How is the brain involved in depression? Does the brain actually change?
Is Depression a Brain Disease?
“How does one go about proving that their mental illness is real without self harming or planning suicide?
I've been trained to use a 'show not tell' method of communication. Growing up, I couldn't ask for help or attention; I had to have an observable reason for those to be given. I'm trying to get better, but I keep pulling myself back because my mental illness is no longer real. Unless I cut or make suicide plans, my behaviors are described as laziness and unwillingness instead of symptoms of depression and anxiety. How do I convince myself and others that I'm still sick and deserve treatment?”
Many people in our communities have strong opinions about what constitutes a mental illness, which cases truly require treatment, and whether the problem stems from a person’s character or habits instead of true brain disease. Despite the noise, the scientific community has demonstrated consistently that depression is a real, biological phenomenon. In this section, let’s explore the evidence demonstrating that MDD is a real, biological phenomenon, and therefore, why we must tell a professional when we’re depressed - not show our loved ones we’re depressed.
When considering diseases, many envision binary diagnoses - instances where a test tells you that you either have the disease or you don’t. Such is often the case for certain infections (like HIV or hepatitis C), traumatic injuries (like broken bones or brain bleeds), or genetic conditions (like Down Syndrome or Hemophilia). Nevertheless, these binary diagnoses are not the norm in the field of medicine; in fact, they are quite rare. Binary diagnoses account for a small fraction of medical illnesses and are responsible for the minority of deaths. The majority of deaths are from nonbinary diagnoses: diseases where there is no clear transition between ‘you have it’ and ‘you don’t have it’. These common nonbinary diseases are often chronic (like diabetes mellitus, high blood pressure, or high cholesterol) are defined as being on the extreme end of a spectrum - not the simple yes/no of a binary test. While humans have a spectrum of blood sugar, blood pressure, or cholesterol levels, we nonetheless know that these factors can be deadly at their extreme. As we move towards the more severe end of the spectrum, our likelihood of death increases. Therefore, we are forced to draw lines in the sand to determine when someone moves on the gradient from normal to diseased, and the same is true for cases of major depressive disorder.
For many diseases in most medical specialties, like psychiatry, cardiology, endocrinology and rheumatology, a “disease” is therefore understood as the extreme end of a spectrum. For instance, to diagnose diabetes mellitus, the medical community has researched the spectrum of blood sugar concentrations and defined the “extreme end” as a blood sugar level (hemoglobin A1C) of 6.5% or higher. This threshold has been informed by decades of medical research, but ultimately, it’s a line drawn in the sand. The threshold could be higher or lower, and it may shift as research evolves. Nevertheless, diabetes is simply a blood sugar level associated with a significant degree of insulin resistance and therefore poses a significant risk to a person’s health. Don’t be fooled - diseases diagnosed on a spectrum are no less dangerous or legitimate than those diagnosed in a binary manner. These diseases are the most commonly diagnosed in clinics, the most medicated illnesses, and the top causes of death in America. Despite being defined as the extreme end of a spectrum of insulin resistance, diabetes mellitus is certainly a real, biological disease. And so is depression. Major depressive disorder is a biological, chronic, deadly disease, which exists at the extreme end of the spectrum of human brain function. Just as heart disease is a disease involving an organ, which can result in life-threatening complications like heart attack and death, so too is major depressive disorder a disease involving an organ (the brain), which can result in life-threatening complications like self-injury, malnutrition, or suicidality.
“Through research we know that mental disorders are brain disorders.”
National Institute of Mental Health
There are several theories which, in combination, describe how depression is a real, physical, and biological disease - just like any other organ disease of the body. In other words, depression is a brain disorder. Certain diseases of the body, like AIDS, are very specific and have a single cause: HIV. Other diseases of the body, like hepatitis, are less specific and can have numerous causes: alcohol, drugs, changes in blood flow, autoimmune issues, genes, and viruses. MDD is more like hepatitis; it likely has numerous causes which contribute to the disease in isolation or in combination with one another. Despite not always having the same singular cause, both hepatitis and MDD are real, biological diseases of vital organs that can be deadly if left untreated. By better understanding their possible causes, we can better formulate each person’s case and develop more targeted ways of treating their depression. This section is written to help us understand the biological factors that often contribute to the disease of MDD.
