Scott Webb (Host): Antidepressant medications are commonly prescribed but widely misunderstood by the public. And my guest today is back to tell us how antidepressants work, discuss the common side effects, and more. I'm joined today by Dr. Benjamin Griffeth. He's a psychiatrist with Prisma Health.​

This is Flourish, the podcast brought to you by Prisma Health. I'm Scott Webb. Doctor, it's nice to have you back on the podcast. Last time, we sort of did some myth-busting about mental health, mental illness. Today, we're going to talk about antidepressants and how they really work because I think some of us think we know, but you would know because I know you went to school for like 12 years or something like that. So, you definitely know. So, what are they? How do they work? And what types are most commonly prescribed?

Dr. Benjamin Griffeth: So, antidepressants, the idea behind them is for patients who suffer from depression and a number of other illnesses, because we use antidepressants for a lot of things, and we can come back around to that.

Host: Sure.

Dr. Benjamin Griffeth: But most patients with mental illnesses where we're prescribing antidepressants, the challenge is they usually have a deficiency of neurotransmitters. And what neurotransmitters are, are the natural hormones and chemicals that one nerve cell uses to talk to the nerve cell next door. And if you don't have enough of those, then the signal is not complete. And so, that leads to other illnesses like depression, anxiety, things like that.

And so, what the antidepressants do is they increase the number of neurotransmitters available to the nerve cell so that it can talk to its neighbor. The way they do that is kind of fun. The metaphor I use with most of the patients that I work with and the medical students that I teach is a bathtub. So if you have a bathtub, and you want it full of a certain amount of water, there are two ways to get that certain amount of water full in the bathtub. The first is you have to turn on the spigot and have some of that water in, but you also have to plug the hole so that the water's not just running right back out.

Host: Sure.

Dr. Benjamin Griffeth: Almost all the antidepressants work by plugging the hole. None of the antidepressants create new or more of these neurotransmitters. What they do is they keep the body from breaking down or taking back in absorbing the neurotransmitters. And so, it's like if you had a bathtub, and you need to have the bathtub half full. If you don't have the plug in the bottom, it doesn't matter how much water's coming through the spigot, it's going to just pour right back down.

And so, the idea is I'm going to stick a plug in the tub, and that's going to allow me to fill the tub where I want it to be so that, in this case, I have enough neurotransmitters for my nerve cell to talk to its neighbor. There are large numbers of classes of antidepressants out there. The most common group right now are the SSRIs, that's selective serotonin reuptake inhibitor. And I'll break each one of those words down, and I'll kind of work from the middle out.

So, serotonin reuptake, that's the process of taking serotonin, which is one of those neurochemicals, and eliminating it from the gap between the two nerve cells. And the way that it does that is by reuptake. So, my nerve cell who wants to talk to its neighbor doesn't want to lose the serotonin, because that serotonin's valuable. It spent a lot of time building that serotonin. So to some degree, one of the things that it has is it has a shop vac that's sitting out in the yard between the two nerve cells. And so, when I throw the serotonin flag out there for my neighbor to see, since I don't want that flag to disappear, I'm going to use my shop vac and I'm going to suck it back up so that I can get it out and use it again and again and again and again. So if I want that flag, that serotonin flag, to stay out there longer, what I have to do is I have to plug up the shop vac so the shop vac doesn't suck up that flag again. And so, that's the job that it's doing.

And then, the selective, the very first word, so that's the inhibition, is plugging up the shop vac. The first word, selective, means originally some of our early antidepressants, and those are called tricyclic antidepressants, worked by doing serotonin reuptake inhibition. But they worked in a lot of other ways. And so, the fact is that this group works selectively just on the serotonin reuptake shop vac. All it does is turn off that one shop vac.

Now, there are other antidepressant classes that are commonly used. The second big group is the serotonin-norepinephrine reuptake inhibitors. So, the same reuptake process, the same stopping up the shop vac. But in this case, we have a red flag for serotonin and a blue flag for norepinephrine, which is just another neurotransmitter. And so, my job is I now have medicines that stop up both the red flag and the blue flag shop vacs so that those flags hang out so my next-door neighbor nerve cell can see the signal I'm trying to pass.

Host: Yeah. Yeah, it's really interesting, and I'm trying to follow you along. I wish I had some diagrams, but I'm hanging on tight, Doc. So then, what mental health conditions can antidepressants really help treat, and what kind of benefits can patients expect?

Dr. Benjamin Griffeth: Sure. So, I'll take the second piece first. So, let's talk about depression, because that's what these were originally built for.

Host: Sure, it's in the name. Yeah.

