Transcription
If you clicked on this video to learn about the long-term risks of anti-depressants, you're in the right place. But first, a quick heads up. What you're about to hear may make you feel uncomfortable, especially if you or someone you love is currently taking these medications. Because you've probably heard the reassuring statement that anti-depressants are safe and effective for long-term use. But as a psychiatrist, I have to say I disagree with this because I don't actually believe the evidence supports their effectiveness over the long term. And additionally, there are significant concerns that anti-depressants might even worsen depression over time in some people. And so, if you're open to discovering the uncomfortable truth about the shaky evidence behind long-term anti-depressants, keep watching.
And for those of you who are new to my channel, I'm Dr. Yseph with Duran, a board-certified psychiatrist with specialized training in psychiatric drug development. I previously served as a medical officer in the FDA's division of psychiatry and I now help people safely taper off medications. So, let's start with the FDA's shaky rationale for the long-term use of anti-depressants. To date, the long-term use of these medications is largely justified by relapse prevention studies. These are studies that the FDA relies on to approve drugs for extended use. But there's a fundamental problem here. These studies are designed in a way that makes it nearly impossible to distinguish between true depressive relapse and withdrawal symptoms caused by stopping the drugs too quickly. In order to better understand this, you need to understand the design of these studies. Let's go into that.
So, here's the typical design of a relapse prevention trial or a maintenance trial as it may also be called. So, typically what they do is they'll enroll 500 people into a study and they'll put them on an anti-depressant for 6 to 8 months. After they've been on the medication for that period of time, half of them will be randomized to stay on the drug and the other half will be randomized to a placebo. After the randomization takes place, the researchers will follow both groups for a period of a year and measure the frequency of relapse. But an important thing that you need to understand is how people who get put on the placebo will actually transition to it. Now, what typically happens is that people are tapered from the drug to the placebo in a maximum of two weeks. That's a very fast taper. In some of these studies, they're even transitioned without a taper at all. But on average, when researchers have looked at all of these studies, they're tapered for an average of about 5 days. This is really short.
Now, what these studies typically show is that there is a higher rate of relapse in the placebo group. Usually it's around 40% compared to a relapse rate of around 20% in the group that remains on the drug. Now the FDA and drug companies have interpreted this as proof that anti-depressants prevent relapse and consequently that these medications can be used long-term indefinitely. But there is an obvious flaw to this and that is that none of these studies made a serious effort to differentiate withdrawal symptoms from a genuine return of depression. And this is crucial because withdrawal can look identical to depressive episodes. Most participants who get into these studies have been on these drugs for months, sometimes even years. That's right. Yes. When people come into these studies, many of them may have already been on anti-depressants before they actually transition into the study. So although the study monitors people for 6 to 8 months, some people may have been on medications for years before then. And so if you take people who have been on the drugs even for six to eight months, sometimes even longer, and you taper them over less than two weeks, you are going to get withdrawal symptoms, and sometimes they're going to be severe. Typically, people experience symptoms like severe anxiety, insomnia, brain zaps, and even mood instability. And since these symptoms can easily mimic depression in these relapse prevention studies, this is going to inflate the relapse rate in the placebo group, making the anti-depressants look more effective than they really are.