One convincing biological feature of MDD is changes in brain circuitry. This brain circuitry model explains that our repetitive thoughts, feelings, and behaviors create stronger connections between certain brain circuits, worsening connections in unused circuits, and creating an overall tendency of more restricted brain activity. As the sayings go, “Neurons that fire together, wire together” and “If you don’t use it, you lose it”: the brain circuitry model is all about the strengthening of common pathways and decay of uncommon pathways. The brain’s circuits can be easily conceptualized with the Sand and Water Metaphor.
The Sand and Water Metaphor for brain circuits: In order to understand the brain’s development of brain circuits, one can begin by imagining a flat bed of sand. As the brain develops in the fetus and neuronal connections become more and more established, each thought, feeling, and action is like a small current of water being poured on the dry sand; little by little, the water forms mini-valleys in the sand, trickling downhill towards the edges. With each thought, behavior, or action, more water travels down these small valleys, and certain valleys open up, deepen, and become more and more established. As the valleys become more established, it becomes more difficult for new splashes of water to form a new valley and follow a new path. The valleys are more established - the currents are flowing down the same paths, and certain areas become dry or unused. In the brain, certain areas can become underutilized - like a dry bed of sand between valleys. In these areas, there is less activity of the neurons, since other repetitive pathways (like repetitive thought patterns, repetitive emotions, or repetitive behaviors) become more established. As our valleys become more and more deep & permanent, so too, does it become more difficult to change our thoughts, feelings and behaviors. The water gets pulled into the biggest, deepest valleys. Many treatment modalities - like brain stimulation and therapy, which we’ll discuss later, help adjust our brain circuits. They can be conceptualized as a tsunami wave washing over the entire topography or as a hose that repetitively and incrementally develops certain small, but important streams in important dried-out areas so they receive more water current.
Like a valley that widens and deepens with more water, the repetitive, depressive thoughts of MDD create depressive brain circuits and restrict one’s thoughts, feelings, and behaviors. This narrows the use of brain circuits and increases the neglect and underutilization of the other areas of the brain. We can see these changes in brain imaging. For example, brain imaging studies have demonstrated that those with MDD have increased activity in the middle of the frontal cortex (ventromedial prefrontal cortex (VMPFC)) and decreased activity in the sides of the frontal cortex (dorsolateral prefrontal cortex (DLPFC)). To confirm these findings, studies have compared those who injured their depression area (VLPFC) versus those who injured their anti-depression area (DLPFC), and as expected, those with injuries to the depression area had less depression and those with injuries to the anti-depression area had more depression. While these two areas are not the only areas related to MDD, this information helps to fortify our understanding of the brain circuitry changes in MDD. Changes in brain circuits are therefore a compelling biological cause of MDD.
Another likely biological component of MDD is chronic inflammation. In the human body, there are several inflammatory substances (known as cytokines) that are released in response to different stressors. Threats to our bodies - like infections - leads to an inflammatory cascade, causing the release of these substances, like tumor necrosis factor alpha (TNF-ɑ), interleukin-1 (IL-1) and interleukin-6 (IL-6). These inflammatory cytokines are our body’s way of activating our white blood cells, fever, and other immune defenses that kill the foreign invader. Growing evidence in scientific research has been suggesting a role of these inflammation mechanisms in MDD. Patients with MDD were found to have higher levels of inflammatory cytokines in their blood and fluid surrounding their brains. They were also found to have more inflammatory cells in their brains, further strengthening the hypothesis that depression is related to chronic inflammation.
In addition, chronic inflammation can affect how well we respond to our depression medications. Researchers have noticed that increased inflammatory markers in the brain are associated with a decrease in our neurotransmitter concentrations. Curiously, those who have not been able to feel better with antidepressants have been seen to have increased inflammatory markers. Therefore, while antidepressants normally increase certain neurotransmitters to relieve depression, this effect might be offset by the decrease of neurotransmitters that inflammation causes. Also, when we give people the inflammatory cytokine IFN-ɑ or a substance to turn-on their inflammatory response (like a toxin or vaccine), these people will form more depressive symptoms. There is also evidence that blocking these inflammatory cytokines in people with inflammatory and autoimmune disorders helps their depression symptoms to go away. While there is much evidence behind a relationship between inflammation and depression, many other mental illnesses are also related to inflammation. So, inflammation likely contributes to depression through a complicated interaction with neurotransmitters and brain circuits instead of being the direct cause of MDD.