Dr. Benjamin Griffeth: Yeah. That's why they're named antidepressants. So in depression, a good example is if you choose to start a medication for depression, it's most likely going to be one of these groups of medicines, the SSRIs or the SNRIs. From that, what you should expect to have happen is over time, because we have plugged up that shop vac, is the signal across your brain starts to elevate. It starts to come back to normal. And since that signal is coming back to normal, you should see the reduction of the symptoms that go with depression. So, you should see things like your sleep becomes regulated. You're more likely to sleep at night than in the day. That your appetite comes back to normal, your energy improves, your ability to enjoy things that are enjoyable comes back. Your sense of being able to enjoy the world, not feeling depressed and blue and down all the time improves. And so, that's the effect that we're looking for with any of these medicines.

Now, we talked about that in regards to depression. These medicines are used in a lot of other illnesses and have been found to be effective in a lot of other illnesses. So, this works in anxiety. We have found that this works for post-traumatic stress disorder. We will use these in addition for other mental illnesses, so things like bipolar disorder, where we will sometimes add an antidepressant for the treatment of the depressed piece of bipolar disorder. And so, we use them in a lot of different arenas.

Again, we first found out that they worked in depression, but then some people don't have just depression. Some people have depression and anxiety at the time, and one of the things we found out was, "Well, let's try this medicine for the depression," and they came back and said, "My depression's better, but so is my anxiety." And so then, we started taking these to patients who just had anxiety, and they said, "Yeah, it works for my anxiety even though I don't have depression." And so, that's why to some degree, the term antidepressant is maybe you could argue a little misleading because they're actually just good medicines for helping stimulate and returning people to normal mental health.

Host: Yeah, it's so interesting. And I've spoken with other Prisma Health experts about GLP-1s. And it kind of reminds me of that, that, you know, they create a pill for one thing, and then you find out, oh, it helps with all these other things as well, right? It's just like magic pill. And I know that antidepressants are magic per se, but they do seem to help with far more than just depression, right?

Dr. Benjamin Griffeth: Correct. Yeah. And that's the way that medicine has worked since. The late 1700s medicine has worked by observing. And sometimes what we do is we try something and we say, "Oh, that creates this effect. Can we recreate that consistently?" And that's how you determine that this thing works.

Host: Right. Yeah, wondering, Doctor, and this is anecdotal, but I know that I've heard this, especially with one of my kids, teenager when they were in high school, and lots of kids were on different types of pills. Like, why one antidepressant might work for one person but not another, even though they have the same diagnosis?

Dr. Benjamin Griffeth: Yeah. So, there are two answers to that. So, the first answer to that is even though the diagnosis may be the same, the way that diagnosis presents may be very different. So, if you think about what's a good example? Diabetes would be a good example. Some people have diabetes where they lack the ability to produce insulin. And so, therefore insulin is a required part of their treatment.

For other people, they have diabetes because they're insulin resistant. Their body produces enough insulin, but their body doesn't respond to the insulin the way that they used to. And so, sometimes insulin's the answer, but often other medicines are the answer. And so, even though the diagnosis may be the same, it may be different in different people. And so, that expression sometimes will change the medications we use or how you respond to the medication. So, taking depression that we've already started talking about as an example. Some of my patients with depression notice that they have a lot of trouble sleeping at night. They have a lot of trouble with loss of appetite, not eating a whole bunch.

But I have other patients with depression who because of their depression, would prefer to sleep 22-1/2 hours a day. And when they're not asleep, they're eating everything they can lay their hands on. And so even though the diagnosis is the same, it expresses it differently. And so, sometimes that helps us choose which medicines to use based on the symptoms of illness that they have. And so, that goes back towards the first half of why does this antidepressant work for this person and not for the other, is sometimes that variance of expression changes what antidepressant we would use.

The other piece is everybody is biologically, genetically, psychologically, and socially unique. And I have difficulty being able to predict because our science has not gotten that far. I have difficulty predicting which medication directly off the first time I see you is most likely to work for you. But the interesting thing is, just like illnesses tend to run in family, for instance, in our last podcast, we talked about arthritis in your family. Also, mental illnesses tend to run in families, and response to medicine tends to run in families. So if you have a mother, a father, an aunt, uncle, cousin who has the same illness as you, who improved with a specific medicine, as the prescribing doctor, I'm more likely to start there because if the illness is the same, that means that maybe you all share the genetics for that illness, and you all may share the genetics for the response to medicine. And so, that's how that decision sometimes gets made.

