Dr. Grammer: So a couple things, antidepressants aren’t happy pills. Alright, so if you take someone who’s not depressed, you put them on an antidepressant, it doesn’t do much except give them potentially side effects. So it’s not like we can all make ourselves just euphoric all the time from being on an antidepressant. I see a lot people say, I don’t want to be I don’t want change who I am. Well, your depression is what’s changing who you are. This is just restoring you to it.

[Life to Live by Grace Mesa (Instrumental Version) begins]

Beyond Depressed is a mental health podcast for people who want to know the science behind emerging treatments and if those treatments are right for them or a loved one. New therapies using psilocybin, magnetic stimulation, ketamine and medical marijuana are bringing people much needed relief. Together, we’ll take a deep dive into depression and how therapy, medications and drugs can help you feel better.

Beyond Depressed is hosted by Dr Geoffrey Grammer. Dr. Grammer is a decorated retired Colonel with the United States Army and is currently serving as the Chief Medical Officer for Greenbrook TMS. He has experience in psychiatry, internal medicine, and behavior neurology.

Disclaimer: The following podcast is for information and educational purposes only and should not be considered official medical advice.

[Life to Live by Grace Mesa (Instrumental Version) ends]

Joe Clements 

Hey everyone, Joe here back for another episode of the Beyond Depressed podcast. Of course, I am joined by the primary reason for this podcast, the mental health expert himself Dr. Geoffrey Grammer, here in the studio with me.

Dr. Grammer 

Hi, and you’re too kind, but thank you.

Joe Clements 

Couldn’t be kind enough, given the expertise that you shared in the prior episodes, and this episode I think is going to be maybe one of the most important in the series because so many people are on antidepressants, or know somebody who’s on antidepressants, but no one has idea… any idea how they work. Like, what do you think is the key question when it comes to antidepressants?

Dr. Grammer 

Yeah, this is a really important episode, because for a lot of people, their first entry into behavioral health care can be when they’re prescribed antidepressants. 80% of antidepressants are actually prescribed in the primary care environment to your internist or family physician or pediatrician. Only about 20% actually are prescribed by mental health specialists. So the question I think that people should be asking in this is, how do I know that the right antidepressant was prescribed for my unique clinical condition?

Joe Clements 

Okay, so the issue there that you just said is most of them are prescribed by a family practitioner who maybe has one or two things that he or she just goes to repeatedly. But that is not how antidepressants should be sub.. subscribed… I almost said subscribed. Maybe your antidepressants do come as a subscription for your…

Dr. Grammer 

App-based mobile things, yeah.

Joe Clements 

Prescribe medication. And so what is the first question or what is the first thing you look at when it comes to choosing an antidepressant for a certain patient?

Dr. Grammer 

Yeah, I think it’s matching the symptom complex and matching the diagnoses with the mechanism of action and the FDA approved indications of that specific drug. So Joe, I’m curious, what do you think is the most unanswered question regarding antidepressants out there amongst people?

Joe Clements 

So, I have a little edge on that question, because we’ve been talking pre-show. And I think it’s this, it seems like to me, most antidepressants are prescribed by the family doctor, and the family doctor maybe has one or two, go-to antidepressants at a go-to dosage. And that’s just what they’re going to try everybody on first. What I think is interesting from talking to you, is there’s such a diversity in the types of depression, there’s a diversity in the types of antidepressants, side effects, you know, could be modestly effective for somebody could be very effective for somebody. So the big question for me is, how does anyone select out of this pharmacopoeia, the right antidepressant for the right type of depression?

Dr. Grammer 

Yeah, that’s a great question. And it can seem like it’s a bit random, and, and candidly, it probably shouldn’t be. And just to put this in perspective, so if you go see your internal medicine doctor or your family practitioner, that person does four years of med school, and then three years of residency, where they learn about adult medicine, you know, hypertension, cardiac disease, and in there, they get a little bit of psychiatry. Psychiatry, you do four years of med school, and you do four years of residency, where all you do is therapy, medications and understanding psychiatric illness. So there can be a lot of sophistication to how you select one medication over another, how you combine medications. And and while a lot of people may go see their primary care and get put on a med and do great, for in whom those that doesn’t work, it’s time to go see the specialist who went to school for a long time to learn just that one thing. So question is how does someone pick, and I think there are several ways. One could be in primary care, someone may be familiar with an antidepressant and they get the dose down, they know the side effects, they know what to look out for. And so one of the most commonly prescribed antidepressants out there is something called escitalopram or Lexapro would be the old trade name of that. And so you go see your primary care, they’re like, take 10 milligrams for a couple weeks and go to 20 milligrams, and let’s follow up and see how you do, and and that actually may work for, you know, roughly about half of people. But what do you do when that doesn’t work, right? And is that necessarily the right one for you, if you’re not lucky enough to…

Joe Clements 

Why is that two week rule… I’ve heard that a lot, like I have to take it for two weeks. Why is that such a common thing with antidepressants versus you know, other medications you just like, take two and you’re better in the morning?

