What are SSRIs and how do they work?
Published on
May 23, 2023

What are SSRIs and how do they work?

Tyson once again talks with Matias Massaro, Psychiatric Nurse Practitioner, PMHNP. They discuss SSRIs, the most common (and most reliable) form of psychotropic medication. They explain what is known about how SSRIs work, the risks and side effects, and how to discuss SSRIs with a provider. They also talk a lot about messenger pigeons and serfdom.
Hosted by 
Tyson Conner, MA

Tyson Conner  00:10

Do you want to learn about psychological growth without sorting through the jargon? You're in the right place. This is the Relational Psych podcast. I'm your host licensed therapist, Tyson Conner. On this show, we learned about the processes and theories behind personal growth and experience a little bit of it ourselves. Join me twice a month for candid conversations about therapy and psychological concepts with real mental health professionals using understandable language and simple experiments that you can try yourself. Keep in mind this podcast does not constitute therapeutic advice, but we might help you find some.  And today, my guest once again is Matias Massaro. Mati is a clinical psychologist from Argentina, and a Psychiatric ARNP who is completing his doctorate in nursing and psychiatric prescribing. And he is also the founder of Cognia Health. Mati, welcome back to the podcast.

Mati Massaro  01:10

Hello. Thank you for having me.

Tyson Conner  01:12

Absolutely. I'm excited, because today, we are going to answer the question, what is an SSRI? And when might it be helpful?

Mati Massaro  01:21

Yeah, no, I'm excited to talk about this. It's a very common topic for good reason. And we'll cover that in a minute. But it's a thing that I am always looking forward to discuss and see how we could be helpful and get a little bit more understanding on how these very common medications work.

Tyson Conner  01:41

Yeah. Listener, from the very first time that I talked with Mati about coming on the podcast, this was like, what I wanted to do, so I'm a little excited today. You'll know why hopefully. Cool so let's, let's just start with the beginning. What does SSRI stand for? What are those letters and what do they mean?

Mati Massaro  02:05

Of course. So, SSRI stands for selective serotonin reuptake inhibitor. And this is kind of like a weird, complicated name. But it honestly is almost self explanatory. To be honest. It's all in the name. So let's start by saying what is serotonin, right? Serotonin, for those who may not know, may never heard of this word, is essentially a little communicator, it's technically called a neurotransmitter. And among the neurotransmitters it's particularly one that belongs to a family of the monoamines. But essentially, this little neurotransmitter is a way to communicate between the cells in our brains, those famous neurons, right? Cells in our brain communicate with each other using these messengers, these neurotransmitters. And among these neurotransmitters, we have a very important one, which is serotonin. Serotonin is not even just in our brain, it's in different parts of our body. It's particularly in our central nervous system. But it can also be found in our GI or even in parts of our platelets. And that's why serotonin does a little bit more than what we think or traditionally have thought.

Tyson Conner  03:33

So just to like, review the things that you just said, and try to restate it, make sure that I'm following you correctly. So serotonin is a neurotransmitter, which means it's a molecule that travels between neurons, brain cells, to help them communicate to one another. 

Mati Massaro  03:56

Yep, you got it, man. 

Tyson Conner  03:57

We know at least it does that. But there's other stuff it does that we don't really know exactly -- because we see it in other parts of the body besides just neurons, it's also in blood. It's also in our gut. It's just kind of through our whole body.

Mati Massaro  04:14

Exactly. And because it's in different parts of the body, and it's a complicated element, it can have all kinds of effects in our body. So even though there are many ways that those effects may not be fully understood yet, there are a few elements that have been observed through clinical trials.  So for example, we understand that, to a certain degree, serotonin has effects on our mood, on our experience of anxiety, cognition, our reward system, learning, memory, our sleep and alert cycle, our bowel movements --

Tyson Conner  04:57


Mati Massaro  04:58

I know, and our general peristalsis, which is why we may be talking about this in a minute with adverse effects--

Tyson Conner  05:05

Ah-ha! Haha, a preview 

Mati Massaro  05:09

I know! Also related to this is nausea and vomit response, clotting and wound healing. So, as I mentioned a minute ago, there are serotonin elements to platelets in our blood. So sometimes when we have some wounds, you know, like a little scratch or whatnot, and our body's trying to clot, essentially, and stop the bleeding, platelets do release serotonin to aid in that clotting and healing for that wound. Weird, right?

Tyson Conner  05:48

Yeah. So it sounds like - from what you've described so far - it sounds like there's three broad categories of things serotonin impacts. The first is this sort of mental neurological function, and that's the cognition/memory/learning. And then the second is this sort of gastrointestinal, GI gut function. Pooping, nausea. 

Mati Massaro  05:52


Tyson Conner  05:58

And then the third is this sort of, like blood and healing function, where it's involved in clotting and healing.

Mati Massaro 06:10

And I might even add either a fourth or a subcategory related to our brain, which is related to sexual functions, 

Tyson Conner  06:23


Mati Massaro  06:26

(Whispering) Which is also a preview!

Tyson Conner  06:37

So much foreshadowing!

Mati Massaro  06:41

We have found serotonin to have a relationship with sexual functions, and why sometimes serotonergic medications may have sexual dysfunctions. But as exactly as you were summarizing amazingly, serotonin has effects on a variety of things. And like I was saying before, these are just the ones we understand so far.

Tyson Conner  07:09

Right. It sounds like this is a particular -- Is it a hormone? 

Mati Massaro  07:13

Well, it's a neurotransmitter. To be precise.

Tyson Conner  07:18

To be specific, it's a neurotransmitter. 

Mati Massaro  07:19


Tyson Conner  07:20

And we don't fully understand everything going on with it.

Mati Massaro  07:26

Correct. And not only we don't fully understand all the possible effects of serotonin. But this ties to the second important point, we don't also understand all the possible effects that an SSRI can do. So going back to the name SSRI, selective serotonin reuptake inhibitor. What do those weird words mean? So we were talking about cells communicating with each other, right? Through messengers, through these neurotransmitters like serotonin.

Tyson Conner  08:07

Drawing molecules back and forth, like they're passing notes.

