Vladimir Maletic, MD

Integrative Management of Depressed Mood: Evidence and Treatment Guidelines

Role of Acupuncture in the Treatment of Depression

Because you are unlikely to die young of 

, you will almost certainly succumb instead to the ravages of time, delivered-paradoxically enough-by the very “danger” systems that evolved to protect us from the predators and pathogens that-until recently-stole away most of humanity’s finest in the first flower of youth.

In a world of predators and pathogens, it was a fair trade-off. The long-term damage to body tissues that ensued from each episode of danger pathway activation was more than recompensed by an increase in short-term survival.

 Who cared whether oxidative stress from repeated danger pathway activation led to 

 at 65 or to dementia at 80 if it saved you from death by infection repeatedly at 10 or 20 or 30? But what about a world in which predators teeter at extinction’s edge and pathogens are (at least for now) beaten back by sanitation, 

, and antibiotics-a world in which danger pathway activation is more likely to occur in response to a yellow light than yellow fever?

The central argument in our series of articles is that depression and related diagnostic conditions (eg, generalized anxiety, social anxiety, 

, bipolar disorder) are characterized by-and frequently result from-chronic hyperactivity/dysregulation of CNS and peripheral danger pathways in response to conditions in the modern world for which this activity is of little, or no, value.

, and innate immune inflammatory response, as well as CNS circuits that activate, modulate, and down-regulate these pathways-including many prefrontal, paralimbic, and limbic cortical regions.

Significant data demonstrate that depression is characterized in the CNS by reductions in prefrontal executive network activity and increases in fight-flight–related limbic and paralimbic activity.

 In the periphery, depression is characterized by reduced cortisol signaling and parasympathetic activity and by increased sympathetic and inflammatory activation.

The surest way to help our patients is to set remission up as the guiding star toward which our efforts strive. If our patients approach this goal, we are moving in the right direction, no matter what intervention we are employing. 

This pattern of abnormality results from complex interactions between multiple “vulnerability” genes and environmental adversity. We put quotation marks around vulnerability because, by contributing to the regulation of danger pathway activity, these genes play essential roles in maintaining physiological homeostasis necessary for survival. Indeed, in the context of health, these genes contribute to the ability of danger pathways to activate regulatory feedback loops (eg, cortisol is both a stress and antistress hormone) that help craft responses to the actual needs of the current environment. However, when overwhelmed by stress or disease, vulnerability genes tend to promote multilevel disruptions in the functioning of this regulatory circuitry. When this occurs in the CNS, inadequate neurotrophic support leads to impaired neuroplasticity in key danger pathway regulatory areas (ie, hippocampus, prefrontal cortex), which interferes with limbic-paralimbic-cortical processing necessary to restrain ANS and inflammatory activity and to maintain sufficient cortisol signaling. (For a complete discussion of these issues, please see Maletic and Raison.

Depressive symptoms are the most common manifestations of this pat-tern of danger pathway dysregulation. However, many other modern diseases (cardiovascular disease, diabetes, dementia, cancer) and emotions (loneliness, chronic stress) share this pattern,

 which almost certainly accounts for the multiple lines of comorbidity between sickness, stress, and depression.

Any scientific theory worth its salt should be able to make falsifiable predictions about matters of importance. In the case of mental illness, nothing is more important than treatment, so here, in the final installment of this series, we’d like to give a sense of how emerging mind-body understandings can benefit our patients now and will further benefit them with the development of new treatments.

Of the many hypotheses that are suggested by a mind-body perspective, we offer 3 here that we feel are especially relevant.

1. Anything that turns down danger system activity and/or corrects insufficient cortisol signaling should be of benefit for depression.

To discuss this hypothesis in a manageable fashion, let’s focus primarily on inflammation as an example of a danger pathway that is hyperactive in the context of depression. It is a clear prediction of a danger system view of depression that anything that reduces inflammation should be a useful addition to our current treatment armamentarium. For years, people would respond to our talks with a very obvious question, “So why doesn’t aspirin work for depression?”

Well, in fact, recent data-although preliminary-suggest that aspirin might indeed have antidepressant properties, on the basis of data showing that the addition of aspirin to fluoxetine converts nonresponders to responders.

 These findings are in keeping with studies showing that COX-2 inhibitors augment antidepressants in medically healthy patients with major depression.

 Finally, several studies show that cytokine antagonists (which are powerfully anti-inflammatory) diminish depressive symptoms independently of their effects on primary disease processes in patients with autoimmune disorders.

