting food, seeing, smelling and hearing, and the astounding ability we have to feel and think.
The report in BMC Medicine focused on mRNA in blood cells, which might serve as an easily obtainable proxy for the mRNA in the brain where it influences neurotransmitters, stress hormones, inflammatory proteins and cell growth factors, all of importance in the development of major depression. What's more, mRNA (in the brain and body tissues) has incorporated how our environment has affected our genes (called epigenetics or nurture) and the dynamic gene interactions that have altered the final expression of what nature (DNA) has provided. Might these scientists have found a way of identifying, through mRNA found in blood, a biological marker for the disease of depression?
The young woman I met and her family, like so many others, could benefit from biomarkers if:
1) There were definitive biological markers of psychiatric disease, in this case depression. Mental disorders are real, yet there is no measure like high blood sugar, bad lipid levels or elevated blood pressure to demonstrate the presence of a physical illness.
2) If there existed more of what is termed "personalized" treatment. Some medications work better for some people than others. This is true in cancer as well as with mental illness. But how can we know -- aside from trial and error -- which one is better so it can be used sooner and more effectively?
Depression biomarkers potentially could physically demonstrate the presence of the illness and might inform doctors how to better select which medication for which patient. But there is often a long road, full of right and wrong turns, between promise and practical application. People with mental illness, and their families, are often on the watch for useful innovation. But their precious resources, financial as well as hope, must be carefully protected. Biomarkers are being marketed today, including those for depression. Should you spend your money on these tests? Are they ready for prime time?
The authors of this study conclude that while there was a "... pattern of altered expression in several genes of interest ... the temporal [timing] relationship with other factors, such as exposure to stress, is still unclear." They add that: "... we also do not know whether some of these changes in gene expression represent the marker of a genetic predisposition ... [or might represent an] association between depression and inflammation."
In other words, there is promise but not more, not yet. My answer to the family I met would not change: I had said that while there is reason to believe we will see reliable biomarkers in the future, I would not advise they go for this type of testing right now.
Genetics and neuroscience rival the complexity of the physics of the universe. With genetic inheritance alone, there is hardly a single or simple pathway. Often, many genes are involved in complex diseases like diabetes and depression. The genes themselves actually vary in their form and expression (called genetic alleles). Those many genes, and their alleles, also are subject to highly-variable expression as a result of the physical and emotional environment they encounter in individual human beings -- with genes being turned on and off continuously by countless factors to which the person is exposed. And even within the specific cells that the genes send their messages to (via mRNA), ever-changing intracellular activity exerts further influence on what proteins are then synthesized that drive cellular functioning. As if that cascade were not complex enough, genes mutate. They change. Some changes are quite common and some rare, but our genes are constantly undergoing changes that may be adaptive or maladaptive to our everyday lives.
Yet science is remarkable, and by dint of effort, good luck and (often accidental) discovery our species enjoys vastly greater health and life prospects than our ancestors. But brain biomarkers are not what distressed patients and families should invest in right now as they seek better diagnosis and treatment of depression. Careful clinical assessment, systematically-developed and followed treatment plans created between patient and doctor, ongoing monitoring, and course corrections when needed remain the state of the art and science. That is how the predominance of people with depression today can improve and experience greater pleasure, purpose and productivity.
Dr. Sederer's book for families who have a member with a mental illness, The Family Guide to Mental Health Care will be published by WW Norton in April 2013.
The opinions expressed here are solely mine as a psychiatrist and public health advocate. I receive no support from any pharmaceutical or device company.
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