Mati Massaro  08:11

Yep, almost like a little messenger owl. Sending you Hogwarts letters and all kinds of things. And sometimes, if not all the time, cells over-produce the amount of messengers. 

Tyson Conner  08:32

Oh, interesting. 

Mati Massaro  08:33

And between the cells, there is a little bit of a recycling enzyme, or a recycling transporter. And this transporter is in charge of the reuptake of these leftovers. So those leftovers are recollected and reuptaked to go back to the initial communicating cell. And see in a way, you have a little bit of an excess of serotonin that the second cell didn't need. Let's recollect it. 

Tyson Conner  09:15

So my mind has given me a picture, like as an analogy, so I'm going to kind of put it out there. If we think of it as like messenger pigeons, we say that you've got one cell that's like a castle over here and it's trying to send a message to the other cell using these messenger pigeons. And it sends out seven or eight pigeons with the same message. Assuming that half of them will make it. So that's what our brains do. One neuron sends out a bunch of the serotonin assuming that a certain amount of it will get lost along the way. It sounds like - to use this castle analogy -there's one of these little serfs, little peasants, whose job is to go out into the countryside and collect those lost messenger pigeons and bring them back so that they can be used to try to send another message in the future.

Mati Massaro  10:08

Exactly. They are recollected and brought back to the original castle. Now what does the serotonin reuptake inhibitor do? It inhibits the reuptake. So you are telling this peasant to take a break. 

Tyson Conner  10:29

You have a day off today, sir. 

Mati Massaro  10:31

Yep, and it leaves more of these pigeons, more of these messengers in the space between neurons called the synaptic cleft. So in this analogy, the pigeons are not immediately recollected and you're essentially telling the person, "you know, we're going to chill for a minute, we're going to let the pigeons fly around a little bit more."  Because the second castle may benefit from a few extra pigeons right now. 

Tyson Conner  11:06

So it, like gives the pigeons more time to get to... is that where the serotonin ends up? Does it eventually get to the cell it was going for?

Mati Massaro  11:15

Yes and no. So what we see is that the second castle, or neuron has more serotonin available in the space for incorporating into the castle or the cell. But having a little bit of an excess of serotonin in the synaptic cleft, in the field of pigeons, has been observed to create an effect on the originator cell as well - creating a downstream effect on how the originating cell could adjust how their pigeon process could function differently.

Tyson Conner  12:00

So it's like, the castle that sent out the pigeons keeps a stable of like 16 pigeons, they sent out eight, four of them make it to the new castle, four of them are left out in the field. Usually, you send out the serf to go and collect the extra four and bring them back, and then you breed more pigeons to make sure you always have at least 16 ready to go. What the SSRI does, is give the peasant a day off. And as a result, those four pigeons in the field, some of them will end up making it to the second castle. And at the first castle, they're going to breed more pigeons more quickly, so that they can keep up to their quota, basically.

Mati Massaro  12:42

And some of those pigeons might eventually, you know, for the purpose of this analogy, come back. But with, let's say, more information. Let's say in this analogy, "look, we realize that this path between castles usually has a tornado in the middle. And maybe we should design a new route to communicate between castles." Again, this is an analogy.

Tyson Conner  13:13

Yeah, the pigeon comes back a little bit tattered, and we think maybe we should train them to avoid the tornado.

Mati Massaro  13:19

And it will create adjustments in both ends. That's kind of what we are observing. So, in technical terms, if you will, it will increase the serotonin signal between both neurons eventually. Having these extremely interesting and a little weird, if you will, of an effect that we don't completely understand. But by blocking that serotonin reuptake, by giving time off to that peasant, we see a lot of these effects. One of them is the one that we just talked about. But we also see other things that I don't completely understand.

Tyson Conner  14:08

So the analogy will fall apart here, but I'm curious to hear --

Mati Massaro  14:12

We go from pigeons to cyber punk robots in a second. But essentially, besides this effect that has been, sort of the traditional understanding of what's going on, past recent years we are observing even more and different effects that SSRIs can have. One of them is how there is a particular factor called BDNF - that stands for brain derived neurotrophic factor. We see that -- through SSRIs, we see an increased expression of these processes, which eventually, it's understood or hypothesized, that contributes to increased neuroplasticity.

Tyson Conner  15:05

Cool. So I want to define some terms for our Listener, because I know what most of those are. Neuroplasticity is basically the ability of a brain and neurons to adapt to changes. Plasticity in this case means kind of like flexibility. You want your brain to be able to respond to new information, you don't want to just do the same thing over and over and over again, you want to be able to adapt. Think of it like the difference between driving a car and getting on a train, right? A train can just go one way. And you can change how fast you go. But like you've got one track. With a car, you can go different paths to get to the same place. Neuroplasticity is your brain's ability to adapt to new situations.  So to try to bring it back to that analogy in a way that might stretch it a little too far, the process by which you give your pigeon collecting serf a day off, leads to a pattern where the castles start to pay more attention to the routes they're sending neurotransmitters on - the routes they're sending their pigeons on. And now we're not talking just two castles talking to each other, we're talking a whole network, a countryside full of castles, that as they start to pay attention to how they're sending messages to one another, it's not just changing the way they're sending out pigeons. It's changing the way they're sending out carts with donkeys. It's changing the way they're sending out knights. It's changing the way that the entire network of castles is rethinking how they connect.

Mati Massaro  16:43

Exactly. And what we've observed with some of these processes, it's also a possible effect on inflammation. So one of the etiologies and current hypotheses of depression, it's related to inflammatory markers. Inflammation in general, some tests for something that's called C-reactive protein, which can be a marker for general inflammation in the body. So by decreasing inflammation, possibly through this mechanism, we may start observing some of the SSRI effects on mood, anxiety, and other indications that we'll discuss in a minute.

Tyson Conner  17:25

Yeah, and for the Listener, inflammation doesn't mean that you're on fire. It means, as I understand it, from my anatomy and physiology class from when I was a senior in high school, inflammation usually means there's more blood in a space than it's meant to hold. The space is a little stretched full of fluids, usually blood. Is that accurate?