Now, this is not a new criticism of these studies. In fact, people have been talking about this for decades. And in order to address these concerns, the FDA actually did their own meta-analysis of 15 relapse prevention studies that were submitted to them back in 2014. And here's what they found. They found that 37% of people relapsed on placebo and about 18% relapsed on anti-depressants. This translated to an absolute difference of about 19% between the two groups. But they knew that the confounding because of the withdrawal symptoms was an issue. So they decided to adjust for it. And how did they handle this? Well, they did something called a sensitivity analysis, which is just a fancy way of saying they did an additional analysis where they changed a few things. And what they did in this analysis was that they censored events. Now censoring essentially means you're going to exclude certain cases that meet a criteria. And what the FDA did essentially is that they said we're not going to count any relapses that happened in the first 2 weeks assuming that this would be the period where there would be the most withdrawal. And when they did this they found that the absolute difference between the two groups dropped to about 17%. So you know it dropped about 2 percentage points. They then did another sensitivity analysis on top of this where they censored events going up to four weeks and it showed that the absolute difference dropped to 12%. And here is where the FDA made an absolutely absurd and ridiculous leap in their paper. They assumed that withdrawal ended by 4 weeks because what they concluded after that was that they said, well, there's still a difference after 4 weeks. This is when withdrawal happens. And because of that, we're still going to say these studies show that these drugs essentially prevent relapse. But this is actually completely inconsistent with the actual patient experience of withdrawal and research into this that has been out there for decades. And in fact, when you look at surveys on anti-depressant withdrawal, such as the one conducted by the Royal College of Psychiatrists, that looked at a mixed group of anti-depressant users, some short-term, some long-term, it showed that withdrawal symptoms typically last around 6 weeks and that 25% of the patients that they interviewed said that withdrawal symptoms from anti-depressants lasted longer than that.
Now, this suspicious conclusion by the FDA did not escape researchers because some people wanted to look further into this. And Professor Michael Hengartner and another researcher called Plotal over in the EU took a closer look at these studies in 2021 and they analyzed what would happen if you extended the censoring to see how the difference changed over time. And what they found was that essentially if you extended the censoring out to six weeks where the most people have experienced withdrawal, the absolute difference between the two groups dropped by about 50%. So that would be about 10 points absolute difference. So again, it just keeps on dropping down the difference in relapse between the two groups. At 2 weeks it was 17, at 4 weeks it was 12, now it's at 10. And then they extended it out to 12 weeks and what they found that the effectiveness dropped by 69%. Essentially making that difference between the drug and the placebo group roughly around a 5% absolute difference. And then when they did it one more time at 24 weeks, they found that the absolute difference between the two groups completely disappeared. Let me quickly show you what this looks like on a graph. This is a representative study from the FDA meta-analysis and it shows essentially what's happening to the two groups over time. On the Y axis you have the cumulative event rate which is essentially relapse with zero being no relapse and one being 100% of people have relapsed. The dotted line is the placebo group. The group on the anti-depressant is a solid line. The x-axis at the bottom is the number of days and then this is the number of people still enrolled at each step. Now what we're really looking for here is the rate of relapse. And the rate of relapse is actually the slope of the curve. And so if the slope of the curve is kind of going more up in this way, it means that there's a higher rate of relapse over time. If the slope is more gradual, it means that there's a lower rate. And so essentially what you see is that the placebo group rapidly increases over time and then it flattens out. And that the drug group kind of increases over time and then also flattens out. Now, if we were to censor events here at around 90 days, so 3 months into it, essentially what you're seeing here are very similar slopes, meaning that the rate of relapse is essentially the same. Now, this wouldn't really make sense if anti-depressants had this protective effect because you would assume that the group on the placebo would continue to have a slope that would slightly increase gradually over time as depression set in. Not one that would essentially mimic what's happening to the groups who are still on the drug. And the second point, which is a bit of a reiteration, is really that the majority of the change between the two curves is really happening in the first 3 months before things flatten out. And that is completely in line with what Michael Hengartner and his colleague found. Essentially what this shows is that the longer that you track people for the clearer it becomes that the relapse difference disappears. And this suggests that most of what the FDA called relapse depressive relapse was actually withdrawal and it lines up with what clinicians see and what patients have reported about withdrawal effects.
