Ep 183 SSRIs Part 2: Action

with very minimal relief. I attempted to explain my fears to pediatricians and school counselors, but I was never given any real concrete answers. I began to believe this was just who I was. College is when things began to worsen. When the pandemic hit in spring of twenty twenty, my anxiety exploded. I remember obsessively locking my windows and shutting the blinds, convinced that someone'd break in or try to

bring the virus inside. I was diagnosed with an adjustment disorder and was even taken off my birth control because that was believed to beet the issue. Eventually, in the fall of twenty twenty, I was able to get an appointment with our head college doctor. She truly listened and said, I think this might be an anxiety disorder, and she started me on fifty milligrams as Soloft, and for the first time, I felt like I could breathe. I had very minimal side effects, only some sleepiness and some GI

upset for the first two weeks. The next fall, I began wondering if it might be OCD. I began tracking my thoughts, looking into patterns, but unfortunately, in the spring of twenty twenty two, my depression took over. My depression manifested into intrusive thoughts, telling me to hurt myself, even though I really didn't want to. I knew something was really wrong, and so I went back to my head college doctor. She increased my soul off to one hundred

milligrams and that definitely helped. Still, none of my doctors felt qualified to diagnose OCD. My pediatrician later admitted she had suspected it for years. In twenty twenty four, one year out of college, I finally got my OCD diagnosis for my current therapist. My new primary caper provider was really thrilled to hear this and one defy me a

regimen that worked. So typically for OCD, you give the patient a top dose of their preferred SSRI, but for me, she kept me on my one hundred milligrams of zolof and added a dose abuse bar and that worked for me. In my thoughts got quieter and I was able to finally start making progress again in my OCD therapy. SSRIs have truly changed my life. I used to spend every day fighting my own mind, and now I'm able to achieve goals that I had set for years, such as

applying to medical school. I'm really lucky to have had very few side effects and not have to go through many different medications. I really cannot imagine going back to a life where I was not on SSRIs. They don't just help me function, they have given me back my future.

to people for things I imagined i'd done. I was diagnosed with obsessive compulsive disorder and originally tried to manage it with just cognitive behavioral therapy, which helped a bit, but it reached the point where I was very unmanaged and was having suicidal ideation and thinking I had to

drop out of school. So I began to use an SSRI, and after the first few weeks when it started to take effect, I had this amazing experience of that used to be thoughts that I would obsess over and would ruin my week because I would spend all of my time in service of those obsessions. Now, as the SSRIs kicked in, my brain would just sort of slide off of those thoughts and I could go on to do

other things that day, and it was really wonderful. So with that under control, I was able to complete my master's degree and publish some work from that, and after several years of being under good control, I've been able to start studying for my PhD. So I'm very fortunate that for me, SSRIs have not had substantial negative side

effects and that they've been effective and helpful. And because of that, I've been able to really enjoy my work and do research that I think is significant and impactful for the world, while actually getting joy from that instead of just anxiety.

other reasons for that, which I'll get into. So I want to start by just setting the stage for what I am actually going to cover today, because it's a lot of things and not a lot of things at the same time, huh. I'm tempering expectations. That's what I'm doing. I will not just end with we don't know how these work, Okay, Okay, though I will probably still say

that a lot of times as usual. But this is not an episode where I dive deep into the neurobiology of depression or anxiety, because those are topics that deserve their own episodes, definitely, and we'll have them at some point. I Am not going to get super nitty gritty on the five HT one A autoreceptor blah blah blah. Like we're talking. There are so many serotonin receptors and I'm not gonna I'm not gonna get us, you know, up

to our eyeballs in it. Okay, okay, But my goal is to give us all a real sense of how we actually use SSRIs today, Like how are they used in kind of clinical practice? How are they thought of? Not in social media circles or political circles or popular media circles, but how are they thought of by the medical and scientific communities that use them and that research them. What do we think that we know about how they are treating the disorders that we use them for? Are

they effective? And what does that mean.

depressive disorder or MDD, but there's others. There's persistent depressive disorder, there's design yet like there are a lot, Okay, and also first line one of the possible first line therapies for anxiety disorders, of which there are many, Generalized anxiety disorder,