Mati Massaro  17:47

Yeah, I would describe it in the terms of swelling. And one other part, to make this analogy even a little more, you know, testing, is that there's also a component to SSRIs that shouldn't be ignored, which is a placebo effect. There is a component to SSRIs -- it depends on different clinical trials - but sometimes it can go you know, 15 to 30%, of an SSRI having a placebo component, which is not to be mistaken, in general, as something bad. The placebo effect is incredible, right? It truly is incredible. And it's effective. And what we've learned with research is that the placebo effect is basically immune to knowledge. In other words, folks can understand that something might be a placebo effect, and it does not prevent the effect from working.

Tyson Conner  18:56

That's incredible. Listener, if you're not familiar with the placebo effect, there's a really good early radio lab episode about it that I'll probably link in the show notes, which I think is great. But the short version is sometimes the act of taking something that you think might help you will be effective in helping you, even if there's no reason why that thing should help you. So, for example, if you have a headache, and you take a pill thinking it's a painkiller, but actually, it's a tic tac, your headache might go away. That's the placebo effect. And the thing that's really interesting that Mati was just talking about, to me at least, is that even if you know it's a tic tac, that it's not going to make the pain go away - like it's not going to be ibuprofen, it's not going to be acetaminophen, it's not going to be oxycontin, whatever - taking it will still work. 

Mati Massaro  19:55

Yeah, it's amazing, isn't it? 

Tyson Conner  19:57

And I think part of what's important is that oftentimes, people can talk about the placebo effect like it is a bad thing. Like, "oh, it's JUST a placebo effect." Which, if you're researching specific drugs and their effectiveness, then sure you don't want to find out your drug only works by placebo. But if you are trying to feel better, and to recover and to heal, the placebo effect is absolutely your friend. Because it's part of your healing process. 

Mati Massaro  20:27

Absolutely. And so we just covered so many of the ways that we are trying to understand how an SSRI has this impact. But the bottom line is that, even though we continue to learn about these medications that we we've studied for decades at this point. The bottom line is that through a lot of research and clinical trials, by disabling or blocking this reuptake, through the SSRI mechanism, what we observe is that overall, we see improvement in a lot of these serotonergic related components that we mentioned earlier. Like, for example, mood, or anxiety. And we see that these things improve through research on these medications in a safe way, without concerns at a drastic level or at a population level that would prevent us from using this medication.

Tyson Conner  21:36

I'm hearing a hypothetical Listener who's listened thus far and is interested and is like, "okay, pigeons, castles, I'm following your crazy analogy. But how does an SSRI -- how does this whole process actually improve mood?" And I think what I'm hearing you say is, we don't really know, after decades of research, but we know it does.

Mati Massaro  22:00

Right, right. So what happened is that the way we understand or, if you will, not understand medications, it's actually very common, which is a surprise to most folks outside the medical field. "Wait, are you telling me we don't completely understand how a lot of these medications work?" Yeah, I'm telling you that,

Tyson Conner  22:28

If I'm a listener at home, what medications might I have in my bathroom cabinet, that we don't actually understand how they work? 

Mati Massaro  22:37

You might have NSAIDs like ibuprofen or acetaminophen, which sure we've continued to discover how they have, for example, anti inflammatory properties that, by effect can reduce, let's say, pain - muscular pain or headache. They also may have some other properties like antipyretic properties, which can decrease a fever. But these are two separate things that we discovered with time. It's just like we discover in other medications that were intended for one purpose, and somehow, we realize they had a purpose on something else. Like, for example, medication for blood pressure used historically in veterans for different purposes, that eventually we realized that they were treating chronic nightmares. So that's how a lot of these drugs come to be.

Tyson Conner  23:41

So I guess, Listener, you and I are both getting our little existential crisis of the episode, learning that the painkillers that you've been taking likely your whole life to deal with headaches, muscle aches, and high fevers. You can't sit down and diagram out how they do what they do. We just know they do.

Mati Massaro  24:04

Now, look, we have educated guesses, though. 

Tyson Conner  24:07

Sure. Sure, sure, sure. 

Mati Massaro  24:08

But we continue to discover more and more and some of these are more complicated than others. Some medications have, for the lack of a better word, simpler methods of action. Some of them are a little more complicated. So what we've seen historically in some psychiatric things is for example, with antidepressants or SSRIs. We see most of these things are derived from other medications that were previously being studied, or from herbs and other things. So historically, we've seen things like St. John's Wort, a supplement or natural herb that some folks were consuming, and they noticed that there were some possible improvements in mood. And through research, we started understanding that the component, among several, in St. John's Wort that seemed to contribute to these changes, was the serotonergic component. So we isolate and purify that. We realize and understand, "oh, this works by blocking the reuptake." And lo and behold, we create an SSRI. And we start seeing how can we take this medication to improve symptoms of mood and anxiety? Safely? And this is how a lot of the drugs are discovered.

Tyson Conner  25:43

Yeah. So we've talked broadly about how SSRIs work, and the kinds of things that they have an impact on. Specifically, if a patient comes to you, what kinds of symptoms or experiences that they're reporting would make you think maybe an SSRI would be a good thing to try?

Mati Massaro  26:05

Yes. SSRIs have a variety of indications. That's why we also like this family, because they are effective at addressing several things. Typically, we're talking in the mood realm, in the anxiety realm, and the obsessive-compulsive side of things. So generally speaking, we can break it down into med by med, but generally speaking, the family of SSRIs is indicated for major depressive disorder, for generalized anxiety disorder, for social anxiety disorder, for panic disorder, for PTSD, for OCD, and premenstrual dysphoric disorder. These are folks who experience severe symptoms related to more than anxiety, previous to their menstrual cycle. But we also have research indicating more off-label indications for SSRIs. Among those, some of the most common are basal motor symptoms of perimenopause, just like hot flashes or night sweats. And for some folks, premature ejaculation can be treated with SSRIs. And that's why I was referring to sexual functions and SSRIs earlier on, it's serotonin.

Tyson Conner  27:37

Because when you're talking about things that are the result of sexual development, normal sexual development, and something like premature ejaculation, at that point, the impact on sexual functioning isn't exclusively a psychological impact. But there's something physiological there. And Listener, just so you know, the difference, psychological means that something happening in your mind, primarily in your brain, physiological means there's something happening with the mechanics of your body, something happening in your organs separate from your brain or central nervous system.

