Beware the Post-Vaccine Blues

Brenna McMannon

Illustrations by: Darling Garcia

Have you ever had the post-vaccine blues? It’s hard to imagine that such a minor experience could manage to impact your mental health. However, in recent years, evidence has emerged supporting a possible link between bodily inflammation and depression. This idea — that inflammation, the body’s natural response to injury, can have a psychological impact — has expanded our perception of mental health, adding to the enigma of the human brain. The mystery of the brain has made mental health, and depression specifically, incredibly hard to study and even harder to treat. This is mainly due to the fact that no one brain region or molecule has been identified as the sole cause of major depressive disorder (MDD), despite the fact that about 21% of women and 12% of men in the United States alone will experience depressive symptoms at some point in their lives [5]. This gap in understanding poses a real threat to people suffering from MDD across the world. However, recent research suggests a link between bodily inflammation and depression, expanding our understanding of the many causes of depression and aiding in the development of treatments. Before we get into that, let’s explore our existing knowledge of depression.

Depression: What We Know

Many of the key players in depression are concentrated in the limbic system: the set of brain structures involved in emotion and memory. Despite this knowledge of where depression occurs in the brain, the treatment of depression doesn’t focus on these brain regions; rather, it targets the tiny chemicals that send messages between them. Yes, I’m talking about neurotransmitters, the famous chemical messengers of the brain. Brain cells called neurons send signals to one another via neurotransmitters. Therefore, the amount of neurotransmitters being produced are important to their functionality, because having too little or too many can cause problems. 

Over the past half century, psychiatrists have prescribed depressed patients with drugs that aim to correct a chemical imbalance in the brain, usually involving a reduction in the neurotransmitter serotonin. Enter: Prozac. Also known as fluoxetine, this drug is currently the most commonly prescribed antidepressant and is classified as a selective serotonin reuptake inhibitor (SSRI). The drug functions to correct serotonin imbalances in the brain by allowing more serotonin to accumulate in the spaces between neurons, called synapses, through which neurotransmitters travel from one neuron to another. Then, neurotransmitters bind to the receiving cell and convey their signal. SSRIs work to keep serotonin from being recycled back into the neuron that released it, leading to an accumulation of serotonin in the synapse. When the concentration of serotonin in the synapse increases, the neuron receiving the signal can be activated more frequently. 

SSRIs work for many people with depression, boosting their mood and stripping them of their depressive symptoms. However, the causal link between serotonin and depression is still widely unknown. While a serotonin imbalance may play an important role in some patients’ depression, this is not the case for every person with MDD. Unfortunately, SSRIs and other antidepressants don’t work for everyone suffering from depressive symptoms. In fact, about 30% of people with depression do not respond to any antidepressant treatments [1]. These patients suffer from treatment resistant depression (TRD) and end up trying every kind of treatment you can imagine (meditation, talk therapy, medication, and medical procedures), often to no avail. 

Depression research is ongoing and consistently funded, so why don’t we know more about its cause, especially in people with treatment resistant depression? Because most people suffering from MDD display such a wide array of responses to different treatments, its root cause remains elusive. Many people with TRD resort to electroconvulsive therapy (ECT)  — one of the most effective TRD treatments, with a response rate of 50%-70% [3]. ECT uses electrodes to send an electric current through the brain, inducing a brief seizure. But here’s the kicker: nobody really knows how or why ECT is an effective treatment for TRD. This common theme in the study of MDD makes it difficult to formulate consistently effective solutions. Treatments like SSRIs and ECT reveal the high degree of variation among MDD patients, signaling how important it is to examine each case individually and treat the patient based on the suspected cause rather than employing a universal approach. This is where the immune hypothesis comes in as another potential cause of depression. 

The Immune Hypothesis

The immune hypothesis proposes a possible link between inflammation in the body and depression in the brain. However, the existence of an important brain structure, called the blood brain barrier (BBB), has made it hard for scientists to causally link bodily inflammation with depression. The BBB is a filtration mechanism built into the endothelial cells that surround the brain. These cells form an important layer within blood vessels that regulate the exchange of materials. The primary function of the BBB is to prevent toxins and other potentially harmful substances from entering the central nervous system (i.e. the brain and spinal cord). The filter also blocks out large molecules, cells, and other structures, meaning that many substances — like immune cells — circulating in the periphery of our bodies are not able to enter and affect the brain. For example, when you stub your toe, it usually becomes inflamed. However, scientists never thought that this simple inflammatory response could reach the brain because the immune cells are too big to cross the BBB. Now, we know that this is far from the whole story. 

In order to fully understand the connection between inflammation and depression, we must first familiarize ourselves with some important members of the immune system. Inflammation is the body’s natural reaction to injuries or viruses. When you sprain your ankle or get a root canal, your body generates a cytokine storm. Cytokines, the messenger cells of the immune system, are released from immune cells and sent out to promote inflammation and protect affected areas. In other words, your body starts vigorously pumping out cytokines to spread the word that there is an injury or foreign invader. This maelstrom of angry cytokines arrives on the scene and removes damaged tissue so that the healing process can begin. The main player in inflammation is a proinflammatory cytokine called tumor necrosis factor (TNF). While TNF is too big to cross the BBB, in the past few decades, scientists have discovered a correlation between increased blood levels of proinflammatory cytokines, like TNF, and depressive symptoms [4]. But, how is this possible if cytokines can’t cross the BBB?