While the use of anti-inflammatory agents for medically healthy depressed individuals is not yet quite ready for prime time, a mind-body perspective suggests that strategies currently in use for depression should include anti-inflammatory agents. Indeed this appears to be the case. Multiple studies suggest that both pharmacological and somatic (ie, ECT) treatments reduce inflammatory biomarkers in medically healthy depressed patients and that these reductions correlate with clinical effect.

Recently, cognitive-behavioral therapy has also been shown to reduce inflammation,

 and compassion meditation has been found to reduce inflammatory responses to stress.

 Other effective interventions-from exercise and diet to getting enough sleep-also reduce inflammation.

Given recent interest in glucocorticoid antagonists for depression,

 it is an especially germane prediction of our model that these medications will not be shown to be effective for depression or, if they are effective, that they will actually enhance, rather than antagonize, cortisol signaling.

 (In fact, recent studies are mixed in terms of effectiveness for psychotic depression,

 with no effect being observed for depressive symptoms.

) The model also predicts that strategies for reducing sympathetic activity and/or increasing parasympathetic activ-ity should help to ameliorate depression and related conditions. Recent studies suggest that biofeedback methods that accomplish this improve symptoms in depression, in posttraumatic stress disorder, and also in patients who have fibromyalgia.

2. Because depression and other modern illnesses are linked via danger pathway hyperactivity, things that are good for depression should be good for your health, and things that are good for your health should be good for depression.

There are so many obvious ways in which these hypotheses are true that we hesitated to include this point, but the topic is so important that we feel it deserves emphasis. If you went to a cardiologist and asked for a list of recommendations for being heart-healthy, what response would you expect? Exercise, meditate, eat an anti-inflammatory diet (ie, Mediterranean diet), maintain a normal weight, reduce your stress. A better lifestyle prescription for preventing and/or treating depression couldn’t be found. Many studies show that exercise elevates mood and treats depression, and an emerging literature points to the usefulness of meditation for psychological disturbance.

Diets rich in omega-3 fatty acids are associated with reduced depression,

 and diets high in processed sugar are associated with increased depression.

 (Of course, association does not prove causality; for example, depressed persons may turn to sugar as “self-medication.”) Obesity predicts the development of depression38 and is associated with nonresponse to antidepressant therapy.

 Disturbingly, recent evidence suggests that obesity may be independently associated with the types of reduction in cerebral gray matter volume that are also seen in depressed persons.

A more controversial, but unequivocal, prediction is that antidepressants and psychotherapy should improve medical illnesses characterized by danger pathway activation. Although not completely concordant, at least some studies suggest that antidepressants protect against or reduce morbidity and/or mortality from cardiac disease, stroke, and diabetes, and that lithium may protect against dementia.

 However, it is important to recognize that like all medications, antidepressants are not infrequently beset with adverse effects that may counteract beneficial actions. So, for example, negative effects of tricyclic antidepressants on cardiac function may outweigh their benefits, and agents associated with weight gain may ramp up danger pathway activity via this mechanism in ways that obviate such effects as anti-inflammatory activity. Again, although the data are mixed, at least some studies suggest that psychotherapy may extend survival in the context of cancer,

 and a recent meta-analysis indicates that psychological interventions reduce mortality in men with heart disease.

Conversely (and as already suggested), medications that treat medical illnesses by reducing danger pathway activity should also be good for preventing and/or treating depression, even if they are not currently on our radar screen for this indication. Statins are especially intriguing in this regard. Although originally administered to improve lipid status, it is now clear that anti-inflammatory properties are central to their beneficial vascular effects.

 Because inflammatory processes are increasingly implicated in depression, one would predict that statins should function-at least to some degree-as antidepressants, and indeed data suggest that these agents enhance positive mood and diminish negative mood.

 Lacking a danger pathway view of depression, these findings might be regarded as curious oddities. With such a view, they make eminent sense and point to the possibility that other medications currently in use for wear-and-tear disorders may hold promise in the treatment of depression.

3a. Because symptoms emerge probabilistically from danger pathway hyperactivity/dysregulation, similar patterns of physiological activity should give rise to an array of behavioral disturbances currently classified as separate disorders, and individuals at risk for dysregulated danger pathway activity should manifest different patterns of symptoms at different times and/or meet multiple 

3b. At the end of the day, putting the full range of specific symptoms that any given patient has into remission is the best guarantee that appropriate physiological functioning has been restored.