Mati Massaro  28:10

Sure. So we can use SSRIs, effectively for so many of these things. And again, to summarize, typically related to depression, anxiety, or OCD like experiences.

Tyson Conner  28:25

So let's say I'm a patient, I've come to you reporting one of these or multiple of these, because that's pretty common, right? A lot of people report anxiety and depression at the same time, trauma and anxiety, trauma and depression. They tend to cluster. And you said, "Okay, I think an SSRI would be a good fit for you." I say, "Yes, sir. I'll start taking it." What happens next?

Mati Massaro  28:49

Yeah, no, that's a great one. So once we discuss starting a medication, there are different things that would be prudent or important to discuss. The first thing is to discuss timeline, and possible expectations on how the medication might contribute to some effects. Now, generally speaking, we have some, let's say standard expectations on how things should progress. But it's important to highlight that this does depend on the person. Everyone has different mental health experiences, different bodies, metabolisms, genes. So it's important to consider the individual when expecting how the medication may have an effect. That being said, usually, within the first week or two, we should start noticing some effects, particularly in our sleep, energy, appetite, and some things may take a little longer to produce a noticeable effect. And sometimes within four to eight weeks, we start noticing improvements in our mood, anhedonia, amotivation, anxiety. And for those who don't know, amotivation it's the lack of motivation or difficulties with motivation. In anhedonia, it's essentially difficulties experiencing pleasure or joy. The way I typically describe it, when someone is experiencing anhedonia and depression, it's not that they are particularly feeling dramatically down or acutely depressed, but that their life is just grey. Flavorless. It's just grey, joyless...

Tyson Conner  30:49

Yeah, I feel like anhedonia is one of the symptoms of depression that we don't talk about as much. And I'm glad we're underscoring it here. Because there was research that I heard about way back in grad school, and I've never checked up on it, so for all I know, it might be completely made up. But what I heard is that people who are experiencing depression, clinical depression, if you give them a color spectrum, and say, identify for me where one color becomes another, they'll take like a section of a rainbow, and they'll identify three or four colors. If you take people who aren't clinically depressed and give them those same color spectrums, they'll identify five or six on the same spectrum. So what this research suggests is that literally, when you're depressed, your world is more gray. Colors are less vibrant. Food is less tasteful. When you say like, the taste is gone, literally, physiologically, (again, there's that word,) you experience less of the world. And the way that people get to this in like questionnaires and things like that, oftentimes uses the phrase, or the idea of "things being less pleasurable than they used to be." "I used to enjoy watching football with my friends. Now. I just go through the motions, or whatever." And anhedonia is a more common symptom of depression than like, being really weepy all over the place. So if I'm hearing you, right, if I'm taking an SSRI, and it's gonna work for me, and I'm taking the right amount, it can take up to two weeks before I notice any effect - and I'll probably notice it first in my sleep, and my appetite, the amount of energy I have day to day. And then it can take up to two months, even if it's the right med for me, for me to notice an impact on my mood.

Mati Massaro  32:46

Yes. And that is a little bit related to the mechanisms that we were discussing earlier. The ways these pigeons start communicating and having a downstream of effects and making route changes and incorporating donkeys and maybe incorporating more castles to network with. This takes a little bit of time, right. And that's when we see some of these things taking a little bit longer to improve.  And I liked that you mentioned something about the right dose. Because this is something that I unfortunately see a lot. I see a lot of folks who come to me and unfortunately think that SSRIs don't work. And I understand why they say that, they unfortunately had a poor experience with them. And once we dig a little deeper, their experiences with SSRIs were with subtherapeutic, tiny doses. Maybe they were the right initiation doses. You know, let's start with a small dose. That's perfect, and we'll talk about it in a minute. But after starting with a tiny baby dose, we need to increase that dose to therapeutic levels. In other words, most folks take ibuprofen for let's say, a little bit of a headache or muscular pain in general. And as you may or may not remember, the smallest typical tablet of ibuprofen is 200 milligrams. Now some folks are receiving what would be the equivalent of 10 milligrams of ibuprofen and told me "hey, look, man, I've tried ibuprofen, but it doesn't do anything for my headache." And it's unfortunate because, they are right. They truly are, the medication they tried didn't help them, unfortunately. And honestly, that sucks. But it's part of our role as clinicians to explain why there's still a good chance that this medication might be helpful. We just need to use the right dose.

Tyson Conner  35:01

To use to use maybe a more illicit analogy. I think most of our listeners are probably familiar with feeling the effects of alcohol, right? It sounds like what you're describing is like someone being given a thimble full of wine and drinking it and saying, "You know what, I tried drinking alcohol. And I didn't really feel the euphoria and the loss of inhibitions and those things that people drink it for. I guess it doesn't work for me." And you're saying, "Well, yeah, it's because you had a thimble full of wine, right? People drink that much on Sunday mornings and give it to babies like, you're fine." You kind of need more to actually feel the effects. 

Mati Massaro  35:39

Yes. Now, one of the things that I also see often is sometimes thinking that the medication may not work, because it didn't work before. We just mentioned how dosing could be an issue. Sure, but also, the trial time can be another factor. You and I were talking about how some of these things like mood or anxiety, take maybe up to eight weeks to start producing a noticeable effect. And I see folks who sometimes try the medication for a month, didn't notice any improvement and stopped the medication. So usually, we don't consider that necessarily an adequate trial of the medication, where we may have noticed some of these improvements. But we didn't give the medication enough time, if I'm making any sense.

Tyson Conner  36:40

Yeah. Yeah. I mean, what I'm hearing is like, if you are trying out a new SSRI on Halloween, like, you won't really know if it works until the new year. And that's actually a pretty long time. It requires some patience. It sounds like.