Dr. Grammer 

Well, a couple of things going on and coming off of antidepressants, your body has to adapt to it. Okay, and it’s not necessarily dependency. I think a lot of people say I don’t want to get dependent on these. They don’t work that way. Okay. It’s more getting your body used to it so that issues of nausea, dizziness, headache, and some of these things can come have time to subside at a lower dose until you can get to a therapeutic dose. The other thing, particularly for those under the age of 25, occasionally antidepressants can be associated with increases in suicidal thoughts and behaviors. And usually that starts to manifest around the two week time frame. Some people hypothesize that we’re activating people into their suicidality. I don’t think that’s the entire, you know, answer to that. But we want to check in at two weeks to see Hey, how are you doing overall? And are you tolerating the medication, and then we can go up. So some people have their familiar, like, I know this med, I’m going to prescribe this because I’m familiar with it. I think another way to prescribe is the FDA indications, right? So let’s say for example, you had generalized anxiety disorder and depression. So generalized anxiety disorder is kind of the classic worrywart, if you will. Someone who’s worried with everyday events, they fatigue because of that, they often have trouble sleeping because of that, they feel on edge, and they can be irritable, you have to have like three of those, okay? And up to 60% of people with generalized anxiety disorder will develop comorbid depression, because when you’re anxious, it takes away your ability to be in the moment, right? And so your ability to enjoy life around you is constantly going to be interfered with this idea of worrying about the next threat. So you’re not going to do the person a whole lot of favors if you can’t control the anxiety with the depression. And in that case, actually, Lexapro or escitalopram might be a good choice, because it’s been shown to be effective for both those conditions. Is that common with antidepressants? Because one of the things I’ve learned recently is several of them work for anti-anxiety and as an antidepressant. Exactly. There are several that work for both, there are some that don’t. And that’s what gets really important, right, is picking the right antidepressant depending on what the patient has. So another example would be is if you had say post traumatic stress, there are two medications that are currently FDA cleared for post traumatic stress disorder. One of those would be Sertraline, which is Zoloft, the other one’s Paroxetine, Paxil. So if you had someone come in with depression and PTSD, you may say, hey, let’s try one of these two agents, because it works for both. Now the problem with that is, a lot of times there are studies that show benefits for certain drugs, but they don’t go through the rigors of FDA approval, particularly if the drug is generic, because you have no sponsor, essentially, for the study. So that does kind of run short a bit. Now, another way of doing it is you look at the mechanism of action. And in this, what you’re looking at is what does the drug do? Okay, so some drugs, for example, will increase serotonin by inhibiting it being recycled back into the cell, so it sits in that space between two nerves a little bit longer. Okay. Some drugs interfere with the reuptake of norepinephrine with maybe a little bit of serotonin or a lot of serotonin, depending on the drug.

Joe Clements 

So tell me what is the role of serotonin?

Dr. Grammer 

Right? So I’ll get to that in a second. Because you know, so we got serotonin and you have a little bit of norepinephrine, and then some drugs actually interfere with dopamine. Okay. And so earlier in a previous episode, we talked a little bit about these monoamine, serotonin, norepinephrine and dopamine.

Joe Clements 

And what what does that mean again, monoamine?

Dr. Grammer 

Monoamine is basically these, this class of neurotransmitters that essentially are of interest in psychiatry. These big three. There are a bunch of neurotransmitters, but these are the three that kind of have consumed the medication, psychiatric medication world.

Joe Clements 

So a neurotransmitter is just a, like a chemical that sits between the endings of your neurons in your brain or that’s what a neurotransmitter is?

Dr. Grammer 

Yeah, so a neurotransmitter transmits between nerves a signal. So when a nerve fires, it fires at a certain chemical amplitude and frequency. And that then dictates how much of that neurotransmitter is let out from that nerve to tell the next nerve, what to do.

Joe Clements 

Okay.

