Genes influencing depression also bolstered our ancestors’ immune systems — an understanding that’s informing experimental therapies.
Van Gogh, At Eternity’s Gate (Wikipedia)
More people die from suicide than from murder and war combined, throughout the world, every year. In the United States, suicide recently surpassed automobile accidents as the leading cause of violence-related death, according to a study appearing in the American Journal of Public Health.
The majority of individuals who commit suicide suffer from depression or another mood disorder. Depression is a devastating illness characterized by persistent sadness and myriad well-known symptoms. Increasingly, researchers are identifying how genes contribute to depression. As we learn more about the human genome, scientists are finding evidence that while depression seems incredibly maladaptive, it was actually adaptive (helpful) to our ancestors.
Recently Dr. Andrew Miller and Dr. Charles Raison, physicians at Emory University and the University of Arizona, respectively, authored a paper “The evolutionary significance of depression in pathogen host defense” in which they proposed that some of the alleles (forms of genes) that increase one’s risk for depression also enhance immune responses to infections.
Commenting on their hypothesis, Dr. Miller noted, “Most of the genetic variations that have been linked to depression turn out to affect the function of the immune system.” Dr. Charles Raison of the University of Arizona added, “The basic idea is that depression and the genes that promote it were very adaptive for helping people — especially young children — not die of infection in the ancestral environment.”
As recently as 1900, the top 3 causes of death in the U.S. were via infectious agents: pneumonia, tuberculosis, and diarrhea. Infants and young children were especially susceptible as 30.4% of all deaths occurred before the age of 5 years.
Thanks to improvements in public health and medicine (improvements like antibiotics), not a single one of the previous 3 leading causes of death are among the top 5 killers in the U.S today. Over the past century, infant mortality has dropped substantially, so that by 1997 only 1.4% of all deaths occurred before the age of 5 years. Although infection is no longer a top killer, infection was the primary cause of death for many of our ancestors.
Today, certain mutated versions of a gene called “NPY” are associated with increased inflammation (an immune process helpful in fighting off infections). Mutated NPY genes likely allowed our ancestors to better fight off infections (especially in childhood), and individuals with the mutated NPY gene were more likely to pass along the mutated NPY gene to offspring.
Interestingly, researchers at the University of Michigan’s Molecular and Behavioral Neuroscience Institute discovered that individuals with major depressive disorder were more likely to have the mutated NPY gene. The normal NPY gene codes for higher levels of a neurotransmitter known as Neuropeptide Y, which appears to help ward off depression by increasing one’s tolerance of stress. So the same mutated NPY gene that likely protected our ancestors against pathogens also increases our chance of developing depression.
Drs. Miller and Raison believe that acute (or severe but short-term) stress can not only lead to depression, but also jump-start the immune system. The physicians note that in the environments in which our ancestors lived, acute stress was often associated with the threat of physical harm or physical wounds. And unlike today, wounds readily led to infection and death. Therefore, Drs. Miller and Raison believe that evolution favored individuals whose immune systems operated under a “smoke-detector principle.”
Although smoke detectors often react to false alarms (for me, burnt toast), if you removed the detector’s battery and a real fire occurred, the consequences could be severe. Similarly, immune responses to acute stress are typically not necessary — not every stressful situation results in a wound and infection. However, if our ancestors became wounded even a single time and didn’t experience a piqued immune response, they might die from an infection.
It turns out that depression may not be a mere trade-off for a vigorous immune response. Dr. Miller suggests that depressive symptoms like social withdrawal, lack of energy, and a loss of interest in once enjoyable activities were actually advantageous to our ancestors. For example, a loss of energy might ensure that the body can leverage all of its energy to fight an infection. Also, social withdrawal minimizes the likelihood of being exposed to additional infectious agents. In this way, Drs. Miller and Raison note that “depressive symptoms are inextricably intertwined with — and generated by — physiological responses to infection that, on average, have been selected as a result of reducing infectious mortality across mammalian evolution.”
Recently Dr. Miller and Dr. Raison completed a separate study in which they attempted to treat patients with “difficult to treat” depression with a novel drug infliximab. Infliximab works by disrupting communication between immune cells and consequently reduce inflammation.
While infliximab did not significantly improve depression symptoms in the group being studied as a whole, it did reduce depression symptoms among a subset of study participants who showed elevated levels of inflammation. Inflammation was measured using blood tests for “C-reactive protein” (CRP). The higher the participants’ level of CRP, the more likely the participant was to respond positively to infliximab.
As Drs. Miller and Raison suggest, the theory that depression evolved to better resist infectious agents could lead to improvements within the field of immunology and novel treatments for depression. The physicians also suggest that in the future, we may be able to utilize simple biomarkers (like CRP) to predict which individuals will best respond depression treatments that modulate our immune systems (like infliximab).
Drs. Miller and Raison concede that chronic stress has been shown to impair the immune system. However, evolutionary processes may still allow for improved infection responses to acute (or short-term) stressors.
The physicians also noted that inflammatory biomarkers are not elevated in all individuals with depression. Individuals with major depressive disorder and elevated levels of inflammation may represent a unique subset of individuals with depression. Therefore, while immune-modulating therapies may be effective in treating some cases of depression, these therapies may not be effective against all types of depression.