Social anxiety disorder PTSD, OCD and more. If anyone listening needs convince sing as to the importance of these mental health disorders, the Global Burden of Diseases study from twenty twenty two, which importantly includes data only up till twenty nineteen and does not include the massive increase in mental health disorders worldwide that we saw due to COVID, But in twenty nineteen, depression and anxiety were top ten causes

of disability adjusted life years in adolescence and adults worldwide. Self harm behaviors, which often coincide with depression, was the third leading cause of disability adjusted life years in adolescence age ten to twenty four. Yeah, gosh, And there's no evidence that these disorders are decreasing over time. If anything,

they are on the rise. Anxiety disorders and depressive disorders are estimated to affect three hundred million people each worldwide, with an estimated lifetime prevalence of depression of close to twenty percent like lifetime risk.

But in this study, which looked at like I think a five year period helps, seeking behavior has not been increasing, right And in a lot of studies, less than half of people with depression reported having spoken to any healthcare professional about their depression or receiving any treatment for their depression.

In Europe, according to the European Psychological Association, Nearly one in five people is diagnosed with depression at some point in their lives, so that's pretty much that twenty percent lifetime prevalence, and they estimate twelve month prevalences of depression around six percent, and anxiety in the UK is estimated at around four percent, with worldwide estimates that vary from

like one percent to about six percent. And like I mentioned last week, depression and anxiety often co occur, and when they do, it can be more refractory to treatment, especially when it comes to depression that like overlaps with anxiety.

in things that you used to like to do. There's energy issues, so you don't have as much energy as you used to. There's issues with concentration. There's actually feeling depressed, like having a low mood or maybe crying more easily than you used to. There's appetite issues, which could be

eating more or eating less than you usually would. Sometimes we see psychomotor issues, so walking or moving very slowly or like more rapidly than you used to in the case of like anxiety for example, okay, and then there of course can be thoughts of suicide or suicidal ideation when it comes to anxiety kind of one of the biggest ones is generalized anxiety disorder, and there's separate criteria there, but a lot of it comes down to are you

worrying about things like unnecessarily? Are you not able to sleep or you know, do the things that you need to because you're up all night worrying, so you're having insomnia? Are you And what's really important and that's not an exhaustive list, but there's a bunch of different questionnaires basically that you go through and you have to score certain

scores in order to meet criteria. But the thing that's important about all of these, almost all of our mental health disorders, is that one of the criteria in order to diagnose them is they have to cause some kind of functional impairment, which means that the last question on any of these questionnaires, whether it's an anxiety questionnaire depression questionnaire, is how much is this How difficult is it making

your life? How difficult is it making you to be able to do your work, to be able to do your home life, to be able to do the things that you need to do right? And that is the kind of like final criterion. So that's like a very brief overview of how it's not perfect with us, how we define a lot of those things. And I've got papers you could read more. Okay, okay, So full disclosure. Also because we use SSI eyes for anxiety disorders as

well as depressive disorders, yea. But a lot of the data on them and a lot of the like mechanistic looking into how do they work relates to how we use SSRIs and think about them for depression. So that is most of what I'm going to talk about, but I will also mention their use in anxiety, and know that a lot of the data in terms of like is it effective or not, how much of a placebo is there or not, it's also true in anxiety the numbers might be slightly different, but I'm mostly focusing on

SSRI I use in depression. They're also really important for anxiety.

monoamine hypothesis of depression. And like you told us last week, Aarin, this is not the cause of depression. Serotonin decreases in serotonin is not the cause of depression. But it has led us down the road of understanding a lot more

more about depression than we used to. And because all of the different antidepressants that we use, including the kind of what are called atypical antidepressants that are not SSRIs or SNRIs, all of these, even the new fancy ones that people are very excited about, like ketamine and like zilocybin, all of these, to some extent or another, do in fact modulate some of our monoamine neurotransmitters serotonin, yes, also

nor epinephrine and dopamine. Okay, So clearly there is something to the fact that these monoamines are involved in depression and anxiety and modulating these to one degree or another can help reduce the symptoms of depression and anxiety, even if we don't quite understand why or how. So to do a quick recap on what serotonin is so that you know how it's working in our bodies, I'm gonna actually take a quick step back and just talk about the idea of a neurotransmitter because I want to be

able to explain what they're doing in our brains. Yeah, okay, And we've talked a lot about neurotransmitters on this podcast, like I've said the word a lot. But let me recap what these really are. These are compounds. These are chemicals that we make in a bunch of different parts of our brain and throughout our body. Serotonin, like ninety percent of our serotonin we actually produce in our gut, in neuroendocrine cells in our GI tract.