Mati Massaro  36:58

I would say, arguably, my least favorite thing of SSRIs -- they are incredible. And we'll continue to talk about why -- I think probably my least favorite thing is that they take a little bit of time. You know, we want to prescribe safely. And, you know, it might take time. Now that being said, most folks I see notice a response earlier than eight weeks. But you know, it's important to be mindful that we might need a little bit of extra patience. And while adjusting that dose, a lot of folks and I have a discussion where adjusting a higher dose doesn't necessarily mean more acuity. In other words, a lot of folks are having discussions about dosing and may feel a little guarded about increasing the dose, thinking that, "I don't know if I need a higher dose, because I'm not, let's say, suicidal right now." And that's not necessarily what dosing means. Someone might not be acutely suicidal at the time, but they may still actually be severely depressed or severely anxious. But noticing what we call a partial response to the medication -- in other words, we see that some things are feeling a little better, but there's some room for improvement. And what this typically means is not necessarily that there's more or less acuity, but that your body, your genes or your metabolism might benefit from a higher dose.

Tyson Conner  38:51

Right. It makes me think about how it's kind of known that like, people who are redheads oftentimes require more anesthetic to actually go under for surgery. Why? I dunno, their genes are just that way. So like, if you have a 5'2" 110 pound woman with like bright red hair, she might need more anesthetic to make it through a tonsillectomy than a 6'2" 225 pound man with blonde hair, right? That's just a thing that doctors know. It doesn't mean that the shorter woman is going to be experiencing significantly more pain or is a problem or has something wrong with her. It's just a different body's way of processing the dose. 

Mati Massaro  39:50


Tyson Conner  39:50

So being on like, a much higher dose of an SSRI doesn't necessarily mean that you're more broken or more depressed or have more trouble than anyone else. It just means your body needs a certain dosage for the SSRI to do its job.

Mati Massaro  40:06

Yes. So what I try to joke around with folks in general is, "look, we're gonna see this a little bit like, we're gonna go to the back of Target, and try a few shirts. I don't want a shirt that's too little for you, I don't want a subtherapeutic dose that's not gonna do anything. And I also don't want this humongous shirt on you and over medicate for no reason. I want the right shirt for you, for your body, your experience, your genes, and your metabolism. And I think working together we can figure that out."

Tyson Conner  40:44

With how long the timelines are for SSRIs, does that mean that it can take a long time to find the right dose for people?

Mati Massaro  40:52

That's a good question. And typically, within the initiation period, four to eight weeks, it should be enough guideline for us to see. In other words, we should notice at least a partial response. Similarly to what I was saying before, where we notice some improvement. And sure, there might be some room for improvement where we can continue addressing and improving our mood and anxiety. But by eight weeks, we should notice some effects. If for some reason, we don't notice any improvements on this medication, or it's an extremely rare case where -- we'll talk about adverse effects in a minute, but -- where things are feeling this uncomfortable, it's appropriate to change medications. And this would be appropriate to change to a second SSRI to assist our medication that's similar enough to produce good effects. But different enough to create a separate response, a response that ideally would be better and more tolerated.

Tyson Conner  42:12

Gotcha. Yeah, cuz there's not just one SSRI. So it's kind of like, to use our pigeons analogy, different SSRIs are kind of like, different time off schedules for your surf, who goes out and collects the pigeons, right? They'll have different impacts, different ways of working.

Mati Massaro  42:14

Right, just like the NSAIDS, you have acetaminophen or Tylenol. Or ibuprofen or Advil.

Tyson Conner  42:26

The same class of drug the same mechanic, but slightly different effects. 

Mati Massaro  42:43


Tyson Conner  42:44

And so you use them for different situations. Let's talk a little bit about timeline and starting and stopping. Because I know that unlike something like a stimulant, you know, Adderall or something like that, or even like a hydroxyzine are certain anxiety medications. SSRIs kind of have a rhythm to them. That it's not a good idea to go off script.

Mati Massaro  43:11

You're absolutely right, man. And here's the thing, when we start or stop a medication, we want to do it progressively. That's the best way to prevent any adverse effects. And to do it safely, and to make this a smooth transition for you and your body. So by starting the medication, low and slow is the way we say, we can do two things. Try some of these shirts in the dressing room, and make sure we find that right size for you and not do under or over prescription and also prevent possible adverse effects. Particularly if someone is to have an excessive amount of serotonin out of nowhere, by SSRIs, or other serotonergic medications, including terrible things like St. John's wort, they might experience something called serotonin syndrome, which can be concerning. It can be a reason to be hospitalized. Where we are experiencing tremors, high fevers and sweating and other possibly concerning symptoms. So to prevent something like serotonin syndrome, we go progressively through small increments. On the other side, if we've been taking a serotonergic medication for a little bit, and we discontinuous cold turkey, we might experience serotonin withdrawal. Our body starts experiencing what we call flu like symptoms, for example, some malaise, headaches, nausea. So typically, both to start or to stop medication, we recommend everyone to do it with their provider and do it progressively to do it safely to prevent any uncomfortable experiences.

Tyson Conner  45:10

It sounds kind of like the -- because we know, however these drugs are doing their job, it involves making big slow changes to a big complicated process. And so if you make a sudden change in the drug, then your brain has to react quicker than it's prepared for it. Whereas if you make the slow changes, then your brain is able to respond slowly.

Mati Massaro  45:38

And all the pigeons get confused.

Tyson Conner  45:40

Haha! Confused pigeons wandering around.

Mati Massaro  45:45

When it comes to timeline, which was one of your questions, it obviously varies case by case. But what we've learned through research, is that once we achieve at least some response on the medication - partial response, maybe full response - it's recommended to take this medication for 12 months. Depending on the literature, 12 to 16 months. Because what we learned is that folks who stopped the medication earlier than this timeline, might have a higher risk for relapse. So what we want is to set up folks for success and, you know, treat this major depressive episode and not have another one. So by following this timeline that we've observed through research, we create the best success chances.

Tyson Conner  46:43

It's kind of like when people get braces, you're encouraged to wear a retainer for a certain amount of time afterwards, to prevent them from returning.

Mati Massaro  46:51

Yes, I like that analogy, too. And I often also talk about antibiotics and how, you know, you might get a prescription for 10 days of an antibiotic. And you might start feeling better and great around day four. But to prevent from these infection from resurfacing and to fully eliminate it, it's good to do the whole 10 days of the treatment, right? 

