Depression can be likened to a psychological veil which shields us off from everyone and everything that matters in the world. The psychic veil of depression can obstruct our breath and vision, leaving us short of energy and unable to experience the world’s beauty around us. Life’s minute tasks become difficult and it’s true challenges, seemingly unbearable. Just how one can unveil and free oneself from this dark and heavy cloak can be difficult to discern, and when you are depressed, you feel isolated; helpless; alone. But you aren’t alone.
Globally, more than 300 million people suffer from some form of depression, including approximately fifteen percent of the adult population in the United States. What’s more, suicide tragically proves to be the second leading cause of death in the world amongst human beings aged 15 to 29 years old, with nearly 800,000 people ending their own lives every year (1). One must wonder—what brings a human being to such a state of psychological pain?
Whoever and wherever you are, I hope you—reader—will think of this post as an attempt to document important and wide-ranging (yet interconnected) portions of the current scientific understanding of depression. I am not a doctor or medical professional, but one of more than 300 million people on this planet who has, at different points in my life, struggled under the psychological veil of depression. The paragraphs below do not consist of medical advice, but of an effort to convey some crucial biological and environmental underpinnings of depression and in the process, shed some light on this dark and all-too-common state of the human mind.
Depression has taken on a rather vague definition in recent years, with so much as a spilt cup of coffee being assigned the status of “depressing.” So while the issue seems semantical, I want to take a moment (to attempt) to sort out a workable definition of depression.
The Merriam-Webster Dictionary assigns depression the laughably blunt definition of, “a state of feeling sad.” A secondary definition more reasonably describes depression as, “a mood disorder marked especially by sadness, inactivity, difficulty in thinking and concentration, a significant increase or decrease in appetite and time spent sleeping, feelings of dejection and hopelessness, and sometimes suicidal tendencies.”
According to the criteria established in the Diagnostic and Statistical Manual of Mental Disorders (DSM–5) (2), an individual may be diagnosed as depressed if five or more of the following symptoms persist for a period of two weeks or longer:
- A sad or depressed mood
- Loss of interest or pleasure in previously enjoyable activities
- Change in appetite
- Excess weight gain or excess weight loss
- Changes in sleeping patterns—sleeping too much or sleeping too little
- Increased fatigue
- Feelings of worthlessness or guiltiness
- A decline in cognitive ability—difficulty thinking or decision making
- Thoughts of suicide and/or death
While depression can only reliably be diagnosed by certified medical professionals, human beings certainly experience a wide range of emotions—some of which overlapping with the criteria characterizing depression above—and some of these emotional fluctuations are contextual to the ups and downs of an individual’s life events. Hence, different subtypes of depression may develop under different circumstances—as in the cases of bereavement related depression, postpartum depression, seasonal affective disorder, bipolar disorder, psychotic depression, and persistent depressive disorder.
- Bereavement-related depression describes the depressive psychological state which often follows the death of a loved one. Depression is not typically diagnosed as being related to bereavement until depressive symptoms have persisted for two or more months following the loss of a loved one (3).
- Postpartum depression is defined as “a mood disorder that can affect women after childbirth.” (4) Mothers experiencing postpartum depression often have extreme feelings of sadness, anxiety, and exhaustion, making daily care activities for both themselves and others potentially problematic.
- Seasonal affective disorder is a form of depression related to a change in the seasons, with depressive symptoms occurring at the same time each year (5). People suffering from seasonal affective disorder often experience more severe depressive symptoms during the winter months and more mild symptoms during the spring and summer months.
- Bipolar disorder—formerly referred to as manic depression—is a subtype of depression in which an individual experiences severe mood swings from the psychologically high states of mania to the low states of depression (6).
- Psychotic depression is a subtype of severe depression in which an individual often experiences some form of psychosis (i.e., hallucinations, delusions, and/or another type of psychological break) and often requires hospitalization (7).
- Persistent depressive disorder describes a subtype of depression which lasts for a period of two years or longer, during which an individual may experience fluctuations in the severity of his or her depressive symptoms (8).
Major depressive disorder (MMD)—a subtype of depression overlapping significantly with persistent depressive disorder—has been described as a “chronic, remitting syndrome involving widely distributed circuits in the brain,” and is characterized by symptoms such as “depressed mood, anhedonia, disturbed sleep, appetite, and energy, reduced concentration, excessive guilt, and suicidal thoughts.” (9) Major depressive disorder does indeed ‘run in families,’ as the condition displays between 31 and 42 percent heritability (9, 10). However, genetics alone do not account for the complexity of major depressive disorder (or any other subtype of depression for that matter), leaving environmental factors to constitute a significant portion of the biological basis of depression.
