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(Drug information on 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(Drug information on 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