Unfortunately, for any illusions we may have of being on the cutting edge in this article, the truth of hypothesis 3a is hardly controversial. Multiple studies show that genes and environmental factors that increase the risk of depression also increase the risk of many other psychiatric conditions. Similarly, although much has been written about danger pathway dysregulation in depression (eg, reduced cortisol signaling and increased inflammation), these abnormalities have been observed in an array of conditions-from fibromyalgia to mania.

 psychiatric disorders are highly comorbid goes without saying. So while not exposing novel truths, a danger pathway understanding of depression provides a coherent framework for understanding why things are the way they are in the world of psychiatry. Contrast this with the current (but disintegrating) dogma that each psychiatric condition is a separate disease with a unique cause. If this were true, why do psychiatric diagnoses so often co-occur, and why do they share so much pathophysiology?

Hypothesis 3b points to a delicious paradox inherent in the mind-body view of depression we espouse. Despite its vulnerability to criticism for being overly general (ie, explains all psychiatric phenomena on the basis of several simple postulates), a major implication of this theory is that psychiatric generalities (ie, diagnoses) don’t really exist. They are categorical descriptions for nondiscrete and shifting patterns of symptoms-nothing more. Because of this, nothing is more real than the actual symptoms experienced by individual patients sitting in our offices at any given moment. It is the idiosyncratic mlange of symptoms and situations suffered by each patient that must be put right if the well-documented benefits of remission are to be achieved. It is not the diagnoses that go into remission; in the end it is not even the symptoms. It is the individual in all of his or her unique complexity.

We leave you with a startling implication of this line of thinking. Although symptoms are not perfect guides to the underlying biological abnormalities from which they arise, they are our best guides to the intricate workings of brain and body, given the current limitations of our knowledge. Therefore, anything that leads to the remission of symptoms (and that is not illegal, immoral, or fattening as one of our fathers used to say) should be in our treatment armamentarium. The surest way to help our patients is to set remission up as the guiding star toward which our efforts strive. If our patients approach this goal, we are moving in the right direction, no matter what intervention we are employing. If they move away from this goal, we need to analyze why and take steps to correct the arc of the patient’s emotional/physical life. In a world in which antipsychotics have been shown to work as well as antidepressants for panic disorder

 and in which placebo appears to affect the brain in ways similar to active treatments,

 many of our old certainties are crumbling.

Who are we to say what combination of interventions will heal any given patient? What we can say-on the basis of the new mind-body science-is that whichever therapeutic pathway we tread with any given individual under our care is right if it leads to symptomatic remission and a full human life. And it is wrong, or incomplete, if it fails in this regard. When we find the right interventions, we can feel fairly sure that we have brought a patient’s underlying danger pathway activity into line with the actual needs of the real world he faces, and that we all share-at least for now.

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Articles

What the New Mind-Body Science Tells Us About the Pathophysiology of Major Depression-Focus on Treatment

From Chaos to Consilience: Part III

As we begin this brief review of the neurobiology of major depressive disorder (MDD), we face these fundamental questions:

• Will the provided information be clinically relevant?

• Can current scientific research provide us with a coherent, comprehensive, and relatively accurate description of the underlying neurobiology of MDD?

 are all characterized by a significant genetic contribution to their etiopathogenesis. Heritability estimates for MDD have exceeded 70%

 in some studies, and BD may be even more genetically based, with estimates reaching the 80% to 90% range.

 Interestingly, MDD is more frequently reported in the families of bipolar patients than is BD itself; this finding suggests a partially shared diathesis and likely a “correlated liability,” if not an affiliation with the same continuum.

 Similarly, the genetic and clinical overlap between MDD and GAD is so extensive that some authors have gone so far as to suggest that they are dual manifestations of the same underlying pathophysiology.

It is becoming increasingly clear that relationships between MDD, GAD, and BD run deeper than symptomatic similarities shared by these conditions. Although not always consistent, studies point to shared genetic underpinnings for these disorders, emphasizing genes involved in the regulation of monoaminergic and peptide transmission, inflammatory responses, diurnal rhythms, and neurotrophic signaling.

 All of these are important modulators of anxiety, mood, and stress responses. Furthermore, symptoms of anger, depression, and anxiety are strongly correlated with one another.

 Stress, in turn, is a major precipitant, perpetuant, and aggravating factor of all 3 conditions. However, one must temper any rampant “clumping” enthusiasm with the recognition that-as with similarities-differences between symptom presentations have also frequently been found. Simple links between genes and symptom–based disorders are complicated by a number of factors, including:

• The most common “vulnerability genes” for mood and anxiety disorders account for relatively little variance.

