We have all bumped up against the limits of the current model of antidepressant treatments for depression: the patient who comes in with a laundry list of failed medication trials, or a number of other complaints depicting a portrait of malaise—aches, pains, anhedonia, fatigue, brain fog, digestive woes—that don’t really respond to currently available agents. What if shifting our thinking about underlying causes might hold the answer to treatment of these individuals?