From Chaos to Consilience

Psychiatric TimesPsychiatric Times Vol 26 No 5
Volume 26
Issue 5

Lecturing around the country has left us with the powerful impression that both psychiatrists and primary care physicians are hungry for new ways to think about and treat depression and the myriad symptoms and syndromes with which it is associated-including attention deficit disorder, insomnia, chronic pain conditions, substance abuse, and various states of disabling anxiety. Primary care physicians also seem especially excited to learn that depression is not just a psychiatric illness but a behavioral manifestation of underlying pathophysiological processes that promote most of the other conditions they struggle to treat-including cardiovascular disease, diabetes, cancer, and dementia.1,2

From Chaos to Consilience: Part II

From Chaos to Consilience: Part III Focus on Treatment

Complementary, Alternative, and Integrative Rx: Safety Issues

Nonconventional Approaches in Psychiatric Assessment

Nonconventional Modalities

More > >

Chaos-definition [from]: A state of extreme disorder or confusion.

Consilience-definition [from Wikipedia]: Literally a jumping together of knowledge by the linking of facts and fact-based theory across disciplines to create a common groundwork for explanation.

Lecturing around the country has left us with the powerful impression that both psychiatrists and primary care physicians are hungry for new ways to think about and treat depression and the myriad symptoms and syndromes with which it is associated-including attention deficit disorder, insomnia, chronic pain conditions, substance abuse, and various states of disabling anxiety. Primary care physicians also seem especially excited to learn that depression is not just a psychiatric illness but a behavioral manifestation of underlying pathophysiological processes that promote most of the other conditions they struggle to treat-including cardiovascular disease, diabetes, cancer, and dementia.1,2

In hopes of simultaneously quelling and stimulating this hunger and excitement, this article kicks off a 3–part series that sets forth a new view of major depression that synthesizes multiple converging lines of scientific evidence from an array of fields relevant to mind–body neurobiology. While this new science is fascinating in its own right, our emphasis is to clearly enunciate the promise these new findings hold for improving our ability to diagnose and treat depression and its many comorbidities. We also hope to show that an integrated mind–body view of depression helps explain many aspects of mood disorders that have long been enigmatic. As a result, we hope to enhance our ability to provide our patients with an honest prognosis for their long–term functioning and survival.

We begin with a general discussion of how a mind–body neurobiological approach to depression improves on our current diagnostic understanding of mood and related disorders. In part 2, we will detail the primary elements of a mind–body view of depression; in part 3, we will describe treatment implications that arise from the new science. We will highlight ways in which neurobiological understandings of mood disorders can help us move toward a personalized medicine approach to the treatment of depression and its multiple comorbidities-both psychiatric and medical.

The strange case of Tumor Town, USA

Let’s start with an analogy for major depression…the Strange Case of Tumor Town, USA.

Suppose lots of people in a small town begin coming down with cancerous tumors. Some of these cancers are in the thyroid, some are in the parathyroid, some are in the pituitary, some are in the adrenals, and some are in the pancreas. Some families have multiple members with tumors. Other families in town are completely tumor–free, despite having lived in the town for years. These tumors are more likely to develop in people who move to town than in their kin who live in other places. Not everyone with these tumors dies from them, although having one of these tumors increases one’s risk of an early death. However, whether people live or die, the tumors cause a great deal of anguish.

Now imagine that the government sends scientists and doctors into town to figure out how to treat these cancers. After many meetings and much discussion, these experts reach the following conclusions:

• The tumors that affect different organs probably represent different cancers. Thus, each type of cancer needs a separate name to allow it to be studied in isolation as a unique disease process.

• Because tumors specifically affect the function of the endocrine gland they involve, these glands are probably causing the individual cancers. Therefore, the best course of action is to find genes that are uniquely associated with the functioning of each gland in which tumors have been found.

Given this logic, it is not surprising that it becomes a source of great frustration that so many people have more than 1 of these cancers, either sequentially or at the same time. For example, having a tumor in the thyroid complicates understanding of what a pancreatic or adrenal tumor is doing, and vice versa. Especially when it comes to treatment trials, researchers and clinicians expend a great deal of effort identifying the minority of patients with a tumor in a single location so that they can better understand how to treat each individual illness.

But is this the correct approach? Are all these tumors really of separate origin with distinct etiopathologies, disease courses, and prognoses? Or are they perhaps the same disorder, presenting with varying manifestations in different individuals, despite shared genetic and other risk factors?

What’s wrong with this scenario?