• A gene for 1 product may produce an array of behavioral outcomes, given that its product is typically ensconced in larger circuits that tend to demonstrate final common pathway–type phenomena.

• Symptom presentations in any given person are likely to result from intricate interactions between multiple genes and environmental factors.

Examples of these types of interactions include 

 (influences of life experience on gene expression).

Acknowledging these important distinctions takes us a step closer to more effective personalized care.

It is no surprise that brain circuits involved in the regulation of mood, anxiety, and the stress response overlap to a significant degree with components of a “pain matrix” (areas mediating emotional and cognitive aspects of pain processing) as well as with structures involved in sleep regulation.

 From an evolutionary perspective, it is apparent that sleep deprivation, negative emotion, and physical pain all play key adaptive roles. All these apparently disparate phenomena provide a clear signal that current conditions are a threat to an organism’s survival.

Before we further elaborate on the roles and interactions between “danger, reward, and executive circuitries and pathways” in mood disorders, it is important to define these constructs more precisely. Reference to “circuitry and pathways” denotes discrete dynamic functional states of neural network rather than specific neuroanatomic entities. For example, depending on the pattern of “inputs,” nucleus accumbens, amygdala, hippocampus, anterior cingulate cortex [ACC], and paralimbic prefrontal cortex can be alternatively considered as components of either “reward/opportunity” or “danger/threat” pathways.

 Their cumulative interactions generate corresponding “outputs” or symptoms (much as one set of musical instruments can be used to produce a joyous or a mournful tune). Given the constant flow of internal and external information, there is a continuous flux of functional states, perpetuating the neural network’s adaptive and homeostatic roles.

In keeping with their shared role in alerting an organism to danger in the external or internal environment (ie, infection/tissue damage), peripheral and central “pathways” of anxiety, depression, and pain overlap significantly.

 They are all woven into the mammalian stress and immune response systems. While there are important differences in the sensory processing of anxiety, stress, and pain signals at the cortical and subcortical levels, (eg, dorsal column, thalamus, and primary and secondary somatosensory cortices [SI, and SII]), striking similarities are apparent in the involvement of limbic areas and paralimbic prefrontal cortex, amygdala, hippocampus, insula, ACC, ventromedial prefrontal cortex, as well as more “cognitive” and integrative brain areas, such as rostral ACC, dorsal ACC, dorsomedial prefrontal cortex, and dorsolateral prefrontal cortex.

 Imaging studies of persons experiencing depression, anxiety, spontaneous pain, social isolation, or sleep deprivation, bear more than little resemblance.

It is important to recognize that “stress circuitry,” “reward circuitry” (including nucleus accumbens, amygdala, hippocampus, ventral tegmental area, and orbital prefrontal cortex), and “executive circuitry” are not independent and mutually exclusive entities; they are better conceived of as intersecting and overlapping components of a common 3–dimensional neural network.

Disruption in their dynamic balance may give rise to excessive negative emotions, combined with cognitive impairment and withdrawal of hedonic tone. Moreover, anxiety, pain, and depressed mood appear to have a shared capacity to engage autonomic, neuroendocrine, and neuroimmune components of the stress response.

 are all associated with altered sympathetic/parasympathetic balance; neuroendocrine disturbance, manifested by insufficient HPA regulation; and altered immune function, characterized by inhibition of acquired immunity and enhancement of innate inflammatory signaling.

 In turn, these peripheral responses signal back to neural structures to further drive CNS danger pathway activation; this leads to a maladaptive feed–forward circuit that increasingly appears to be implicated in the production and maintenance of symptoms.

Within the CNS, microglia seem to be the principal recipients of bodily distress/pain signals. Microglia are increasingly implicated in the development of mood (depression and mania)1 and pain symptoms and disorders.

Indeed, increasing evidence suggests that different patterns of interaction between microglia, astroglia, and neurons may engender diverse symptomatic manifestations (eg, pain, depression). Peripheral distress signals are “amplified” via reverberating communication between microglia, astrocytes, oligodendroglia, and neurons.

 The result is suppression of neurotrophic trafficking and an increase in the production and release of proinflammatory cytokines and reactive oxygen and nitrogen species.

The combined effect of this inflammatory and oxidative “surge” may damage astrocytes and oligodendroglia, thus contributing to demyelination and consequent disruption of CNS regulatory circuits required to restrain peripheral stress/inflammatory responses.

