The Serotonin Hypothesis: Controversies and Nuance with Awais Aftab, MD

Is depression really caused by low serotonin? Dr. Awais Aftab joins Dr. David Puder to explore the serotonin hypothesis, antidepressant efficacy, and the controversies surrounding SSRIs. They dive into the history of the serotonin deficiency theory, key research on antidepressants vs. placebo, and how neuroplasticity, psychotherapy, and lifestyle changes factor into depression treatment. The episode also examines differences between major treatment guidelines, including RANZCP and NICE, and what the latest evidence suggests about the future of mental health care. By listening to this episode, you can earn 1.25 Psychiatry CME Credits. https://www.psychiatrypodcast.com/cme-program Link to blog. https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-235-serotonin-hypothesis-controversies-awais-aftab Link to YouTube video. https://www.youtube.com/watch?v=zrHrjQOIqhw Links for Dr. Awais Aftab: Substack https://www.psychiatrymargins.com/ World Psychiatry https://onlinelibrary.wiley.com/doi/full/10.1002/wps.21194 Conversations in Critical Psychiatry https://www.amazon.com/Conversations-Critical-Psychiatry-Awais-Aftab/dp/0192870327/

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:14David Puder?

  All right, welcome back to the podcast. I am joined with Avess Aftab. He is a psychiatrist in practice in Cleveland, Ohio. He is into psychiatry and where sort of anti-psychiatry meets psychiatry. He is a practicing psychiatrist who runs an IOP partial program with about 40 patients. He publishes on the psychiatry and philosophy. And he has a very popular Substack. What is it called?

• 0:45Speaker 01

  Psychiatry at the Margins.

• 0:47David Puder?

  Psychiatry at the Margins. I wanted to get that right. And he also is very popular on X, formerly known as Twitter, with about 23,000 followers. He often engages topics that are conflictual with nuance and articulation. And I am happy today to have him on to talk about the serotonin hypothesis and antidepressants. And we have, or he has pre-written, which I have commented on, a article that is 21 pages right now. And it goes through all of the different articulations on this, the different theory, the conflicts in the theory,

• 1:31David Puder?

  and the main article, Moncrief et al., 2022, which we'll be talking about, which was a meta-analysis and critical review, and then people that countered that. So I hope this is a discussion that's helpful for you. And so, welcome to the podcast.

• 1:48Speaker 01

  Thank you, David. A pleasure to be here.

• 1:51David Puder?

  So yeah, let's talk about the why this is an important conversation to have today. I feel like this, you know, someone who is on X quite a bit, there's, there's kind of this new push against antidepressants that we should get rid of them completely almost. And lots of antipsychiatry folk often saying things like, you know, this is, there's, there's no research behind this and such. So tell me from your perspective, why this is an important topic to talk about today?

• 2:19Speaker 01

  Yeah, so a number of forces have been developing and kind of converging over the years to create the situation where antidepressants have come under immense scrutiny. And people have very strong and heated opinions about these issues. And, and part of this has to do with the fact that there, there, there has been a general sentiment that antidepressants are over prescribed. And it is the case that many adverse effects of antidepressants have, have historically been neglected or not as well recognized. So in particular, issues with regards to antidepressant withdrawal, issues with regards to sexual dysfunction.

• 3:00Speaker 01

  So given the large number of people who are on these medications, we have growing numbers of people who have had very negative, you know, in some cases, life derailing, negative experiences with these medications. And so there has been a growing sentiment that, you know, these medications are dangerous in some ways and, and that the profession has not been, has not been paying attention to that. And there are other kind of academics, sometimes politicians, political commentators who have been cashing in on that resentment that has been building against antidepressants and to, to kind of generate more and more provocative claims. So this has happened in the scientific world where people have advanced scientific critiques

• 3:45Speaker 01

  against, you know, the chemical imbalance, the so-called chemical imbalance, or the serotonin outbursts, they have advanced critiques against the efficacy of medications and they have generated debates around how antidepressants work, if they work at all. And then on the, on the political side, there has been an emerging tendency, especially among right wing commentators, to, to see antidepressants as a false solution to life problems. And, and people have been eager to blame antidepressants for things such as, you know, gun violence, school shooting, et cetera. So, so the end result is that

• 4:25Speaker 01

  a number of different people with, with their own different agendas have developed some solidarity around characterizing antidepressants as a threat.

• 4:35David Puder?

  Right. And so, okay, just real quick, do you have any conflicts of interest?

• 4:40Speaker 01

  No, no.

• 4:42David Puder?

  Do you have any pharma companies that are paying you to come on this podcast?

• 4:45Speaker 01

  No, yeah, no.

• 4:46David Puder?

  Okay. Have you, have you never, have you ever received any pharmaceutical money?

• 4:51Speaker 01

  I have not, yeah.

• 4:52David Puder?

  Okay, me neither. I have no conflicts of interest either. So we're going into this as, as intellectuals. And I've even heard online, like, was your residency paid for by pharmaceutical companies? Did the, did they deal, did they create the, the curriculum of your residency at all? Do you know?

• 5:12Speaker 01

  And there was no influence at all during, during my residency training.

• 5:16David Puder?

  Me neither. There was no, there was no drug companies paying for meals for us and stuff like that. Okay. So I think that's really important to get out of the way there.

• 5:25Speaker 01

  Yeah.

• 5:25David Puder?

  And then the other thing is, I've, I've covered mass shooting. I've had two experts on, I even published on my website, every single mass shooter, what medications they were on. There's, they were on all sorts of different medications. And not all of them were on medications. And there's no link, there's, there's no like one type of medication that they were on. Some of them were on months before, some of them not on at all, some of them were prescribed, never take. But yeah, there is this interesting thing with mass shooting and medications that like, oh, it's because of the medications. But, and I, when I first heard this, I was like, oh no. Like, I was really scared. I was like, I, I don't want to give something that contributes to that. So I really looked at this.

• 6:08David Puder?

  And didn't find anything. Anything you want to comment on that before we jump into the the bigger?

• 6:12Speaker 01

  No, I I agree. I think, you know, anyone who has looked at this issue with with an open mind and, you know, some kind of neutral objective perspective has come away with the conclusion that that that there is no solid or reliable link between antidepressant use and and any of these kind of instances of school shooting or gun violence that we have been seeing.

• 6:30David Puder?

  Yeah. Um, okay. So we're going to zoom in on serotonin today. Serotonin, the serotonin hypothesis. So so break this down. What is the serotonin hypothesis?

• 6:43Speaker 01

  So people have, you know, talked about a serotonin hypothesis, or in some cases, a serotonin theory, but in the literature, there's actually no precise or single articulation of what that is. So when we talk about serotonin hypothesis, we're talking about a vague cluster of ideas that that are linked together in which serotonin plays some kind of a role either in the either in the ideology of depression or in the in in the manner in which how antidepressants work. This all got enmeshed in the in the late 90s through the pharmaceutical industry

• 7:24Speaker 01

  advertising trope of chemical imbalance that that then became a more widely known cultural idea as well. And even many physicians started using that language in in their communication with patients. The the most concrete understanding that that some people had of that of that idea was that depression is caused by a deficiency of serotonin, that there are lower levels of serotonin in the brain or in in synapses, and antidepressant medications correct that deficiency by boosting the levels of serotonin. So when when a lot of people hear serotonin hypothesis, serotonin theory, that's what that's the idea they they think of immediately.

