11. Through the Methylated Door

11. Through the Methylated Door


Imagine you’re in a room. It’s 110 degrees, you’ve drank the last of your water and you know you’re approaching dehydration. However, there are five doors in front of you and all you know is that behind one of them is an unending supply of water. Desperate, you pick door number one (because it’s your lucky number) only to get punched in the face. Ouch. So you try door number two; there’s a glass of water which eases your thirst a little bit, but it’s not enough. You try door number three and hear the faint sound of running water coming from…somewhere. When people first start on antidepressants, the period of finding the “perfect” cocktail works a lot like this. It can take weeks before they find the medication and dosage that works best for them. 20 million people in the United States suffer from depression. This is greater than the population of the five most populous US cities, Los Angeles, New York, Chicago, Houston, and Philadelphia, combined. Depression is characterized by extreme feelings of sadness, anger, and frustration that persist for a long period of time and result in interferences in a person’s life (Sweatt et al., 2013). About one out of every five people will suffer from depression at some point in their life (Sweatt et al., 2013). This is therefore a large public health concern that could be improved with the discovery of new treatments and medications. Research into the development of antidepressants is important because more than half of people who take antidepressants have inadequate responses to the first antidepressant they take (Sweatt et al., 2013). In addition, antidepressants take six to eight weeks to have any effect on mood and behavior (Sweatt et al., 2013). As a result, it is highly probable that a patient with depression could have to wait a long time to find the medication that works for them at a time when they require immediate help.

Neuroepigenetics research is the study of how the environment around us and our personal experiences lead to changes in our genes that can affect behavior, specifically, our DNA. DNA is the material we inherit from our parents; it’s what accounts for the similarities and differences in our behaviors and appearances (for more information, please see the intro essay written by Sam and listen to his interview with David Sweatt). Scientists think that studying these underlying, “invisible” factors may lead to the development of new medications that can act more rapidly and more effectively. As one of the most prevalent conditions plaguing our country, a lot of time and effort has been put into developing and refining pharmaceutical solutions. Currently, the leading treatment for depression is antidepressants. While effective, antidepressants are also subjective; in fact, when patients are first put on these drugs, they go through a trial period of guess-and-check. The physician essentially prescribes their best educated, well-researched guess to the patient, and then over the following time period, adjusts the dosage and medication according to the effectiveness of said drug. This “guess-and-check” period can last anywhere from one week to years, throughout which the patient goes on a roller coaster of emotional and physical ups-and-downs, while having to deal with the stigma of being “crazy.” Minimizing the length of this unfortunate limbo is often the goal of recent research, and neuroepigenetic research in particular suggests that there may be a connection between the effectiveness of antidepressants and some pre-existing conditions in each individual. These conditions have something to do with how the unique set of genes (the instructions that make our cells work) we are born with are changed by the environment we are exposed to during our lives.

There are currently various antidepressants available that act in different ways to treat depression. One of the most common types of antidepressants are SSRIs, or serotonin-reuptake inhibitors. How do these work? SSRIs target the communication pathway in our brains. Our brains communicate information throughout our bodies by sending messages from cell to cell. To transmit a message between cells, it must travel across a tiny gap by using chemicals called neurotransmitters. One such chemical is serotonin, which is involved in controlling mood and emotions, as well as other body functions. You may have heard of serotonin before as the “happy molecule.” Once the message travels from one cell to the next, the serotonin is reabsorbed by the first cell and waits for the next message to arrive. The mechanism of the SSRI antidepressant drugs relies on the idea that when a person is suffering from depression, their serotonin levels may be low and may be reabsorbed too soon, before the complete message can be sent to the next cell. This would result in poor communication between the cells and impact the person’s mood and emotions. SSRIs are antidepressants that help to increase the amount of serotonin in the gap between the cells by blocking the reabsorption of serotonin by the first cell (Figure 1). This increase in serotonin may allow the cells to communicate more normally and help to improve the symptoms of depression. Another type of antidepressants, tricyclic antidepressants (TCAs), work in a similar way to SSRIs. TCAs target the same communication pathway from cell to cell by blocking reabsorption of serotonin and norepinephrine, another neurotransmitter that is involved in regulating cognition, motivation, and intellect. This allows more chemicals to stay in the gap between the cells longer, even if there are less of them to start with, so that they can transfer the complete message from the first cell to the next cell (Figure 1) just by hanging out in the gap more. This is akin to letting the phone ring, 10 times, instead of 3, so that the “receiver” has more time to pick up the phone and get the message.