Okay. So let's turn back now to the FDA's conclusion on what happened. Well, the first thing that I will say is that the FDA's attempt to control for withdrawal really looks more like an effort to protect itself than a genuine attempt at scientific clarity. I'm going to go on to that in a minute. And this is because they prematurely declared withdrawal to be over at 4 weeks, even though the data showed a steady decline in the so-called benefits of these anti-depressants over time. And that there's a lot of research out there that shows that anti-depressant withdrawal can last longer than 4 weeks, sometimes much longer than that. Now, why would the FDA do something like this? Well, from my perspective, it has to do with protecting reputation. Because the FDA had been using these studies for decades at this time to justify long-term anti-depressant use. And if they admitted that these studies were unreliable, they'd essentially be admitting that the entire foundation for long-term anti-depressant use was shaky at best. And this would have been such a scandal that I'm sure they would have preferred to sidestep it by making that kind of interpretation of the data. So let's wrap this section up now. What do these studies actually show? Well, from my perspective, not much except that if you abruptly withdraw people from anti-depressants who have been on them for months and potentially even years, they experience withdrawal, not necessarily relapse. The two groups, drug and placebo, are going to separate dramatically in the short term. But as time goes on, the difference in the rate of relapse is going to disappear. This is why my colleague Mark Horowitz has made the glib comparison in these studies to essentially getting a group of smokers and telling half of them to quit and then noticing that the people who quit had extreme anxiety and then drawing the erroneous conclusion that there's something about cigarettes that treat anxiety. Clearly, this is absurd. What you're picking up on is actually withdrawal. And I think that's actually what these studies are showing. To be clear on this, I don't want to throw the baby out with the bath water because these studies don't show that essentially everyone that comes off anti-depressants is essentially in withdrawal and there was no benefit to taking them long-term. I mean, that wouldn't make sense either because clearly these drugs have a drug effect. I know because I've taken them. You know, they can be numbing, they can be sedating, and they can be energizing, and this can be therapeutic for some people. And withdrawing those medications would make those effects go away and some people may actually do worse over time because of that. But the point that I really want to make about these studies is that they are too confounded and poorly designed to actually serve as reliable proof that these anti-depressants prevent relapse over time or that they are even effective in the long term.
And so if the FDA approved studies aren't helpful for assessing the long-term effectiveness of these medications over time, well, what would be? One logical solution would be straightforward. Simply conduct longer randomized placebo control trials. Just like the short-term efficacy studies they do where they get one group of people, they go to placebo, another go on the drug, they follow them for 3 months, and then they look at the effectiveness over time. You could simply extend that study over a year or actually several years. Now, this approach would directly address whether anti-depressants are truly beneficial to people over extended periods of time. And it also makes sense practically because anti-depressants appear to cause tolerance, meaning that the beneficial effect of these drugs often fades with prolonged use. This is due to the principle of homeostasis. Although I know a lot of people think about anti-depressants as working on this sort of like little unique area in the brain, that's not what they do. They disrupt your neurotransmitters. Your neurotransmitters are involved in the way your heart beats, how your gut works, even your immune system. And when you take these medications over time, your body sort of pushes back against them and it causes adaptations in the brain to bring the body back to a state of physiological balance or homeostasis. And this matches up closely with what we see in clinical practice because most people you give anti-depressants to, you know, they'll start with the low dose, it'll work for a period of time and then 6 months later, 12 months later, 18 months later, they usually come back and they need a dose increase because the effect has worn off. And that's why I think it would be great to actually extend the duration of these placebo control trials because then we would know exactly how long these drugs are beneficial for before the tolerance sets in. And there is precedent for doing these longer type studies. For instance, with statins, some of those studies go for like two to three years or more. I'm not this is not an endorsement of statins, but what I'm saying is that there is precedent in the pharmaceutical industry to actually do these longer type studies. And it wouldn't be that hard in depression. And this would also be a very important thing to do because it would actually give us data that matches the way people use these medications in the long term. Because when you look at how long people have been on anti-depressants in the US especially, 50% of users have been taking them for at least 5 years. And so understanding their effectiveness over those multiple years would be very useful to inform clinical care.
