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Predicting Treatment Response in Major Depression: The Use of Biosignatures

A new national study on "biosignatures" for depression treatment is groundbreaking in its approach and sophistication; it could usher in a new frontier of brain science.
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Recovery from a major depression is as reliant on clinical art and chance as it is on science. The consequences are that too many of the one in five Americans affected each year, whose suffering and disability are legion, go unrecognized and are not effectively treated. For some individuals, their debilitating symptoms and feelings of hopelessness and worthlessness push them to suicidal thoughts and life-threatening behaviors.

There are, however, effective, proven (called evidenced-based) treatments for major depression. These include antidepressant medications and a variety of psychotherapies, including cognitive-behavioral and interpersonal therapies. A very big problem, in psychiatry and other medical specialties, is that physicians cannot predict which treatment will work for a given individual. This is especially true for psychopharmacological treatments.

Personalized medicine is the delivery of health care tailored to a unique person based on her/his individual characteristics, rather than on information about what works for groups of individuals. Personalized medicine may deliver answers regarding which medication will work for which person, and perhaps when in the course of their illness. A specific element of personalized medicine is the use of biomarkers, or medical tests that can help specify treatment choice. For major depression, this would be the equivalent of the Holy Grail. Since the 1970s, depression researchers have searched for factors that might predict treatment response, including: differences in the patient's symptoms, administration of synthetic stress hormones, levels of neurotransmitters and other biologically active agents in spinal fluid, and how our genetic makeup affects the way we metabolize medications.

However, like many conditions in medicine, depression is protean -- its symptoms are highly varied and its differences in course and outcome among individuals even more so. Thus, it is not a surprise that it will be difficult to identify which treatment will work for whom. In fact, it is unlikely that any single test will be sufficient to determine which antidepressant is better suited for a particular patient. Instead, a more fruitful approach may be to fashion a panel of tests that together can better identify who is likely to respond to a specific medication and who is not. Ideally, such a panel would be a group of biological markers that together creates a unique "biosignature" that could identify the precise drug to help each affected individual recover. Not only would such precision reduce (or eliminate) today's trial and error, it would save a lot of time, since a medication trial typically takes four to six weeks, with more than one trial possible. Biosignatures represent a means of dramatically reducing suffering and disability associated with depressive illness.

An example of one approach to identifying a biosignature is to research whether responses to antidepressants are associated with abnormalities in what are generally considered the causes of depression. Current causal models of depression are varied: abnormalities in how specific genes, or patterns of genes, are "turned on or off"; how our environment interacts with the expression of genes (the nature-nurture dynamic); abnormalities in the function of neurotransmitters such as norepinephrine, serotonin or dopamine; and the inability to produce new brain cells (deficits in neurogenesis). Another promising area of current depression research involves alterations in how brain circuits or specific brain structures relevant to depressive symptoms impair emotion regulation (how we modulate our emotional responses), the experience of feelings of reward (neurochemical reactions to positive stimuli), and intellectual performance, also known as "executive functioning."

The National Institutes of Mental Health (NIMH) has launched an ambitious, exciting study to identify biosignatures. The study combines the research talents of an internationally recognized group of experts at the New York State Psychiatric Institute/Columbia University, the University of Michigan, Harvard University, and the University of Texas, Southwestern. The work will include using magnetic resonance imaging (MRI) to generate maps of the brain's structure, including tracing paths connecting different brain parts, to search for abnormalities in brain anatomy and the connections between brain regions through the circuits that run between them. Functional MRI (fMRI), a form of MRI where actual brain activity is measured when the brain is at work, will generate information about what parts of our brains are over or underactive during performance of specific tests of mental functions; fMRI may also provide information about responses to medication. In addition, there will be recordings of electrical currents in the brain (electroencephalography, or EEG, another safe and non-invasive test) when individuals are processing sounds considered an index of serotonin function, which may predict response to a specific class of antidepressants. Tests of mental performance, including the rapidity with which an individual responds to a cue, may also help in the design of a biosignature. Like all careful medical research that tries to distinguish a true response from the placebo effect (important and often robust), participants in the research will be randomly assigned to either an antidepressant or an inert, placebo pill. This strategy will allow investigators to discover biomarkers that predict improvement with a specific antidepressant, but also could uncover whether those who respond strongly to placebo have a unique biological makeup that itself warrants research.

Biosignatures for depression treatment are not ready for primetime. Only research will determine if and how they are. This national study, at four academic medical centers, is groundbreaking in its approach and sophistication; it could usher in a new frontier of brain science.

If you would like to learn more about this research or participate in a center local to where you live, visit

Written with Drs. Patrick J. McGrath, Ramin V. Parsey and Myrna M. Weissman

For more by Maria A. Oquendo, M.D., click here.

For more on brain science, click here.