Dr. Grammer 

Okay, so and then, you know, there are different nerves that do different neurotransmitters, and then that sort of results in changing of brain function. Okay, so a good example is cocaine will inhibit the reuptake of norepinephrine and dopamine. And those are sort of adrenaline like compounds. And so cocaine makes people activated and energetic and hyper and so forth. So if we get back to like, sero… So when you say inhibits the reuptake, it leaves more in the brain for a longer amount of time. Bingo. Exactly, exactly. So let’s take serotonin. Serotonin is associated with kind of a ruminative neurotic kind of depression, where people will… like think of Woody Allen, I might date myself here, actually I’m very much dating myself, but you know, hand wringing, like, Oh, what am I going to do? Is this going to work out? I can’t… I’m not happy. I just feel very dissatisfied. I’m on edge. We think of norepinephrine as sort of the energy wakefulness concentration kind of neurotransmitter and everything associated with kind of adrenaline, like you get from, I don’t know… When you get energized for a football game or something, right? You’re gonna go out there and be like, Oh, we’re gonna go do this! And so people who have lower levels of activation within that norepinephrine network are going to, you know, sleep more have difficulty concentrating, and feel tired all the time. Dopamine is what allows for that kind of novelty and reward seeking behavior. So dopamine is what allows us to be like, Oh, this was really fun. I want to go do this again, right? This is cool. And so people with low dopamine often just don’t enjoy anything, right? And so they they’re, they slow down because dopamine is part of motor activity and just kind of sit there.

Joe Clements 

So you’re not getting the rewards out of life. So there’s no reward structure built in to help you modify your behavior towards things that are in theory, good for you.

Dr. Grammer 

Yeah, so I think of like a low norepinephrine state is like Jabba the Hutt. And I think of a low dopamine state as like Eeyore from Winnie the Pooh.

Joe Clements 

And what’s a low serotonin state?

Dr. Grammer 

Woody Allen or George Constanza.

Joe Clements 

Okay.

Dr. Grammer 

So and so, you know, what you can do is look at the person’s symptom complex. If someone comes in and they’re like, I can’t have fun, I’m tired, I’m stuck on the couch. I don’t enjoy anything. And I’m sleeping 12 hours a day, right? They probably need some degree of dopamine and potentially norepinephrine increases, and one drug that can do that is something called Wellbutrin or Bupropion. And so you would choose that drug for that indication, okay. Or if someone came in and they’re like, oh, you know, I’m tired, but I’m nervous all the time. And no, I can’t settle down. But even though I’m tired, I go to sleep at night and I have trouble falling asleep, but when I do fall asleep, I’m sleep for 12 hours or whatever. That person may benefit from something called an SNRI serotonin and norepinephrine reuptake inhibitor. Whereas if someone comes in like, Hey, I’m just purely anxious, I maybe have some OCD or panic disorder, and depression, like SSRIs have been shown to be effective for those kinds of things. So you’d might put them on Prozac, Paxil, Zoloft, Lexapro, Celexa.

Joe Clements 

So, what is the difference between those everyday anxiety medications? And things like say, Xanax?

Dr. Grammer 

That’s a great question. So, Xanax, or is essentially alprazolam is the generic name for that and there are others out there Lorazepam for Ativan, or clonazepam or Klonopin, and probably the most commonly diazepam for volume. Those are benzodiazepines. Right, and those are basically sedatives. They will decrease overall cerebral function. And there’s some theories that anxiety is associated with an over activation of sort of an excitatory neurotransmitter called glutamate. And the balance to that is GABA. So GABA and glutamate, think of like the yin and yang. You need to be in perfect balance. So if you have an over activation of glutamate, you give them a benzo to increase the GABA activity. And, and then that brings the anxiety down. Problem with those is they’re short term. So Xanax actually is not a particularly great drug for long term anxiety. Xanax is not necessarily the best medicine for long term anxiety because it’s got a very short half life, right? So let’s say you have generalized anxiety disorder and you take a Xanax in the morning, three to four hours later, you need another Xanax, and three to four hours after that you got to take another Xanax. And then you start to develop tolerance to the Xanax. And so you might need a little bit more to feel that same level of anxiety relief. Now, we could talk about tolerance, it’s a little more complicated in that but if you can get away with an everyday medication, you can prevent the anxiety from ever being an issue. In addition, there are some anxiety states, like panic disorder, where benzodiazepines have not been shown to be very effective at preventing the attack. It does decrease the anxiety between attacks, but SSRIs like Paxil, Prozac, Zoloft, are actually extremely effective at preventing panic attacks from ever occurring. So like a good example of a more sophisticated medication solution is if you came in with new onset panic disorder and depression. I may put you on sertraline, or Zoloft, and Klonopin to take for a couple of weeks until the Zoloft starts kicking in. That way I’m giving you some immediate relief. So you’re like, oh, wow, this is actually helping me feel better. And then when the Zoloft starts kicking in, we can pull the Klonopin away. If you think about it, a lot of times when people start an antidepressant, one of the hardest things is it takes several weeks to work. Okay, and we can talk about why that is, but it takes several weeks to kick in. So when you start, you get all the side effects of the drug, and none of the benefit. What a disincentive for staying on the med, right? So you really got to get some buy in from someone that’s like, hang in there for a bit because it will, you know, for a lot of people it will start working but you got to keep taking it every day for, we say four to six weeks, the reality is probably more like six to eight, before you start seeing that kind of maximal effect.

