What the New Mind-Body Science Tells Us About the Pathophysiology of Major Depression-Focus on Treatment
From Chaos to Consilience: Part IFrom Chaos to Consilience: Part IIIntegrative Management of Depressed Mood: Evidence and Treatment GuidelinesRole of Acupuncture in the Treatment of Depression
Because you are unlikely to die young of wounding or infection, 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.1
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.2 Who cared whether oxidative stress from repeated danger pathway activation led to cardiovascular disease 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, public health, 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, posttraumatic stress disorder, 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.3 Chief among the danger pathways are the hypothalamic-pituitary-adrenal axis, autonomic nervous system (ANS), 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.4 In the periphery, depression is characterized by reduced cortisol signaling and parasympathetic activity and by increased sympathetic and inflammatory activation.5
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.6)
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,7-14 which almost certainly accounts for the multiple lines of comorbidity between sickness, stress, and depression.
But so what?
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.1
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.15 These findings are in keeping with studies showing that COX-2 inhibitors augment antidepressants in medically healthy patients with major depression.16,17 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.18,19
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.20 Recently, cognitive-behavioral therapy has also been shown to reduce inflammation,21 and compassion meditation has been found to reduce inflammatory responses to stress.22 Other effective interventions-from exercise and diet to getting enough sleep-also reduce inflammation.23-25
Given recent interest in glucocorticoid antagonists for depression,26 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.27 (In fact, recent studies are mixed in terms of effectiveness for psychotic depression,28,29 with no effect being observed for depressive symptoms.28) 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.30-33
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.34,35 1
Diets rich in omega-3 fatty acids are associated with reduced depression,36 and diets high in processed sugar are associated with increased depression.37 (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.39 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.40
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.41-44 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,45 and a recent meta-analysis indicates that psychological interventions reduce mortality in men with heart disease.46
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.47 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.48 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 DSM diagnoses concurrently.
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.6,49 That DSM 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 disorder50 and in which placebo appears to affect the brain in ways similar to active treatments,51 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.
Westendorp RG. Are we becoming less disposable?
McEwen BS. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders.
Ann N Y Acad Sci.
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of major depression.
Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ. A meta-analytic study of changes in brain activation in depression [published correction appears in
Hum Brain Mapp.
Hum Brain Mapp.
Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.
Am J Psychiatry.
Maletic V, Raison CL. Neurobiology of depression, fibromyalgia and neuropathic pain.
Tzoulaki I, Murray GD, Lee AJ, et al. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study.
Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
Ridker PM. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
N Engl J Med.
Pyter LM, Pineros V, Galang JA, et al. Peripheral tumors induce depressive-like behaviors and cytokine production and alter hypothalamic-pituitary-adrenal axis regulation.
Proc Natl Acad Sci U S A.
Abercrombie HC, Giese-Davis J, Sephton S, et al. Flattened cortisol rhythms in metastatic breast cancer patients.
Kuo HK, Yen CJ, Chang CH, et al. Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis.
Cole SW, Hawkley LC, Arevalo JM, et al. Social regulation of gene expression in human leukocytes.
Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, et al. Chronic stress and age-related increases in the proinflammatory cytokine IL-6.
Proc Natl Acad Sci U S A.
Mendlewicz J, Kriwin P, Oswald P, et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study.
Int Clin Psychopharmacol.
MÃ¼ller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine.
Akhondzadeh S, Jafari S, Raisi F, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial.
Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial.
Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab.
Aliment Pharmacol Ther.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.
Zautra AJ, Davis MC, Reich JW, et al. Comparison of cognitive behavioral and mindfulness meditation interventions on adaptation to rheumatoid arthritis for patients with and without a history of recurrent depression.
J Consult Clin Psychol.
Pace TW, Negi LT, Adame DD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress.
Kohut ML, McCann DA, Russell DW, et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults.
Brain Behav Immun.
Dai J, Miller AH, Bremner JD, et al. Adherence to the Mediterranean diet is inversely associated with circulating interleukin-6 among middle-aged men: a twin study.
Irwin MR, Wang M, Ribeiro D, et al. Sleep loss activates cellular inflammatory signaling.
Schatzberg AF, Lindley S. Glucocorticoid antagonists in neuropsychiatric [corrected] disorders [published correction appears in
Eur J Pharmacol.
Eur J Pharmacol.
Lewis-Tuffin LJ, Jewell CM, Bienstock RJ, et al. Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active.
Mol Cell Biol.
DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression.
Blasey CM, Debattista C, Roe R, et al. A multisite trial of mifepristone for the treatment of psychotic depression: a site-by-treatment interaction.
Contemp Clin Trials.
Karavidas MK, Lehrer PM, Vaschillo E, et al. Preliminary results of an open label study of heart rate variability biofeedback for the treatment of major depression.
Appl Psychophysiol Biofeedback.
Hassett AL, Radvanski DC, Vaschillo EG, et al. A pilot study of the efficacy of heart rate variability (HRV) biofeedback in patients with fibromyalgia.
Appl Psychophysiol Biofeedback.
Zucker TL, Samuelson KW, Muench F, et al. The effects of respiratory sinus arrhythmia biofeedback on heart rate variability and posttraumatic stress disorder symptoms: a pilot study.
Appl Psychophysiol Biofeedback.
Siepmann M, Aykac V, Unterdorfer J, et al. A pilot study on the effects of heart rate variability biofeedback in patients with depression and in healthy subjects.
Appl Psychophysiol Biofeedback.
Mead GE, Morley W, Campbell P, et al. Exercise for depression.
Cochrane Database Syst Rev.
Arias AJ, Steinberg K, Banga A, Trestman RL. Systematic review of the efficacy of meditation techniques as treatments for medical illness.
J Altern Complement Med.
Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland.
Westover AN, Marangell LB. A cross-national relationship between sugar consumption and major depression?
Roberts RE, Deleger S, Strawbridge WJ, Kaplan GA. Prospective association between obesity and depression: evidence from the Alameda County Study.
Int J Obes Relat Metab Disord.
Kloiber S, Ising M, Reppermund S, et al. Overweight and obesity affect treatment response in major depression.
Soreca I, Rosano C, Jennings JR, et al. Gain in adiposity across 15 years is associated with reduced gray matter volume in healthy women.
Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina.
Robinson RG. Treatment issues in poststroke depression.
Abrahamian H, Hofmann P, Prager R, Toplak H. Diabetes mellitus and co-morbid depression: treatment with milnacipran results in significant improvement of both diseases (results from the Austrian MDDM study group).
Neuropsychiatr Dis Treat.
Yeh HL, Tsai SJ. Lithium may be useful in the prevention of Alzheimer’s disease in individuals at risk of presenile familial Alzheimer’s disease.
Spiegel D, Giese-Davis J. Depression and cancer: mechanisms and disease progression.
Linden W, Phillips MJ, Leclerc J. Psychological treatment of cardiac patients: a meta-analysis.
Eur Heart J.
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy.
N Engl J Med.
Young-Xu Y, Chan KA, Liao JK, et al. Long-term statin use and psychological well-being.
J Am Coll Cardiol.
Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature.
J Clin Psychiatry.
2009 Jun 2; [Epub ahead of print].
Prosser JM, Yard S, Steele A, et al. A comparison of low-dose risperidone to paroxetine in the treatment of panic attacks: a randomized, single-blind study.
Benedetti F, Mayberg HS, Wager TD, et al. Neurobiological mechanisms of the placebo effect.