• 8:05Speaker 01

  But in but that kind of idea was recognized even in the 90s as most likely false because because research had not really supported that. In fact, researchers were considering other Aspects of serotonin functioning, they were looking at, for example, receptor distribution, receptor sensitivity of, you know, within the serotonin system, they were, they were looking at how, how different people are susceptible to things like tryptophan depletion. And whether this is something, you know, that predicts the onset of depression, or whether this is something that is more of a general risk factor. So, so they were trying to examine what kind of alterations can exist in the serotonin

• 8:49Speaker 01

  system in the depressed, you know, individuals. While at the same time recognizing that depression is not one thing, that depression is a heterogeneous cluster, it's a heterogeneous syndrome, different people, you know, become depressed to different pathways. And the idea was that some of these pathways perhaps involve alterations of serotonin. So, so people were studying that using different techni-, uh, different scientific methodologies. So there were pet receptor studies, there were tryptophan depletion studies. The, the overall quality of that literature is some, is somewhat weak, you know, characteristic of the scientific research of late nineties, early two thousands, you know, smaller samples, other metallurgical issues.

• 9:31Speaker 01

  But they do consistently, relatively consistently point towards some kind of serotonin alteration existing in some people. Then there's the, a broader kind of hypothesis, uh, uh, uh, under the umbrella of serotonin theory, which is that there may not be an alteration or abnormality of serotonin itself in depression, but serotonin pathways are generally involved in the regulation of mood and behavior. And because serotonin as a pathway is involved, it provides a target for us to intervene on. So, uh, so most of the, kind of, enter depression, second generation enter depression that were developed in nineties, two thousands are serotonin based or other monomeric based.

• 10:16Speaker 01

  So this broader hypothesis recognizes that they may not be correcting a deficiency, there may not be a serotonin deficiency, but they, they're still acting on those serotonin pathways. And through acting on those serotonin pathways, they're producing desirable therapeutic effect. So we have to keep these different types of hypotheses in mind and the range of them. So when people like Professor Moncrief and others say that a certain hypothesis doesn't have enough support or is being rejected, or when people say that chemical imbalance hypotheses have been rejected, they have to be clear about what it is that has been disproven, what it is that, you know, for which there is varying degrees of scientific support, and what are still the open scientific questions in this area.

• 11:00David Puder?

  Hmm. Yeah. When I, when I think about this, I think about, you know, it's, it's, there's a broader question of is depression a neurological thing? Like, are there neurological things going on in the brain when someone's depressed? Right?

• 11:17Speaker 01

  Yeah.

• 11:17David Puder?

  And one of the most convincing things that I've looked at when I've looked at this is, you know, the depression rates in people with brain diseases is actually a lot higher than in a normal brain, you know, a healthy person. For example, frontal temporal dementia, depression rate is 40%. Someone with cerebral basal degeneration, 73% of them have depression. Suicide rates and Huntington's disease is quite a bit higher. There's 50% rate of depression in people with Parkinson's disease, which, you know, have issues with dopamine. And the list goes on with Lewy body, Lewy body disease, higher

• 11:58David Puder?

  rates, people with strokes, higher rates. So there is stuff going on in the brain. The question is like, what is that stuff? Right?

• 12:06Speaker 01

  Yes. Yeah. And I think that there, you know, the, the mind-body relationship is, you know, it's a complex scientific and philosophical issue. But I think these cases where depression is clearly a result of, of medical, you know, general medical disorders or neurological disorders, to my mind, that provides clear evidence that there are pathways that are involved in regulation of mood and behavior. And sometimes these pathways can be disrupted by, you know, pathological processes, you know. So you, you mentioned a lot of these clear examples. Autoimmune disorders are another one, you know, very high rates of depression in people with autoimmune

• 12:47Speaker 01

  inner conditions. In treatment of hepatitis, for example, interferon treatment recognized as producing high rates of depression and hypothyroidism is a very well recognized. And in subsets of people with melancholic depression, we recognize that there is HPA axis dysregulation going on in the regulation of cortisol. So we recognize that these cases happen now. An average person with depression as a clinical problem is probably not going to have an abnormality of thyroid or abnormality of autoimmune processes. But but generally, when we look at depression as a syndrome,

• 13:29Speaker 01

  we can see that all of these biological pathways are involved.

• 13:34David Puder?

  Yeah. And then there's another group of people who think like, oh, it's just trauma, right? Any any any mental health issues, just trauma. And I did a huge deep dive on adverse childhood experiences and their lasting impact. And, you know, we know that if you have the more adverse childhood experiences, you have the higher the risk of pretty much every mental health issue and every physical issue as well, right? So it's, of course, it impacts, like even things like cancer. It doubles the rate of cancer. It doubles the rate of skeletal fractures. But it's not one equals one, right?

• 14:15David Puder?

  So it just increases the risk. It doesn't necessarily doom someone to a specific issue.

• 14:24Speaker 01

  I agree with you. Yeah, I mean, the association between childhood adverse experiences and, you know, not just depression, but but other other mental health problems is pretty strong and robust. But even there, the effect sizes usually tend to range from point three to point four, you know, kind of in the in this mediumish range. And the most consistent evidence tends to point not towards the adverse experiences themselves, but rather the Perception of those experiences. So for example, in prospective studies where they follow people who have had them. The association is weaker versus in retrospective studies where the kind of the report of these adverse experiences is based on the person's recall and their perception of it.

• 15:09Speaker 01

  The association is more stronger. So there's that aspect too. And if you, but it remains decades that, you know, adversarial experiences are some of the most, you know, important and well-recognized, well-replicated risk factors. But that's not the whole story. In fact, you know, probably some of the biggest risk factors that have identified are temperamental ones with neuroticism showing up in most studies as a pretty robust and reliable factor. So at the very least, we're looking at this interaction between neuroticism and other aspects of temperament with childhood experiences in combination with, you know, acute stressors and in combination with other

• 15:49Speaker 01

  biological risk factors, including genetics, but including immune factors and, you know, other relevant things.

• 15:58David Puder?

  Okay, before we get into the Moncler et al. Study, let's go through a couple of these studies on like Salvan et al. 2023, which basically shows that serotonin helps control impulses and also affects how we feel about rewards and our mood. Explain to me this study and why you think this is important.

• 16:22Speaker 01

  Yeah, so this study generally highlights it. It provides a good illustration of how serotonin system is generally involved in the regulation of mood and behavior. So research into, you know, behavioral effects of serotonin has been going on, you know, for decades. And sometimes there are kind of conflicting findings in the neuroscience literature. And people have been trying, figuring out ways how to integrate, you know, how this makes sense. So Salvan et al. 2023 paper is one of them in which they they use both kind of animal data as well as human data to map out.

• 17:02Speaker 01

  The functional connectivity of the serotonin receptor symptom and trying to see what corresponds to what. And basically, they find two different clusters of functional connectivity that are targeting two different types of problems or two different types of experiences. One aspect of serotonin functioning seems to be based on issues around impulsivity and aggression. Versus the other aspect of serotonin functioning seems to relate to kind of emotional processing, in particular, how kind of negative bias shows up in various kinds of information processing and reward processing. So serotonin seems to, one, inhibit impulsivity and inhibit aggression.

• 17:47Speaker 01

  And on the other side, it seems to shift emotional information processing into a less negative and more positive direction. So Salvenetall kind of showed that mapping based on functional connection. But then a later study by Kalvedal in 2024, they actually carry out this really elegant experiment in which they directly increase the level of serotonin in the synapses without using SSRI. So they use an alternative strategy of increasing serotonin levels. And similarly, they essentially find out the same kind of effect that serotonin enhances behavioral inhibition and that it reduces sensitivity for outcomes in aversive context.

• 18:29Speaker 01

  Basically, you know, showing its effects on emotional processing. You know, and these are just some of the more recent, you know, well-designed rigorous studies. There are so many others. And to my mind, the literature is very robust on this, that serotonin is involved in behavior. It's involved in regulation of impulsivity and aggression, but also regulation of emotional information processing.

• 18:54David Puder?