In addition to brain circuit and inflammation theories, another theory for the biological basis of MDD is that of neurotransmitter imbalance. Often referred to as a “chemical imbalance”, this figure of speech doesn’t fully capture the complexity of MDD. Nevertheless, it is perhaps the most well known explanation for how brain biology might be involved in the development of MDD. The theory suggests that MDD is caused by changes in the brain’s mixture of neurotransmitters. Known scientifically as the “monoamine hypothesis”, this theory suggests that MDD is due to abnormal quantities of the monoamine neurotransmitters (specifically serotonin, norepinephrine, and dopamine), which have effects on the parts of the brain related to our mood, attention, reward systems, sleep, appetite, and thought processes. Since these neurotransmitters are important for these functions, many have suspected that changes in their quantities create the depressed mood, decreased attention, lack of motivation, decreased sleep, poor appetite, and clouded thoughts of MDD. Nevertheless, many critics have been able to poke holes in this “neurotransmitter imbalance” theory. While MDD might not exactly be caused by specific neurotransmitter levels being too low or too high, these chemicals are certainly involved in the billions of complex reactions happening in the brain, especially those related to our mood. The exact mechanism of neurotransmitters in MDD is still being defined, but we nonetheless find that, for many, the symptoms of MDD go away as these neurotransmitter levels are adjusted with antidepressants. There is also evidence that changes in norepinephrine quantities in mice, adrenergic receptors, tryptophan and homovanillic acid levels,, and the 5-HTTLPR gene composition are specific ways that MDD relates to our neurotransmitters - but such nuanced discussions go beyond the scope of this book. Our understanding of the monoamine theory of MDD is still being clarified, yet the positive effect of antidepressants suggests that MDD may be related (at least partially) to our neurotransmitters.
Another biological feature of MDD is the stress hormone, cortisol. We all know what stress feels like. Our heart starts to pound, our muscles tense, we start breathing more quickly, and we start to feel beads of sweat forming on our foreheads. This response is the same whether a physical threat is approaching us (like a hungry lion) or a mental threat is approaching us (like missing the train). Worried thoughts in the brain’s outer cortex produce the feeling of anxiety. Anxiety triggers the hypothalamus to release corticotropin-releasing-hormone, which tells the pituitary gland to release corticotropin. The corticotropin tells the adrenal glands to release the ‘stress hormone’, known as cortisol. This stress hormone has profound effects on the brain and body, firing up our memory, increasing the amount of sugar in our blood, increasing stomach acid, and reducing our bone formation. Women tend to have higher levels of stress hormone, and subsequently, higher levels of depression than men. People with MDD and childhood trauma have been found to have especially high stress hormone and higher rates of MDD. Those with especially severe MDD have been found to have high levels of stress hormone, and there is evidence that a stress-hormone blocking drug may help with their feeling of depression. Additionally, the long-term medical consequences of depression (including heart disease, type II diabetes, and osteoporosis) may very likely be due to increased stress hormone levels. These correlations suggest that stress hormone may be a biological factor in the development of MDD.
One final biological factor of MDD is the strong genetic component of the disease. Every part of the human body, including our brain, is created by our genes. Our genes make our brain’s proteins and can be turned on or off, creating different effects in the brain. Dozens of genes have been found to play an important role in our moods. Studies of families and twins have demonstrated that, on average, genetics are responsible for approximately 30-40% of our risk for developing MDD. The remaining 60-70% of risk for developing MDD are attributable to the environment. While these percentages differ for each individual, these are the averages for the population. It is important to recognize that genetics do not predict or ‘hard-wire’ anyone for MDD. Rather, those with a strong genetic makeup for depression are predisposed to developing MDD in the context of environmental stressors or triggers. In other words, their risk of developing MDD is greater. MDD is more common in those whose relatives have had MDD, but the individual genes involved in this are still being studied. All in all, our genetic makeup affects our physical brain, and these factors in the physical brain contribute to the disease of major depressive disorder.