There's a gap called a synapse or between a neuron and say a muscle, right where it's going to have an effect, and signals are passed in our neurons and in our brain with electricity essentially, And when these signals get to the end of a neuron, in order to cross that gap, that synapse and send the message onwards,

these electric signals have to be transmitted via chemicals. Chemicals are released, they cross that gap, bind to receptors on the other side, and whatever neurotransmitter is released and whatever receptor it binds to sends whatever message it is that we're trying to send. Is that right? Generalized enough?

involved in our clotting cascade. What so, serotonin is truly everywhere. Selective serotonin reuptake inhibitors or SSRIs are drugs that bind to a transporter protein on the presynaptic side. That is where we are releasing serotonin from on our nerve cells on our neuron, and this transporter's job is usually to collect the serotonin after it's been released. The catcher, the catcher, exactly. Wow, we're gonna keep going the baseball analogy.

that might be the end of it. So what these drugs do is they bind to these transporters and block them so we cannot re uptake, repackage this serotonin back into the presynaptic part of our neurons. What that means is there is an increase in serotonin in this synaptic space, this extracellular space. Okay, that is how they work mechanistically, all right. So the thought was, okay, we're increasing serotonin

in the extracellular space, and that is improving depression. But like you mentioned aarin, that happens pretty quickly after the introduction of SSRIs. But the effects that we see in terms of its improvement these drugs improve on depressive and anxiety symptoms takes some time, and so that tells us that it is not just increasing this extracellular amount of serotonin. There's actually a lot more complicated mechanisms that happen because, surprise, surprise,

our brain is a complex creature. What I know, right, So what ends up happening is that the parts of our neuron that usually release serotonin m hm, the picture, I guess. I know this is really getting out of control here.

all of this serotonin. Because there is an increase in the synaptic serotonin, they also kind of modulate their sensitivity to that serotonin where they're like, I'm not gonna swing at every ball. That's a really bad analogy. But the receptors aren't going to bind to every molecule of serotonin

because there's so much out there. Because there's more out there, okay, and because our brain is trying to keep things to some degree homeostatic, it recognizes, Hey, there's been a shift in something, and we don't want that to get out of control.

what else is going on? And the more that we have started to look at it, what we also see is these downstream effects because it turns out that SSRIs and a lot of other antidepressants, they end up modulating by one degree our gene expression. Okay, okay, let me tell you what I mean by this. Yeah, okay, Because serotonin and other monoamines are involved in so many different processes.

Down the line, antidepressant drugs seem to have effects on adjusting the upregulation and down regulation of other factors that are produced in our brain. So the drug is not doing this but downstream over time. I know your face is like, this makes no sense.

changes in gene expression. We see increases in things like brain derived neurotropic factor or BDNF, as well as other growth factors, vascular endothelial growth factor, genes that are linked to neuroplasticity, activity dependent genes, other signaling molecules, and antidepressant treatment is associated with a wide array of changes in gene expression, and we think that some of these might be mediated by other serotonin receptors, not the transporter that

is being affected by the drug itself, but by various other serotonin receptors, because there are literally dozens of different types of serotonin receptors in different parts of our brain and different parts of our body who do different things. Okay, so once you've then increased the amount of serotonin down the line, what other receptors are some of these serotonins acting on that is changing other pathways in our brain.

especially with treatment resistant depression. Both of these have actions on a lot of different receptors and are not mediated directly through serotonin, but they do seem to have action on other types of serotonin receptors that more directly modulate

things like neuroplasticity. And the more that we look at things like neuroplasticity, which is your brain's ability to kind of change and like continue to change over time, the more that we think that that is very, very involved in depression and anxiety.

