[SSRIS] Selective Serotonin Reuptake Inhibitors - A Brief Discussion

>> This podcast provides general information, not a substitute for professional medical advice. Please consult your physician for personalized guidance. >> Hello, hello, and thank you for tuning into PsychRounds. My name is Dr. Tanner Hewitt, and I'm a first-year psychiatry resident. >> I'm Dr. Larry Wang, a second-year psychiatry resident. I'm really excited to be doing this. We're going to talk about a diversity of topics, psychopharm ecology, maybe some therapy, we'll do some board style practice questions, and yeah, we're going to have lots of fun. >> All right, so let's talk about some SSRIs. So with the history of modern anti-depressants, it kind of began with the monolaming hypothesis. And this began when they observed patients, you know, have to press depressive symptoms with resurping, which is a V-MAT2 inhibitor. >> Dr. Wang, just for the audience that's listening, can you remind us what a V-MAT2 inhibitor is? >> So V-MAT inhibitors are now used for Tarteif dyskinesia. So there's ingreza, osteto, those are the brand names. And they essentially block the presynaptic release of monolaming such as dopamine, norepinephrine, and serotonin. And, you know, continuing about the monolaming hypothesis, one of the first, I guess, modern anti-depressants developed was hibernize it. So this is a cousin of isonize it, which is a drug for tuberculosis. And they found in 1952 that it had anti-depressant properties and the patients they were using it on. And, you know, they did some more studies, and they found that this was actually an MAOI inhibitor, and they subsequently developed things like isocarboxazid, phenylzene, trinocypramine, and selegelene. >> So maybe Dr. Wang for some of the medical students that are listening. Can you just go over briefly what an MAOI is? >> Yeah, an MAOI, it inhibits the breakdown of things like dopamine, norepinephrine, serotonin, and tyramine. There's the, there's two enzymes, there's MAOA and MAOB. Most of the ones I mentioned act on both of them, but selegelene is selective for MAOB. So the side effects tend to be a little bit more tolerable, and that's why it's used more commonly, at least in the modern era. And then they also developed something called a mipermine from Promethazine. So a mipermine is a tricyclic antidepressant, and you know, they also found that it was quite effective for depression. So this kind of spurred this model amine hypothesis in the case of the two antidepressants that just talked about, they kind of reverse engineered this hypothesis. >> So Dr. Wang, you talk about this reverse engineering of this hypothesis, these drugs, et cetera. So how does that lead us to where we get to SSRIs? I mean, give me a timeline here. How many years were SSRIs that we're making? >> Sure. So for the MAOIs and the TCA's, the first ones, they were kind of found in the 1950s. But the problem with these medications was not that they weren't effective, but they had, you know, significant side effects. So in 1974, Eli Lilly tried to develop antidepressant that would, you know, hopefully be just as effective, but be more tolerable for patients who had maybe only milder modern depression. And this is when fluoxetine came to be, and it first became FDA approved in 1987. >> So Dr. Wang, you're saying that back in 1987, we had our very first SSRI that was approved by the FDA. Yeah, first approved by the FDA. However, five years earlier, in 1982, they had released the Melodyne in Europe. And this was actually the first SSRI that was released internationally. And this was a very unique one because it actually caused weight loss and it had no sexual side effects. However, it ended up becoming discontinued because there were some rare cases of Guillain-Barré and some hypersensitivity reactions, unfortunately. >> So Dr. Wang, or more question for you here. I know you're going into all of the history and everything. But my biggest and most burning question is, when do we have the golden child, the poster boy, Mr. Isoloft, or Certraline coming into the picture? >> So Certraline came out a few years later, first approved in 1991. After that, you had things like peroxetine being approved. Certraline was approved in 2002. So, in your opinion, Dr. Wang, do you think it was the Prozac or Zoloft that led the revolution of the SSRIs? >> Well, I would say probably fluoxetine just because it came a little bit earlier and actually an author, Elizabeth Wirtzel, so she was quite big in the literary community at the time, launched a book called Prozac Nation. So it kind of shows how this medication captivated the country at the time. >> So I have another question for you. I have heard this before from another co-resident that the development of SSRIs are actually linked to the Benadrill. Is this true? >> Yeah, so actually quite a few of these medications were derived from anti-istamine. So, Zomelodyne was from Fenermine, and Fluoxetine was actually derived from Diphon Hydramine, also known as Benadrill. >> All right. Thank you, Dr. Wang, for giving us a brief background on the history of SSRIs. So, the nearest burning and during question that I have is the mechanism of action. So, can you get some breakdown on how SSRIs work? >> Sure. I mean, the simplest one and the one that they all have is blocking the serotonin re-update transport. So, they block certs. This causes increased serotonin, which can modulate the limbic system. Also, important note, this transport can't be affected by inflammation. And there's also some genetic variation. So, there's the short and long arm. They found that the short arm or the S allele may be less potent, so may pre-expose people more to depression because of this. >> So, one of my questions is basically back in medical school. You know, we learned about the pre-synaptic neurotransmitter in the post-ynaptic neurotransmitter. >> So, when you talk about cert, where are we thinking about the