  Yeah, that's good. So low serotonin, being impatient or acting without thinking, or seeing rewards as less valuable. Is that a good summary of the first one?

• 19:06Speaker 01

  Yes, yeah. And so people who have reduced serotonin transmission, they tend to be more impulsive and tend to, you know, act out in an impulsive manner, aggressive manner, and they tend to interpret neutral stimuli, for example, in a negative, emotionally negative manner.

• 19:24David Puder?

  Yeah, and I was, I was thinking to myself, okay, what are all the animal studies that have shown natural things to increase serotonin? And I found things like exercise increase serotonin, and you know, there's a lot of other things, right, too? So it's not just, it's like, it's in there for a reason. We have serotonin in our brain for a reason, right? And we're just trying to like, figure this out. So these are good studies from 2023, 2024, coming after the Moncliffe et al., which was in 2022.

• 19:55Speaker 01

  Yeah, and there's a, there's a very rich, you know, biological history to the evolution of serotonin itself. You know, evolutionary biologists have been interested in, in, in the role serotonin has played, you know, in, in, in kind of behavior of biological organisms. So the, so the interesting thing is that Moncrief has publicly kind of made the claims that, oh, this, this whole kind of, you know, scientific literature on serotonin behavior is essentially junk and it's worthless. And the only thing we can confidently say is that serotonin inhibits sexuality. And this is, this is something she, she wrote herself and can comment. And it's hilarious to me, I, I get that, you know, that, that someone can say that, given the wealth of scientific literature we have

• 20:40Speaker 01

  on this topic.

• 20:41David Puder?

  So let's, let's dive into this specifically. Let's talk about what it did say. And then we're going to go through some of the main critiques of this article. So this is a 2022 umbrella review that focused on serotonin association, not antidepressant efficacy.

• 21:00David Puder?

  So it was really just looking at like, is serotonin associated with with different genetic things? Is it associated with different mood issues? So take me through the study and what it showed.

• 21:16Speaker 01

  Yeah. So the first thing to recognize that this is an this is an umbrella review, or what you can kind of a big picture overview of the literature. It is not a systematic review. So they did not kind of, you know, set out systematic criteria of, you know, kind of conducting a literature surf and identifying study. So it is not a systematic review, and it is also not a meta-analysis. It does not take data from individual studies and pool it together. Essentially, it is a somewhat narrative narrative style review of larger meta-analysis systematic reviews and large genetic data set studies, you know,

• 21:58Speaker 01

  that have been done, looking at, you know, various associations between serotonin and depression. So it outlines what those, you know, other systematic reviews meta-analysis that found, and then presents a kind of critical evaluation of those. And the main thing it highlights is that there's no evidence of serotonin deficiency or kind of, you know, reduced low serotonin in depression, which, you know, everyone, you know, even in the 90s was kind of agreeing that, yeah, there's there's no direct evidence of that. But then it kind of says that it says that there's also kind of no good evidence that serotonin abnormalities of any sort are, you know, have been associated with depression. And

• 22:43Speaker 01

  then in the in the discussion, even though the review itself is only looking at association between serotonin abnormalities and, you know, depressive, you know, diagnosis, it kind of implies that it generalized into saying that there's no relationship between serotonin and depression at all, and that it cannot be inferred that that antidepressants are working through their serotonin system. So even though they did not, you know, directly look at any of the literature around antidepressant mechanisms or antidepressant efficacy. So these these claims generated a pretty fierce response from from the academic and scientific community.

• 23:23David Puder?

  Right. Let me let me pause there and emphasize something. The author extended that antidepressants do not have a benefit and just cause a general blunting rather than an action, you know, on serotonin, right? So it's like, it's changing from like, this is association studies on serotonin to antidepressants, which she doesn't really go into antidepressant trials, right?

• 23:49Speaker 01

  Yes, she doesn't, yeah, and it's not. But she kinda, she gashes in on the, on the popular misunderstanding. So what is a layperson's idea of what an antidepressant doing? It is that, oh, there's a chemical imbalance and the antidepressants are fixing or correcting that chemical imbalance. So Moncrief essentially just kinda uses that, you know, same structure of argument. And she says, you know, well, if there is no chemical imbalance, then there is nothing to fix, you know, therefore, you know, it's questionable that antidepressants are effective or, or that they, they have any kind of specific serotonin related effects. I mean, it's a clearly fallacious argument. It's logically invalid and scientifically invalid, but, but that's what she uses.

• 24:32David Puder?

  Yeah. And I've been doing this podcast for like seven years and I would challenge any of my listeners to go back and find one time that anyone said this fallacious claim. So she's kind of, you know, that, that, that depression is from low serotonin in the brain. But this is, you know, this is how people think, right? This is, this is a very simplistic way. And I've heard patients say, you know, well, I need this because I have low, I have low serotonin in my brain. But this is not something I learned in residency. It's something that I learned that was a simple way that some people understand very complex things.

• 25:12Speaker 01

  Yeah, I agree with that. And I think because there's this disconnect between the academic understanding and the, and the general understanding, this became, this article, when it was published, became a viral sensation overnight because the, the media covered it as saying that, you know, the chemical imbalance hypothesis have been proven to be wrong and, you know, and they focused on, on the antidepressant angle, saying that. Antidepressants don't fix any chemical imbalance. And so, I mean, I think in retrospect, it's very clear that the publication of that article was used as a launching pad for a very effective media campaign against, you know, antidepressant use and also to challenge the general idea that depression is a medical problem or a medical disorder.

• 25:57David Puder?

  Right, which, which I come back to, well, lots of brain diseases have much higher rates of depression. There is, you know, especially when you have, I think to myself, every time I see someone in antipsychiatry, I'm like, let, open up a door that I could send you some catatonic patients and you will soon believe in the power of good treatment, you know, like you cannot heal someone who's catatonic with your pseudoscience.

• 26:28Speaker 01

  Yeah, and I mean, and it's, and I think there's a, you know, there's an inadequate recognition of, you know, depression as a heterogeneous spectrum, you know, some people on the milder end, you know, their depression is, you know, an exaggerated version of life difficulties, life distress or situational distress. But then there are other patients with depression who have severe psychomotor retardation and severe anhedonia and, you know, other, other kinds of, you know, severe sleep issues and, and we see these in studies as well. We see cortisol dysregulation, we see REM sleep abnormalities, you know, we, you know, we see kind of genetic associations, kind of, you know, in, in, in certain cases.

• 27:08Speaker 01

  So, you know, I think any, anyone who just tries to paint depression with a broad brush, you know, anyone who says that, oh, this all of depression is a normal, understandable reaction, or all of, all of depression is an organic style disorder like Parkinson's, I think, I think it would, it would be inadequate because, you know, things are very different.

• 27:27David Puder?

  Yeah, and I'm not, I'm not saying that either because I, I think there are many pathways there and there are people with family histories, like, you know, multiple people have committed suicide, those people may need a different treatment, you know, than someone without a family history, is someone who's highly, high in neuroticism. They may need a different treatment than someone who's lower in neuroticism. Yeah, so it's like depression is kind of like, to me, like a fever almost. I don't know. It's like this is the final common pathway of a lot of different things, right?

• 28:03Speaker 01

  Yeah.

• 28:04David Puder?

  And so, you know, I'm someone who advocates for psychotherapy, for exercise, for diet changes, you know, and when I see a patient, you know, I'll sometimes get an email like, hey, why do you think I have depression, blah, blah, blah? And I'm like, well, I don't know if I can tell you over just an email because I, it takes me sometimes 50 minutes to come to a conclusion on what's going to be the biggest win for someone.

• 28:28Speaker 01

  Yeah.

• 28:29David Puder?

  And, you know, there's a lot of different things that, you know, I may ask questions and based on how you answer that question, I may go in a completely different direction in question asking.