And so have these longer placebo controlled studies been conducted? And if so, what do they show? Metaphorical drum roll here. Duh duh. They're essentially non-existent. This has never been studied before. And in fact, a recent systematic analysis of anti-depressant trial duration conducted by Vinet Prasad actually found that no trials with placebo controls have extended any longer than 1 year. And here is a graphic from his study essentially showing that most of the placebo control studies are less than 12 weeks and there are a short number that extend a bit longer but none of them go past a year. So let that sink in for a second. We essentially have no placebo control data comparing long-term depression outcomes for anti-depressant users versus placebos beyond one year. Even though half of the people using anti-depressants in the US take them for 5 years or more. This essentially means that people taking long-term anti-depressants are guinea pigs. We we don't have any clinical trial research showing that they actually are effective over long-term use. That should be very concerning to the public. And this absence of data really underscores just how shaky the widely held belief is that anti-depressants are safe and effective for long-term use.
So let's move on and let's talk about some other types of data out here that are really important to understand. We've now seen that long-term placebo controlled studies of anti-depressants are virtually non-existent. So what about real world studies that don't use placebos, ones that actually reflect clinical practice? Well, the most significant real world study that looked into this is the STARD trial. This was a government-funded study that cost $35 million and was meant to assess the effect of anti-depressants in typical patients. These are people that are often excluded from the pharmaceutical clinical trials. These are people who may have multiple health problems. They take multiple different medications or they could have problems with substance use. And so, let's talk about the study study. Well, like I said, it was a big study and it concluded around 2006. And essentially, the way it was designed was to mimic real life practice. It gave the researchers four attempts to try and help patients find an anti-depressant or a combination of anti-depressants that worked. Each medication trial lasted up to 12 weeks, and patients who reached remission at any stage during this were followed up for an additional year to see if their remission was sustained. This is a graphic essentially showing the way patients progress through this. You know the first trial was citalopram and then the researchers pick any of these options for the second trial and then they could pick any of these options for the third trial and then any of these options for the fourth trial. And just to reiterate again, remember this is a study that has no placebo group. So we don't know how to compare treatment to those who never got the medication.
Now, when this study was published in 2006, the authors originally reported that 67% of patients actually achieved remission during that short-term phase of the study that lasted less than a year. At face value, the short-term efficacy seems kind of encouraging. It's okay, but it's not great. But the long-term outcomes of what happened to people after a year were suspiciously unclear. Because despite the fact of enrolling 1500 patients into the long-term follow-up, the study researchers remained notably quiet about these outcomes in their original manuscript. In fact, the only way they acknowledged what happened to these people who remitted in a short-term phase and then were followed for a year was with this very confusing graphic which was essentially uninterpretable. There was no way of deciphering what had happened to them with the instructions in the paper. And here it is up on the screen now. Do your best to figure out what this means. Researchers much better than I am could not figure out what this meant.
Now, this didn't sit right with the academic community and eventually a group of researchers went to take a closer look at this using the Freedom of Information Act to access the original protocol for the study which was not available online and the patient level data and this soon became one of the biggest controversies in psychiatry. Now, why does this matter if researchers change the way they analyze the data from what's in the protocol? Well, it's because if you alter the original plan, it allows researchers to selectively pick data, manipulate outcomes, and essentially create misleading conclusions. This is really bad scientific practice. And when the independent researchers analyzed the STARD data using the original unaltered protocol, the results looked dramatically worse. What they found in the short-term phase of the study was that only 35% of patients reached remission compared to the originally claimed 67%. Let that sink in for a second. That's quite shocking. In real-world patients given multiple lines of anti-depressant therapy, treated just like they would be in clinical practice, only 35% of patients actually responded to anti-depressants and entered remission. However, that is not the most shocking outcome. When they looked at the long-term remission, they found that only 3% of people who were in the study were still in remission after that one-year follow-up. Let me say that again. Of all the people enrolled in this study who were given this top-of-the-line, you know, anti-depressant treatment, only 3% of people were still in remission after a year.