Host: For sure. Doctor, let's go through the process, you know, working with a doctor like yourself to determine whether an antidepressant is appropriate for us. And as you're saying, like, oftentimes you're sort of trying to predict, "Well, I think maybe this one will work." But as we go through this process and try to find the right medication and dosage and all of that, take us through that process.

Dr. Benjamin Griffeth: Yeah. So, we kind of opened the door to that with the previous question. So, I'm often going to marry my medication with the symptoms that the patient presents. So, some of my antidepressants tend to create energy, kind of drive people to feel a little better, sleep a little less, maybe even suppress appetite a little bit. And so if I have a patient who's sleeping 23-1/2 hours a day and eating everything in sight, I'm going to choose that medicine for them because the effects of my medicine directly look at the effects of their illness.

But that illness, if I gave that to the person who's already having challenges eating, already having challenges with not sleeping, if I energize them and decrease their appetite, I'm actually going to make them worse or transiently worse, not better. And so, that's the first thing I'm doing, is I'm doing a good thorough history, trying to understand not only, "Hey, check the boxes, tell me which symptoms you have," but also how do these symptoms impact you? How does your life work right now? And figuring out which medications, because of their effect, best fit the symptoms of the illness that you have just like I don't have the ability to unravel your genetic code and figure out exactly which medicine may be right for you, that's the same issue with dosage. Some people need lower doses, some people need higher doses.

As a conservative physician, which almost all physicians are, we want the least amount of medicine that's going to make the impact that we want. And so, we always start at the lowest doses and give you the opportunity to see is the low dose going to work? ause no reason for you to be taking more medicine than your body needs to improve. And so we start at the low doses and recognize that a large number of people will respond to low doses, but some people may need more. And so, when we see you in follow-up, that's what we're checking. How has the medicine made a change? How much change have we seen? Do we need more change from the medicine, or do we perceive that we're on the right trajectory, right? If, you know, I see you and I start a medicine. And two weeks later, three weeks later, I see you back for follow-up and you're 50% improved, well, I don't need to do anything because by the four to six weeks, which is where we are going to see the maximum effect of that antidepressant, well, if you went and half the time you're half better, by the time we get to full time, you should be fully better. And so, I don't have to. But if you come back at that three-week, four-week appointment and you're only 20% improved, aha, we need to change the dose towards trying to get you to remission, getting you to the place where you're not having symptoms

Host: Right. Yeah, I'm sure, a part of this anyway, this is just an inference of course, but I'm sure that sort of talking to patients and getting a sense of any side effects is beneficial as well as a part of this. So, like, maybe what are some of the most common side effects, the risks of antidepressants, maybe concerns about serotonin syndrome and so on?

Dr. Benjamin Griffeth: Yeah. So, there are a wide variety of side effects potential to antidepressants, and they vary class to class. But in general, almost all antidepressants, there are one or two that this doesn't apply to, but nearly all work on the serotonin molecule, the serotonin neurotransmitter that we discussed at the very beginning—serotonin and when we start to modify how much serotonin is in your system. Recognize serotonin doesn't just exist in the brain. It also exists in the nerve cells of your stomach, for instance. And so, it's well known that starting an antidepressant, about 20% to 25% of patients when they first start out may have some GI upset. One of my patients described it probably the best I have ever heard. It's not like nausea and vomiting, but he described it, it's like if you drank a couple of cups of coffee too fast, that kind of just jittery butterfly feeling, because serotonin's impacting the nerve cells in your stomach. And so, that's where that comes from. And sometimes some people, that GI upset will even follow farther down the gut, leading to maybe some mild diarrhea within the first couple of days of starting the medicine.

But in general, reasonably well-tolerated. It happens to a minority of patients who start the medicine, and it's time-limited. It goes away within two or three days. Likewise, headache tends to be very, very common with starting any medicine having to do with serotonin. That mechanism is much less understood as to where the headache is coming from. The good news is, is for a vast majority of patients, Tylenol, Motrin, whatever they would normally take if they had a headache anyway, tends to work for this headache. And again, it's time-limited, tends to go away.

Less common side effects, but one that I talk about very, very frequently is sexual side effects. The SSRIs are known to cause sexual side effects. Now, the good news is, it happens in only about 10% of patients, so a vast majority of patients don't have the challenge. But for those that have this side effect, what it leads to is delay in orgasm or no orgasm at all, for males and for females. And unfortunately, sex is important to pretty much all adults. And so, I usually tell most of my patients about that side effect so they're aware. They know that, "Hey, the problem in your sex life is coming from something that I did, and it's something that I can correct if you're one of that unfortunate minority that have that side effect." And that sexual side effect, for whatever reason, tends to stick, as opposed to the headache, the upset stomach that tend to go away in a couple, three days. That sexual side effect tends to hang out as long as you're on that medicine. But I can solve that by switching to other medicines.

