Charles L. Raison, MD, Vladimir Maletic, MD, Rakesh Jain, MD, MPH, and Jon W. Draud, MD, MS
A pdf of this article will be provided on request. Please contact Dr Vladimir Maletic at
vmaletic@bellsouth.net.
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 Maletic is clinical professor in the department of neuropsychiatry and behavioral sciences at the University of South Carolina School of Medicine in Columbia. Dr Jain is director of adult and child psychopharmacology research at R/D Clinical Research, Inc, in Lake Jackson, Tex. Dr Draud is medical director of psychiatry and addiction medicine at Baptist Hospital in Nashville and at Middle Tennessee Medical Center in Murphreesboro.
Disclaimer: 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 on speakers’ bureaus for Lilly, Takeda, and Novartis and serves on advisory boards for Lilly and Takeda. Dr Draud is on speakers’ bureaus and serves as a consultant for Lilly, Pfizer, Cephalon, Forest, Takeda, AstraZeneca, and Sanofi-Aventis. Dr Jain is on speakers’ bureaus for Jazz, Lilly, Pfizer, Takeda, and Shire; he serves as a consultant for Addrenex, Impax, Lilly, Shire, Takeda, and Pfizer.
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.18
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.19,20 In good times or when exposed to supportive early environments, these alleles contribute to individuals who are perhaps more successful and happier than most.21-23 Even in bad times, these genes probably promote reproductive success by engendering creativity and intelligence24—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?25,26 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?27