Now, this probably sounds too crazy to be true because if there were findings like this saying, "Hey, anti-depressants only really work in a third of people and you know at one year's time only about 3% of people are still in remission." Now, if you're someone who's heard that and you feel like that is almost too crazy to be true because how could we be putting essentially 13.2% of the American population on medications where only a third of people benefit in the short term and 3% of them are still well in a year. That sounds crazy to you, it is because it is. Now, this is not just some fringe criticism out there held by Dr. Ysef and you know a few of his friends who you know think psychiatric medications are overused. This research has been published in reputable medical journals. It has gone through peer review and all of this was published within the British medical journals open sections and if you even look at the authorship line these aren't like anti-psychiatrists or fringe people. We've got Jay Amsterdam who is a professor from the University of Pennsylvania. We've got Irving Kirsch who's one of the most widely cited researchers when it comes to clinical trial design. He talked all about the placebo response with anti-depressants. There are very credible people who have stood behind this reanalysis and it's even been picked up by establishment psychiatric journals. For instance, John Miller who is the editor of the psychiatric times. This is the most widely read trade magazine for psychiatrists. He even acknowledged the gravity of this revelation saying for us in psychiatry if these authors are correct this is a huge setback as all of the publications and policy decisions based on these study findings have become clinical dogma since 2006 and they will need to be reviewed revisited and possibly retracted.
Now because these findings are so shocking you might be thinking to yourself is this some kind of conspiracy? And what I would say is not exactly because there's actually something simpler and a lot more common going on. Because if you look at who this STARD trial was run by, it was run by psychiatrists who had extensive conflicts of interest with the pharmaceutical companies. And if you look at the original publication, they listed nearly an entire page dedicated to disclosing these relationships. And these conflicts naturally incentivize overstating the benefits and minimizing data that might be uncomfortable to those who really work a lot with drug manufacturers in developing drugs and selling psychiatric medications. In many ways, this is actually absurd that we even allowed researchers who were so conflicted to conduct this supposedly independent NIMH research that would have the stamp of the government and the government's impartiality over it.
Okay, so we've now seen how disappointing the long-term effectiveness of anti-depressants can be in real world patients and really how flawed the relapse prevention studies are. But before concluding our literature review, let's briefly consider how anti-depressants compare to non-drug treatments over the long term. And the first study that I want to look at is a systematic review and meta-analysis by Voda Hoer and his colleagues which compared randomized control trials that looked at psychotherapy, anti-depressants, and anti-depressants plus psychotherapy in adults with depression. This paper was published at the end of 2024. And for studies to be included in this review, they needed to have been conducted between 1980 and 2022. And they needed to have a follow-up period of at least 1 year. So let's go and see what they found.
Well, firstly, what they found when they looked at psychotherapy versus drug treatment in these studies, remember that went on for at least one year, they found a statistically significant result showing that outcomes actually favored psychotherapy. When they looked at psychotherapy versus combined treatment. So this is medication plus psychotherapy. They found a slight benefit for psychotherapy only. Psychotherapy only compared to combination treatment over long-term. This did not reach statistical significance. But on average it did seem to favor psychotherapy. And then when they looked down here at combined treatment, so this is psychotherapy plus medication. And they compared it to just medication. They found that people did better on combined treatment. And this was statistically significant as well.
Let's move on now and have a look at what the evidence shows for lifestyle interventions compared to anti-depressants. And there was a great study, a meta-analysis published in the British Medical Journal last year and it looked at around 14,000 participants and it generated this really nice graphic showing the effect size for different medical interventions. And check this out and remember this isn't long-term, this is short-term. Now walking or jogging, nice effect size there. Cognitive behavioral therapy, nice. Yoga, nice. Exercise plus SSRI medication also performing quite well. And aerobic exercise plus therapy, strength, mixer, tai chi, qigong, aerobic exercise plus strength. And then down here we have SSRI and it's the lowest compared to these other interventions. Now, the surprising thing about this systematic review is that it found that exercise is actually highly effective in treating depression and actually kind of looks better at treating depression. Now I'll say again this was short-term so we don't really know how that it would perform long-term but it begs the question, you know, how would these interventions perform long-term.