And again, one of the things we haven't talked about, because this one is focused on antidepressants specifically, but sometimes you then also can have the discussion about, do we need medication, or can we start talking about psychotherapy, or other treatment processes other than medication that may be just as effective for the treatment of your illness?

You asked about serotonin syndrome. Serotonin syndrome is a very rare event. So, let's go back to that bathtub metaphor that we used at the very beginning. So, I've taken my SSRI, and I've stuck it into the plug. And so, now my bathtub is not draining. Well, as anybody who has had kids or been a kid knows, if you plug the plug and you turn the faucet on, eventually you may overflow the tub.

Host: Of course.

Dr. Benjamin Griffeth: My description for what serotonin syndrome is. Serotonin syndrome is very, very rare by just plugging up the tub. It usually has to have a combination of plugging the tub and turning the faucet on. And so, sometimes that is plugging the tub and your diet accidentally happens to be exceptionally rich in the amino acids that you take in that create serotonin. I have never seen that happen in 25 years of practice of psychiatry, but it does exist. There are certainly journal articles and paper reports of those very, very rare instances. It's substantially more likely when I've taken a medicine like an SSRI and I have plugged the tub, and then not knowingly, I've taken another medicine that opens the spigot, that increases serotonin expression.

A good example of this is, and one of the things that we tend to warn patients about, if you take medications for migraines. Migraine medicines, most of them work by increasing serotonin temporarily. And so, sometimes patients who are prone, who take an SSRI for their depression, and then they take their anti-migraine medicine, they put themselves at potential risk. And so, most of us who prescribe SSRIs ask, "Hey, do you take anything for migraines?" Most of the doctors who prescribe for migraines say, "Hey, are you taking an SSRI?" Because that combination has the potential to create serotonin syndrome. Serotonin syndrome is very uncomfortable. You have a bit of a fever, your heart rate goes up. You're going to feel sweaty and clammy, and you just feel kind of terrible, a lot like if you had the flu. It can get worse, where you actually need pretty aggressive medical care. So if you happen to be somebody taking an SSRI, and then you take something and you start feeling really, really cruddy, You need to call your doctor or need to consider going to urgent care or even the emergency room just to make sure that if you happen to be having serotonin syndrome, you can be monitored because it can be dangerous if it becomes severe.

That said, that's a fairly uncommon process to have serotonin syndrome to begin with, and also very, very uncommon if even if you have it, that it becomes severe enough that it requires monitoring, hospitalization, and so forth.

Host: Yeah. Our last podcast, Doctor, was the myth buster, the myth-busting podcast. But I have a myth for you here that, once you start an antidepressant, you're on it forever

Dr. Benjamin Griffeth: Not true. What you have to do is to have a good discussion with your prescribing doctor about expectations. So, let's talk about antidepressants and depression, because the rules change when you change the illness that you're treating. But let's take depression because it's the most common that we use antidepressants for.

If you were to come into my office and you were having depression for the first time and we choose to use medicine for your treatment. And so, I start the medicine, you get better. What I tell every patient is where the data is, is you need to, from the time that you feel well, we put a pin in the calendar and we go at least six months, preferably a year. Because anybody who comes off the antidepressant earlier than that have a fairly high likelihood of returning to depression. But if I get you well, I get you to remission, and I keep you at remission for six months, preferably a year, then we take you back off the medicine. And the good news is you have a 50/50 shot of never having depression again in your life, which is outstanding.

Host: Right?

Dr. Benjamin Griffeth: Now, let's assume that you're one of the unfortunate half that has it come back a second time. Well, when you have the second time, then we're going to say you need to be on the medicine. And once we get you to remission where you're having no symptoms, we need to put the pin in the calendar, and we need to go two years. Because the increased length of time improves the chance that you don't have recurrence. Now, the problem is with the second time, the chance that you never have depression again lowers. Only about a quarter of the people who have had two episodes of depression never have it again. That's the unfortunate number.

So if you've had it twice, there's a reasonable likelihood that you're going to have it again. And so when the patient comes to me with their third episode of depression, typically then I'm talking lifelong treatment because the side effects of the medicine are minimal, right? We talked about the transient headache. We talked about the transient stomach upset. We talked about the low chance of sexual side effects from these medicines. And if you look at that very, very mild risk versus being depressed, not able to concentrate, no energy, poor appetite, low concentration, and depression's impact on physical function, psychological function within their heads, social function within their lives, impact on work, impact on families, that impact is so much bigger than that very, very low risk of challenge from the antidepressant. And so, typically, after the third episode of depression, we start talking about lifelong treatment.