This is where we find out that stubbing your toe can actually affect your mental health, bringing a mind-body connection into play. Pathogens, like influenza or Salmonella virus, have previously been associated with depressive symptoms, such as feelings of sadness or apathy [14]. Interestingly, these pathogens have the ability to cause the release of cytokines and the consequent activation of microglial cells in the brain [12]. Microglia are the first line of immune defense for the central nervous system, as the immune cells of the brain. Inflammatory cytokines are able to get their message across the BBB and to the microglia without actually entering the brain, by binding to receptors within the endothelial cells. When microglia pick up the signal that there is inflammation in the body, they start pumping out their own cytokine storm into the brain. The involvement and function of cytokines in the brain is still poorly understood, but we do know that it is the brain’s response to receiving an inflammatory message. Although this is a natural biological response, microglial activation can be harmful, especially in the context of depression.

When these angry microglia activate cytokines in the brain, they often impact serotonin production. Normally, cells in the brain produce serotonin from an amino acid called tryptophan. But when cytokines are released into the brain and start causing trouble, they can potentially instruct cells to use tryptophan to create other products in place of serotonin. Not only are these new products toxic to other cells in the brain, but they also decrease levels of serotonin. In this sense, it is no surprise that depressive symptoms tend to correlate with an increase in non-serotonin, tryptophan-derived molecules, resulting in a decrease of serotonin in the brain [9]. Decreased serotonin levels may also render some SSRIs ineffective, which may help explain why some people don’t respond to them. SSRIs work to inhibit the reuptake of serotonin, so if there is not enough serotonin being produced to begin with, they would have no effect. In fact, one study found that MDD patients who don’t respond well to SSRIs and other antidepressants are more likely to already have some sort of inflammation present in their body [8].

Inflammation: Where Do We Go From Here?

There are so many ways for the body to become inflamed— it’s downright unavoidable. For instance, simply being female puts you at higher risk of inflammation due to factors such as childhood adversity, obesity, and interpersonal stressors,  all of which disproportionately affect women [2]. Coincidentally, women also experience depression at a higher rate than men [5]. However, one of the most common causes of inflammation is psychological stress, as sustained feelings of stress can result in the chronic release of pro-inflammatory cytokines in the brain [6]. What’s more, chronic stress can lead to severe conditions like coronary heart disease (CHD) [13]. Even episodes of short-term stress can induce CHD in a more vulnerable subset of people [13]. This subset of patients has one thing in common: all are inflamed. Furthermore, the events of your childhood can affect levels of inflammation during adulthood [7]. Recent studies have found that experiencing some kind of childhood adversity (e.g. parental separation, low socioeconomic status, or familial mental illness/disorders) is often coupled with both inflammation and depression later on in life [7].

There’s a good chance that you will experience some level of inflammation-linked depression at some point in your life. So, how can you get ahead of it? There is compelling evidence that exercise can have a protective effect against the danger of stress, specifically chronic stress [11]. Of course, exercise is not going to be the perfect solution for everyone. What about people with chronic inflammation that isn’t caused by psychological stress, like rheumatoid arthritis? Conditions like these are considered to be autoimmune, meaning the immune system is overactive and producing inflammation where it isn’t needed. Scientists have started to develop experiments to invent drugs targeting this inflammatory response, though very few studies in the past decade have rendered promising results. One study conducted in 2013 included 60 people with MDD, half of which were taking antidepressants and half of which were resistant to treatments (moderate TRD). They were given either a placebo drug or a drug that contained a TNF antagonist, which worked to block the binding of TNF and prevent an inflammatory response. Over a 12 week period of drug administration, they found no overall differences in depressive symptoms between the placebo group and the antagonist group. However, when they reexamined the data, researchers found that when they took into account baseline inflammation, the drug had a significant effect. In other words, the participants that had a higher baseline level of inflammation at the start of the study experienced significantly more antidepressant effects than those who had less inflammation, suggesting that inflammation may have greatly contributed to their symptoms of depression [10].

This brings us back to the importance of individual differences and creating treatments based on the individual rather than the condition they suffer from. It’s clear that various risk factors, including childhood adversity, biological sex, and disease, produce different experiences of depression. In the same way that SSRIs may not work for those who are struggling with a serotonin imbalance, TNF antagonist drugs may be ineffective in treating those without inflammation. Eventually, there needs to be a comprehensive diagnostic test to determine the cause of a patient’s symptoms. Then, an individualized treatment plan could be developed to target that cause. But don’t hold your breath — these kinds of things take time. Depression research is constantly evolving, and this new link between inflammation and depression is simply the beginning of another chapter in understanding the complexities of the brain. 

Only when future developments enable us to look past the diagnosis of MDD and determine the specific causes for each person, will relief be an option for everyone. For now, this developing link between inflammation and depression may clear the way for the development of new and effective treatments. And it may explain why you feel a little down in the dumps after getting your COVID-19 vaccine.

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