• 28:40Speaker 01

  Yeah.

• 28:41David Puder?

  And that's something that I've developed over, you know, 11 years of seeing patients as an attending is when I hear a couple of things, then I will ask a couple of other things, but I won't know to ask those couple of other things until I hear some of the story, you know?

• 28:57Speaker 01

  Yeah.

• 28:57David Puder?

  You know what I mean?

• 28:58Speaker 01

  Yeah, I know, I agree, yeah. I mean, I think depression is just, it's a, it's a descriptive characterization and people end up in a depressed state for very, very different reasons with a wide variety of combinations of risk factors and a wide variety of combination of, you know, breastfeeding factors. So it's the, you know, it's a, it's a good clinical conceptualization or a good case formulation that drives the treatment and, and, you know, kind of sorts the person into the appropriate, you know, treatment, you know, strategies. So there's, there's no one size fits all. And that's one of the reasons, I think, you know, because depression is such a heterogeneous cluster, treatments in general, you know, if you, if you pool their effects as averages,

• 29:41Speaker 01

  the effects are generally weak, you know, but, you know, are modest, you can say, you know, whether this is antidepressants or psychotherapy or, you know, exercise, this is because there's different people that are responding to things in different ways. And for, for all of them, I think, you know, some people respond robustly to psychotherapy and they You you get wonderful clinical response. Some people respond robustly to exercise. Some people respond robustly to antidepressants. And then there are others who just kind of, you know, who who get better, but not enough. And in in many of those cases, you end up using multiple treatment strategies in coordination. Because because no one strategy is going to be sufficient to take care of, you know, those problems.

• 30:20David Puder?

  Yeah, absolutely. A new one I like is creatine. Five grams a day. There's some new study. There's I've been looking at those studies for years, hesitant to talk about it. But now it's that some of the newer studies are coming out. I'm like, oh, I could. I can talk about this publicly, you know. And so there's some things like that where I'm like. Yeah, I'm hesitant to talk about this because the data is so early. And I know people listen and people people take it for what it is. But there was a new study we're going to talk about. I'm going to do a deep dive on creatine in a couple of months. And we're going to go through. There was a new one on CBT with creatine versus placebo. And there was like a six point difference in the creatine group versus the placebo group for the. And I was like, wow, that's amazing. So it, you know, and why creatine?

• 31:05David Puder?

  There's a metabolic impact, just like maybe an improvement of the mitochondria. We'll go through the mechanism. It's very detailed, but yeah.

• 31:14Speaker 01

  Yeah, no, I mean, right now metabolic psychiatry and lifestyle psychiatry is having a having a kind of a booming moment. And we're seeing a lot of attention being, you know, devoted and diverted to, you know, addressing metabolic aspects of depression. And I'm excited to see as well where this leads and what kind of, you know, scientific evidence emerges from this.

• 31:36David Puder?

  Yeah, OK, let's go. Is there anything from the study we want to highlight as like this is what the study actually found? Like, is there anything from the Moncleef at all study?

• 31:45Speaker 01

  I think the the main thing to highlight, I think, you know, the central conclusion that, you know. One, that there is there is no serotonin deficiency, you know. Established serotonin deficiency in, you know, in depression widely recognized, I think, you know, that that I think, you know, makes sense. And then I think that there are some of the other implications that we talked about. But we can, we can, you know, maybe perhaps transition into the. Into the reactions.

• 32:10David Puder?

  Yes.

• 32:11Speaker 01

  To the Moncrief paper.

• 32:12David Puder?

  Yeah.

• 32:12Speaker 01

  So, so since the, the original paper was published in, in Molecular Psychiatry, over a period of, of a year after its publication, it, it published a series of commentaries and critical responses to, to the Moncrief paper. And, and included some very distinguished names. In fact, the, the leading kind of critical response was by Sameer Johar and colleagues. And it was kind of thirty five people and was kind of a who's who of people involved in mood disorders research. And it, it was titled, A Leaky Umbrella Has Little Value. Evidence clearly indicates the serotonin system is implicated in depression. And, and, and they went through kind of a number of different methodological issues with, with their approach,

• 32:54Speaker 01

  as well as kind of highlighting things that they, they had ignored or minimized. So one, as I mentioned, you know, they, they chose to essentially just eyeball the results of these other systematic reviews and meta analysis, rather than trying to take the data and, you know, do a meta analysis of, of their own, which, you know, which would have been the more productive thing to do, especially with things like,

• 33:18Speaker 01

  kind of try to find depletion studies or things like, you know, pet imaging studies. So, so, so, so that's one kind of, you know, methodological issue that they brought up. And then their approach towards bringing up the use of antidepressants as a confounding factor was, was pretty inconsistent too. If the, if the results were like, were such that they implicated the serotonin system in, in some way, the Moncrief and colleagues had a tendency to say, oh, this could have been due to antidepressant use. But if the results were kind of in accordance with what they were expecting, they, they wouldn't bring that up.

• 33:55David Puder?

  Let, let me ask you a question on that. So, so what did Moncliff at all do in terms of people on psychiatric medications versus not on psychiatric medications?

• 34:04Speaker 01

  So they themselves did not conduct any specific analysis of people on or off. They just essentially, like I mentioned, you know, they were relying on the results already reported. So for example, for tryptophan depletion studies or, you know, PET imaging studies, if the results indicated an association, they'll simply bring it up as a point that, oh, you know, these people might have been on antidepressants or the people, you know, some of them were antidepressants. So perhaps the results are explained by these people being on antidepressants rather than, you know, not. So they were essentially, they essentially brought it up as an objection, but they didn't conduct any analysis of their own in this regard.

• 34:45Speaker 01

  So I think the two areas where existing research seems to be the, you know, suggestive of serotonin, you know, alteration in some manner, are the tryptophan depletion studies and, you know, serotonin receptor PET imaging studies. So in the tryptophan depletion studies, what they had done was that they had taken individuals, kind of both with history of depression, both kind of, you know, you know, healthy individuals, but who may have had family history of depression. And they kind of artificially depleted the levels of tryptophan in their, in their, in their body. And they saw, and then they see, you know, did something happen to their depression? Did their, their mood worsen?

• 35:29Speaker 01

  And the, the previous meta-analysis that, that had, had been done on that, it, it had in fact shown that in people with a family history of depression and in people who have been diagnosed with depression, tryptophan depletion worsens their mood. And so that's a, that finding that had been established before, Moncrief essentially just minimized that and did not give it due, due consideration. And the second thing was that in, in PET studies that had been done of examining at serotonin receptor binding, they had simply kind of dismissed those results as saying that different studies had done, you know, had reported different results or inconsistent results. But the, the critical responses point

• 36:14Speaker 01

  It out that if in fact they had done a meta analytic kind of approach, they would have seen that some areas show up consistently as implicated. And in particular, serotonin receptor binding in midbrain and amygdala seems to be consistently lower in in these previous studies. But but again, that was not properly kind of recognized or acknowledged by by the Montgret et al. paper. And another thing was that after the Montgret paper came out, there was a small study published, which was the first direct assessment of serotonin release capacity. So so all of the existing, you know, scientific studies so far, they had relied on indirect assessments of serotonin, because we didn't have the methodological tools

• 36:56Speaker 01

  to kind of directly assess serotonin release capacity. So this was the first one that actually developed the methodology to measure that. And what they found was that in a in a small sample of people who were experiencing major depressive episode, and these were not on on antidepressant medications, they they found that people with depression had lower serotonin release capacity compared to healthy controls. Now, this is a this is a small study, the sample size, but not that large, and and the statistical significance was just kind of bordering on on significance. So the the general understanding has been that this is at best a preliminary demonstration, and not a conclusive result. But but it shows again that, you know, this is an area of open

• 37:39Speaker 01

  scientific inquiry, and that available evidence that we have suggests or points towards some kind of serotonin alteration in some people. But but, you know, whether this is conclusively demonstrated, you know, kind of remains to be seen.

