From Chaos to Consilience: Part IIWhat the New Mind-Body Science Tells Us About the Pathophysiology of Major Depression

From Chaos to Consilience: Part IIWhat the New Mind-Body Science Tells Us About the Pathophysiology of Major Depression

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We would suggest that psychiatry has spent so many years taking its diagnostic categories as God-given that it has become inured to the fact that these categories tell us very little about the etiology and fundamental nature of the conditions they purport to encompass.1

Nowhere is this truer than in the case of depression. While the DSM—like all mythopoetic creations—has been forced to grapple with the complexities of reality by creating an ever larger cast of characters related to one another in ever more complicated ways, the types of deep, consilient understandings of depression that would unify rather than splinter, and that would empower rather than enfeeble, our therapeutic efforts have been consigned to the province of future science.

In this—the second installment in our series on mind-body approaches to mood disorders—we suggest that the future is now. Although we are far indeed from a full understanding of all the intricacies of depression, scientific advances during the past decade in fields ranging from immunology to evolutionary biology already provide the outlines for a theory of depression that is consistent, inclusive, and (most important) provides intellectually satisfying and testable answers to many basic questions in front of which the DSM must raise a finger to its lips in silence.

Because of space constraints, we can provide only the barest overview of this theory here. We invite you to log on to for a longer and more rigorous discussion of these ideas.

What is depression?
All over the world, depression is the most common emotional/behavioral breakdown pathway for human beings in response to environmental adversity. It is highly stereotyped but also irreducibly probabilistic.2 It is how humans tend to feel and behave when the internal or external environment seems unmanageably threatening. Tethered to systems necessary for survival, depression is a tendency and a vulnerability, an Achilles heel of hominid evolution.

Recent data increasingly suggest that depression is an emotional/behavioral manifestation of hyperactivity in brain-body systems that evolved to cope with danger and to adapt to changing environmental demands.3-10 Hyperactivity in these systems is linked to—and perhaps causes—reductions in the activity of CNS pleasure/novelty and executive decision-making circuitry.11,12 Across human evolution, these “danger pathways” have been most often activated by psychosocial struggles and by pathogen invasion, which goes far toward explaining why psychosocial stress and sickness are the 2 primary environmental risk factors for depression.

Why does depression have the symptoms it does?
The short answer is that depression looks so much like a combination of terrible stress and physical illnesses because, in our view, it is essentially a disorder of pathways in the brain and body that evolved to cope with stress and infection and that produce depressive symptoms when chronically hyperactive.3,5,6,13 Strong support for this idea comes from studies showing that when bidirectional stress—inflammatory danger pathways are chronically activated—such as occurs during treatment with the cytokine inter­feron-alpha—most people become depressed or, if not depressed, then exhausted, achy, and upset.14,15 Conversely, interrupt hyperactivity in key stress-related brain regions, such as the subgenual anterior cingulate, and many profoundly depressed patients have an immediate surcease of their internal torture.16 Recent data also demonstrate that stimulating activity in cortical areas that suppress stress pathway activity, such as the dorso­lateral prefrontal cortex, also leads to profound and rapid improvements in depression.17

Consider a young mammal separated from its mother. First comes the terror—the wailing and the calling out. And then with time a strange thing happens. The little animal grows silent, dull, and perfectly still. This all makes eminent sense: scream out when there is hope of rescue but conserve energy and hide from predators when the time for hope has passed.


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