Now moving on, I want to touch on another important lifestyle intervention and that is dietary interventions and what I want to say is that currently there are no randomized placebo controlled trials that are directly comparing dietary interventions to anti-depressants in the short term or even in the long term. However, multiple observational studies have consistently linked healthier dietary patterns with lower depression risks. And there's actually a systematic review and meta-analysis exploring these dietary patterns published in 2019. And here is what they found. They found that there was a statistically significant association between a Mediterranean diet and decreased depression. They also found that there was a statistically significant association between an anti-inflammatory diet and lower rates of depression compared to controls. And from my perspective, this is compelling evidence that we at least need to be looking at diet as being legitimate treatments for depression. And although I'm not going to cover them in this study because I've covered it in other places on our channel, there is a growing body of evidence right now that dietary interventions such as the ketogenic diet, which is very low carbohydrate, have actually been shown to seriously reduce symptoms in serious psychiatric conditions like schizophrenia and bipolar disorder.
And so to sum up this research, here's what it shows. Essentially, it's showing a couple things. One, it's showing that psychotherapy appears to outperform medications in the long run. And it's also shown that lifestyle adjustments like regular exercise and healthier eating all seem to show effectiveness in treating depression. And you know for exercise it even looked a little bit better than medications. But we have to ask ourselves what is it about these non-drug interventions that is working with these people? And what I'm going to share with you is that these things work because depression is so much more than this chemical imbalance that we've been led to believe. It is tied to the way we live our lives and our everyday behaviors. For instance, exercise is going to help because our bodies evolved for regular physical activity, not a sedentary lifestyle where we just sort of sit behind a computer all day. When you move your body, your physiology actually makes you feel less depressed and anxious. And dietary improvements help because we aren't built to handle the ultra-processed, super sweet, inflammatory foods that we consume today. And when we move towards more of these whole food anti-inflammatory diets, we are actually matching diets that are much healthier for us because that's what we evolved to eat. Obviously, things like therapy are going to help because humans have emotional and existential needs. If you're having relationship problems, going to a therapist may help you with those. If you're having problems with work, working on those things with a therapist, trying to find meaning in what you do, those things can help. These are all fundamental human needs, and that's why they can be very helpful. And I know I didn't discuss this here, but I feel like it's important to just touch on this quickly, and that is that sobriety helps as well. This is not just from hard drugs. This is also from things like cannabis. It's also from things like excess nicotine and caffeine and alcohol. All of these things are also going to lead to depression and anxiety. And although I'm not going to review the evidence here, it is all included in our comprehensive free drug tapering course, which we're going to be linking below this video. And there's sections in there that specifically address how different types of recreational substances, even ones that aren't illegal, can contribute to anxiety, depression, and insomnia.
So given the scientific evidence that we have showing that lifestyle interventions and therapy can be at least as effective as anti-depressants and possibly even better, I think it's striking that we don't have large-scale rigorous studies that directly compare these approaches. And unfortunately groups like the NIMH and academic psychiatrists, they rarely fund these types of studies. And this is because they become so narrowly focused on searching for biological explanations for mental illness. This narrowing of perspective has emerged over the last several decades largely due to the immense profits from selling psychiatric medications. And this has sort of acted like this kind of gold rush. And it's funneled huge investments into understanding how this drug works. And it has fundamentally recast mental health problems in the eyes of professionals as primarily being biological. And this has discouraged research into equally promising lifestyle-based interventions which honestly could be much more helpful for people. And as a result, many real-world super important clinical questions remain unanswered. For instance, we don't know how, you know, standard of care, you know, first-line anti-depressant therapy, which is kind of what we do in the US. We don't know how that compares to say like lifestyle interventions like exercise, dietary interventions, you know, combined with some targeted therapy that, you know, is aimed at maybe relationship problems if the person's having it or maybe existential problems or work problems. We don't know how those two things differ. Does one approach lead to fewer suicides? Does one of them lead to less hospitalizations or less chronic mental health issues? Does one of those approaches lead to, you know, fewer healthcare expenditures? And unless we have this data, we can't use it to actually change the way we deliver psychiatric care. We can't say, well, you know, based on these studies, we need to be supporting family medicine doctors with more non-drug interventions. And that's why it's so important that we we need to, you know, pull this weed out at the root that all mental illnesses are like predominantly biological. We need to change the research agenda and start looking at a more holistic approach to fixing these things because until we do that, we're not going to be able to use that evidence to actually change the way we deliver mental health care in the US.