Tyson Conner  47:18

So let's talk about it. This is the number one thing I hear about SSRIs - partially probably because I work with a lot of adolescents. And I know that's especially concerning, the blackbox warning, the adverse effects, what scary, scary things can happen?

Mati Massaro  47:35

So, like with any and every single drug, and this includes not just medications, but I'm talking alcohol. I'm talking cannabis, I'm talking caffeine. Every drug has possible adverse effects. That being said, let's focus on SSRIs. Here's one of my favorite things, SSRIs are amongst the best tolerated medications in medicine.

Tyson Conner  48:08

So best tolerated. That sounds like it means SSRIs are some of the medications that the fewest people have negative side effects to, or that the most amount of people can take without having any side effect at all.

Mati Massaro  48:25

Yeah, many folks can take these medications without any adverse experiences.

Tyson Conner  48:31

Better than Tylenol? Better than ibuprofen? 

Mati Massaro  48:34

In the long term. Yes. 

Tyson Conner  48:36

Wow. Oh right, because if you take that stuff too regularly, you get like liver/kidney issues.

Mati Massaro  48:42

Most folks don't or shouldn't take some of these medications regularly, like ibuprofen or Tylenol. But in the research that we've done with these folks that some of them take these medications chronically or long term, they are extremely well tolerated. However, there are poor experiences. And the main focus, or let's say period, to experience adverse effects is during the initiation.

Tyson Conner  48:42

So those very first few weeks. 

Mati Massaro  48:47

Yeah, and I would say the first few days. Even before any positive effects? So we've mentioned how, let's say sleep, energy might start, you know, producing an effect within the first week or two, mood and anxiety within four to eight weeks. Side effects are going to appear in day one. If you're someone who may experience side effects on SSRIs, you're going to have them right away. If you're among those folks who experience side effects, it's very, very, very likely that the side effects are limited to the first week. Why is this? One of the most common side effects are related to our GI system. Many folks experienced some diarrhea or nausea during the first few days. That's it, it self resolves, they never have it again. As you may or may not remember, when we were talking about the impacts that serotonin has in our body, we talked about peristalsis. We talked about nausea and vomiting systems, which means that our gut not only produces but has serotonin receptors. So this mechanism of production and receiving has to adjust to a new drug that's affecting serotonin. So for a few days, things get a little funny in our stomach and folks may experience some diarrhea or nausea. Again, a lot don't. But those who do experience side effects, may have some of these GI side effects. Other folks may experience headaches for the first few days. And for similar reasons; there's some adjustments in our central nervous system related to serotonin. Again, GI symptoms, headaches, these are likely temporary. We try to, for the lack of a better word, to push through those first few days while managing those symptoms. So maybe we take an ibuprofen for the headaches, right? Maybe we drink a little bit more water for our GI side effects or not. And after the first few days, those who experience side effects, don't experience these anymore.

Tyson Conner  51:54

Okay. Well, that doesn't sound too bad.

Mati Massaro  51:57

Right? So which makes these medications in the long term after these first few days, extremely tolerable.

Tyson Conner  52:06

It sucks that it's likely to be the first thing you're experiencing. That's unfortunate.

Mati Massaro  52:13

It is, it is. And that's why I think it's important to have these discussions so that folks know this may happen. And it doesn't mean that the medication may not work on you, doesn't mean that medication may be worse for you. This may happen. We may have a little bit of diarrhea or headaches, but it should self resolve. And you know, what, if for some reason, it doesn't, we will change this medication, we're not going to continue. Our purpose here is to improve the quality of your life, not to add another problem. Right? Now, that being said, there's another common side effect, which typically, I think should be talked about more, which is sexual dysfunctions. We mentioned how serotonin has an effect on our sexual functioning. And I think a lot of patients, clients, and clinicians, shy away from this conversation.

Tyson Conner  53:17

Because it's awkward to talk about sex.

Mati Massaro  53:18

It's awkward to talk about sex. And I think it's important to create a space and a framework where we can provide the opportunity to talk about this in a tactful way. Not forceful, but just normalizing and educating that this is a possibility. And that if you feel comfortable, I would be more than glad to talk about this to address it. And like I said a minute ago, our purpose is to make your life a little better, not to take things away like sex.

Tyson Conner  53:56

And I might -- I'll decide if to include this in the episode or not -- but one of the things that I've heard before from people, not just in the therapy office, but online, friends in my life, is how sometimes you'll be really depressed, you'll feel awful. And one of the few things that will predictably make you feel good might be sexual activity either with a partner or alone. And then you take this medication that's supposed to help you feel better eventually. And the first thing it does is take away the one pleasurable activity you could rely on. And that sucks. 

Mati Massaro  54:34

Oh, I agree. 

Tyson Conner  54:35

And what I'm hearing you say is like, yeah, it's super sucks. And if you can talk to your doctor and talk to your therapist about it, talk to your providers, then you will hopefully learn this is probably short term. Yes, this sucks. And if you push through it, then you will see the benefit of the drug. These functions will come back and maybe - I don't know - there are things that you can do and things that you can adjust to compensate for that loss of sexual function.

Mati Massaro  55:05

Yes. And it all starts with being able to talk about it, right? I can't remember from the top of my head, the number - we can obviously search it after -but there was, from previous research, a huge percentage, like something tells me like 80% of female identified patients who experienced sexual dysfunctions on SSRIs. Don't feel comfortable to bring them up during the visit during the appointment, which eventually contributes to them stopping the medication on their own, because they were experiencing these adverse effects. And the bottom line is that that sucks. I want us to be able to talk about anything that may be stressing you. And sexual dysfunctions, and your sex life in general is important and relevant. And if we want to improve the quality of your life, I want us to talk about it. And it doesn't have to be unnecessarily awkward.  So the way, you know, I'm obviously paraphrasing, but the way it usually goes in an appointment, I will say something like, "look, among other things that we may experience on these medications, there's also the possibility to experience sexual side effects. Some folks experience decreased libido, orgasmia, erectile dysfunctions, and I hope that if you are experiencing any of these, you can feel comfortable letting me know, because we can address it. There are things we can do for that." And, and honestly, once you bring it up like that, you know, normalizing it, typically, folks say "you know what, I actually wanted to talk about that." And if folks are experiencing that, there's a chance that they will self improve, just like you were saying, but if it doesn't - and that happens to some people - there are typically three routes. One of them is adding a second medication that cancels the sexual related component of serotonin. And usually, these are medications that have a bonus effect, for whatever the patient is experiencing. So it might be a medication that is also useful for depression. So we have a medication that helps depression and sexual side effects. Other possibilities is switching to a different medication, to create the similar therapeutic response without the sexual side effects. And then the third, and honestly, common option for many folks is keeping the medication. Some folks told me, "You know, I noticed some decreased libido, but I'm not concerned about it." And that's the key point. Some folks, decreased libido and orgasmia is something that we need to address. And it's a big no, no. And look fair enough. For other folks, they told me "Look, I, you know, I, I've noticed decreased libido, and me and my partner talked about it, but it's not a problem, at least for now. And I'm feeling so much better that I don't want to change this medication." And, you know, fair enough. If for some reason the circumstances change. Let's revisit this.