Joe Clements 

So it’s just taking time for enough of that compound to build up in your system for your body to start to account for that it’s there, or what’s going on over that six to eight week period.

Dr. Grammer 

Yeah, great question, because we talked earlier in a previous episode about this kind of, you know, hypothesis that depression is associated with a low serotonin. But it’s more complicated than that, because when we see what happens is when we inhibit the recycling of serotonin, it sits in that space between two nerves longer. The receiving nerve will actually down regulate, decrease the number of receptors that serotonin binds to, okay. And that happens at a genetic level, where the cell itself says, oh, there’s too much serotonin out there, I need to decrease the receptors it binds to to compensate. And it’s when those receptors decrease that we start to see the antidepressant effect. It’s not actually the serotonin binding to the receptor itself, it’s your body’s reaction to it. That leads to the antidepressant effect.

Joe Clements 

So it’s… So what’s going on? That’s interesting. So what’s going on is now your body has this abundance of serotonin, or at least more than it did before. And so your nerves start to say, hey, there’s too much serotonin around here, let’s change how much we’re letting in. And then it’s that change of how much is going back and forth through the nerves that actually creates the response that you experience as an antidepressant effect or an anti-anxiety effect?

Dr. Grammer 

Yeah, exactly. And, and that’s important, because not only does that mean, you have to kind of adapt to it, and have time on it. But if you stop the medicine suddenly, particularly if it has a short half life, okay, meaning it gets cleared from the body quickly, then your body’s used to seeing all that extra serotonin and suddenly you have a serotonin deficit, because your receptors are down regulated, right. And so now you, you go off the med, the med washes out, and you don’t have as much serotonin in the… And then people feel sick. So a lot of people make this, I think, incorrect assumption that… because they use the word, I don’t want to become dependent upon something as if it’s like a happy pill and they’re afraid of getting addicted to it. I’m not aware, nor I’ve ever seen a patient who got arrested for dealing Prozac on the street, right? It’s not a drug of psychological dependence, per se, what they’re experiencing is a withdrawal from that physiologic adaptation to the medicine. And when you suddenly peel it away with no taper down or anything else like that it can make people sick. That doesn’t mean you’re dependent on it in the kind of classic sense of drug addiction. It does mean your body got used to it.

Joe Clements 

So does that withdraw potential get higher the longer somebody is on it? Is it you know, once you’re adjusted to it, you’re adjusted to it and withdrawal potential is the same? How does that work?

Dr. Grammer 

So there are some people that are probably just innately more sensitive to withdrawal. The higher the dose, the longer you’re on it, and the shorter the half life of the med, the more likely you are to have withdrawal. There are some drugs that are notorious for bad withdrawal syndromes. Paroxetine, which is Paxil is one. Venlafaxine, which is Effexor is another. Duloxetine, which is Cymbalta is another. And so all of those have a relatively short half life. Now that being said, most people can have side effects coming off of a medication or effects from coming off a medication, regardless of its half life.

Joe Clements 

Is there from a clinical perspective, is the optimal use of an antidepressant used as long as say you need it. So say you get on the antidepressant, you do the talk therapy, you do whatever other therapy your going through to try and change the thought patterns, the behaviors, wait out the situation that’s causing the depression? Or is the idea of clinical use that there is a permanent chemical imbalance in your mind or your brain or whatever’s happening and so it’s just once you start them, you should just be on them indefinitely as long as they work?