• 37:55David Puder?

  So this was airtose at all?

• 37:59Speaker 01

  Yes.

• 38:00David Puder?

  Called Brain Serotonin Release is Reduced in Patients with Depression, a 11c, CMB36, positron emission tomography study with a D amphetamine challenge. And so it did it did find that there were people, the people with depression, the brains reacted differently. We and, you know, part of when I look at these types of brain studies, and, you know, there's a certain percentage, different reactivity. It's like, very hard for me to understand what that means in terms of like, does that decrease reactivity?

• 38:36David Puder?

  Is it clinically significant? Right? And with a small number change, it could be really significant. Right? And it's hard. It's hard for us to know because it's like, but there is a change. But it's like, is it? When it's clinically significant, it's like, okay, does that mean we could test depressed people? And if they're low in this, then they're reliably, yes, that that person is depressed. Right? Or if you took a thousand people and you tested it, could you pick out from that thousand people? How many of them are depressed based on it being lower?

• 39:12Speaker 01

  Yeah, it's difficult to extrapolate, you know, the clinical utility of these kinds of things. So what it essentially, what happened in the study was that there was a shift in the distribution of the serotonin release capacity. But but the distribution is still very overlapping. So, you know, so for when you, when you look at the distribution of serotonin release capacity, you know, like a lot of other variables, you get a range. So there's a range in the healthy controls and there, there's a range in, you know, individuals with major depressive episode. And and the range, if you look at that, is shifted in a kind of, you know, a reduced kind of capacity direction. So so that there's an average difference between those ranges, but there's also a big deal of overlap, you know? And so that makes, you know,

• 39:57Speaker 01

  the clinical application of tests like that very challenging that, you know, if there's broad overlap in the, you know, in the distributions, then, you know, the sensitivity and specificity of that kind of measure for the purposes of clinical diagnosis or treatment gets reduced. But I think, you know, right now, it's really kind of premature to even say what kind of, you know, what kind of clinical application this could have? Because that's just, you know, the first study that has come out. And hopefully, you know, with larger studies, they can examine, you know, some kind of predictive value for for clinical treatment, too.

• 40:34David Puder?

  Okay. So in summary, Johar and colleagues say to summarize, the methodology is inconsistent with an umbrella review and substantial bias created by the author's chosen quality criteria, selective reporting and interpretation of results. There is an underappreciation of the complexities of neuroscience and neuropsychopharmacology, and therefore impossible for the reader to draw a valid and reliable conclusion. A more accurate and constructive conclusion would be that acute tryptophan depletion and decreased plasma tryptophan in depressed indicate a role for 5-HT in those vulnerable

• 41:15David Puder?

  to or suffering from depression, and that molecular imaging suggests the system is perturbed. The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position.

• 41:32Speaker 01

  Yes, yeah, I think it's pretty well stated. I think I do want to emphasize that, you know, the literature, the available scientific evidence is suggestive that, you know, suggestive of some serotonin alteration in a subset of people, but it is still not like very high quality, super conclusive evidence. So I do think we have to keep in mind that, you know, scientific evidence comes in degrees, and, you know, we're still looking at scientific evidence that is in the low to moderate range. But again, that point, recognizing that does not mean that we say that, oh, you know, now we can confidently say that no one with depression has any serotonin alterations or abnormalities.

• 42:16David Puder?

  Yeah, and I think the other thing I think about is like, how do you like parse out the different types of depression, like, and then study those individually? Because I imagine they would have different types of things going on, you know? Someone with borderline personality disorder, who we know is not going to respond to antidepressants.

• 42:40David Puder?

  Right, we know that the APA just came out with a stance on like for BPD symptoms, you know, medications really aren't the answer.

• 42:49Speaker 01

  Yeah, I mean, there's a huge, and I think that, you know, people have been trying for decades to try to come up with some kind of adequate, you know, subtyping of depression that would, that would guide a treatment in a meaningful way. And it has been, it has been challenging because a lot of the usual descriptive categorization that we have had in the past, for example, atypical depression or, you know, neurotic depression, anxious, etc., etc., you know, they don't seem to reliably predict response to, for example, antidepressant treatments, like a therapy, things like that. The only thing that really stands out somewhat, the test of time, is melancholic depression, that melancholic depression consistently kind of shows higher kind of percentage of

• 43:34Speaker 01

  cases that have HPA disregulation and they show a poor response to SSRIs and standard antidepressants and a comparatively better response to tricyclics as well as things like ECT. So with melancholic depression, we have some evidence that there's something different going on with that. And then there, then based on comorbidities, we can make some reasonable inferences as well. So as you mentioned, the comorbidity with borderline personality disorder is one of the ones that has been repeatedly shown in literature to have poorer outcomes in the treatment of depression, which shows that, you know, until we address that underlying,

• 44:17Speaker 01

  you know, underlying psychodynamics and underlying self and interpersonal dynamics of borderline in some way, the person would remain susceptible to, you know, their emotional difficulties.

• 44:28David Puder?

  Right, so melancholic depression.

• 44:31David Puder?

  Define that, just so that we were all on the same page here.

• 44:35Speaker 01

  Yeah, so, and, you know, different people would come up with slightly different operationalization of that, but essentially melancholic depression is the depression that is characterized by very prominent anhedonia, severe psychomotor retardation, often an existential quality of despair and distress, early morning awakening, and usually tends to show REM sleep abnormalities. And in general, it is not that strongly associated with acute life stressors. So it tends to come and go with a weaker link between with life stressors, and it tends to have a more kind of independent biological flavor to it.

• 45:20David Puder?

  Yeah. So, huge, huge anhedonia, huge loss of pleasure, right?

• 45:26Speaker 01

  Yeah.

• 45:27David Puder?

  Depression worse in the morning, so there's this diurnal mood variation. There's early morning awakenings, at least two hours earlier than usual, marked psychomotor agitation or retardation. So slowed or restless, you know. Sometimes there's weight loss, anorexia, excessive guilt. So usually about three of those, at least, for the...

• 45:55Speaker 01

  Yeah. And this was melancholic depression was the one that was kind of classically recognized as being, you know, a depression prior to our modern era of DSM three. If you look at, you know, what cases were being diagnosed as depressed in the first half of the 20th century, or who were being admitted to psychiatric hospitals as depression, then they were by and large people with melancholic depression and psychotic depression.

• 46:21David Puder?

  And my experience of working in a psychiatric hospital, these patients do not get better in three days.

• 46:27Speaker 01

  Yeah.

• 46:28David Puder?

  Someone with BPD, borderline precise, or could come in, get put on some meds, three days later, they're completely back to normal. It's like they've completely flipped out of it. Someone with melancholic depression, three days later, looks exactly the same. Very little change.

• 46:45Speaker 01

  Yeah, it tends to be kind of more the course of improvement tends to be slower. It takes weeks often, you know, sometimes, sometimes even longer for these people. And so in in other cases, we see this rapid, you know, emotional reactivity where where people, especially kind of, you know, with with borderline personality dynamics, they can be very sensitive to, you know, whatever is going on in their life, they can be very sensitive to rejection, abandonment that precipitates an acute depressive crisis, and then it very quickly resolves. Whereas that is not the situation in melancholic depression at all. It is severe, more kind of persistent, more protracted, and it it takes time to for for these people to get better.

• 47:28David Puder?

  Very good. Okay, let's let's jump back. I like our little tangents here, teaching tangents. Okay, let's jump back into the critique of this study. Let's talk about this. Bartova, colleagues, 2023 critique, anything you want to mention on this?