Tyson Conner  58:40

Yeah, it sounds like the most important thing is to be able to talk about it. Because if you decide that the side effect is worth the benefit of the drug, great. But if you don't have room to talk about it and think about it, then you're not really deciding. And that's the problem. 

Mati Massaro  58:59

Yeah, that's right. 

Tyson Conner  59:02

Oh, listener, editor Tyson here. I just wanted to make a quick note before we continue this conversation. Mati and I are about to discuss the blackbox warning, and I realized I never actually defined it in our conversation. He and I just know what that is and just rolled with it. The black box warning is what used to be called the "black box warning," now just call a "box warning," is something that the FDA puts on medications that could have potentially life threatening side effects. It's the highest level of warning that the FDA gives a drug in the US. And on SSRIs there is a blackbox warning to indicate that people under the age of 24 years old may take the drug and then their risk for suicide might go up. So Mati and I are about to discuss that warning. And that potential side effect of taking SSRIs. Okay, back to the show.  So let's talk about it. Let's talk about the big scary one. The blackbox warning I hear about all the time. It sounds like that is among some of the more rare side effects.

Mati Massaro  1:00:22

Yes. In contrast to maybe headaches or GI side effects, the blackbox warning is on the rare side of things. Now, this is particularly a very controversial point in psychiatry. So get your swords and your pigeons going. 

Tyson Conner  1:00:43

Okay, here we go, we're going to war.

Mati Massaro  1:00:48

The history behind that blackbox warning is a controversial one, because the research used for it had some possible flaws or design flaws, arguably. When we are studying different groups of younger folks, particularly below 24 years old, we may have observed selection bias. So what we did while researching this is separating based on depression acuity. And what we did is, okay, maybe the mild to moderate depression could be addressed with therapy only. And the third group of the very acutely depressed may benefit from starting on an antidepressant like an SSRI. So what we've seen in that third group, some of the folks that were 24 year old or younger, had more episodes of suicidal ideation versus the other two groups. My opinion, and this is based on the literautres, what others may agree on, is that this is expected. There's a clear expectation that the most severely and acutely depressed will have a greater chance for suicidal thoughts, right? With or without medication. So you have to take that little black box warning with a grain of salt.  Now, the second important point about it, regardless of that research, comes with the timeline of response for these medications. We've talked before how some things improved earlier than others, energy improves way faster, more than anxiety. So what's hypothesized is that folks who were severely depressed, possibly already having some suicidal ideations, they were experiencing tiredness, fatigue, lack of motivation to act on the suicidal thoughts. Now, you give them the medication that may increase their energy before their mood. And it's hypothesize that in some of these cases, you are helping get some of the energy they may have "needed" to act on those suicidal thoughts. Am I making sense? 

Tyson Conner  1:03:42

Yeah, it sounds like the research around, that initiated this blackbox warning is controversial. And it may be designed so that it's more likely to be studying people who are already at really high risk of suicidal thoughts. And the way that the mechanisms work, your mood is one of the later things that actually improves. And if you're really depressed, and really, really down and really low energy, and then all of a sudden you have energy, but you're still really depressed and still really down, you might have the energy to explore and think about and act on things that previously might have just been kind of a passive background idea. Because you were too depressed and low energy to do anything. The energy comes first. But it's the question of where does that energy gets pointed at until the mood kicks in?

Mati Massaro  1:04:36

Yes. Now, all this being said, we talked about common side effects, and we talk about some of these rare ones. Regardless of common or rare, there are two important things that I want to reiterate. The first one is to prevent a lot of these, that's why we start slow and we go gentle with you and your body. And the second point is that's why we also check in. Why it's not that we should prescribe this medication until you come back in six months. Right? We typically tell you come back in a few weeks. So we check in, and I'm around for messages, for calls, for anything, in case you're feeling unwell or concerned, I want you to talk to me. Because we can do something about it.

Tyson Conner  1:05:24

Yeah, that feels really huge, because I know a lot of people -- I was talking to someone recently who was given a prescription for an SSRI by a provider. And they're just kind of holding on to it and they don't really have a follow up planned. And I think partially based off of this conversation, I will encourage them, "hey, look, if you do decide to start taking it, schedule a follow up with your provider, pretty soon afterwards." Because kind of like with psychotherapy, we don't want you to be on your own in the process - with psychopharmacology, we don't want you to be alone in the process. So it's a complicated thing. And having access to your support network is pretty important.

Mati Massaro  1:06:12

And it's important to keep this communication going.  Just like I was mentioning about sex, now about starting or stopping medication and about everything else. The idea is to create this collaboration between us and clients or patients, and figure this out together and safely.

Tyson Conner  1:06:31

And I think a lot of people can get the sense that like, my doctor wants me to take this medication. If I don't want to, then we're in an argument, right? And what I'm hearing you say is like, no, you want your patients to feel better -- 

Mati Massaro  1:06:45

I really do.

Tyson Conner  1:06:45

And if the medication isn't working for them, it's not like you're on the side of the meds, you're on the side of the patient.