Dr. Grammer 

It’s it’s a good question. And there were studies that constantly marched for the length of time you should be on an antidepressant after you’ve recovered. So let’s say you come in 25 years old, and it’s your first episode of depression. I’m like, here’s your antidepressant take this, and you come back six weeks later, and you’re like I’m cured, I feel all better. Well, we know that if you stopped the medication within the first year after recovery, your risk of having the depression comes back is substantially higher. It takes about a full year for the brain to heal from a depressive episode. Okay, so even though it’s like getting a cast off a broken arm, the cast may be off, but the arms still weak, you’re not going to go out and start doing all the stuff you did before, you have to give it time to heal, the brain’s the same way. So then every time you get depressed, it increases the risk that you’ll have another depressive episode at some point in your life. So one episode, 60%, two, 80%, three episodes of depression, you got like a 90 to 95% chance of having a fourth, okay. And particularly if you have even say one episode of depression, but it was so bad that you became catatonic or actively suicidal and tried to take your life. The risk benefit ratio may say like we don’t ever want to risk that happening again, we know that if you stay on a med, it’s going to decrease your risk long term. Let’s just keep you on this. Okay, you can make that argument too. One of the use cases I’ve seen be relatively common among friends is stressful period negative life event, they become depressed or anxious. Their doctor prescribes them an antidepressant, they weren’t depressed before they get on the antidepressant. What about somebody in that scenario? Should they be on for a year, or just until that like period, like you know, they’re changing jobs or there’s a breakup or there’s a death in the family? Yeah, it’s a good question, and so what you’re talking about is something called an adjustment disorder, which is a little bit different than a major depressive episode. Okay? Now, if they meet full criteria for depression, you treat it like depression, regardless of what’s going on. But let’s say someone comes in and they’re doing relatively okay, you go through the kind of criteria of depression, they don’t quite meet it, but they’re upset, they’re not sleeping well, and so forth. There is some literature that suggests giving an antidepressant can help ameliorate the symptoms and just make the time more comfortable. And withdrawing that when the situation resolves might be reasonable. What I typically will do in that circumstance is a little bit different, I will usually treat much more the somatic symptoms, so if someone has trouble with appetite and sleep, I might choose a medicine that’s effective for appetite and sleep, for an example. So most people will try to help people work through an adjustment disorder without antidepressants. But if they don’t have access to therapy, if the symptoms look like they’re heading in the wrong direction, I’m not going to say it’s absolutely wrong to give them an antidepressant to kind of help them through that timeframe, and then peel it back when it resolves. But I think that that gets a little tricky, because what may end up happening is, you know, if they have like an allergic reaction to the drug or something else, you know, then you’re gonna go back and say, Well, did I really need it? So you got to use it with a bit of caution.

Joe Clements 

And so this would lead to probably, I think one of the third things that’s common with antidepressants is medication failures, which is not all antidepressant treatments work for everyone all of the time. And so why is that? Why do people have such variant responses to different sorts of medications? And then from a physician’s perspective, or from a clinical perspective? How do you work through? Well, if this one didn’t work, then let’s try this other one.

Dr. Grammer 

Yeah. So the one thing that we didn’t talk about is another way of selecting antidepressants can actually be based upon someone’s genetics, okay, which is actually super cool, but also somewhat controversial. So we know there are some genetic variations that are associated with a less likelihood of responding to an antidepressant. I’m going to throw out a bunch of letters and numbers, they’re not as important except for those that are probably already familiar with them, but there’s a genetic variation of something called SLC6A4, which is what encodes for the serotonin reuptake receptor, and some people that have say a short short promoter region or SS promoter region on that are going to be less likely to respond to the class of meds called SSRIs, which is Paxil, Prozac, Zoloft, Lexapro and Celexin. And Fluvoxamine’s in their, Luvox. But we only use that for depression. So, you know, I see a lot of people come in, and they’re like, Well, my doctor put me on Prozac, it didn’t work. Zoloft, it didn’t work. Paxil, it didn’t work. I’m like, well, your short short promoter, region SLC6A4, you’re gonna have a higher likelihood of side effects and less likely to respond, that’s probably why, and they’re like, Oh, I just thought it was my fault. No, it may be your genetics. Likewise, there’s another enzyme called MTHFR, which is, stands for methyl tetrahydrofolic acid reductase. I had to practice that in the mirror like 50 times to be able to say that, but that enzyme converts folic acid to a compound called L-methylfolate, which then binds to the enzymes that make serotonin, norepinephrine and dopamine to turn them on. And if you don’t have that enzyme working correctly, you never make enough nerve neurotransmitter for the antidepressants to work on in the first place. So the answer is to give them what that enzyme’s supposed to make, which is L-methylfolate, which is like that, like no side effects, is essentially a water soluble vitamin metabolite. And your likelihood of responding increases several fold if you fix that deficit in those people with that genetic variation. So some people don’t respond because they didn’t get that fixed.

Joe Clements 

So that’s interesting. Is there the potential in the future for an mRNA therapy that basically structures cells to produce exactly those compounds for you. So your, you know, sort of like the COVID vaccine works, except instead of producing a spike protein, you’re producing an enzyme your body needs?