that are other serotonin type receptors. Yes, okay, so it would be like, here's my baseball analogy if we could, if we could continue, it would be like if you're changing the settings on that pitching machine, and that pitching machine is then being like send out fewer balls in decrease frequency. Wait, and then those settings though, are also somehow impacting the tennis court and the soccer ball court or the soccer field, and the basketball court and the

pickleball because everyone's into pickleball. It's all of those things.

perceptive state. Right, So, like how we perceive positive versus negative stimuli, which then makes it easier for our brains to are interpreting things with a positive bias rather than

a negative bias in our emotional processing. And we can actually see some of that like positive versus negative stimuli bias change even with like short term, like really short term, like like a couple of days or like one dose of SSRIs and so then is it that change in bias over time that allows us our brain to but we don't know. Okay, this is some of our ideas. Okay, So that's what we know about SSRIs and how they work. Can Can I be done with the brain part for now? Okay?

depression score, it's usually the Hamilton Depression Rating scale. It drops below a threshold usually seven. It means you don't really have any symptoms of depression. There's also response, and response means that you've got a fifty percent reduction in your score or in your symptoms. Okay, so there's two different metrics remission and response. Neither of these specifically address the fact that depression is defined by its effects on your life and function.

many ways that all of these studies are flawed. But I'm just going to give you the data that we have in studies that have looked at people on like a wait list or what they call care as usual, which I'm not even sure exactly what that entails. Basically, people who are in a study about depression but who are not getting any specific depression treatment. Short term rates of remission over like three months or twelve weeks or

so range from about twelve to twenty percent. So about twelve to twenty percent of people who are in a study about depression not receiving treatment will get better, will have remission. Long term, we think that about half of people fifty percent or so will have remission of their symptoms.

second episode at some point in their lives. Okay, Then if we look at placebo controlled studies, because all of these pills had to be tested against placebo pills, sugar pills, and there is so much out there about the placebo response, but in these studies, placebos tend to have a response rate, so that means a reduction in your symptoms at twelve weeks.

Because almost all these studies are short term of about thirty five to forty percent on average, so thirty five to forty percent of people in a clinical trial that are given a sugar pill to treat their depression might improve in their symptoms. Only about twenty percent might meet that remission threshold.

does that mean overall? What it means is that on the whole, SSRIs are consistently and significantly better than placebos alone.

thirty percent remittance rate rate at eight weeks or so. Okay, so better than placebo again and relatively comparable honestly to SSRIs.

very severe depression. Certainly, they don't include people who have SEU sitle ideation, because that would not be considered safe to like not offer someone any treatment ethical, Yeah, And so similarly, like there can be a lot of variation, there's also a ton of variation in like how people are doing these studies, like the settings and everything. And when we're thinking about placebo responses, which is a combination of the effect of someone taking a pill that doesn't

actually have anything in it. That's the placebo effect part, okay, but the response that we see is also the setting of a clinical trial where participants having regular and frequent contact with a healthcare environment, where someone is asking them, often on a weekly basis, how are you, How is your mood? Please fill out this questionnaire about how your mood is. Check in with yourself, chork in with yourself,

check in with me who's asking you these questions. You're also having an expect dictation that something could help, right, and so we know that all of that is going to like, I mean from the data that those things are effective for some people in improving symptoms of depression

and anxiety. And still on the whole, the improvement rate of SSRIs over placebos is significant in terms of whether you're looking at effect size, whether you're looking at the response and remission rates in terms of percentages, the other thing that we can calculate from this, And I think this is an important number because some people with depression or anxiety will improve on their own without any treatment.

Some people with depression or anxiety will improve if you give them a pill or a something that says this will help you. And some people will improve because of the effects of the SSRIs.

of about five. So for every five people who are in therapy or who are prescribed therapy for their depression, one person will improve who would not have approved otherwise. And for SSRIs it's like seven to nine.

months of therapy. Okay, so there is good data to suggest that you want to continue therapy for at least six to twelve months to reduce the rate of relapse. It does not mean that someone wouldn't have another episode in the future, but that can kind of help to prevent that.