All right. So, now that we've reviewed the evidence or lack thereof supporting long-term anti-depressant use compared to non-drug alternatives, it is crucial that we discuss an often overlooked risk associated with chronic anti-depressant use and that is anti-depressant induced worsening of depression which is a phenomenon known as tardive dysphoria. So, what is tardive dysphoria? Well, tardive dysphoria refers to a state of chronic persistent depression directly caused by long-term anti-depressant use. And many might initially dismiss this concept or be suspicious of it because it sounds kind of crazy, right? What? Taking anti-depressants can make you worse over the long run. However, I wouldn't be so sure about that because this condition has been clearly described in the medical literature by prominent psychiatrists for a long time because in fact a version of this was actually introduced by Giovanni Fava who is a very well-respected psychiatrist. He's a professor at the University of Buffalo and Bologna in Italy and he's also the editor of I think it's either the third or the fourth most widely read psychiatric medical journal, psychotherapy and psychosomatics. And back in the '90s he started introducing the idea of drug induced worsening on anti-depressants under the umbrella of something called operational tolerance and he used this to explain how anti-depressants may actually worsen the very condition they were supposed to treat. And this was based off observations that he was seeing clinically back in the '90s. And this idea of drug induced worsening was actually then further expanded in the 2010s by a psychiatrist called Riff Al-Malk. He's a psychiatrist from the University of Louisville and he expanded on this phenomenon and he actually named it Tardive dysphoria.
So let's talk a bit more about what what this is. Well, tardive dysphoria is really best understood as a form of drug induced neurotoxicity arising from prolonged exposure to anti-depressants. Now, this is nothing really new because neurotoxic effects following prolonged drug exposure aren't new or rare. In fact, many substances taken chronically have known neurotoxic consequences. For instance, alcoholics. If you consume a lot of alcohol for a long period of time, a proportion of people will go on to develop a condition called Wernicke-Korsakoff syndrome. This is essentially irreversible neurological damage that looks like dementia. Next, we know that people who consume high amounts of cannabis, especially high potency cannabis, that this is associated with neurological damage and it can lead to a higher incidence of people going on to develop things like bipolar or schizophrenia. We know that with methamphetamine that this leads to visible changes on MRIs in the brain and cognitive impairment. And this type of neurotoxicity isn't just limited to recreational drugs because in fact it happens with most psychiatric medications. Antipsychotics if you take them long term a proportion of people will develop a permanent movement disorder called tardive dyskinesia. They also will develop things like brain shrinkage as well. We know that people who take lithium long term, a small proportion of them will go on to develop a condition called silas syndrome, which is again irreversible cognitive damage. And we know that the widely used benzodiazepines can cause a condition called benzodiazepine induced neurological dysfunction which can cause a whole range of neuropathic pain and also cognitive impairment as well. So simply put, when you look at it in this context, the human brain for some people really does not handle chronic chemical exposure well. And to me, that seems like something that's very intuitive.