Dr. Grammer 

That would be cool. I don’t think we’re there yet. So you know, this idea of being able to insert genetic code to fix different medical conditions certainly is a very exciting part of medicine. I think in psychiatry, one of the challenges is, most disease states are heterogeneous, meaning it’s probably no one single thing that a silver bullet can fix. And so even if you try to fix that one thing, it doesn’t necessarily fix the constellation of events that led to that depressive episode. So it’s a little bit more complicated, but definitely very, very cool. So why don’t people respond? Well, again, it can be your genetics, you can also choose meds based on genetics. But even with all of that, you know, we still don’t entirely know everything about depression. In fact, there’s a whole lot we don’t know, okay, just the science isn’t quite there yet. What we do know is, no matter how many antidepressant trials you have, you have a 30% chance of never responding. Right? And every time you don’t respond to a trial, your likelihood of response goes down substantially. So by the time you’ve been on four meds, the chance the fifth will work is 5%. Like think about that. So I see people that come in that have been on 13, 14 meds, you’re down to single digit likelihoods of responding to it ever. And at that point you need to think, is an antidepressant the solution set for me or do I need to look at other things? In addition, if you take 100 people and you put them on to antidepressants, and you take 100 people, you put them on one antidepressant, the outcomes are the same. More antidepressants are not better, okay, necessarily, and they may have more side effects. Now, there are absolutely people who can legitimately quibble with some of that data, but the reality is…

Joe Clements 

What would be common side effects? By the way, I don’t think we talked… we talked about withdrawal, but we didn’t talk about common side effects.

Dr. Grammer 

Yeah, so it depends on the class, worsening anxiety, feeling overly sleepy or not being able to sleep enough, stomach upset, particularly nausea and diarrhea are real common. Some of the agents that affect norepinephrine can also cause constipation, which can be problematic. Sexual Dysfunction is a real common one. And then finally…

Joe Clements 

Sexual dysfunction, inability to be sexually stimulated or being too sexually stimulated.

Dr. Grammer 

So in men, it’s usually a problem with either libido erectile function, or a difficulty achieving orgasm, or an abnormal orgasm something called retrograde ejaculation, which is a very painful kind of orgasm. In women, it’s usually difficulty achieving orgasm and decreased libido. So less satisfying sexual functioning. And the last one is weight gain. And what I’ll tell you is asking a patient to give up a healthy sex life or to gain weight in lieu of being depressed. I think it’s an unfair trade.

Joe Clements 

I mean, push back, what were the odds that if they were that depressed, they had a healthy sex life to begin with?

Dr. Grammer 

Well, that’s part of the argument, right? But when their mood improves, they’re not going to keep taking the med. I mean, whether you think it’s a fair trade or not, the bottom line is the compliance rates if someone develops sexual dysfunction drops substantially.

Joe Clements 

And same for weight because if they’re not depressed, and they’re going out of the house, they’re gonna want to lose weight, get back out again. And so if the drug is keeping them on, they stopped, okay, got it.

Dr. Grammer 

One of the common fears I hear concerned, I hear people voice about starting an antidepressant is that it will change their ability to feel things in their life, they won’t feel as happy, they won’t feel as sad, they won’t feel as whatever about things that they think they should have strong emotions about. Yeah, I used to do internal medicine, and I would tell you, people would rather have a heart attack, or rather give up a chemotherapy agent than have to gain weight or have sexual dysfunction at times. I mean, it’s just those are things that it’s I think it’s unfair to ask people to tolerate, and the thing is, we have meds that are less likely to cause those side effects. So that’s another selection choice. So if someone gains 40 pounds on Lexapro .Well, Wellbutrin is actually associated with a modest amount of weight loss, for example. So a couple things, antidepressants aren’t happy pills. Alright, so if you take someone who’s not depressed, you put them on an antidepressant, it doesn’t do much except give them potentially side effects. So it’s not like we can all make ourselves just euphoric all the time from being on an antidepressant. I see a lot people say, I don’t want to be I don’t want change who I am. Well, your depression is what’s changing who you are. This is just restoring you to it. A good metaphor is think of it like taking Motrin for a bad knee. If you take Motrin and nothing hurts, it doesn’t do anything that maybe upset your stomach, but if you if your knee does hurt all the time, it keeps it from hurting all the time. However, if your knees hurt, and you take Motrin and you fall on your knee, it’s still going to hurt. Antidepressants are the same thing. If something bad happens in your life, you’re still going to feel sad. Now, there are some people that can have a sense of graying out almost like a zombie like effect from certain antidepressants, probably the SSRIs are most likely to cause this. Those are sort of the older of the new generation of drugs. Again, I’ll keep saying these over and over again, Paxil, Prozac and Zoloft being the most commonly prescribed. Lexapro and Celexa. And one theory as an example of what can happen is, serotonin may actually influence the amount of dopamine that goes to the pleasure center of the brain – the nucleus accumbens, is the area where that’s called. And so there’s people who will take an antidepressant and what it does is it blunts that pathway. So they may not feel depressed, but you’ve also taken away their ability to feel joy, right?

Joe Clements 

Could that lead to more risk taking behaviors or…

Dr. Grammer 

Actually quite the opposite because there’s no motivation to do anything just because you’re like, eh, why bother?