Host: Yeah. Yeah, this has been really interesting. It's been great to have you on both times. Hopefully, we'll talk again in the future. Let's just finish up today, Doctor. We're having this conversation with someone like yourself about antidepressants and which one is right for us. What types of maybe foods, drinks? You mentioned with serotonin syndrome, the migraine pill's interaction with antidepressants. But just generally, what would we need to know about our sort of behavior, lifestyle, eating, drinking habits that we would have to avoid?

Dr. Benjamin Griffeth: Outstanding. So, that can be very, very specific to the medicine or class of medicine. So, the first answer to that is when you're starting any medicine, whether it's an antidepressant, whether it's a diabetes medicine, whether it's a cholesterol medicine, which I happen to be on, having that discussion with your doctor about, "Okay, what should I be doing about food, drink, other medicines?" should be an automatic conversation that you and your doctor have with any medicine, period.

Now, getting very, very broad with antidepressants as a group, I will tell you that there's no real impact from food and the medication. What I can tell you, though, if you look at depression, anxiety, bipolar illness, other post-traumatic stress disorder, those places where we use antidepressants, food's impact on the illness is significant.

And so, there, talking with your doctor about, "Hey, plant-forward, whole foods-based, making sure that you have a well-balanced diet that has lots of dark leafy green vegetables, fresh fruits, those kinds of things all make a significant positive impact on the illness irrespective of what medication you may be taking." So, no food impacts antidepressants, and all foods have the ability to improve the illness independent of the medication.

Now, I'll put a minor caveat in the food because there is a one group of antidepressants, I'm not going to go into any specifics, but they do have specific food problems. But any physician who's going to be prescribing those is going to go at great lengths over many, many days to make sure you understand the diet that has to be adhered to for those medicines. And those are very rarely used medications, and so probably don't need to be discussed for the general public who's going to be listening to this podcast.

Host: Right. Right. We're covering broad strokes here, for sure.

Dr. Benjamin Griffeth: Very broad strokes. When we talk about drinks, the only thing that you have to be aware of is alcohol. And alcohol with antidepressants, it's not because alcohol impacts the antidepressant, it's that the alcohol impacts the illness. So, taking depression, alcohol, if it's consumed more than one or two drinks a week, alcohol acts as a depressant. It makes depression worse. And unfortunately, alcohol's a more powerful depressant than any of my antidepressants. And so for most of my patients who have depression, even people who don't have, an alcohol use issue, but they just have moderate drinking, "I have, you know, a glass of red wine every night with dinner for my heart disease or for my cholesterol," which there are a number of people who do. So, you can take alcohol without having an alcohol use issue, I'm still going to recommend limiting your alcohol to only one or two drinks a week because the depressant effect of alcohol is going to overpower the antidepressant.

Host: Right. Yeah, almost sort of defeat the purpose, right?

Dr. Benjamin Griffeth: Exactly right. Yeah. So, it's not that there's an interaction, it's just that, "Hey, doing one with the other doesn't make any sense."

Medications that you should avoid, they're really very, very few. Though I brought up migraine medicines and SSRIs, that's a really uncommon situation to see serotonin syndrome as an interaction. So for those who are listening who happen to be taking an SSRI and happen to have migraines, yeah, have a discussion with your doctor about, "Hey, what should I watch? What should I be aware of?" But that's a very rare thing. Some of our antidepressants do affect blood pressure. And so, I tend to tell folks, "If you have blood pressure problems or you are taking one of the ones that affect blood pressure," they happen to be that serotonin-norepinephrine reuptake inhibitor group, then, hey, when you go to get your over-the-counter cold remedies, you need to be looking for the ones that have the blood pressure indication. Because the SNRI with a traditional cold remedy, your blood pressure may increase a little. And we're not talking, you know, through-the-roof increase, but it can be somewhat of an increase. And any increase in your blood pressure over time is not good for you

Host: Right. Yeah, absolutely. Well, listen, it's been great to have you on, great to have your time, your expertise. You're so compassionate and knowledgeable and full of, you know, metaphors and analogies. I just loved it all. Thank you so much.

Dr. Benjamin Griffeth: My pleasure, Scott

Host: For more information and other podcasts just like this one, head on over to prismahealth.org/podcast. This has been Flourish, a podcast brought to you by Prisma Health. I'm Scott Webb. Stay well.