Figure 1: Mechanism of SSRIs
Figure 1: Mechanism of SSRIs

Not all patients suffering from depression improve after taking SSRIs, TCAs or other medications currently prescribed by doctors. People have different responses to these medications because not everyone experiences depression in the same way. There are many different types of depression, from minor depression to major depression to chronic depression. Scientists have yet to identify the exact physiological processes that are associated with depression. There is only research to suggest that there are certain correlations between depressive symptoms and what is going on in the brain of a person with depression. Continued research, related to neuroepigenetics, which is, remember, about the effect of the environment on the body and brain, is needed to better understand the underlying mechanisms behind depression in order to create new and more effective medications.

To see if neuroepigenetics play a role, studies often look at abnormalities in DNA. DNA is made up of genes, individual pieces of information that when turned on, control for the appearance of specific behaviors or appearances. Gene expression is how we measure the presence of these behaviors and appearances. DNA methylation and histone acetylation are two processes that we use as tags to find areas where there has been a change in gene expression. To put it briefly, methylation turns off a gene’s expression, like an “off” tag. Acetylation is kind of the opposite in the sense that it turns on a gene’s expression, like an “on” tag. While there are many areas of the brain implicated in depressive symptoms, we’ll be focusing on two specific areas associated with behavioral disorders (ie. Attention Deficit Hyperactive Disorder, Obsessive Compulsive Disorder): the hippocampus – the little sea-horse shaped area near the bottom of your brain – and the amygdala – the tiny bulb on the end of the hippocampus.

Figure 2. Effect of stress on DNA methylation and gene expression.
Figure 2. Effect of stress on DNA methylation and gene expression.

There are little molecules released in the body that control our emotions and bodily functions; for example, there’s a happy molecule named dopamine who cheers up our brain and there’s a memory molecule named serotonin who likes to make sure we pay attention in class and learn. These molecules are called hormones. For example, BDNF is a hormone that helps feed and socialize a neuron. And when there isn’t enough of this food, like us, neurons have difficulty communicating with one another, resulting in symptoms similar to depression. Recently, we’ve found that individuals born with normal levels of social hormone aren’t safe from this, though. People can still end up having decreased levels of it, if they experience some type of stress. A scientist found that when mice were bullied by a more aggressive mouse, they were more likely to have high levels of the “off” tag in their social genes. This means that there wasn’t enough social hormone for the cells to communicate with each other, leaving them lonely and depressed. When treated with antidepressants, however, the opposite happened; there were more signs of the “on” tag in the social hormone, allowing for normal, if not more, communication between cells, producing more happy symptoms (Tsankova et. al, 2006).

A different scientist found another marker that seems to have a connection to increased levels of depression. acH3, a smaller marker of BDNF (that social hormone!), gene expression is usually at pretty high levels; but when a person is exposed to stressful stimuli, the levels of this marker do a weird rollercoaster thing, where the levels increase and then rapidly drop. The decrease in this marker is where our problems come from. By finding a drug that can reverse that decrease – make it so that we don’t have to come down from the rollercoaster – we may be able to reverse depressive symptoms. Luckily, our dear scientist found a drug that did just this. Fluoxetine is our jetpack, it keeps acH3 levels from dropping down, reducing social avoidance behaviors (Covington et. al, 2011). If we can test for the acH3 levels before prescribing patients medication, we may be closer to “guessing” the correct dosage of antidepressants, decreasing that uncomfortable time spent in antidepressant-induced limbo.

Working toward developing faster acting antidepressants and on the underlying mechanisms that work for a higher percentage of people is important to the lives of the many people suffering from depression. There is an even larger implication when other mental disorders are taken into consideration, because antidepressants are commonly used to treat other mental health and anxiety disorders (Sweatt et al., 2013). The stigma behind antidepressants that medication is a quick and all-encompassing option for treating depression is too generic, and quite frankly, wrong. There are many underlying, unseen factors that play a part in the appearance of depression and the effectiveness of antidepressants, and by understanding this, we can try to recognize and create treatment plans that are specified to the individual, instead of our definition of the illness. Imagine you’re back in that room again, except, before you open door number one, you hear the sound of running water coming from behind door number four. You could avoid getting punched in the face, avoid wasting time as your condition worsens. Wouldn’t you prefer that?

References

Baudry, A., Mouillet-Richard, S., Schneider, B., Launay, J. M., & Kellermann, O. (2010). miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science, 329(5998), 1537-1541.

Covington, H. E., Vialou, V. F., LaPlant, Q., Ohnishi, Y. N., & Nestler, E. J. (2011). Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition. Neuroscience letters, 493(3), 122-126.

Sweatt, J. D., Meaney, M. J., Nestler, E. J., & Akbarian, S. (2013). Epigenetic Regulation in the Nervous System: Basic Mechanisms and Clinical Impact. San Diego, CA: Elsevier.

Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., & Nestler, E. J. (2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature neuroscience, 9(4), 519-525.

Vialou, V., Feng, J., Robison, A. J., & Nestler, E. J. (2013). Epigenetic Mechanisms of Depression and Antidepressants Action. Annual review of pharmacology and toxicology, 53, 59.

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