Joe Clements 

Yeah, not happy. Sit here, okay.

Dr. Grammer 

Exactly, You know, and so, you know, again, this is a good example of where, like, I think that’s an unfair trade off for someone to make. So there are different ways to contend with that. And you can either change the drug to a drug that’s less likely to cause that or you can augment with an evidence based augmentation strategy. And so one of the cool things that’s happened in the last 10 years, 10 to 15 years now, is you know, we have this new class of medications that we use, they’re older drugs, but they we use them for antidepressants, augmentation, now, called the atypical antipsychotics. Now, don’t get caught up on the name that’s just the class and the molecular structure and stuff like that, but it low dose, those agents can actually sometimes increase the dopamine transmission and that can help offset some of that apathetic syndrome that can happen from any depressants, in addition of all the things that we can do to take a single antidepressant and make it work better. Adding that class of medications has the most evidence with it. You know, within psychiatry, more of a drug is not necessarily better, and in a lot of cases is worse. There’s some drugs that have sort of a inverted U shaped efficacy curve where too low or too high is actually counter therapeutic, you have to get the dose just right. I can’t tell you how many people I see where they’re like I’m taking 120 of Prozac. After 40 milligrams, the number of people you capture is like 2%. I mean, it’s just not that much. So rather than just pushing the dose up to the point that the person is having tons of side effects from the med, you’re much better off augmenting with an evidence based strategy like using, and people have probably seen the commercial alot, commercials on like Aripiprazole, which is Abilify, or Brexpiprazole, which is Rexulti.

Joe Clements 

So one of the things I think culturally people look at is the increase in the prevalence of people taking antidepressant or anti-anxiety medication. Is the opinion in the medical community that there’s always been this level of psychiatric issues in society, we were just never able, we just didn’t call it that we didn’t recognize what it was, or is the opinion that something about the way we live is triggering an increase in psychiatric conditions, for which now there’s all these medications available to be created, but if something were different in the way we live, we’d have a much lower prevalence.

Dr. Grammer 

Yeah, I think that’s a complicated question with a complicated answer that we could spend forever talking about, but I’ll try to do it some justice. We’ll take ADHD – Attention Deficit Hyperactivity Disorder, Attention Deficit Disorder. And nowadays people will say, well, that’s over diagnosed, we’re over treating people. There’s probably truth to that, you know, and they’ll be like, well, no one ever had ADD, when I was a kid. They did. We just didn’t call it that. That was the class clown. That was the kid that kept getting sent to the principal’s office, that was the guy who never did well on his test, but we didn’t have a name for it, so we just let them fail, right? Now, if I take someone who doesn’t have ADD, and I give them a stimulant, yeah, they’re gonna do better on testing, like they will. It’s a performance enhancer, but there are side effects to those meds, there are risks associated with those meds. So we want to make sure we use them in the people who would benefit most from them, for example. And I think antidepressants and anxiety are the same thing. Like we all, you know, probably wish we could be happier. We all wish that we could be less anxious, you know, or many people do. And certainly that may lead to maybe in over diagnosis, and some people for whom they are part of a normal variant. And certainly, in medicine, the ability to screen for something and treat it, unfortunately, does get dictated by what treatments are available, we get much more motivated when there’s something we can do. And we’re like, Aha, your cholesterol is high and have all these cholesterol meds. Take this, right. So I think with antidepressants, same thing. Now that being said, I think both there’s sort of decade phenomenons occurring. And then the pandemic related phenomenons occurring that impact the prevalence rates, so we’re better at detecting them… detecting diseases than we used to be. We use validated rating scales, screening tools, and so forth. Primary Care is more educated about this. So I think we do a better job of identifying when people are depressed. But I also think that society can get more challenging. And while we’ve seen a higher prevalence, we don’t know if that’s because we’re better at detecting it, or because of the challenges associated with modern society are bringing that about. You know, I can make an argument that the over idealization of social media, for example, setting up our young adults and teenagers to look at their life with heightened scrutiny and not be able to measure up to that. On the other hand, austerity measures of World War II are nothing to you know, really have a whole lot of joy about when all – everyone was deployed overseas and things were rationed in the States. That was a tough time, too. So how much of that truly plays a factor right now? Well, I think it doesn’t help. So it definitely is worthy of conversation. But I don’t know that answers the entire equation. Now, the pandemic has been, obviously, pretty convincingly catastrophic, because what we’ve seen is our ability to detect the disease, and treat it hasn’t changed in the last two to three years dramatically. But we’ve seen an exponential increase in the rates of depression and anxiety in people in affected by the pandemic, which is just about everyone, right. And that can happen from ongoing fear of the environment cut off from social isolation, decreased ability to engage in those activities that used to bring us resiliency. I haven’t been to a movie theater in two years, and I love the movies, right, but it just, they haven’t been open where I’m at. And even now, whether it’s worth the risk or not, I think it’s something that me and my family have to continue to contend with. That affects my quality of life. So I think that’s a factor as well. I think if I had to guess I do think rates are increasing. But I think the reason that that is occurring is very complex.