We suspect almost everyone would agree that the government scientists and clinicians are not thinking as clearly as they might be about the situation in Tumor Town and that, indeed, they have missed a number of very important clues about what’s going on. First, the high rate of tumors in this one town strongly suggests a huge environmental component to the problem. However, because some families are affected and others not, it is also likely that genes play an important role. In fact, because family members in other towns don’t come down with these tumors, disease genes may only pose a risk in the context of environmental risk factors unique to the town. Here is the most important point of all. Whatever the environment is doing to people’s bodies is almost certainly related directly to processes that are causing the cancers, regardless of the specific endocrine organ they are in. Also, it’s a good bet that genetic risk factors are related to the same pathophysiological pathways that are activated by the risk factors in the environment.

What are we to make of the striking comorbidity between tumors in different endocrine organs? Are you more interested in understanding why some people have a tumor in the pancreas and others have a tumor in the thyroid…or do you suspect that it is more important to ask what is causing the larger phenomenon of all these multiple endocrine neoplasms? Wouldn’t you guess that the shared, underlying factors that cause any one of these tumors are probably more central to the cause of the problem than whatever exigencies lead a particular tumor to sprout up in the pancreas or the adrenals-especially given that most people have tumors in multiple endocrine organs, which suggests that the specific locale is not essential to the underlying pathological process?

What mind–body neurobiology tells us about depression and related conditions

Conditions characterized by sadness, loss of pleasure, anxiety, fatigue, irritability, nonspecific aches and pains, sleep disturbances, appetite alterations, and difficulties in thinking and concentrating share important similarities with the cancers in our mythical Tumor Town. We psychiatrists have often behaved like those benighted government researchers who failed to see the importance of some very simple facts and figures. Fortunately, scientific discoveries in psychiatry itself, as well as in fields ranging from neuroscience and psychoimmunology to cardiology and evolutionary psychology are taking approaches more like what we would take were we to commit ourselves to solving the riddles of Tumor Town.

Thus, recent research suggests why:

• Depression has the genetic and environmental risk factors that it does. (These risk factors dysregulate activity in brain–body pathways in ways that produce depressive symptoms.3,4)

• Depression typically co–occurs with other symptoms, such as anxiety and pain, and with syndromes. (These symptoms/syndromes share similar pathophysiological abnormalities.5)

• Depression is so strongly associated with such conditions as cardiovascular disease, diabetes, and dementia. (Depression reflects the same type of wear and tear on body and brain that causes or contributes to the development of these medical illnesses.6,7)

• Remission of symptoms matters greatly to long–term outcomes. (This is not because symptoms somehow cause brain damage but because symptoms reflect states of brain–body function that are damaging over time and are inimical to optimal functioning in the modern world.8)

Pathophysiological and treatment implications of these propositions will be covered in greater detail in parts 2 and 3 of this series. Here we turn instead to a discussion of what recent findings in the arena of mind–body neurobiology tell us about issues of diagnosis and comorbidity involving major depression.

What does mind–body neurobiology contribute to the diagnosis of depression?

As with the various classification strategies for cancers in Tumor Town, our current diagnostic schemas do not “cleave nature at the joints.”9,10 Said another way, given the current state of our brain–body science, conditions such as major depression are better thought of as smaller pieces of larger and more physiologically coherent wholes, not as discrete disease states. This idea is not new to this article, of course, but has been articulated many times in concepts such as “affective spectrum disorder,”11 which marries mood disorders to an array of other frequently comorbid conditions (eg, chronic pain and fatigue, attention deficit disorder, posttraumatic stress disorder, and social anxiety disorder).

But these discussions frequently give short shrift to 3 key implications of recent scientific findings. The first implication is that swapping a smaller rigid diagnostic category for a larger rigid one misses the important truth that all conditions such as major depression are probabilistic in their presentation and very likely probabilistic in their underlying pathophysiology as well.12 They are not the hard–and–fast certainties that DSM diagnoses have become over the years but rather like Darwinian species that blend into each other at the edges and show significant variations between individuals in the same groups. From this perspective, asking where major depression ends and anxiety begins is biologically meaningless. They fade into each other at their edges and coexist in each other’s centers.

The second implication is that grouping of conditions such as major depression, anxiety disorders, and states of pain and fatigue into a larger whole doesn’t just parsimoniously account for high rates of comorbidity between these syndromes and symptoms.13,14 Rather, viewing these conditions as components of a larger whole more accurately reflects the astounding similarities that have been uncovered between these syndromes in terms of shared genetic and environmental risk factors, as well as underlying brain and body pathophysiology.5 Indeed, the fact that no 2 depressions look exactly alike or that depression bleeds into many other diagnoses is no accident but rather reflects the neurobiology of depression itself.