• 47:44Speaker 01

  Yeah, I think a lot of it mimics the similar kind of points that that Johar and colleagues had made, but I think it's it's worth emphasizing, you know, you know, their their assessment of the study too, just to consolidate that this wasn't just one group of scientists. So so Barto and colleagues, they say, since Moncrief said all's deduction is based on selected literature covering serotonin exclusively, and hence addressing only a part of the complex understanding of depression, we argue that the author's conclusion that the serotonin theory cannot be empirically substantiated, cannot be derived from the present work. A meta-analysis revealing spatial-temporal dynamics of the serotonin neurotransmission

• 48:29Speaker 01

  in depression underlines the fact that serotonin represents a crucial but dynamic neurobiological underpinning of depression. And and the meta-analysis that they're citing is is one from 2014 of molecular imaging of serotonin transporters in major depression, which revealed reduction in serotonin transporters in in midbrain and amygdala, which is also consistent with some of the other kind of, you know, pet imaging work that that has been done. So again, kind of highlighting that, you know, Moncrief at all looked at, you know, a few selected reviews and analysis, and then they extrapolated, you know, you know, their own assessment to the entire literature.

• 49:11Speaker 01

  And and you know, people more familiar with that literature pointed out, you know, things that they have missed or neglected or misinterpreted.

• 49:20David Puder?

  Great. So what I'm what I'm getting from this is that in the midbrain, in the amygdala, there are a reduction in serotonin transporters. And this this is likely to be the spatial temporal dynamics, meaning like as the depression progresses from not treated yet to treated, we may see this change over time. Is that is that how you're reading this?

• 49:49Speaker 01

  Yes, I think that they are they are referring to that. And I think this this probably provides a kind of, I think, useful transition into what we currently know about how antidepressants work. So, you know, if I guess the question is that if antidepressants are not correcting a serotonin deficiency, you know, then what are they doing? And that has been a focus of some of my kind of public writing as well, because I think the actual scientific literature is, you know, very, very interesting and very informative. And what we see is that we have we have several lines of research in this area, and they focus on a few different

• 50:34Speaker 01

  things. There is one that focuses on shifts in emotional information processing, that kind of monamergic medicines that work through serotonin and other other, you know, systems, they produce shifts in emotional processing, either in a, you know, making it less negative or kind of, you know, making it more positive in response. And this this directly ties in with some of the serotonin research that that we showed. We, for example, like, you know, we saw that. You know, serotonin system is implicated, you know, not just in behavioral control and impulse control, but also in emotional processing. So this, you know, this hypothesis bases on that, on that fact that serotonin, SSRIs are boosting

• 51:18Speaker 01

  serotonin, and by doing so, they shift the emotional processing in a more positive direction. And there's some preliminary evidence showing that SSRIs seem to primarily affect the processing of negative emotions versus norepinephrine uptake, reuptake inhibitors can affect how participants respond to positive or rewarding stimuli. So, so there are some differences there, you know, preliminary basis. And this is, this is an effect that starts showing up very rapidly when, when we give people SSRIs. So sometimes even after one dose, but you know, often after a few doses, on these cognitive tests, where if you ask people, for example, to rate neutral faces, previously depressed

• 52:02Speaker 01

  people would rate them as being more sad or showing negative emotions. And now if they're on SSRIs, they would rate those same neutral faces as either showing positive emotions or showing less negative emotions. So, so these are kind of, you know, operational cognitive tasks that the researchers are using to measure emotional processing. So they start showing these changes pretty rapidly after taking, after starting an antidepressant. And then the researchers hypothesize that this shift in emotional processing interacts with the environment. So if the person is in an environment in which they can relearn negative association, and if they can start to interact with other people, you know, in a more positive manner

• 52:45Speaker 01

  thanks to those emotional shifts, that sort of like shows up as progressive improvement in, in, in depression over, over, over the course of several weeks. So it's a, it's a interaction between shift in emotional processing, interacting with a positive social environment, which also They said in the literature we have that accessorized work better when there's a more therapeutic environment around the people and if people are in harsh environments, adverse environments, you know, antidepressant efficacy correspondingly goes down. And to my mind, it also highlights the value of combining antidepressants with psychotherapy

• 53:27Speaker 01

  too, because psychotherapy provides that opportunity to relearn those associations. A kind of complementary aspect of this is the hypothesis around cognitive flexibility and neuroplasticity. So there's a whole line of research showing that antidepressants, including certain energetic antidepressants, they increase the levels of brain derived neurotrophic factor and they activate a receptor TRKB, which enhances synop- synoptration and maintenance. Now, there's still kind of ongoing discussion of, you know, is this processed, you know, independent of serotonin or is there some kind of, you know, link with serotonin happening? And that's still up for debate.

• 54:11Speaker 01

  I think there's a general sentiment that many people think that serotonin is going to be involved in some way versus there's a group of researchers that think that this is entirely independent. But regardless, it provides another method of action that boosts those changes in emotional processing that we see because the psychological manifestation and neuroplasticity is cognitive flexibility, the person being able to modify and kind of change their unhelpful patterns in which they are stuck. So that's another kind of pathway through which it is hypothesized that antidepressants improve thing.

• 54:46David Puder?

  Yeah. So the first one's interesting to me because, okay, so you have neutral facial expressions.

• 54:55Speaker 01

  Yeah.

• 54:56David Puder?

  And you'll have people who are depressed, they have this negative filter that they put on and they're imagining these neutral faces to be more critical or more angry or more sad, right? This is a like micro expression essentially, like small moments of facial expressions and how they're reading it and how they're interpreting it. And the thing that comes to my mind is I had a patient just the other day who like I empathized with as I normally would and he said, I feel like you're being sarcastic. And it was, it's like a paranoid transference, right? He's, he's projecting onto me that I am being critical towards him, that I'm making fun of him.

• 55:37David Puder?

  And of course, of course, I wasn't, you know, I'm not making fun of him in my brain. That's not my experience. But imagine going through the world, imagining that everyone's kind of making fun of you or critical towards you. And then you get the right medication and maybe that shifts or therapy, right? So therapy can also help with this over time. And then subsequently, you're in many interactions with people where you're having more, you know, you're, you're thinking the best of them, which leads to more affiliative attachments. Right?

• 56:10Speaker 01

  Yeah.

• 56:10David Puder?

  And then your second thing about the BDNF, this is something I've covered. Of course, SSRIs aren't the only thing that increases BDNF. Ketamine has been shown to, exercise, diet even. So there's, there's a bunch of different types of things that have been shown to increase BDNF that lead to less depression. So this is another good mechanism for SSRIs as well. ECT increases BDNF quite a bit. Okay, so the third one's neuroticism.

• 56:43Speaker 01

  Yes. Yeah. And this one, Ken, has, has, if you look at the, the general kind of scientific literature on, on, on, on endob aggression mechanism, this one doesn't usually get as much, you know, doesn't get highlighted as much, but, but there's a very well respected tradition of, you know, examining this as, as a pathway. And in fact, we, we have a, a very beautifully done kind of placebo controlled random astral from 2009 that, that investigated this issue. So they kind of, they took people with kind of, you know, who were experiencing major depression and they, they treated them with, with an SSRI paroxetine or placebo or cognitive therapy.

• 57:26Speaker 01

  And then they kind of examined the outcomes in relationship to personality traits. And in particular, they were looking at neuroticism and, and extroversion. Neuroticism, you know, it's a, it's one of those kind of, you know, big five personality dimensions. And it refers to this general pattern towards, towards negative emotions, a heightened sensitivity to stress. And kind of, you know, um, negative emotional processing. So it's, it's one of the more kind of, uh, it's one of the personality traits that's closely linked to vulnerability to depression and anxiety. And so in this particular trial, uh, what they found was that people who took paroxetine, they experienced significantly greater changes in neuroticism and extroversion compared to those who took placebo.