location of these SSRIs working? >> Yeah. So, the cert transporter is going to be in the pre-synaptic region, and there's also pre-synaptic 5-1-A autoreceptors there. I guess we'll talk about that later on when we talk about how long, why they take so long to work? Because this reuptake happens pretty immediately, but the general, we tell our patients to wait 4-6, sometimes 8 weeks until they start to work. >> So, one of the other questions I have, Dr. Wing, is the gut. I know we have a lot of patients that are on these SSRIs, and we always run into the side effects. I know we haven't really dealt into this side of them yet, but I always get at least one patient who has some nauseous, vomiting, maybe even diarrhea. Can you go into that a little bit? >> Sure. So, this is actually pretty recent. They found that all of the SSRIs actually alter the gut microbiome, and this is actually quite important. A recent study found that I'm going to butcher these names, by the way, but they found that Gloutia, Coprococcus, and Bifidyl bacterium was correlated with the juxtaposition in hand-B scores. People are also always looking for biomarkers for depression, and actually looking at the gut microbiome is a pretty good biomarker for it. And if you think about it, I mentioned earlier that Iprenisid was one of the first antidepressants that's used to treat tuberculosis. So, there's some correlation there. There are some small studies using fecal transplants that are actually very effective to treat depression. So, there's definitely something going on there. We still don't know exactly what's going on, but there's definitely a correlation between SSRI and altered gut microbiome. So, one of the things that I've been reading about is that SSRIs actually can contribute to some anti-inflammatory properties, etc. Yeah. So, they've found, and this is some research done by people like Dr. Charles Rayzon, that in certain subtypes of depression, they have elevated CRP, elevated baseline inflammation, and SSRIs do have some anti-inflammatory activity, some anti-microlyloctivity, which you just talked about. And this may be another way that, you know, they do help depression. So, I think this is all great talk about these mechanisms of action, especially, I think God, that brings me back to my original question is, you know, starting an SSRI or actually any medication for that matter, we're always trying to discuss the side effects with our patients. And so, I know for a fact, and I know we think back to, you know, what do the boards ask us? What is the medical school, you know, or the medical student pimping question of what is the side effects of these SSRIs? And I always think in my head, I'm thinking GI side effects, I'm thinking the sexual dysfunction and I'm thinking the hyponatrimia. And we can talk about those each individually, but Dr. Wayne correct me if I'm wrong, there's a lot more side effects to SSRIs than those big three that I just mentioned. Absolutely. So you mentioned the GI, which often happens within a couple of days of taking the medication, the sexual dysfunction which can happen up to 50 to 70% of all the patients on these medications, the hyponatrimia. There's some other things we have to look at such as bruising, bleeding, and I find this most common in the elderly population. So these medications, they can inhibit platelet aggregation. They are on the beer's list. The other big one that I want to talk about is they can cause some suicidality in younger patients and specifically patients younger than 25. And this is kind of scary because a lot of patients that I've wanted to start SSRIs on, I educate them about this and they're like, I thought this was supposed to help me with my mood. Why is it going to cause suicidality? So these medications, they often improve the kind of neuro vegetative symptoms. So the energy, the sleep, the appetite first, and then the mood later. So you take someone who's depressed, but they don't not eating, they're not sleeping much, they don't have much energy. They might not be motivated to have suicide attempts or right suicidal notes, engage in self-cutting, but you take someone who's still depressed, energize them, then sometimes these behaviors start to happen. It's really important to note that they don't increase completed suicides, only suicidal behaviors and fox. So correct me if I'm wrong, Dr. Wayne, but what you're saying is that it's the energy that we typically see that can improve first with the initiation of these SSRIs. Yeah, so we tell our patients, these medications take four to six, sometimes eight weeks to work, but generally they feel some of those facts that I just mentioned, so the energy to sleep the appetite, those tend to improve quite a bit earlier. So sometimes one to two weeks, and then the mood tends to improve around four to six weeks. Gotcha. So when starting these SSRIs, it's basically we're thinking about the patient having some physical improvement, maybe some more mechanical improvement, but the emotions and the mood is what's going to take the long haul for the treatment to work, is that correct? Exactly. And I've been asked many times why it only seems to be in younger patients, less than 25. So I think part of it is younger patients tend to be more impulsive. So at that age, the prefrontal cortex is still developing, but in older patients, that prefrontal cortex is done developing, they generally are less impulsive, generally are thinking more about what they're doing before actually doing it. So we don't see that suicidality in patients who are middle age or older as a rule of thumb, I generally try to warn my patients that are 30 or younger just to be safe, even though the official recommendation is 25 and younger. Dr. Wayne, another side effect I feel that we need to go over because I have heard a lot from my patients about this is weight gain. I'm not going to get into any gender specifics because I hear weight gain as a complaint from