be more likely to see sustained improvement. But there is a big study that was a pretty huge moment in like depression research that tried to look at more real world scenarios. And I'm not going to dig like super super deep on this study design. I do link to it, and there's been a ton of papers published from it. It was called the star D Trial, and this was pretty huge because A it was a very large study. B It included a much more realistic sample of people

who were experiencing depression. It was like community based kind of where it wasn't just you know, it included people who had comorbidities, who had other mental health disorders, who had substance use disorders like it just a more realistic sample than was usually included in these pharmaceutical trials. And then it walked them through this kind of step wise therapy where we see, we give everybody one drug, and then we see who responds and who doesn't, and then

if they don't respond, then we randomize them. It wasn't perfectly landom but we randomize them to a bunch of different possible treatments, either stop that and switch to something new, or add things or add therapy or whatever it was. And then after level two they go to level three, level four. There was like four levels overall. Bottom line results from this were that about one third of people reached remission with only the first line SSRI, which was

satalopram in this case. Okay, by the end of the second stage, the cumulative remission rate was fifty percent, and by the end of the study about seventy percent of people. So if you went through all these different possibilities, about seventy percent of people had remission. Again, that doesn't mean

they might never relapse, but it certainly is meaningful. Now, before you even ask a question, I have to caveat this because the study is old at the point and a more recent kind of renalysis, and I will say by people who seem to not like SSRIs based on all their other published papers, but they reanalyzed this data and actually estimated a slightly lower remission rate. So they said, no, it wasn't you know, a third of people. It was actually like twenty five and a half percent after that

first level. So one SSRI trial and then they estimated only about a forty percent response rate by the end rather than seventy percent. Interesting hm, but either way, it is a much more realistic, real world trial that tells us a few things. One, it tells us that not everyone is going to respond to the first SSRI that they try. Yeah, period, we know this very true. It tells us that they are still effective for a substantial

portion of people. Like some might say, twenty five is not that much, but if you are in that twenty five percent and your depression is is remitted because of this, and usually on a much faster time frame than what we would expect if someone has no treatment whatsoever. Yeah, right, that is meaningful, right totally. What were you gonna ask, Karin?

some of them make you less sleepy. We know why, no, no, no, we don't know why for any of these. Some of them are gonna some of them can cause weight gain, and some of them have much less seem to cause much less weight gain. Some of them, like cetalapram, for example, at higher doses and especially in elderly populations, we have seen that it can cause some effects on your heart. It can prolong your QT interval, which means it could potentially put you at higher risk for a heart condition

in the future. We don't see that with all of the ssries. And then in terms of so a lot of it comes down to the side effects, So the side effect profiles can be different for different, you know, specific ones.

were comparing like side effects versus efficacy. Yes, yeah, but there is not like a oh my gosh, this is the clear winner or anything like that.

on searchralein. But is that again part because of an expectation and because of a familiarity, or is it because of some genetic predisposition things like that.

be transient. Usually improves. Sexual dysfunction, though can be a huge downside to SSRIs, and this can affect any part of like your sexual cycle, from like desire or libido to ability to achieve an erection or to achieve orgasm, which can be pretty debilitating, especially because depression and anxiety can also affect sexual sexual functioning. It does not, though, happen to everyone who is on an SSRI, and we can't predict who it's going to happen to and who

it won't. It usually does not get better though while you're on it, in contrast to the GI side effects.

bipolar disorder. SSRIs can potentially precipitate a manic episode, and so they're not usually used in bipolar depression and there are caveats to every role when it comes to that. But probably the most headline generating warning or side effect as it relates to SSRIs is its relationship with suicide and suicidal ideation. Yeah, an increase in suicidal ideation is often it's a black box warning now on all SSRIs.

The data suggests that this might this association might exist like exposure to SSRIs and an increase in suicidal thoughts or attempts at suicide might exist for pediatric and adolescent populations, right, Yeah, the evidence in adult populations looks like there is actually a decreased risk of suicide, especially in the older populations, like in our older adult populations over sixty five, but in adults over age twenty five, twenty five is the cutoff.