• 58:11Speaker 01

  And that even when you statistically took into account the improvement in depression, the association with neuroticism changes was, was still significant. So patients, uh, taking paroxetine showed, uh, nearly seven times greater reductions in neuroticism. And almost kind of four times greater improvement in extroversion compared to those who, those who had in placebo. And these degrees of, you know, this degree of reduction in neuroticism was also a predictor of these people kind of staying well and not having a, having a lower, uh, relapse rate going forward. Now, in, um, kind of in placebo patients, you know, people who responded to placebo,

• 58:53Speaker 01

  their depressive symptoms went down, but their neuroticism scores and extroversion scores did not change. Kind of highlighting that, that there was this kind of a more specific action of antidepressants on neuroticism and extroversion that was not being seen in placebo-related, um, antidepressant improvement. And so I think that, uh, uh, and again, there, there's rich, rich literature on associations between neuroticism and the serotonergic system as well. Uh, and that, you know, part of the, you know, uh, expression of neuroticism may, may be kind of based on, on how the serotonergic system exists. But that provides another line of kind of, you know, evidence regarding how antidepressants work is that

• 59:36Speaker 01

  they are reducing the severity of the neurotic traits that people have, which, which confers, you know, both acute as well as chronic maintenance benefits.

• 59:47David Puder?

  Okay, I'm looking at this study and I'm really a fan of the big five and I've done an episode on neuroticism, conscientiousness and extraversion. And I run most of my patients on a neuroticism scale, actually, because I think it's very helpful. And actually, I've learned, as well, I'm going to do an update on the big five, you can, you can look at the subdomains of neuroticism. And in someone who's, for example, narcissistic, they'll be higher in anger, but all the other neuroticism domains will be average. You know, there's no link to narcissism. Whereas, for example, in BPD, all of them will be fairly elevated,

• 1:00:26David Puder?

  all the neuroticism subdomains. So neuroticism is kind of a blanket that they may fall into a personality disorder, but not necessarily. But we don't know what personality disorder they'll fall into, because a lot of them are going to be high in neuroticism. In this particular study, they compared the paroxetine versus placebo. And for the neuroticism, the effect size was 0.57. And with extraversion, it was 0.63. So these are big shifts. And I think what your, what your point is, and I think I want to get back to your point for this particular episode, is that it's not just depression that an SSRIs treating.

• 1:01:11David Puder?

  And further, it's not just blunting the mood.

• 1:01:16Speaker 01

  Yeah.

• 1:01:17David Puder?

  As some critics of SSRIs say, like, all this is doing is blunting your mood. Because otherwise, you wouldn't have this shift with neuroticism.

• 1:01:26Speaker 01

  Yeah.

• 1:01:27David Puder?

  And let me just say also, from my experience of treating patients over time, I've seen personality change. So someone may be born more neurotic, right? And someone may have gone through different traumas. We know trauma increases neuroticism, genetics change it. So it's like everything, right? Therapy can improve neuroticism as well. Interestingly, in this study, they compared cognitive behavioral therapy with neuroticism as well. And let's see, proxytein versus cognitive therapy. And the effect size was pretty small and the p-value was not statistically significant.

• 1:02:10David Puder?

  So they both improved neuroticism and extroversion.

• 1:02:13Speaker 01

  Yeah.

• 1:02:14David Puder?

  So that's cool.

• 1:02:16Speaker 01

  Yeah, yeah, I agree. I think therapy is a big kind of factor as well. And my own kind of clinical impression, working with patients, is that the people who seem to do best on chronic maintenance antidepressant therapy tend to be the ones who get the most positive, you know, effects on their neurotic kind of traits. So people who are high on neuroticism and they take an antidepressant and their neurotic kind of traits go down, neurotic severity goes down, they tend to be the one that seem to prefer continuing on an antidepressant on an ongoing basis and seem to show the most outcome. And they also tend to be the ones where we see depression and anxiety kind of mixed in rather than, you know, depression being just kind of a pure syndrome by itself.

• 1:03:01David Puder?

  Right. There's a subdomain in neuroticism of depression. But there are also subdomains of self-consciousness, like how critical do you view yourself? How emotionally reactive are you in anger? How impulsive are you? These are all subdomains of neuroticism. And so, yeah, okay, I want to get through this, though. Let's go. So the controversy of the efficacy of antidepressants. Shall we jump to that?

• 1:03:28Speaker 01

  Yes, yeah. And hopefully, I think at this point, I think a lot of, especially, I think psychiatrists involved would be familiar with the broad details of the controversy around efficacy. But it comes down to the magnitude of the difference between antidepressant response and placebo response in randomized controlled trials, especially randomized controlled trials that have been Committed to the FDA for medication approvals. Now, the one of the largest meta analysis ever done in medicine has been for antidepressants. It included five hundred twenty two clinical trials, one hundred sixteen thousand subjects.

• 1:04:13Speaker 01

  And it clearly shows that antidepressants separate from placebo with regards to kind of, you know, antidepressant response. And, you know, if you look at odds ratios of, you know, response, it kind of, you know, varies from, you know, a little above two for amitriptyline to one point three seven for repoxidine. But if you if you look at the actual magnitude improvement, you know, like what is the change on the Hamilton depression rating scale? That's a relatively small one. It's a two point difference on on average between antidepressants and placebo. And it turned it converts into an effect size of zero point three, generally considered small.

• 1:04:52Speaker 01

  And and this was kind of reaffirmed in a in a twenty twenty two kind of meta analysis of the FDA database, which which again showed that in in the placebo group, the averaged Hamilton depression rating scale kind of score improved by eight points versus in the antidepressant group and improved by about ten points. So so again, a kind of two point difference. So so critics have been saying, well, you know, like the the scale is so big, it ranges from zero to fifty two. What does a two point change matter? It's clearly, you know, clinically insignificant and, you know, we we cannot see on this basis that, you know, antidepressants have any kind of meaningful of meaningful effects.

• 1:05:32David Puder?

  And and to which I would say, yeah, this is a little bit depressing.

• 1:05:36Speaker 01

  Yes, yeah.

• 1:05:38Speaker 01

  Yeah, well, so that that is why I think, you know, the the debate has been so contentious. Like, what, just just a two point difference on on Hamilton depression? How how can that be?

• 1:05:47David Puder?

  Like, two points is like, oh, come on, like, really?

• 1:05:50Speaker 01

  Yeah.

• 1:05:51David Puder?

  But the but the placebo is is. I mean, what this what this also says to me is placebo is very powerful.

• 1:05:57Speaker 01

  They are.

• 1:05:59David Puder?

  But two points is not a huge difference in 52 points. So we're going to go through what this might mean rather quickly because we're trying to wrap it up here.

• 1:06:09Speaker 01

  Yeah, yeah, I'll be quick about that. So I think the first one, the first response can emphasize the heterogeneity of the response patterns, that people don't respond uniformly, rather that some people seem to respond very well. They can experience large reductions in kind of depression, kind of severity. There are others who kind of show like a medium kind of response, and then there are others who show very little. So in the FDA analysis, when they kind of broke it down, they compared it in terms of people having kind of a trajectory of a large response, kind of, you know, around 16 point, you know, change in Hamilton, kind of having a more nonspecific kind of response around nine points, and then minimal response around around kind of two points from baseline.