Excessive excitatory glutamatergic transmission and compromised GABA–mediated inhibition (with ensuing excitotoxicity) appear to be common features of anxiety,

Dysregulation in monoamine, substance P, galanin, and opiate–signaling also characterizes GAD, pain syndromes, and MDD. On the other hand, anxiety and mood and pain disorders are characterized by different patterns in the production of neurotrophic factors: depression and mania are characterized by reduced serum levels of brain–derived neurotrophic factor (BDNF), fibromyalgia is associated with increased BDNF,

 while fear and anxiety appear to be accompanied by elevated levels of nerve growth factor.

 Nonetheless, anxiety, pain, stress, and depression have a similar, possibly even synergistic, effect on neurotrophic signaling in the hippocampus, given that all of them are associated with reduced BDNF synthesis in this critical limbic region.

 This finding is of particular interest, given that the hippocampus represents a veritable “intersection” of pathways involved in emotional regulation, reward, memory, and coordination of neuroendocrine response.

MDD, BD, and chronic pain are all associated with neuroplastic changes in the CNS. In pathological pain states, facilitation of pain signaling, presumably on the basis of neuroplastic changes in pain pathways, is often designated as “central sensitization.”

 Similarly, the recurrent and progressive nature of MDD and BD is often attributed to “kindling,” which-like central sensitization-reflects neuroplastic changes.

 may all be characterized by adaptive processes gone awry as a result of complex interactions between genetic vulnerabilities and environmental factors. In this scenario, persistent aberrant processing of emotional, painful, and stressful signals eventually becomes “hard–wired,” presumably from ensuing neuroplastic alterations.

In some ways, chronic pain and disorders of sleep, mood, and anxiety share dysfunctional psychosomatic and somatopsychiatric communication patterns-indeed they can be seen as behavioral read–outs for these dysfunctional communication patterns.

 Their synergistic and simultaneous occurrence may give rise to a “symphony” of misery. If we assume that a shared biological underpinning gives origin to the clinical symptoms of MDD, BD, GAD, and chronic pain, it is clear that a full understanding of this “synergy” has critical diagnostic and treatment implications.

Despite these powerful commonalities, however, it is important to realize that diverse underlying biological processes may generate similar symptoms and vice versa; that is, similar pathophysiology may drive diverse clinical manifestations. A synthesis of these dialectical perspectives suggests that understanding shared etiopathogenesis may provide an opportunity for the development of new preventive and treatment strategies that transcend diagnostic boundaries. A full appreciation of each person’s symptoms-as the unique result of interactions between genetic vulnerability, adversity, positive life experiences, individual coping skills, and overall health-offers the clearest way forward in our field’s attempt to develop personalized treatment approaches.

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As we begin this brief review of the neurobiology of major depressive disorder (MDD), we face these fundamental questions

And the Orchestra Played On: Activation of Distress Pathways-A Common Feature of Mood, Anxiety, Sleep, and Pain Disorders?

Integrative Medicine Gains a Mainstream Foothold

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.

Nowhere is this truer than in the case of depression. While the 

-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 

, 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.

 is the most common emotional/behavioral breakdown pathway for human beings in response to environmental adversity. It is highly stereotyped but also irreducibly probabilistic.

 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 

 that evolved to cope with danger and to adapt to changing environmental demands.

 Hyperactivity in these systems is linked to-and perhaps causes-reductions in the activity of CNS pleasure/novelty and executive 

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.

 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.

 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.

 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.

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.

Depression is an analogue of this phenomenon, which should come as no surprise given its evolutionary origins. Thus, in addition to the anxiety, fear, and internal pain produced by danger pathway activation/dysregulation, depression is also characterized by a loss of pleasure that can be profound. This reflects the fact that in addition to danger pathway activation, depression is typically associated with hypoactivity in “pleasure pathways” running from midbrain into anterior areas of the basal ganglia (ie, nucleus accumbens). Not surprisingly, many recent studies show that chronic activation of danger pathways-such as the innate immune inflammatory system-compromises dopaminergic signaling in pleasure pathways.

Why are the genes for depression so common?


 Short answer: Because genes identified thus far that increase the risk of depression are not depression genes per se but rather play more general roles in regulating systems that are responsible for multiple physiological functions essential for survival and reproduction. In general, they are genes for operating and regulating danger/ adaptation/pleasure pathways in the brain and body. Most often, risk alleles for depression increase/dysregulate activity in danger pathways and/or reduce activity in pleasure and executive pathways in the face of environmental adversity.