There is not an increased risk of suicide that we see with SSRIs. There may be in those under twenty five, and that still doesn't mean that we don't ever prescribe them because in some cases they still can really help with all of the other symptoms of anxiety and depression. So yeah, but it is like it's an important that is why it's a black box warning, and it's an

important thing that people are really looking into. There are a lot of other potential harms that have been scrutinized very deeply in their literature in these like large scale observational studies to try and figure out long term are there other detrimental effects to SSRIs, And all of the rest of them don't hold up to scrutiny, They don't hold up to the statistical analyzes. There's like, is there effects on autism rates or ADHD rates? In people who

are pregnant who are on SSRIs. So far, those don't hold up to the statistical analyses. It doesn't mean there's not some suggestion, but there's there's not like a clear consensus at this point.

have way too much serotonin. And then there's a mnemonic that I'm sure I learned in med school, but I didn't write it down, so I can't tell you the exact symptoms of it, but it's like it can be quite dangerous. It's an emergency room situation. It is still safer again than overdoses of other older antidepressants, and it is a treatable condition. But one concern is not necessarily like overdose. But when a person is on multiple serotonergic medications.

migraine and sometimes for neuropathic pain or for ibs. And so if you're taking multiple different medications, which we very often see in our elderly populations, you do have to think about how many of these might have effects at some point on serotonin or on serotonin receptors. Because some of them, like zofrin, acts on serotonin receptors.

around SSRIs. There's so much noise, and I think what gets lost in that noise is the signal that for many people, SSRIs are very effective. For many people, maybe they want to weigh the pros and cons of SSRIs, but it's like there are these sweeping statements yes that research groups I think there are one in particular I'm thinking of wants to make and that are harmful. Yeah, SSRIs are not more effective than placebo, which is not.

biology of these conditions. We do not know what these mechanisms are. We do not have biomarkers or tests that we can run to diagnose these conditions. We don't even have a measurement that is not subjective, right, because these are disorders that we diagnose based on timeframes, based on questionnaires of symptoms, and based on their effect on our daily lives and our ability to function. So of course we cannot expect to fully understand how a drug is

working if we don't understand the disease that we're treating. Yeah, and at the exact same time, we cannot ignore, refuse to treat, or withhold effective treatment from millions of people just because we don't understand the mechanism. So I really want to provide everyone a compare contrast. And some people might get mad and say that's apples and oranges, to which I say, those are both fruit, Okay, so allow me to tell it.

one is targeting the primary cause of hypertension. Because we do not know what the cause of hypertension is and it goes further erin not everyone who receives the same benefit from one anti hypertensive is going to receive it the same way. In fact, only twenty five to thirty percent of people with hypertension are going to have their blood pressure controlled with a single agent. Most people are going to require at least two, if not three. The

same can be said for antidepressants. No, we don't understand how they work, because we don't understand depression, but we do know that a substantial proportion of people who try one will derive benefit from it, and those that don't might benefit from a different version of one or a different type of antidepressant. And this is not just because of a placebo effect.

and here's an imperfect solution. That's some that can work for some people.

therapies for mild to moderate depression over SSRIs. But realistically, a lot of people either do not want that, or are not ready for that, or cannot do it because their insurance won't cover it because they always going to provide her because they don't have a time right.

That's probably worth it. Right. We don't have as good of data on the long term effects of treatment versus non treatment and things like that when it comes to depression and anxiety because who's going to fund those studies? Who's going to put up the money for that? Right?

So that I think is another part of this problem is that there is a lot more data that needs to be gathered and a lot more understating that we need of these medicines and alternatives because treatment resistant depression is very real and affects a huge proportion of people. So yeah, there's still a lot but SSRIs are safe and they're effective for a life people.

But that needs to come because we have found better, more effective alternatives, because we've invested in mental health research and in expanding access to services, in normalizing therapy, in taking time off work to do these other things, and because we come to a better understanding of the causes of depression and we have safer, more effective medicines. Not because we lie and say that SSRIs are addictive, They are not there is no data for that that they're

dangerous like Heroin. They are not right like they. This needs to happen for good reason, not just taking something away that has been life saving for a lot of people, even though it is imperfect.

section on the efficacy and effectiveness studies. I've got a separate section on looking at the placebo responses versus efficacy studies, another section on papers specific to children and adolescents. Because it is a very different kind when we're talking about these medicines and children and adolescents and we have less data, and like I said, there's more potential for risk, and that doesn't mean they're not used. I have a few papers on long term data, not great, but I have some.

I have more than I realized actually, And then other papers on untreated depression. I'm just scrolling through all of these areas.