A number of environmental factors have been linked to the development of depression, including various forms of stressful life events (i.e., early life trauma, sustained stress in childhood, the loss of a loved one, chronic inflammation, medical illness, and so on), and the disparity in environmental conditions underlying the various subtypes of depression highlights a key fact: depression is not a disease of nature or nurture, but a disease of nature and nurture. As biological organisms, we exist in a state of perpetual interplay with our environment, and the input from our environment impacts our physiology in a variety of ways.
As a human being, you have about 20,000 functional genes in your genome and with the exception of mutational events, the order of your genes doesn’t change throughout your lifetime (11). However, the expression of your genes—the manner in which particular genes are “turned on” or “turned off”—is regulated by biological processes referred to in biology speak as “epigenetic modifications.”
The word "epigenetic" is defined as a biological phenomena, "relating to or arising from non genetic influences on gene expression," and when considering the Greek roots of the word, literally means "upon" or "above" genetics (12).
About 100 trillion meters of DNA exists within every adult human being’s body, and each cell within our bodies contains approximately six linear feet of DNA packed into an area of six micrometers (or 0.000236 inches) in diameter—a region known as the nucleus of the cell (13). This seemingly impossible feat occurs as the result of the condensation of our DNA into a structure known as chromatin. Chromatin is then wrapped around proteins called histones and packed even tighter through a process known as methylation, in which methyl groups (-CH<sub>3</sub>; a carbon atom bonded to three hydrogen atoms) are added to specific stretches of DNA, resulting in the inability of these genes to carry out their biological function (a process called down regulation) and this is an example of an epigenetic modification.
Genes are exposed or hidden through the addition or removal of biochemical compounds, allowing for the enhanced or repressed function of specific genes. In this manner, certain genes that should be expressed in skin cells, but not in liver cells, for example, are demethylated in skin cells (allowing for these genes to be expressed) and heavily methylated in liver cells (preventing the expression of these genes in the liver). The same is true of genes which are expressed in our brains, but not in, say, our heart tissue.
So, what does any of this have to do with depression?
The field of epigenetic research has been exploding over the last decade, illuminating epigenetic mechanisms underlying diseases like cancer, heart disease, stroke, dementia, and even depression. The food we eat, the amount and intensity of exercise we get, the number of hours we sleep each night, our stress levels, the variety and quantity of toxins to which we are exposed—nearly everything we experience triggers various epigenetic modifications and some of these effects have been linked to novel theories regarding the causes of depression.
For decades, the explanation of depression went something like this: depressed people have biochemical imbalances of the neurotransmitters norepinephrine, dopamine, and serotonin (popularly referred to as the “happy” chemical) within their brains and low levels of these chemicals are directly responsible for causing the symptoms of depression. In turn, an array of drugs have been developed in order to increase the levels of these neurochemicals (particularly serotonin) in people’s brains with the intention of effectively treating depressive symptoms—and the data shows that these treatment methods actually work pretty well. Millions of people have experienced success in the treatment of their depression with the aid of medications such as selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants, and other medications acting on the serotonin (which is also referred to as 5-hydroxytryptamine), dopamine, or norepinephrine receptors of the brain.
However, a significant portion of depressed patients display “treatment resistant depression,” as their symptoms do not improve with the aid of traditional antidepressant medication therapies—and recent research indicates that the neurotransmitters mentioned above constitute only one of the major biological underpinnings of depression.
Numerous theories have been developed in an attempt to understand the mechanisms underlying depression—one of which being the “inflammatory cytokine model of depression,” which posits that chronic inflammation over-activates the hypothalamic pituitary adrenal (HPA) axis (a system of brain structures that triggers the release of stress hormones and stimulates stress responses within our bodies), leading to decreased amounts of neurotransmitters within our brains and the subsequent development of depressive symptoms (14, 15). In response to various forms of stress, chemicals called “pro-inflammatory cytokines”—which function to trigger inflammatory reactions in the body—such as interferon-alpha (INFα), tumor necrosis factor-alpha (TNFα), interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), and interferon-gamma (INFγ) are released into the bloodstream and have been linked to the development of a variety of neuropsychiatric symptoms, some of which mirroring the symptoms of depression (14, 16).
A number of links have been established between depression and inflammation. For example, depression frequently presents in patients with inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis (17, 18, 19). Additionally, people with increased levels of inflammation have a higher likelihood of developing depression, and the reduction of inflammatory biomarkers in these individuals correlates to the remission of their depressive symptoms (14).