both my male and both from my female patients. So walk us through how we deal with weight gain as a side effect of these anti-depressants. Sure. I mean, overall as a class, they cause a lot less weight gain than other psychiatric medications. For example, some of the anti-psychotics, like clasapine or lanzapine, but some studies do suggest that there is some weight gain with taking these drugs. Part of it is due to improved mood and improved appetite. So now, someone's not as depressed, they're eating more. There's some natural weight gain there. Another way that SSRs may cause weight gain is through alteration of the gut microbiome, which we talked about earlier. Studies in mice have shown that this is one of the primary mechanisms in a lanzapine, caused weight gain. And I think there's something there with SSRs as well, but I think more studies need to be done. But one other side effect that I was actually pimped on during my intern year here was an interesting side effect having to do with bleeding potential. Could you elaborate, or do you have any idea what I'm talking about, Dr. Wayne? Yeah. So like I mentioned, often seem more in older patients because with serotonin, it can inhibit platelet aggregation. So with older patients, let's say they're on some anti-platelet drugs, you definitely want to watch out for that. Additionally, some of the SSRs that have more drug-drug interactions like fluvoxamine, they can actually alter the levels of some drugs like clopidic will. So that's a good point there. I mean, a lot of us never expected, at least I didn't when I was in medical school, that there's actually serotonin receptors on our platelets, which is a pretty fun fact. And not to bring up a controversial topic here, Dr. Wayne, but we all run into it whether you are a resident or a medical student, but starting an SSRI in a patient who has a diagnosis of bipolar disorder. Yeah. So I mean, it's pretty clear cut that you would not start one as monotherapy. In the field itself, I think it's quite controversial whether or not to start one in a patient with depression or anxiety with a diagnosis of bipolar disorder with a mood stabilizer or an anti-psychotic. So proponents of starting an SSRI with an anti-psychotic or mood stabilizer, you know, point of things like symbiacs, which we'll talk about later. It's a combination pill of fluoxetine and olanzapine, and it's found to be quite effective for bipolar depression. But of the approved medications, I believe it has the lowest number needed to treat. However, there's other articles that I've read. So there's an article that looks at using satalla pram in bipolar depression with a mood slight stabilizer or anti-psychotic, and it did not show any benefit. All right. And so I know we talked about a lot of the immediate adverse effects of SSRIs. But how about the effects when we stop SSRIs? Sure. So we call it discontinuation syndrome. It's generally worse with some of the SSRIs that have a shorter half-life, like peroxetine and fluoxamine, generally less common with something like fluoxetine, just because the half-life is so long. The longer you take the medication, the more likely you'll get this side effects. So let's say someone's been on an SSRI for 20 years and they all of a sudden stop it and it's peroxetine, very likely to get some of these symptoms. And what types of symptoms do we see? Often flu-like symptoms, headache, nausea, sometimes vomiting, diarrhea. The big one that you hear from patients is a lot of them seem to complain about electrical shocks or brainzaps. And sometimes to help them get through it, we can start something like fluoxetine just because it has a longer half-life. Additionally, we should think about slowly tapering medications, especially if they've been taking it for quite a long time. Good, good to know. So one of the other questions that I always get is these patients who are coming in and maybe they have a really good effect size, they say, "I have my depression, Dr. Hewitt, it has zero out of ten and you're seeing them now and it's a month later, right?" And they say, "Dr. Hewitt, this chemical imbalance in my head has gone away." How do you respond to this term, "chemical imbalance"? So that's maybe less controversial nowadays, but definitely 10, 20, 30 years ago, a lot of psychiatrists would tell their patients that, you know, you are depressed because you have a chemical imbalance, you need to take this medication maybe for life. There was a pretty controversial article last year, "Moncrifial," so it showed that at least at a population level doesn't look like that depressed patients have lower serotonin levels. No, I think that is a great discussion, Dr. Wei, some of the expectations, the side effects in the history of the SSRIs, so I want to switch gears here a little bit and talk about some of the interactions and things that we should be aware of. Sure, so I mean, there's definitely drug drug interactions with some of them, specifically the CYP450 system. The major offenders for this one would be something like Paroxytene, which I'm not a huge fan of, Fluvoxamine as well, which I'm not a huge fan of, and Fluoxytene. So with Fluoxytene and Paroxytene, they're a very potent scene. TYP 2D6 inhibitors. Fluvoxamine, you're mainly seeing TYP 1A2 inhibition, although there are some 2D6 and 3A4. And additionally, with something like searcherling, it's fairly clean at lower doses. But once you start to get above 100 milligrams, it also starts to be fairly potent 2D6 inhibitors as well. So thank you, Dr. Wang, for walking us through a lot of the general class of SSRIs in all of the history, mechanism of action, the side effects, and some key clinical perils. Is there anything else that you'd like to add, Dr. Wang, in our discussion? No, all right. Well, thank you everyone for tuning into psych rounds. Stay tuned. We will be going into each individual SSRI on our next episodes. Thank you for listening and have a great day.