The key point here is that there is no simple land bridge between specific genes and specific symptoms or syndromes. Lying between these twin shores on which psychiatry has staked its reputation is a churning sea of widely disbursed, highly complex, interactive brain–body danger/adaptation pathways that must be comprehended if we are to understand why depression is the way it is.15

A final implication of the new science-which we will return to at some length in the third part of this series-is that specific symptoms are more real and more therapeutically meaningful than the syndromes to which they contribute. Rather than focusing on disease states when we treat mood disturbances, the new science tells us that we would do better to focus on the specific symptoms that any given patient actually has. As a direct result of the neurobiology of depression, all diagnostic categories are part myth and part probability. While these categories simplify our communication with each other, and can aid scientific research when not taken as delivered directly from the hand of God, they are not as real as the unique combination of symptoms that each individual patient has at any given time. It is these symptoms (not the categories they form) that must be resolved if a person is to gain the benefits of remission. Each symptom that a patient has is a marker that his or her underlying physiology remains in a state known to produce long–term emotional, functional, and physical damage.5

Is our view of major depression too big or too small?

As is often the case with these types of questions in psychiatry, the answer is “Yes!” And here our analogy to Tumor Town breaks down, as all analogies eventually do. Tumor Town is a good way of thinking about ways in which our view of depression is too small and too rigid. Our current views are too small because major depression is only one probabilistic syndromic manifestation of underlying patterns of mind–body dysregulation that also give rise to many closely related diagnoses.

What Tumor Town doesn’t capture is the fact that what we currently call major depression-while associated with typical abnormalities at the level of brain–body function-is almost certainly not a single disease process. (Here we are assuming that disease means a condition with a specific biological cause(s) that, when corrected, leads to disease eradication. In this regard, the old disease of dropsy is a better analogy for major depression than is Tumor Town. Before we understood transudative and exudative processes in the lung, before we understood that pulmonary edema could be caused by failures in very different organ systems (ie, heart versus lung), we had dropsy-a single condition that accounted for all cases of “water on the lung.”

As with dropsy, what we call major depression will someday probably be subdivided into myriad more homogeneous and limited biological disorders that link to specific genes, either directly through patterns in the genome or through epigenetic changes in gene expression. Thus, someday under the umbrella of depressive conditions we may have diseases like “hypo–BDNF disease” or “TNF–alpha–itis,” or “stress–sensitive gliopathy disorder.”

Or maybe not. Maybe depression will always remain a complex emergent phenomenon that requires multiple interacting alterations in genes linked to each other in thousands of different ways, all of which contribute a measurable, but incomplete, amount to the risk of developing depression or one of its closely related affective spectrum disorder syndromes.

Whichever of these musings proves true, it is patently clear that the syndrome we currently call major depression will never be unambiguously or completely related to underlying genetic or epigenetic abnormalities. Hence, as researchers are increasingly realizing, the quest to find a gene (or even genes) for major depression is a little like Don Quixote’s quest for windmills. A similar fate almost certainly awaits all attempts to find biomarkers that will prove a person is depressed. Rather, what we are discovering is that certain genes predispose to certain functional and structural patterns in the brain (and probably the body) that promote the manifestation of mood disorder symptoms in certain environmental contexts,16 especially situations of environmental challenge17 (typically adversity, but also opportunity18).

We close this installment by referring our readers to the Figure, which attempts to portray these ideas visually. Although current DSM diagnoses arose in large part from early attempts to create a standardized language to aid psychiatric research, many of us have come to view them as actual disease entities that are related to specific underlying genetically specified mechanisms that we just haven’t identified yet. This view is portrayed on the left side of the Figure, in which primary genetic abnormalities are directly linked to currently articulated psychiatric conditions. In this view, the neurobiology of depression would be expected to mirror both its genetic determinants and its symptomatic manifestations in simple and straightforward ways. Hence, research tends to focus on finding genes that produce clearly demarcated abnormalities that manifest as specific symptoms. Conversely, much research is given over to devising more and more specific symptom–based disease states that might (with luck!) tie more closely to underlying genetic abnormalities.

On the other hand, we would suggest that the diagram on the right of the Figure more accurately reflects recent findings from mind–body neurobiology. In this view, multiple genes contribute in complicated ways to larger, functionally interconnected brain–body systems, with the result that a wide variety of genetic “abnormalities” can have fairly similar physiological effects on this larger circuitry5,15 (or opposite effects when genetic abnormalities cancel each other out19).

In the case of major depression and related conditions, significant evidence implicates genes involved in pathways that evolved to recognize environmental dangers and opportunities and successfully adapt to them, especially predators and pathogens.1 Not surprisingly, these pathways tend to become dysregulated in fairly stereotypical ways in genetically vulnerable individuals exposed to environmental adversity (including overwhelming opportunity-think of young rock stars!). These patterns of disruption have as one of their primary outputs the production of a range of symptoms. Symptoms are markers of these disruption patterns, but these patterns produce symptom clusters only probabilistically, with the actual symptoms experienced by individual patients probably reflecting genetic and environmental vulnerabilities specific to the individual.