Mati Massaro  1:06:51

I tell everyone, my only jersey in my team is Team You. I'm not pro or against drugs, I don't collaborate with any pharmaceutical representatives in particular, my only goal is to help guide what could possibly make some improvements in your life. And I typically tell everyone, "Look, my role here is to give you the best clinical recommendation I have. And that is as far as I go. You are the driver in this relationship. And I'm your co pilot, I will tell you what my science map says, Look, my science map says it might be better if we turn left here. But you're the driver and you should have control and autonomy, on your body, on your recovery. Help me help you. I want to discuss the options, I want you to have time to think about them. And I want to help you feel better. I'm not here to tell you what to do. I'm here to consult with you and give you my expertise, but that's it."

Tyson Conner  1:08:04

Yeah. I like that a lot. So, okay. We've talked now, probably like an hour or so into this conversation. What are the bullet point takeaways? What are you hoping that people will come away from this episode having in their minds?

Mati Massaro  1:08:27

Yeah, no, I love that question. And I want us to have the information on the table, all the cards to make the informed decision that I think everyone deserves to make. So what are the possible cons of SSRIs? They take a little bit of time to work. That's my least favorite thing. The first few days can be challenging for some folks, that diarrhea or headache can be difficult. Will it self improve? Oh, very likely, but we still have to make it for a few days. And that can be difficult. And for some folks, those sexual side effects may not go away. We have options though. And I would love to discuss them with anybody that's interested during our appointments.  However, the reason why these medications are typically the first line of treatment for these presentations related to depression, anxiety, OCD, PTSD, are because they are extremely well tolerated, especially in the long term. They are safe, they are very safe medications, even during pregnancy, which is a difficult part of psychiatry. They are long term safe, and their long term use has not yielded any significant concern for folks who take it for longer periods of time. These are non habit forming or non addictive medications. And they don't produce any euphoria or immediate effects. As we talked, they take a little bit of time to work.

Tyson Conner  1:10:09

They don't really work to get high, they're difficult to abuse in a way that human beings prefer to abuse drugs.

Mati Massaro  1:10:16

And besides being well tolerated and safe, they are effective. They work, they reduce the frequency, the duration and the intensity of the symptoms. They've been studied for so long now that they are generic, which means they are cheap. Most folks can pay around or less than $10 for the whole month. Which in the world of medication cost, that's pretty good. And overall, we use them as firstline for all these reasons. And as a clinical bullet point, if you will, I love working with folks who are experiencing more depression, trauma related responses, OCD, and trying these medications. Because, you know, we work through the first few weeks, it takes a little bit of patience, we wait for some different response variables, noticing that there's some mood improvement, anxiety, and folks start telling me things like, "Man, I think I feel like myself. I don't think I felt like this since I was 18. Since I was in high school, or before COVID," if you will. And people start feeling like themselves. And often they say something like, "Man, why didn't we do this earlier." I know, I completely get it, but look, I'm glad you're feeling better now. And we'll keep moving forward. But overall, these are solid medications. And they, of course, go very well with therapy and what you all do and they can work hand by hand and be a dream team.

Tyson Conner  1:12:03

Yeah, I love that as a way to wrap up, because that definitely fits my experience as someone who doesn't prescribe these things, but does see people as they benefit from them. And I want to acknowledge for the Listener's sake, we have really scratched the surface here. We've talked a lot about SSRIs today, how they work - as far as we know - what sorts of things they work on, how to get started on them, how to get off of them, things to be aware of, things to talk to your prescriber about. Listener, we have pages of notes that we didn't get to. If anyone listening to this is interested in hearing more about SSRIs, email us and let us know. And we'll bring Mati back on. In the meantime, do you have any experiments or further learning to recommend to our Listeners, with the understanding that, Listener, we will never recommend you experiment with drugs.

Mati Massaro  1:13:02

I think my experiment for anybody who's interested in this topic, and/or possibly experiencing concerns related to anxiety, depression, trauma, OCD, is to communicate - just like we were saying before about other things - bring it up, bring it up with your therapist, with your med provider. Open that gap, open that channel and have a discussion about how this may be or not be beneficial for you. And how getting some answers could be the starting point for hopefully feeling a little better, a little more in control. And, you know, not leaving that grey joyless, flavorless life anymore.

Tyson Conner  1:13:50

Yeah. And then what if people are just more intellectually curious? Maybe they are interested in taking meds? Maybe not. But this idea, that this conversation is fascinating to them? Where would you recommend somebody get started to just keep learning more about this stuff?

Mati Massaro  1:14:07

Yeah. You know, there are multiple pharmacology books and different source materials that come to my mind. At times, those might get a little too technical for folks who want to get their toes wet, if that makes any sense. And that's part of what I'm trying to work on. I'm trying to work on digestible information for patients and clients and a little bit of, maybe material for therapists like you were mentioning before. Before going into psychiatric nurse practitioner, I was a clinical psychologist, and I think there might be a little bit of a disconnection between the world of therapy and medications that I'm hoping to provide some material that bridges both worlds.

Tyson Conner  1:15:01

Yeah. So watch this space Listener. We will let you know when Mati produces any materials, whether it's videos, other podcasts, handouts, websites, books. Next time you're published, we will advertise it on this podcast. Thank you so much for coming in today. This was a fascinating conversation. I'm very excited for more. Thank you. This was delightful.

Mati Massaro  1:15:29

Thank you, man. This is always fun.

Tyson Conner  1:15:34

Special thanks to Matias Massaro, Mati can be found at his website, cogniahealth.com where he publishes articles, infographics, videos and podcasts, educating providers and the public about psychotropic medications. The link to his website is in the show notes. Also in the show notes is a link to the radio lab episode about the placebo effect, which I mentioned earlier in our conversation. The Relational Psych Podcast is a production of Relational Psych- a mental health clinic providing depth oriented psychotherapy and psychological testing in person in Seattle and virtually throughout Washington state. If you are interested in psychotherapy or psychological testing for yourself or a family member, links to our contact information are in the show notes. If you're a psychotherapist and would like to be a guest on the show or a listener with a suggestion for someone you'd like us to interview, you can contact me at podcast@relationalpsych.group. The Relational Psych podcast is hosted and produced by me, Tyson Conner. Carly Claney is our executive producer with technical support by Sam Claney and Ally Raye. Our music is by Ben Lewis. We love you buddy. See you next time.