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Video transcript

- [Voiceover] One popular way to treat depression is with antidepressants, and these are drugs that help to relieve the symptoms of depression. But before I talk about them, I want to quickly go over neurotransmission. So here we have a neuron, and neurons receive messages through their dendrites, which are these branching structures here. Then that electrical signal is sent down the axon to the axon terminals at the end. Here it meets up with the dendrites of the next neuron down the line. But these cells aren't really touching, and the electrical signal, the action potential, it can't actually jump between these cells. So how does the message get from one cell to the next? When the action potential reaches the axon terminal, the electrical signal is actually changed into a chemical signal, and here's how it works. The action potential triggers the cell to release vesicles full of chemicals called neurotransmitters, and the vesicles, these kind of cellular sacs, they dock with the cellular membrane and the neurotransmitter spills out into the synapse, which is what we call the space between these two cells. Once there the neurotransmitters bump around, and they can dock onto receptors on the next cell. When they do, this triggers an electrical signal in that next cell. The antidepressants that we are going to be talking about today work on this synaptic level, as do many other medications. Because by increasing or decreasing the amount of available neurotransmitter in the synapse, medications can make it more or less likely that a message will be triggered in the next cell. Depression itself seems to work on this level. Studies have suggested that depression might be caused by low levels of certain neurotransmitters called monoamine neurotransmitters. This includes serotonin, norepinephrine, epinephrine, and dopamine. Different theories disagree about the relative contributions of each one, but this is something I want you to keep in mind when we talk about how these medications work, because all of the antidepressants we're going to cover in this video work by trying to correct this imbalance. They all cause an increase in the levels of these neurotransmitters, but they do it using very different mechanisms. We're going to cover three classes of antidepressants, monoamine oxidase inhibitors, or MAOIs, tricyclic antidepressants, or TCAs, and selective serotonin reuptake inhibitors, or SSRIs. So let's start off with these MAOIs. The clue to how these antidepressants work is in the name. Monoamine oxidase is an enzyme that breaks down neurotransmitters that isn't stored in vesicles. So it's kind of like cellular housekeeping. Monoamine oxidase inhibitors are drugs that inhibit the actions of monoamine oxidase. By inhibiting this enzyme, it actually increases the amount of neurotransmitter that is capable of being released into the synapse. More neurotransmitters in the synapse increases the likelihood that they will dock onto the postsynaptic cell and cause an action potential. The next type of antidepressants are tricyclic antidepressants. instead of being named for what they do, these drugs are named for how they look. I have a few examples here, and you can tell that all of them have this three-ring structure. So tri for three and cyclic for the rings. Tricyclics work by increasing the levels of two specific neurotransmitters, norepinephrine and serotonin. But the way that they do this is very different from MAOIs. Instead of stopping an enzyme from breaking down these neurotransmitters, TCAs work by interfering with a very different housekeeping mechanism called reuptake. Much like you, your body likes to recycle. It likes to be efficient. This is even true at the neuronal level. After the neurotransmitter has released into the synapse, your body doesn't get rid of it, instead it recycles it by taking it back up into the presynaptic cell through these reuptake channels. Then it can be repackaged into vesicles and released again. TCAs work by blocking these reuptake channels. The result of this is that the neurotransmitter stays in the synapse longer, which then increases the likelihood that it will dock onto a receptor on the postsynaptic cell and trigger an action potential. SSRIs, or selective serotonin reuptake inhibitors, work the same way, they work by blocking reuptake channels. But instead of blocking them for both norepinephrine and serotonin like TCAs, they only block reuptake for serotonin, and only for very specific serotonin receptors. So like MAOIs, here we have a situation where the name of the drug is a description of what the drug does. I think of all of these antidepressants, SSRIs are probably the ones that you are most familiar with because this class of drugs includes fluoxetine, which is also known as Prozac. We have three classes of antidepressants, and the question you might have is, how do doctors know which one to prescribe? Your natural answer might be that they should prescribe the one that works best, but it turns out that actually all of these medications are equally effective as antidepressants. So maybe you think, okay, if we can't differentiate by effectiveness, maybe we can differentiate by side effects. This is where the main differences lie. MAOIs and TCAs are the oldest antidepressants. They are what we call "first generation" antidepressants. But because they are