In good times or when exposed to supportive early environments, these alleles contribute to individuals who are perhaps more successful and happier than most.

Even in bad times, these genes probably promote reproductive success by engendering creativity and intelligence

-how else could they survive the threshing of natural selection if they did not confer occasional high pay-off selective advantages to counter their more frequent detrimental  effects?

Nonetheless, these ideas are not settled science, and alternative views exist about potential adaptive advantages of depression or even whether genes that promote depression must confer some type of adaptive advantage to be retained in the human genome. Although genes that are specific for depression or that always cause depression regardless of environmental conditions have yet to be identified, this does not prove that such genes may not yet await discovery. If such genes were ever found, it would be expected that they would be very powerful but also very rare and therefore would account for only a tiny fraction of individuals with depression.

Would it surprise you to learn that genes reported to increase the risk of developing depression in the face of psychosocial stress also seem to increase the risk of depression in the context of sickness?

 Would you predict that these risk alleles might enhance survival in the face of infection early in life and that this might also account for their high prevalence in the human gene pool?

Why is depression a risk factor for other diseases and why is it progressive?


 While these seem like separate questions, the new mind-body science suggests that they are actually variations on a theme. Depression, in our view, is linked to most other modern illnesses because it shares an underlying pathophysiology with them.

 Millions of years of evolution favored the development and retention of extremely robust stress and inflammatory danger pathways. When death and destruction lurked around every corner, the safest policy was to fire off one’s danger pathways first and ask questions later. What did it matter if body and brain tissues were damaged a little each time these pathways activated if this kept one alive for today (an idea that has been popularized as allostatic load).

No need to worry about heart disease, cancer, or dementia if you were likely to die of infection by age 30.

Consider our plight today, however. The boss no longer rips your arm off when he shouts at you, and many of the jobs once done by inflammation have been farmed out to sanitation and modern medicine. But the old danger pathways just go on firing off every time someone looks at us sideways. The more they fire off, the more damage accumulates. When this occurs in the arteries, it is vascular disease

; when it promotes insulin resistance, it is diabetes

; and when it disrupts glial cell integrity and disorganizes neuronal signaling, it manifests as depression.

 Given enough time, the damage usually accumulates everywhere-hence the high comorbidity between depression and most other major modern maladies.


 The new mind-body science suggests that depressive symptoms are a “shout out” that the brain and body are in a state that is inimical to optimal functioning and health in the modern world. Conversely, an implication of the ideas presented here is that depressive symptoms are not likely to improve unless a person’s underlying danger pathway functioning normalizes, at least to some degree.

 So remission is the best indicator we currently have that a person’s underlying physiology has returned to a safer state. Of course, symptoms are not perfect. If they were, remission would heal all ills.

 In fact, we know that even when remission is achieved, patients remain at greatly increased risk for sinking again into depression when compared with those who have never suffered depression.

Join us next month as we apply the implications of recent scientific advances to the practicalities of diagnosing and treating depression.

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

Chaos – definition [from wordnet.princeton.edu]: 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 manage 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.

In hopes of simultaneously quelling and stimulating this hunger and excitement, we have developed 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 in this series is to clearly enunciate the promise these new findings hold for improving our ability to diagnose and treat depression and its many comorby Charles L. Raison, MD, Rakesh Jain, MD, MPH, Vladimir Maletic, MD, and Jon W. Draud, MD, MS bidities. 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. We believe this view can help enhance our ability to provide our patients with an honest prognosis for their long-term functioning and survival.

You will find the first article in our series online at www.psychiatrictimes. com. We begin the series with a general discussion of how a mind-body neurobiological approach to depression is an improvement over 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. Throughout, we will highlight ways in which neurobiological understandings of mood disorders can help us move toward a personalized approach to the treatment of depression and its multiple comorbidities, both psychiatric and medical.

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 manage 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.

From Chaos to Consilience: Using the New Mind-Body Science to Improve the Diagnosis and Treatment of Major Depression

From Chaos to Consilience: Part III Focus on Treatment

Complementary, Alternative, and Integrative Rx: Safety Issues

Nonconventional Approaches in Psychiatric Assessment

Chaos-definition [from wordnet.princeton.edu]: 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 

 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.

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 

 that synthesizes multiple converging lines of scientific evidence from an array of fields relevant to 

 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 

. 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 

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