Relating this back to epigenetics: those suffering from depression possess increased levels of pro-inflammatory cytokines in their bloodstreams, and higher levels of these chemicals have been linked to the epigenetic modification of a gene called IL-6 (16). The IL-6 gene codes for the synthesis of the interleukin-6 cytokine and in depressed individuals, this gene is under methylated—resulting in the overexpression of IL-6 and as a result, more of this pro-inflammatory compound in the bloodstreams of depressed people. In addition to IL-6, other pro-inflammatory compounds such as IL-1ra, C-reactive protein (CRP), TNF-α, TNF-β1, and IFN have been epigenetically linked to the development of depressive symptoms (20). In turn, a number of the pro-inflammatory cytokines mentioned above—as well as stress hormones like CRF and glucocorticoids—have been suggested as markers of inflammation which may additionally indicate the presence (or lack thereof) of depressive symptoms (20).
What’s more, antidepressant use has been associated with the increased methylation of the IL-6 gene and treatment with SSRIs have been shown to both reduce circulating levels of pro-inflammatory cytokines (such as IL-1, TNFα, and INFγ) and increase levels of anti-inflammatory cytokines (such as IL-10), further supporting the theory that depression is—at least in part—a symptom of chronic inflammation while potentially uncovering a secondary mechanism of SSRI treatment (14, 20). Although SSRIs have long been known to work on the brain’s serotonin system, the research mentioned above highlights an additional, anti-inflammatory mechanism of action underlying SSRI treatment—a therapeutic effect facilitated by epigenetic modifications.
But the epigenetic roots of depression go even deeper. Autopsies on suicide victims have shown that those who commit suicide often possess increased levels of rRNA (ribosomal RNA) gene methylation within the hippocampus—a region of the brain that regulates emotion, memory, and the activation of the autonomic nervous system—as compared to those who pass away from other causes (21). These rRNA genes are fundamental to learning and memory formation—and the increased methylation of these genes results in fewer proteins being synthesized within the hippocampus, which in turn manifests in the development of depressive symptoms.
Child abuse additionally leaves epigenetic marks on the brain. Similar studies on suicide victims have shown that those who were abused in childhood possess distinct epigenetic markers on the GR gene and these markers have additionally been linked to an increased liklihood of commiting suicide (21). Curiously, similar epigenetic patterns on this gene have been identified in rat pups who were neglected by their mothers (21).
Patterns of gene methylation aren’t the only epigenetic links to depression, however. In addition to methylation, different forms of epigenetic modifications exist as well, including phosphorylation, ubiquitination, sumoylation, and acetylation. Contrary to methylation, acetylation is an epigenetic modification in which acetyl groups are added to a stretch of DNA and promote the activity of the genes which have been ‘acetylated’. Within the hippocampus, decreased levels of acetylation have been linked to the onset of depressive behavior in response to stress—indicating that acetylation patterns in the hippocampus play important roles in memory formation and behavioral stress response development (22). Acetylation and methylation seem to have important implications in the biology of depression and as a result, growing interests in identifying biomarkers which indicate the epigenetic modification patterns of various brain regions have emerged in the medical field with the intention of developing future diagnostic and treatment methods for depression.
However, depression is a syndrome of incredible complexity and no single mechanism or biomarker can explain the diverse array of symptoms manifested in those who are depressed. Depressive symptoms—as traditionally established—develop when the concentrations of neurotransmitters such as serotonin and norepinephrine within a person's brain are low. Additionally, increased levels of inflammatory cytokines within an individual’s bloodstream have been shown to over-activate the HPA axis and diminish the amounts of neurotransmitters (such as serotonin and norepinephrine) within the brain—resulting in the onset of depressive symptoms (20). Furthermore, those who experience sustained childhood stress often display higher corticotropin-releasing hormone (CRH) levels within their brains, resulting in an increased stress response in adulthood, as well as diminished neurotransmitter levels within the adult brains of these individuals—which (yet again) triggers the development of depression (20, 23).
In this manner, depression can simultaneously be described as an immune response to chronic inflammation, a neuropsychological response to childhood trauma, and a symptom of biochemical imbalances within a given person's brain.
Herein lies the beauty of epigenetic research—the field allows us to bridge the gaps in our understanding of nature and nurture, illuminating the environmental and biological foundations of diseases like depression, as well as innumerable others. While giving rise to the development of novel, more sophisticated theories regarding the basis of depression, the field of epigenetics has also allowed for the enhancement of more traditional models, as in the case of depression treatment with SSRIs.
