On the Etiology of Depression

  Hey team!!

Today I'd like to put into writing my understanding of the causes of depression, that is I'd like to explain a more whole-istic approach to how depression, as a debilitating disorder, arises and persists with biological and psychological manifestations. 

To start I'd like to define depression as a persistent low and unpleasant mood, for long periods of time, where the amount of pleasure attainable is subjectively lowered, where quality of life is so low to the extent that one’s own existence is questioned on the basis of so little reason to go forward. This is more than the pain and hurt one feels as a specific response to an individual event that results in feelings of short lived sadness (ex. Break up, harassment, grief, ect). While these individual events can and are contributing factors to the disorder of depression, in isolation they are far from encompassing the complete and complicated subjective experience of having a depressive disorder.  

My use of the word complicated in the previous sentence is very specific. Depression, as a disorder, is heterogenous by nature. By this I mean it manifests in different individuals as specific and unique negative emotions, behaviors and thought patterns. For example, some people have depression where they: sleep all day, barely eat, and can barely think and solve problems, but you can also have people with depression that: are restless in bed, constantly thinking in an overwhelming manner and can do nothing but eat. Both people can be depressed, and they can also be depressed in a manner that looks different than either of these examples discussed. This means it’s heterogenous, depression is NOT one set of symptoms that all people with depression have. No one experiences depression the same.  

A point on the origins of depression I want to bring up early in this post is that of the “chemical imbalance theory” of depression. To no discredit to the original proposers of the theory, who postulated that low levels of the monoamine neurotransmitters (serotonin, dopamine and norepinephrine) was the cause of depressive symptoms and as such needed to be corrected by medication that would increase these chemicals. This theory was pivotal in the discovery of treatment of essentially all psychiatric disorders, but failed to fully encapsulate the individual cause of depression which manifests (as described above) in countless ways that are not inherently tied to monoamines no more than any other neurotransmitter. It fails to point out larger, big picture approaches to how people become depressed through both psychological and biological mechanisms . Both biological and psychological factors affect the subjective experience of life and whether we deem it “happy” or “sad” (along with  every other adjective), and neither one can be looked at as a cause without the other playing a role. Depression, like all mental illness, is a condition caused by the complex interplay of individual genetics and the environment (which cannot be isolated from one another) and any theory that reduces this or says otherwise is doing a disservice.  

Through reading various textbooks on psychopharmacology (shout out Stephen Stahl), watching neuroendocrinology lectures online and also observing the mindset and behaviors of depressed people and to an extent reflecting on my own experience through depressive episodes, I feel more confident in my view and understanding of depression. Depression is the manifestation of a learned helplessness of both shame and guilt of oneself in relation to the world. This learned helplessness results as the aftermath of a major stressor which was preceded by more minor episodes of stress that eventually got more and more difficult to overcome. Biologically your body’s fear/ anger response, via your amygdala, signals to your adrenal gland, through a cascade of pathways, to release cortisol (the stress hormone). This cascade results in multiple-organ systems changing to prepare your body to essentially put up a fight against the causal stressor. This response puts your body in a state to solve a here-and-now problem which, ideally, is supposed to pass quickly resulting in your body becoming resilient and more flexible. Through a negative feedback system (more of something causing less of something) cortisol release eventually turns off the body's own stress response and prepares for the next chapter ahead. However this doesn’t always happen. Over time, as you face one stressor after another with few positive outcomes, your body's stress response loses its fine-tuning, much like how a diabetic person's body may become resistant to the effects of insulin. In both cases, the body's natural response mechanism is thrown off balance.

In diabetes, the body's cells become less responsive to the insulin that is supposed to regulate blood sugar levels. As a result, more insulin is released to compensate, but the cells still don't respond as they should. This vicious cycle continues, with the pancreas pumping out more and more insulin, yet the cells remain unresponsive.

In the context of chronic stress, a similar cycle occurs. The body's initial stress response is designed to prepare you for immediate challenges, but when stressors persist without resolution, your body becomes overwhelmed. The negative feedback system that should dampen the stress response no longer works effectively. Instead, the body continually releases hormones, such as cortisol, in an attempt to manage the stress. However, the constant exposure to stressors has desensitized your stress response system, much like how diabetic cells become resistant to insulin.