So, as we can see, there are several biological factors that contribute to depression: brain circuits, inflammation, neurotransmitter concentrations, hormones, and genetics. Instead of one theory fully explaining all cases of depression, each person’s case of MDD can be due to one or a combination of these factors. Some may have a strong genetic risk for MDD that, when combined with abnormal brain circuitry, produced a severe case of MDD. Another may have had abnormal hormone levels that, when combined with changes in their neurotransmitters and inflammation, produced MDD. While other possible contributions exist, the purpose of discussing these biological factors of depression is to demonstrate that MDD is a brain disorder. The brain is just another organ of the body. It, too, can become sick.
We must all start giving mental illness the same respect and importance as other medical illnesses. Due to the widespread invalidation of mental illnesses (or brain disorders), these diseases have not benefited from the same medical progress as other diseases in previous years. For instance, in acute lymphoblastic leukemia (ALL), the most common childhood cancer, the mortality has been reduced by 80% over the course of a few decades. As a result of this progress, there are now 6,000 kids in the United States who live each year, who would have otherwise died without our most recent medical advancements. Advancements in heart disease treatment are saving around a million people who would have previously died of cardiovascular disease. Advancements in HIV/AIDS interventions have converted it into a “chronic” disease like diabetes, not a death sentence. These advancements save about 150,000 people each year in South Africa who would have previously died of AIDS.
In comparison to this medical progress, one of the most common causes of death has not seen any significant improvement: suicide. For the year 2020 and beyond, it is estimated that 1.53 million people will die from suicide each year with a total of 15-30 million attempting suicide each year. People are much more likely to die from suicide than homicide and are even more likely to die from suicide than from a car accident. Being depression’s worst outcome, our lack of progress with suicide prevention is a sign of our failure as a society in treating MDD. As patients, we must seek help earlier. As loved ones, we must take mental illness seriously.
In addition to the risk of death, brain disorders like MDD, bipolar disorder, schizophrenia, and others create an extreme amount of suffering in daily life. In fact, these diseases create more disability than any other group of illnesses. The amount of disability caused by an illness can be measured as disability-adjusted life years (DALYs), and indeed, brain disorders are at the top of the list. According to the World Health Organization, brain (or neuropsychiatric) disorders like MDD create more than twice as much disability as cardiovascular disease or cancers. Why? Brain disorders are highly common, with 1 in 5 people experiencing a brain disorder in his or her lifetime. Additionally, in stark contrast to heart disease and cancer, these illnesses start early and often last for most of a lifetime, with 75% of cases beginning before age 24. So, while a few other illnesses may be more deadly than brain disorders, no other set of illnesses creates more disability, suffering, or imposes greater burden on our society than brain disorders.
A major barrier to the widespread recognition of mental illnesses as brain disorders has been the relative difficulty of visualizing mental illness on imaging as compared to other brain disorders like multiple sclerosis or hydrocephalus (also known as “water on the brain”). However, as demonstrated by the fMRI and PET scans showing changes in brain activity during MDD, we can now demonstrate that the brain is, in fact, physically altered in its structure and/or activity when afflicted by mental illnesses. The distinction between neurological illness and mental illness is akin to the distinction between a heart attack and an arrhythmia: the arrhythmia is more difficult to perceive. A heart attack from a clot or plaque in a heart vessel is a large, visible, physical impediment that can result in death. In contrast, a heart arrhythmia is due to conduction problems which are difficult to see, but the illness is equally dangerous and can still result in death. Both are real, both are physical - one is simply more difficult for us to perceive without specialized equipment. So, too, with mental illness, the disease is difficult to perceive but is real and deadly.
Major depression is what is produced when certain parts of the brain are ill. There has been a cultural tendency to recognize the physical or biological role of every organ of the human body except for the brain. Since the brain is commonly conceptualized ambiguously as the ‘mind’ or the ‘seat of the soul’, its illness has often been ascribed to weakness of the mind or distress of the soul - while its biological or physical primacy have been discounted. In order to overturn the stigma of mental illness, it is important for humanity to recognize the physical, biological organ-ness of the brain.
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