“NOTHING MATTERS anymore. What’s the point in trying? It must be my fault. I can’t seem to do anything right. I’ll only mess things up even more.” These are some of my thoughts before I received help for my depression, and I am not the only one. In 2020, the Organization for Economic Co-operation and Development (OECD) showed that 36.8% of the South Korean population showed depressive symptoms—the highest out of all the member states.

   However, there is a lack of awareness of the seriousness of the disease due to its intangibility and the false belief that it is of the weak-willed. Depression is not a weakness that you can pull yourself out of. The illness, which usually lasts for weeks or more, makes it difficult to find worth in yourself, limiting the ability to carry out daily tasks at home and work[1]. However, due to social stigma, it takes an average of ten years for a person with a mental illness to seek help[2], and only a third (35.3%) of adults who suffer get treatment[3]. Thus, many people who leave the disease untreated are vulnerable to extreme deterioration of mental health, possibly leading to suicidal attempts in the worst-case scenario[1]. Thus, better awareness of mental health disorders is paramount especially in South Korea, since it ranks number one in suicide rates out of 38 OECD member states, with an average of 36 Koreans ending their lives every day[4].

   Thankfully, depression can be treated. Through medication and psychotherapy[5], most people with depression show improvements in the ability to regulate mood. Despite the decades-long research behind antidepressants, the complexity of the drugs can make some hesitant about taking the medication. Thus, researchers have looked to not only provide effective medications but to provide answers as to why and how antidepressants work within the brain.

Discovery of antidepressants

   Scientists learned that depression was connected to neurotransmitters when they saw some drugs affected their levels also affected the patients’ mood. Neurotransmitters are chemical agents released by neurons (nerve cells) in the brain to stimulate neighboring neurons, muscle, or gland cells, allowing “impulses” to be transferred from one cell to the next. The most well-known examples of these neurotransmitters are dopamine and serotonin, which are our “feel-good” chemicals. However, when researchers first attempted to understand mood disorders, the connection between neurotransmitters and depression was not so intuitive. The connection was made apparent unexpectedly when scientists were looking into treating diseases other than mental ones. In 1952, a trial conducted by Hoffmann-La Roche company found that a drug being researched for treatment on tuberculosis called Iproniazid showed both improvements in patients’ mood and an increase of neurotransmitters in the brain. On the flip side, drugs that decreased the levels of neurotransmitters in the brain caused depressive moods in patients. In 1955, Bernard Brodie and Arvid Carlsson found that an herbal drug called reserpine caused animals to become apathetic, lethargic, and depressed.

   The findings led researchers to form the “chemical imbalance theory,” which hypothesized that depression could be the result of inadequate levels of neurotransmitters in the brain. Thus, the followers of the theory suspected that depression could be treated with antidepressant drugs that could keep the levels of neurotransmitters at the optimal level. Antidepressants work through a process known as “inhibiting the reuptake.” In this process, drugs prevent the “feel-good” neurotransmitters, like serotonin and dopamine, from being reabsorbed. If the neurotransmitters are prevented from being reabsorbed, then the concentration of these “feel-good” chemicals increases and makes the mood of the brain more positive[6]. Research has suggested that serotonin is the most effective neurotransmitter, which led to the production of the first selective serotonin reuptake inhibitor (SSRI) drug—Prozac—in 1988. Inhibiting the reuptake of serotonin in the brain, SSRIs are now the most prescribed type of antidepressant. Other well-known antidepressants, such as serotonin-norepinephrine reuptake inhibitors (SNRI) and Monoamine oxidase inhibitors (MAOI) are similar to SSRIs, as they limit the reuptake and increase the concentration of serotonin and other types of neurotransmitters in the brain. What differentiates the antidepressants are the types of neurotransmitters they target and the different side effects they might cause. Depending on the antidepressants components, side effects like nausea, headaches, and drowsiness are most commonly experienced[1].

   While the chemical imbalance theory can explain why antidepressants are effective, it has some limitations. The level of neurotransmitters in the brain correlates with depressive symptoms, but it would be hasty to conclude that the lack or abundance of certain neurotransmitters is the sole cause of depression. If the chemical imbalance theory is correct, patients who take antidepressants should experience an elevation in mood relatively quickly, as the levels of neurotransmitters should increase within a few hours after intake. However, antidepressants often take effect weeks later[7]. The limits of the theory pushed scientists to continue to study the cause of depression.

New ways to understand depression

   Thankfully, modern technology such as functional magnetic resonance imaging (fMRI)[8] allows scientists to get a clearer look at the brain of those suffering from depression. Research seems to indicate that depression is not caused by the simple lack of neurotransmitters in the brain but by “miscommunication” between brain cells and the lack of nerve growth[7]. The brain regulates mood by transferring neurotransmitters from one neuron to another, a process that resembles a chain reaction[1]. Under normal circumstances, the brain can regulate the reaction by activating or inhibiting the transfer of neurotransmitters to receptors of other neurons. For people with depression, the regulation of moods is more difficult because the receptors of neurons become either oversensitive or insensitive, which makes their responses to neurotransmitters become excessive or inadequate. The neuron’s abnormal sensitivity disrupts the normal flow of signals in the brain and its ability to regulate mood[7]. Depression is also related to the lack of nerve growth. Research seems to indicate that production of and connections between nerve cells are linked to depression[7]. It has been found that people with depression have a smaller hippocampus, a part of the brain that deals with learning and emotions. Researchers thus explored the links between the slow production of new neurons in the hippocampus and low moods. Stress hinders the growth of the brain cells in the hippocampus, and this deficiency could be a cause of depression[7]. As nerve growth is a process that can take weeks, this idea can explain the chemical theory’s limitation in explaining the time gap between the intake of antidepressants and its effects.

   There is also a radical theory called the “inflammation theory” which suggests that depression may not necessarily be a “disease,” but an evolutionary advantage. Throughout history, inflammation has not just been the body’s response to the invasion of bacteria and viruses but a signal to one's brain that the body could potentially be contagious. Thus, some researchers suspect that the brain evolved to become less interested in social activity when the body experiences inflammation or infection. The brain’s “disinterest” in human interaction occurs when it suppresses moods[9]. While this change could have helped our ancestors limit the spread of infection, the brain does differentiate between inflammation caused by infection versus inflammation caused by stress[9]. Thus, a brain going through stress and the consequent inflammation can be “tricked” into thinking that it is fighting off a virus and cause depressive moods. The theory is further supported by the fact that some drugs that target inflammation were effective in treating patients with major depressive disorders[10]. In short, depression could be a side effect of a mechanism that kept humans alive for millions of years and understanding that mechanism could provide more effective treatments in the future.

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   While the research into depression looks promising, there is still much left to uncover. This, however, is not a reason for concern, but hope. The research on antidepressants so far have provided more effective and safe treatments to those who need it. It also has challenged social stigma against depression, as it is not “a bad attitude” or “laziness,” but actual mechanisms in our brain that affect the regulation of our moods. By consulting with a clinical professional, anyone can reap the fruits of research on depression and not fight the disease alone.

[1] Mayo Clinic

[2] National Institute of Mental Health

[3] American Psychiatric Association

[4] Korea Foundation for Suicide Prevention

[5] Psychotherapy: A collaborative treatment based on the patient and the psychologist, mainly employing dialogue to help people develop healthy habits

[6] Verywell Mind

[7] Harvard Health Publishing

[8] fMRI: An imaging technique that measures brain activity by detecting changes relating to blood flow

[9] The New Mind-Body Science of Depression written by Maletic Vladimir and Raison Charles

[10] Journal of Clinical Psychiatry