And as our understanding of the biological mechanisms underlying depression (or any other disease, for that matter) deepens and complexifies, so too do our definitions of such conditions.
Imagine somebody who is visibly depressed. From a base-level, exterior perspective, this person may simply appear to be feeling sad. For decades, those suffering from depression have been told to toughen up, deemed to be lacking in will power. Zoom into the mind of this individual, however, and one realizes that depression is not a choice, but a psychological condition—as mentioned above—characterized predominantly by sadness, inactivity, difficulty thinking, feelings of dejection, hopelessness, and potentially, suicidal thoughts or tendencies. In this manner, depression is indeed a psychological condition (or at least a collection of psychological symptoms).
But keep zooming into the brain of this person. The cortical areas of the brain are responsible for the development of complex cognitive behaviors, personality traits, decision making, and social behavior. The deeper, limbic structures of the brain govern memory formation and our perceptions of emotional sensation. In comparison to a non-depressed person, the cortical regions of the brain—more specifically, the prefrontal cortex—of somebody who is depressed will display a significant decrease in activity, while the limbic structures of his or her brain—such as the amygdala—will be hyperactive (24). Additionally, the volume of an individual's hippocampus has been shown to decrease with both the severity and duration of depressive symptoms (24). In other words, when we are depressed, the regions of our brains which govern and process conscious, rational perceptions are repressed and over-ruled by our more emotional brain areas. Therefore, depression can also be characterized and defined by changes in brain anatomy.
Keep focusing upon a single neuron within this person’s brain. The neurons of this individual's prefrontal cortex transmit fewer neurotransmitters than those of somebody who is not depressed and additionally, the brain cells within this person's prefrontal cortex will have fewer connections to surrounding neurons (24). Furthermore, the neurons of this human being's hippocampus—depending upon the severity of his or her depression—will be atrophied to some degree and some of these neurons will cease to function, effectively resulting in the death of these brain cells (24). Antidepressant medications function to increase the levels of neurotransmitters produced by the neurons within our brains, resulting in a higher efficiency of these neurons, the formation of more connections between brain cells, and the growth of new neurons within the prefrontal cortex and hippocampus—a process known as neurogenesis. When viewed from this perspective, depression can additionally be defined by changes in neurological activity.
Close in on the nucleus of this particular nerve cell and on the DNA inside this nucleus. The methylation patterns on this person’s genes—the epigenetics of this person—differ from those of a non-depressed individual. Genes which activate inflammatory reactions in the body are under-methylated and expressed at higher rates, while those leading to anti-inflammatory reactions are methylated and repressed. Acetylation patterns on genes within the neurons of the hippocampus are reduced and various genes within the brain cells of the prefrontal cortex are heavily methylated (25). Simply put, the gene expression of somebody who is depressed differs from the gene expression of an individual who does not suffer from depression and therefore, depression can be characterized by epigenetic changes, as well.
Depression is simultaneously a molecular, cellular, neurological, psychological, and social condition—and the epigenetic links between depression, inflammation, and chronic stress open up entirely new perspectives with which we can view this tragically common condition of the human psyche. Not only do genetics play an important role in the development of depression, but life factors as wide ranging as the Western diet, gut health, obesity, sleep deprivation, early life trauma, medical illness, and vitamin deficiency have been linked to the development of inflammation within the human body and in turn, the manifestation of depressive symptoms (20). The study of epigenetics is allowing us—for the first time in human history—to connect the dots between our understanding of the biological basis of depression and these widely variable conditions of life.
Additionally—and of equal importance—this new epigenetic perspective with which we can view depression also helps to erase the stigma surrounding this condition. People suffering from the internal struggles of depression can be alleviated from the judgement with which society has—for far too long—viewed those who are depressed. Through understanding the scientific basis of depression (or any other stigmatized psychological condition), we as individuals can better understand and empathize with one another—and we as a society can progress towards the development of quality treatments for this tragically frequent state of the human mind which plagues so many of us.
Depression, as I have attempted to highlight throughout this piece, is a condition of both nature and nurture—of both genetic and environmental origins. An organism cannot exist in a vacuum; we are engaged in an a constant and deeply complex relationship with our environment—whatever those external conditions may be, for better or for worse—and an incredible number of these environmental factors interact with our biology to contribute to the development of depression. Those who are depressed are not physically inferior or psychologically weak, but experiencing a biological response to the conditions of their environment. Remarkably, the epigenetic links between depression, inflammation, and the various conditions of life which contribute to the onset of depressive symptoms are allowing us—as individuals and as a society—to detangle the scientific knots of knowledge which fastens the veil of depression to so many of our minds.
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