Joe Clements 

So that that’s interesting you mentioned COVID, because that ties into this thinking about COVID, that one of its results was kind of fast forwarding society 10 years in terms of work from home, the way the economy works, people being more reliant on the internet and gig economy services. So that depression and anxiety increased when we were ramping up the amount of life that was lived online – would seem to suggest that the relationship between moving away from this lifestyle where we have more direct interaction with one another where maybe even we’re getting these accidental therapeutic interactions with other people and not knowing it is a problem and that we’re medicating into that world. Do you see… Do you see the future of… Let me rephrase that as a better question. Where do you see the future of antidepressant medication over the next 10 years?

Dr. Grammer 

Well, I think we’re gonna see alternatives to that, right. So I think antidepressant medication like therapy and other modalities that we’ll talk about in future episodes, are different tools. And for years and years in psychiatry, we had very few tools, we had therapy, we’ll call it a screwdriver. And, and meds we’ll call it a hammer. And if you didn’t have a screw, and you didn’t have a nail, that you’re dealing with, you’re out of luck.

Joe Clements 

Yeah.

Dr. Grammer 

So now we actually have a whole lot of things that we can do different than that, and begin to tailor these individual treatments based on the person’s preferences and the kind of disease they have, and so forth. So I think they’ll continue to be part of the solution, but we won’t be as reliant upon them as the only solution.

Joe Clements 

And so this is something I think probably most listeners are unfamiliar with, is once you’re beyond talk therapy and antidepressants, that there’s anything at all past that boundary.

Dr. Grammer 

Yeah, and I what I will often tell people when they come in after not doing well on meds and therapy is your like on exit two on like a five exit road, there are several things available to you that are evidence based, FDA cleared, or currently like just on the cusp of hopefully FDA approval, that can offer you relief. And again, we’ll get to that in future episodes. But medicine therapy is not all that there is out there, there are very well tolerated acceptable treatments like transcranial magnetic stimulation therapy like Spravato, which is nasal ketamine, or S ketamine that we’ll talk about.

Joe Clements 

Great. I know we’re about out of time, anything else before we close and any other important things you think that listeners should know? What should a listener do if they’re taking an antidepressant right now? But they’re not sure if it’s the best one for them? Maybe they’re experiencing some relief from it. They’re getting some side effects. What should they do?

Dr. Grammer 

Well, this is a good point. I mean, because before in psychiatry before we’d started doing these kind of rating scales as a matter of routine, we relied on a subjective report, and a lot of patients when being placed on meds would come in and say I’m doing better. And people thought, a lot of providers thought better meant cured. And what we found out when we started doing rating scales was better meant maybe going from severe to moderate severity. And that wasn’t enough, that’s not good enough, we really want to get people into full remission. Making your symptoms less, while important, isn’t the end state, the mission is remission, so to speak. And so if you’re on meds, and you either have side effects that you find unacceptable, or if you still have residual symptoms that you think aren’t being controlled, it is important to talk to your provider about other treatment options besides meds and therapy. Okay. In addition, what I would really caution people against is, if you bet on more than four meds, you need to have that conversation of alternative modalities now, because the likelihood the fifth, sixth, seventh eighth, is going to work, particularly work completely starts to become less and less likely. And there, there are other things available. The other thing I would say is, and I said it earlier, more is not better. I just I see so many people maxed out on meds. And that doesn’t always make the med work better, you want to be at a therapeutic target dose. And there are some ways that we can measure either serum levels, or we can base it on, again, your genetics to see how quickly metabolize the drug, and then basically predict what your target dose might be. The last thing I’ll say is, and this will be somewhat controversial, but if you have treatment resistant depression, meaning you have not responded to at least two antidepressant trials, there are genetic assays available out there, GeneSight and GeneMind are probably the two most commonly used, but there are others. And while I will readily admit the science on those is not ironclad, the science does offer additional variables to factor into the equation of what works for you. And as long as you look at that report, within the context of how much evidence is behind it, okay. It can be another valuable asset, selecting what treatment modalities and what medications might be best for you and your unique physiology. So with that, I think we’re out of time. I want to thank everyone for listening in today. And coming up, we’re going to be talking about things besides medications and therapy, and that will include things like ketamine, and transcranial magnetic stimulation therapy, as well as a lot of the new work going into psychedelics. So stay tuned for the next episode. Thank you.

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