As a result, your body remains in a state of heightened stress, with increased levels of fear, anxiety, and anger, and a decreased ability to calm down. The amygdala, a key part of the brain involved in the stress response, becomes overactive, and leads to release of key activating chemicals signals in the brain and periphery (everywhere else) like norepinephrine and epinephrine. Meanwhile, the prefrontal cortex, which normally inhibits this stress response, becomes less effective. This imbalance can lead to chronic stress, a condition where the body struggles to regulate its stress levels.

In both cases, whether it's insulin resistance in diabetes or a desensitized stress response in chronic stress, the body's ability to use the specific response it provides becomes compromised. The result is an ongoing cycle of imbalance that can have significant negative effects on one's health and well-being.

Anxiogenic (anxiety producing) amygdala signaling increasing norepinephrine, epinephrine and cortisol runs its course and the inhibitory actions of the prefrontal cortex on this response are decreased producing a chronic stressed state with little brake (inhibition) control on this response. Amygdala increases in size, prefrontal cortex activity decreases and even hippocampal neurogenesis decreases making it atrophy. These are known abnormalities and changes we see in depressed patients. This is more than just a poor stress response; it’s a hyperactive stress (fear, anxiety, anger) response and decreased ability to overcome and stop the stress. And as we know, neurons that fire together wire together and in the case of amygdala activity controlling the stress response to the hypothalamus, this pathway gets stronger!

From a psychological standpoint, the subjective experience of depression often aligns closely with its biological underpinnings. Throughout our lives, we learn to confront the world's challenges, overcome them, and grow in the process. However, in individuals dealing with depression, as well as many other psychiatric conditions characterized by negative symptoms, there is a common thread of adverse childhood events or stressors during formative years. These events can range from experiences related to bullying to challenges within the family dynamic and beyond. It's crucial to recognize that the objective severity of these events is not the sole determinant of their impact; rather, it's the subjective perception that holds greater significance.

These childhood events trigger stress responses, and because children have such limited control over their lives the outcomes of these experiences significantly shape their self-concept and how they relate to the world. As subsequent stressors, often beyond the child's control, yield unfavorable results, they foster a sense of helplessness and a dim outlook on life. Additionally, these experiences indirectly convey that those who should provide care and support are, for various reasons, unable to do so. This sheds light on the diminished pleasure and motivation experienced by individuals grappling with depression, as true rewards stem from autonomy and personal effort. Winning a game with your hands tied, with someone else playing for you and labeling it as life, cannot evoke the same sense of satisfaction and fulfillment as genuine, heartfelt endeavor.

In many ways, this process resembles the development of indifference and desensitization to the physiological effects of stress. A cornerstone of a fulfilling and content life is agency – the ability to exercise control and autonomy over one's existence to the greatest extent possible. The frequency and severity of these adverse childhood events, along with the specific circumstances under which they occurred, can profoundly influence an individual's response and the symptoms they subsequently experience. While depression can manifest later in life, a history of adverse childhood events, particularly those of greater severity, often precedes any additional high-stress events that may occur in later years, with the latter acting as the proverbial 'last straw'.

Aside from the obvious nature of heterogeneity in depression, there are key hallmarks that stick out. Again back to the psychological viewpoint: being in a state of depression involves attachment to permanence. Attached to the permanence in the viewpoint that “bad things are bad because they've been bad and therefore will always be bad”. Humans are creatures of habit/ pattern. We have a beautifully evolved brain with cognitive capabilities that view the past as the future by believing in discrete patterns based on previous phenomena. While I don’t disagree that patterns exist, we clearly utilize them for better and for worse, they are ultimately rooted in ignorance. Life and the universe is beyond complicated and the only true permanence is impermanence. Stars and planets are born, they die and become new forms of energy and truly everything in life is quite similar. You believe you are a certain kind of person one day, a different kind of person the next and a completely different person years from now. You feel reactive some days, calm other days, excited, scared and all kinds of emotions. But they all pass, they never last and never will. They will probably come back, but who knows for certain, and if they do they certainly won’t come back in the very same exact way the next time, how could they? This perspective may instill further negative feelings in some, but to me I see it as something quite beautiful. It allows you to recognize each moment for what it is: the unique manifestation of all events prior that will never come together the same way again. This is hope, rooted in seeing and experiencing  life as-it-is as an ever changing existence where we are forever entitled to the pursuit of enlightenment.