• 1:06:52Speaker 01

  And what they found was that in the placebo group, 10% of people had a large response. So in a response that we correcturize as being, you know, on the large rectory versus 25% of people in the antidepressant group had a large response. So so that that's a pretty kind of substantial difference, you know, 25% large response in antidepressants, 10% in placebo. And and people who show a minimal response was that percentage was lower in in the antidepressant group. So 20 22% of people on placebo had a minimal response versus 12% on antidepressant had a minimal response. So what we are seeing is this shift so that a lot of people are going to have, you know,

• 1:07:35Speaker 01

  kind of like, you know, mediumish kind of response, but a subgroup, about 25% of people are going to have a robust improvement that's going to that's going to show up. And when we look at just the average, that the average hides that heterogeneity because it kind of collapses this variation into this into this average difference. And if you look at the number needed to treat for a large response for antidepressants, that's 6.7, which is, you know, not super great, but a respectable number needed to treat when we when we consider overall medicine. So so that's kind of, you know, that's one. So, you know, the heterogeneity of response pattern is one strategy to do it. The second response, you know, kind of has focused on on Hamilton depression rating scale as an instrument itself.

• 1:08:21Speaker 01

  People have said that a total score on Hamilton Depression Rating Scale is really not the best way of looking at, you know, how people improve. This is because the, you know, the kind of questionnaire, kind of rating scale includes, it's an idiosyncratic mix of many different items. And, and the, the weightage of, you know, like, you know, of items being devoted to different aspects is a little asymmetrical too. So for example, there's just one item about depressed mood, but three items about insomnia. And then all items, you know, all, all items are given equal weight. And also there are many items related to sexual symptoms and gastrointestinal symptoms, which in fact is concerning because these are things that are side effects of antidepressants

• 1:09:06Speaker 01

  because antidepressants worsen gastrointestinal functioning and sexual functioning. So the, if you're looking at just the total score of Hamilton Depression Rating Scale, it's not giving us a fair idea of what's happening with depression. So in, in a 2016 paper by Hieronymus and colleagues, they actually broke it down based on, on items of Hamilton Depression Rating Scale. And you showed, and they showed that if you focus on the, on the core symptoms of depression, if you focus on the core six items, you get a very consistent separation from placebo based on, on those. And if, for example, if you look at just the depressed mood item, the, the kind of effect size separation of that from placebo is point two seven, you know, for the total

• 1:09:49Speaker 01

  score, but for just the depressed mood item, it is zero point four.

• 1:09:53David Puder?

  I think that's worth repeating. So it's, it's higher effect size for when you look at specifically the depression scores. And, you know, for my clinical patients, I want to get them out of depression and then yeah, they're going to have some side effects. We're going to have to deal with that. But when they're not lying in bed all day, it's easier for them to exercise. It's easier for them to do lifestyle stuff. It's easier for them to go to therapy. So sometimes you have to get them a little bit less depressed so they'll actually seek treatment.

• 1:10:23Speaker 01

  Yeah, so the core symptoms of depression improve more robustly compared to the Hamilton Torres score. And then the final kind of, you know, strategy that people have used, you know, in response is that, you know, it's somewhat counterintuitive, but a two-point difference from placebo is not the same as a two-point difference from baseline. And so a two-point difference, every two-point average difference from placebo can still be meaningful. And the way to appreciate that is by comparing this effect size by, you know, with psychotherapy and other medical treatments. So if you look at comparisons of, you know, antidepressants versus psychotherapy, but also kind of psychotherapy versus placebo.

• 1:11:08Speaker 01

  Psychotherapies, especially kind of, you know, short-term manualized therapies that have been studied in research settings, they have the same effect size, average effect size in antidepressants. So if one says that, oh, a two-point difference is not significant at all, one would be forced to say that, oh, you know, then psychotherapies don't have a meaningful effect either.

• 1:11:28David Puder?

  Right.

• 1:11:29Speaker 01

  And if you look at, you know, general medical treatments, which kind of Stefan Lucht and others did in a paper in 2012, they actually showed that an effect size of point three is actually fairly kind of common and standard in general physical health treatments too. And many accepted treatments have effect sizes of point three or lower. So in comparison to treatments in general medicine too, antidepressants don't fare that poorly.

• 1:11:56David Puder?

  Yeah, and I would, I would say if the psychotherapy people are listening to this or like, they would probably say something like, well, it's not the best way to measure it. The best way to measure it is more like the OQ45, which you're going to see about a point eight difference per session in someone with higher reflective function if you're a therapist, it's more like 1.2 or 1.3 per session. And you're going to say, well, you're going, a year of therapy will get 75% in remission, right? Probably, right? I mean, that's like what they would say. And what I would say as a psychiatrist, if I was just doing medication, which I'm not just doing, but if I was just doing medication, I would say, well, that's, this is the first session.

• 1:12:41David Puder?

  If we get a little bit better in the first session, some people are going to respond. Some people aren't going to respond. If they don't respond, we switch up the strategy until we find something that, you know, helps them respond.

• 1:12:53Speaker 01

  Yeah.

• 1:12:53David Puder?

  And so we're not just going to leave them with two-point decrease.

• 1:12:58Speaker 01

  Yeah.

• 1:12:59David Puder?

  And it's not just going to be a two-point decrease because there is a placebo response.

• 1:13:04Speaker 01

  Yes.

• 1:13:04David Puder?

  That's significant.

• 1:13:05Speaker 01

  Right. This is over and above placebo. And there's kind of, there's a very interesting discussion in the literature on whether it is meaningful to subtract placebo response from, you know, an antidepressant response in this manner, because from what we know, it is unlikely that an antidepressant response and placebo response are additive. It's not like, you know, you can add them together and get double the response. So for example, think of, you know, if you combine antidepressants and psychotherapy, you don't get double the response. You get a, you know, slightly more response because antidepressants and psychotherapy are not additive. In a similar kind of way, you know, antidepressant and placebo response are probably overlapping.

• 1:13:47Speaker 01

  So, you know, when we subtract the placebo response from the, from the, you know, total antidepressant response, we're probably underestimating the magnitude of benefit that is being attributed to antidepressants.

• 1:13:58David Puder?

  Right. And one thing I would say to support that is there's a study on placebo for Parkinson's, and they show that the placebo actually increased the dopamine in the brain, which is what we're targeting with Parkinson's medication. So it's possible that just by taking a medication for depression, you're starting to target those areas in the brain where they're depressed, just like a placebo for Parkinson's targets the area in the brain for Parkinson's. And also, you know, there's spontaneous remissions and there's the therapeutic alliance and the connectedness of having a professional and the therapy that goes on even in short visits. So there's all that happening, which complicates it.

• 1:14:40Speaker 01

  I agree. And clinical trials in many ways are designed to amplify placebo responses because it involves very frequent monitoring, frequent assessment, sometimes financial compensation. And so there's this kind of built-in incentive that that can, you know, there's incentive to kind of boost the baseline depression responses to get people into trial, make them eligible. And then, you know, because of all the support and financial compensation, the responses often kind of, you know, the depression scores often decrease pretty, you know, pretty prominently. So the RCT setup does not represent the kind of usual clinical treatment setting in that respect.

• 1:15:20David Puder?

  Avast, Atav. This is amazing. You're an amazing psychiatrist. I was totally enthralled by reading this. This is, this is first, this is top shelf.

• 1:15:30Speaker 01

  Yeah, thank you.

• 1:15:31David Puder?

  Top shelf information here. It's truly articulate and I hope you guys listen to, or I hope you jump on the website, read his article on this and also check him out on X, his Substack. I will link those in the article and in the show notes. What's the best place to reach out to you if people are curious, have questions? Is it your X account, would you say?

• 1:15:54Speaker 01

  Yeah, I would say I think X, X and Substack and Blue Sky are good places.

• 1:15:59David Puder?

  Awesome. Thank you so much for coming on. I have to wrap it up to get to my next appointment, but it's a pleasure and I will definitely want to have you back on to continue the philosophy of psychiatry and the critiques on psychiatry and your perspective. So, thank you.

• 1:16:13Speaker 01

  I'd be delighted to. Thank you.