I n his 1990 memoir Darkness Visi- ble, the American novelist William Styron—author of The Confessions of Nat Turner and Sophie’s Choice— chillingly describes his state of mind dur- ing a period of depression: He [a psychiatrist] asked me if I was suicidal, and I reluctantly told him yes. I did not particularize—since there seemed no need to—did not tell him that in truth many of the arti- facts of my house had become poten- tial devices for my own destruction: the attic rafters (and an outside ma- ple or two) a means to hang myself, the garage a place to inhale carbon monoxide, the bathtub a vessel to re- ceive the flow from my opened arter- ies. The kitchen knives in their draw- ers had but one purpose for me. Death by heart attack seemed particularly inviting, absolving me as it would of active responsibility, and I had toyed with the idea of self-induced pneumo- nia—a long frigid, shirt-sleeved hike through the rainy woods. Nor had I overlooked an ostensible accident, à la Randall Jarrell, by walking in front of a truck on the highway nearby .... Such hideous fantasies, which cause well people to shudder, are to the deeply depressed mind what lascivi- ous daydreams are to persons of ro- bust sexuality. As this passage demonstrates, clinical depression is quite different from the blues everyone feels at one time or an- other and even from the grief of bereave- ment. It is more debilitating and dan- gerous, and the overwhelming sadness combines with a number of other symp- toms. In addition to becoming preoccu- pied with suicide, many people are plagued by guilt and a sense of worth- lessness. They often have difficulty think- ing clearly, remembering, or taking plea- sure in anything. They may feel anxious and sapped of energy and have trouble eating and sleeping or may, instead, want to eat and sleep excessively. Psychologists and neurobiologists sometimes debate whether ego-damag- ing experiences and self-deprecating thoughts or biological processes cause depression. The mind, however, does not exist without the brain. Considerable evidence indicates that regardless of the initial triggers, the final common path- ways to depression involve biochemical changes in the brain. It is these changes that ultimately give rise to deep sadness and the other salient characteristics of depression. The full extent of those al- terations is still being explored, but in the past few decades—and especially in the past several years—efforts to identi- fy them have progressed rapidly. At the moment, those of us teasing out the neurobiology of depression some- what resemble blind searchers feeling different parts of a large, mysterious creature and trying to figure out how their deductions fit together. In fact, it may turn out that not all of our findings will intersect: biochemical abnormali- ties that are prominent in some depres- sives may differ from those predomi- nant in others. Still, the extraordinary accumulation of discoveries is fueling optimism that the major biological de- terminants of depression can be under- stood in detail and that those insights will open the way to improved methods of diagnosing, treating and preventing the condition. Pressing Goals O ne subgoal is to distinguish fea- tures that vary among depressed individuals. For instance, perhaps de- creased activity of a specific neurotrans- mitter (a molecule that carries a signal between nerve cells) is central in some people, but in others, overactivity of a hormonal system is more influential (hormones circulate in the blood and can act far from the site of their secre- tion). A related goal is to identify sim- ple biological markers able to indicate which profile fits a given patient; those markers could consist of, say, elevated or reduced levels of selected molecules in the blood or changes in some easily visualizable areas of the brain. After testing a depressed patient for these markers, a psychiatrist could, in theory, prescribe a medication tailored to that individual’s specific biological anomaly, much as a general practitioner can run a quick strep test for a patient complaining of a sore throat and then prescribe an appropriate antibiotic if the test is positive. Today psychiatrists have to choose antidepressant medica- The Neurobiology of Depression 42 Scientific American June 1998 The Neurobiology of Depression The search for biological underpinnings of depression is intensifying. Emerging findings promise to yield better therapies for a disorder that too often proves fatal by Charles B. Nemeroff OLD MAN WITH HIS HEAD IN HIS HANDS was sketched (right) by Vincent van Gogh in 1882 and resembles Old Man in Sorrow, painted in 1889. The im- age may reflect van Gogh’s own depres- sion, with which he grappled for much of his life. He committed suicide in 1890. Copyright 1998 Scientific American, Inc.