Psychiatry, says Dr. Daniel S. Pine, “might achieve a needed paradigm shift” by adopting a research approach used in other branches of medicine, an approach called “experimental medicine.” It involves not just finding biological markers that correlate with illness—for example, high blood pressure or high cholesterol suggesting elevated risk of heart disease. Rather, explains Dr. Pine, the approach “identifies manipulations that affect biomarkers while substantially changing the course of an illness in patients. An example might be a statin drug that reduces cholesterol levels or a beta-blocker that reduces blood pressure, which in turn can be shown to improve patient outcomes which would lead to reductions in heart attacks.

From data in the “computational psychiatry” experiment described in the main story, it is possible to discover biomarkers—biological patterns of activity in the brain, as discerned by brain imaging—that can help clarify why certain anxiety patients respond better to some treatments than others, or to none of the available treatments. This is the stated goal of a “Viewpoint” article written by Dr. Pine and published in JAMA Psychiatry in July 2015. There, he argues for the importance of finding biomarkers “with a mechanistic focus.”

Biomarkers that reveal mechanisms underlying major depression or anxiety can be contrasted, he says, with biomarkers that are more simply “predictive” of having these diagnoses or symptoms associated with them. It is not that predictive markers are not needed. They are, he stresses. “But in terms of how we use our research funds and our time, we must recognize a need to support both kinds of studies. Nevertheless, I myself prefer pursuing markers that reveal what is causing these disorders. This kind of research is slower to show results and is much harder to perform, because it deals with the incredible complexity of the brain and how changes in different circuits affect behavior.”

Brain imaging could be used to extend insights from neuroscience on mechanisms of healthy brain-behavior relationships, Dr. Pine suggests. “For example, basic research charts how exquisitely orchestrated rapid shifts in the function of circuits connecting the amygdala and prefrontal cortex influence attention when rodents and primates confront threats. Imaging can extend this work by linking individual differences in human anxiety and attention to disturbances in those same circuits.” By refining these techniques, researchers might “generate tools analogous to those used in cardiology, helping psychiatrists of the future identify subgroups of anxious patients—whose circuit patterns could predict unique outcomes and suggest specific treatments.”If we know more about why different people respond differently to the same situations, it should be possible to design better treatments for those whose responses are not normal. In this computer-enabled example of fear conditioning, a young person is shown a succession of faces—some fearful, some neutral, others ambiguous—while his or her responses are measured at different levels: in circuits within the brain’s amygdala; in expressions of emotions, revealed in associated changes in the body’s autonomic responses, measured via the skin; and in clinically observable measures. The idea is to bridge these three levels to arrive at a deeper understanding of the response to danger that can be translated into effective patient-specific treatments.

— Written By Peter Tarr, Ph.D.

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