In reifying our diagnostic categories, in studying and treating them like discrete diseases, we may be guilty of what Daniel Dennett has called “greedy reductionism.”20 We’ve missed an intermediate level of explanation that is essential to understand these conditions and which we know an increasing amount about. This intermediate level reflects the contribution of genes and environment to extended patterns of brain–body dysregulation that, while stereotyped, are not 100% consistent between individuals or even within the same individual over time. These patterns contribute to major depression certainly, but they also promote all other symptom states characterized by misery, ennui, exhaustion, anxiety, pain, and impaired sleep and cognition.12,21,23 (On the other hand, in gifted individuals they may also promote great art or the grit to assume positions of tremendous leadership.24,25)

As we’ll discuss in the next 2 parts of this series, understanding these disruptions in danger/adaptation pathways in brain and body is at the heart of what the new science offers. It presents new ways of thinking about how we diagnose, treat, and make prognoses about many of the world’s most vexing behavioral disturbances-which are the primary requirements we ask of any scientifically based disease state.

“So, what’s in it for me?”

If you are a busy practicing physician, you may be asking yourself: “Interesting stuff…but what’s in it for me? How might I benefit from this new mind–body neurobiology? How does it help me be a better clinician?”

This is, of course, an eminently important issue. Our first response is that because the era of looking at depression as a mind–brain–body disease has finally arrived, we practicing clinicians need to be ready for it. Whether we are psychiatrists or primary care physicians, we need to be ready because it will change how we diagnose and treat a range of psychiatric conditions. These changes will likely be reflected-at least to some degree-in the next edition of DSM. We believe the change will be all for the good. We will be able to make diagnoses more efficiently, completely, and realistically, and this will markedly improve our treatment outcomes, as we’ll discuss in part 3.

While parts 2 and 3 of our series will address key treatment implications of the new science, the central point we are trying to make here is that diagnostic yields will improve if we alter our thinking about depression as a primarily mind or mind–brain disorder to a symptom complex that is activated by abnormalities in the whole person: mind, brain, body, and spirit (although we make no claims toward any special understanding of the spiritual realm!).

Increased recognition of the bodily symptoms of depression means we will less often miss the disorder or undertreat patients who present with primarily physical complaints. Indeed, our acknowledgment of the paramount importance of mind and body symptoms in depression will lead us to watch for the resolution in both symptom domains before we declare an individual’s depression to be in remission. Similarly, we will recognize that the treatment of symptoms such as anxiety and pain-which are not currently on the DSM “short list” for depression-is as essential as the treatment of any other symptoms if we are to help our patients achieve optimal long–term outcomes. Finally, the recognition that depression is intimately linked to the risk factors from which it arises provides a strong rationale for developing preventive strategies that are likely to benefit society in general and our patients in particular.

There is of course much else to discuss together. We invite you to continue this dialogue with us in the upcoming parts 2 and 3 of this series of articles.

Dr Raison is assistant professor and clinical director of the Mind–Body Program in the department of psychiatry and behavioral sciences at Emory University School of Medicine in Atlanta. Dr Raison is paid by CME LLC to provide/present this information. The opinions expressed are those of Dr Raison/CME LLC and do not necessarily reflect the views of Emory University or Emory Healthcare. Dr Raison’s participation in this activity does not constitute or imply endorsement by Emory University or Emory Healthcare. Dr Raison is on speakers’ bureaus for Lilly and Wyeth and serves on advisory boards for Lilly and Wyeth. He receives research support from Centocor.

Dr Maletic is clinical professor in the department of neuropsychiatry and behavioral sciences at the University of South Carolina School of Medicine in Columbia. He is on speakers’ bureaus for Lilly, Takeda, and Novartis, and serves on advisory boards for Lilly and Takeda.

Dr Draud is medical director of psychiatry and addiction medicine at Baptist Hospital in Nashville and at Middle Tennessee Medical Center in Murphreesboro. He is on speakers’ bureaus and serves as a consultant for Lilly, Pfizer, Cephalon, Forest, Takeda, AstraZeneca, and Sanofi–Aventis.

 Dr Jain is director of adult and child psychopharmacology research at R/D Clinical Research, Inc, in Lake Jackson, Tex.  He is on speakers’ bureaus for Jazz, Lilly, Pfizer, Takeda, and Shire; he serves as a consultant for Addrenex, Impax, Lilly, Shire, Takeda, and Pfizer.




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