the oldest, they tend to have more side effects than more recent drugs like SSRIs, which are considered to be a second class antidepressant. MAOIs in particular are notorious for having a lot of side effects, and this stems from the fact that MAOIs affect a lot of different things. Remember we said that they affect all of the monoamine neurotransmitters, but we also have to remember that these drugs don't just increase available neurotransmitters in the brain, they do it in the entire body as well. This can cause a lot of different side effects. For example, MAOIs wind up inhibiting a process in the liver that helps to metabolize medications. As a result, people taking them need to be very careful when taking other prescription and non-prescription medications. This is something that you might have been aware of if you have ever paid attention to drug commercials. Many of them note things like people taking MAOIs should not take drug "X", or talk to your doctor if you are taking MAOIs. The reason behind this is that if your body can't break down certain drugs, it might lead to a dangerous buildup of those drugs in your body, which could potentially be life-threatening. But MAOIs don't just prevent the breakdown of certain medications, they prevent the breakdown of certain foods as well. I don't want to get too much into this, but I would definitely recommend that you Google the list of foods that people on MAOIs can't eat, because it is pretty long. It includes all fruits, alcohols, dairy, some meats. The list is very long, and actually the diet can be so restrictive that people sometimes stop taking the medication. Because of these side effects, MAOIs are no longer a popular choice for treating depression, although they are still used when an individual has not benefited from other treatments. Before when we talked about TCAs we noticed that instead working on all of the monoamine neurotransmitters like MAOIs, we said that they only work on two of them, norepinephrine and serotonin. Because they are more specific in what they affect, they also have fewer side effects. However, for some individuals the side effects that they do have can be severe. TCAs can sometimes affect things aside from norepinephrine and serotonin, things like histamines. This can lead to fatigue and sluggishness. Another problem is toxicity. TCAs are very toxic at higher levels and someone could go into cardiac arrrest if they accidentally or purposefully overdose on them. So individuals taking TCAS need to be carefully monitored by doctors, especially individuals who might be at a higher risk for suicide. Like MAOIs, the severity of these side effects make it so that TCAs are not always the first choice when prescribing antidepressants, although they are prescribed when people aren't successful with other treatments. They are also prescribed for individuals with bipolar disorder, along with other medications like Lithium, and this is because other antidepressants, specifically SSRIs, can sometimes trigger manic episodes in people with bipolar disorder. So TCAs are generally a safer option. But this brings us to SSRIs. With the exception of very specific cases like bipolar disorder, this class of antidepressants are generally the first choice for individuals seeking treatment for depression. This is because they are really effective, like the other antidepressants, but also because they have fewer side effects. This has to do with the fact that they are the most selective in what they act on. But like the other antidepressants, they aren't side effect free, because they also work everywhere in our brain and our body. So there are some side effects, and these can include sleeping problems, weight gain, and sexual dysfunctions. While these are not life-threatening, these side effects could have a negative impact on a person's quality of life. There is one exception to this life-threatening clause though, and that's a condition called serotonin syndrome. This rarely occurs for people who are taking SSRIs on their own, but it can become a problem if they are combined with other substances that also increase serotonin. I've talked about these three classes of antidepressants, but there are other newer substances that are also on the market now. Some of them are combined SSRIs and SNRIs, so they block reuptake for both serotonin and norepinephrine, but only for very specific types of each, so I generally like to think about them as more restrictive TCAs. They get all of the benefits of TCAs with fewer side effects. Another new kind of antidepressants are NDRIs, norepinephrine and dopamine reuptake inhibitors. Also NDRAs, norepinephrine and dopamine releasing agents. One blocks reuptake of norepinephrine and dopamine, and the other triggers additional release of norepinephrine and dopamine, but both result in an increase of these neurotransmitters in the synapse. Both of these drugs are really promising. I'm sure that they'll only increase in popularity as time goes on, but I really wanted to mention them here because I think that they challenge our cultural narrative of depression being caused by a decreased level of serotonin because these drugs relieve the symptoms of depression without influencing serotonin levels at all. That's just something to keep in mind because as our knowledge of this topic increases, how we think about depression from both a medical and cultural standpoint will change as well.