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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
1. Westendorp RG. Are we becoming less disposable? EMBO Rep. 2004;5:2-6.
2. 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. 2004;1032:1-7.
3. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of major depression. Trends Immunol. 2006;27:24-31.
4. 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. 2008;29:736]. Hum Brain Mapp. 2008;29:683-695.
5. 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. 2003;160:1554-1565.
6. Maletic V, Raison CL. Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci. 2009;14:5291-5338.
7. 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. Circulation. 2005;112:976-983.
8. Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327-334.
9. Ridker PM. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-843.
10. 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. 2009;106:9069-9074.
11. Abercrombie HC, Giese-Davis J, Sephton S, et al. Flattened cortisol rhythms in metastatic breast cancer patients. Psychoneuroendocrinology. 2004;29:1082-1092.
12. 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. Lancet Neurol. 2005;4:371-380.
13. Cole SW, Hawkley LC, Arevalo JM, et al. Social regulation of gene expression in human leukocytes. Genome Biol. 2007;8:R189.
14. 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. 2003;100:9090-9095.
15. 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. 2006;21:227-231.
16. Müller 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. Mol Psychiatry. 2006;11:680-684.
17. 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. Depress Anxiety. 2009;26:607-611.
18. 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. Lancet. 2006;367:29-35.
19. 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. 2005;22:101-110.
20. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732-741.
21. 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. 2008;76:408-421.
22. Pace TW, Negi LT, Adame DD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinology. 2009;34:87-98.
23. 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. 2006;20:201-209.
24. 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. Circulation. 2008;117:169-175.
25. Irwin MR, Wang M, Ribeiro D, et al. Sleep loss activates cellular inflammatory signaling. Biol Psychiatry. 2008;64:538-540.
26. Schatzberg AF, Lindley S. Glucocorticoid antagonists in neuropsychiatric [corrected] disorders [published correction appears in Eur J Pharmacol. 2008;592:168]. Eur J Pharmacol. 2008;583:358-364.
27. Lewis-Tuffin LJ, Jewell CM, Bienstock RJ, et al. Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active. Mol Cell Biol. 2007;27:2266-2282.
28. DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry. 2006;60:1343-1349.
29. 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. 2009;30:284-248.
30. 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. 2007;32:19-30.
31. 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. 2007;32:1-10.
32. 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. 2009;34:135-143.
33. 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. 2008;33:195-201.
34. Mead GE, Morley W, Campbell P, et al. Exercise for depression. Cochrane Database Syst Rev. 2008;(4):CD004366.
35. 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. 2006;12:817-832.
36. Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv. 2001;52:529-531.
37. Westover AN, Marangell LB. A cross-national relationship between sugar consumption and major depression? Depress Anxiety. 2002;16:118-120.
38. 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. 2003;27:514-521.
39. Kloiber S, Ising M, Reppermund S, et al. Overweight and obesity affect treatment response in major depression. Biol Psychiatry. 2007;62:321-326.
40. Soreca I, Rosano C, Jennings JR, et al. Gain in adiposity across 15 years is associated with reduced gray matter volume in healthy women. Psychosom Med. 2009;71:485-490.
41. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701-709.
42. Robinson RG. Treatment issues in poststroke depression. Depress Anxiety. 1998;8(suppl 1):85-90.
43. 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. 2009;5:261-266.
44. 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. Med Hypotheses. 2008;71:948-951.
45. Spiegel D, Giese-Davis J. Depression and cancer: mechanisms and disease progression. Biol Psychiatry. 2003;54:269-282.
46. Linden W, Phillips MJ, Leclerc J. Psychological treatment of cardiac patients: a meta-analysis. Eur Heart J. 2007;28:2972-2984.
47. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28.
48. Young-Xu Y, Chan KA, Liao JK, et al. Long-term statin use and psychological well-being. J Am Coll Cardiol. 2003;42:690-697.
49. 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].
50. 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. BMC Psychiatry. 2009;9:25.
51. Benedetti F, Mayberg HS, Wager TD, et al. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005;25:10390-10402.