And so let's move on now and let's talk about what tardive dysphoria actually looks like. So the way it manifests is really as this sort of chronic depression that doesn't improve and actually may even worsen over time. And it worsens even though you try multiple new medications. You try and increase the dose. It's essentially treatment resistant. Now, this is a condition that I frequently see in my practice and there's actually been some diagnostic criteria that have been proposed for this and we'll look at the one by Riff Alm where he describes it. Essentially, it's a chronic dysphoric state that you get after being on a medication for at least one year. And then he says you need to have seven of these symptoms. So dysphoric mood, reduced motivation, reduced interest, reduced energy, reduced pleasure, some sleep disturbance, some irritability, and without disturbance to appetite or self-care. This matches up fairly closely with what I see in my practice when people come to me. However, I usually think of the following things. When people have tardive dysphoria, they usually describe being very apathetic, having low energy, having low motivation to do things. They feel very blunted as well, kind of like they're just coasting through life and not really engaged. And they also frequently describe this low-level anxiety or even moderate anxiety that is in the background that isn't related to stresses in their life. It's just kind of always there and they always feel kind of uncomfortable. Some of them will also describe having some cognitive dysfunction as well like some difficulty concentrating. And the final thing that is really common is that they do not respond to dose increases or additional medications. It just seems that whatever interventions they try, they don't get better. And so from my perspective, that's really what this condition looks like.
So let's talk now about how tardive dysphoria is treated. So if you suspect that you might have this condition, the most critical step is to carefully and safely begin to taper off your medication. In my practice, patients will often gradually improve when they reduce their medications. However, it also is important to acknowledge as Elmal cautions that some individuals might even face lasting problems even after discontinuing the medication especially if significant neurotoxicity has occurred because remember this condition may be a form of neurotoxicity just like tardive dyskinesia where people exposed to antipsychotics develop this kind of permanent movement disorder and for those patients yes some of them improve when they come off the medications but there is a proportion of them where they continue to have movement disorders over time. So there may be some people where this does not improve fully when the medications are reduced.
Now you might be having this question now because this is frankly it's a scary condition. Why isn't this more widely known? Why didn't anyone tell me about this? Why isn't this in the news? And it makes sense that it should be because after all chronic substance use frequently leads to worsening mental states. I mean we've gone over that. That is essentially the rule. There's there's nothing unusual about that. And that we have respected psychiatrists out there who are publicly warning about this. But despite that, mainstream psychiatry doesn't acknowledge tardive dysphoria at all. For example, if you look at the American Psychiatric Association clinical guidelines for depression, they're completely silent on the issue. You would think that with something like this that is potentially scary, I mean, we're talking about putting someone on an anti-depressant and actually makes them chronically sick in the long term. You would think that they would have maybe a whole page or multiple pages in there saying, you know, this is what the condition is. You know, don't worry about it. We can still use medications just the way we are. You know, it's addressed. There's nothing of the sort in there. It's essentially sidestepped and ignored. And so, why would people be so silent about this? Well, it's because openly acknowledging tardive dysphoria would be deeply uncomfortable to psychiatry and the status quo. And and that's because for decades, psychiatrists, family med doctors, OB/GYNs have been encouraged to prescribe anti-depressants widely. This has been guided by pharmaceutical marketing and biological psychiatry researchers who've consistently downplayed the risks and overstated the benefits. And if we were to simply admit now that these medications might be causing chronic harm, it would mean confronting a very embarrassing and difficult truth. And that is that years of these brief medication-focused visits might have inadvertently harmed many patients. I think that's probably what's been going on. And this is a tragedy because on the patient level, the lack of awareness about tardive dysphoria has led to tragic outcomes because there's going to be many individuals out there who are going to be unaware that their depression is actually medication induced and they will spend years cycling through various anti-depressants and combinations and sometimes even interventions like ketamine and TMS and ECT. And in my practice, I've seen patients who have undergone like 60 ECT treatments mistakenly believing that their brain was inherently broken when in reality what was going on was that they were suffering from a drug induced neurotoxicity that was making them more depressed.
And even if we zoom out from like a patient level and look at the broader society, this problem has contributed to an explosion in cases labeled as treatment resistant depression. And just to give you some statistics on this, back in the early '90s, about 10 to 15% of depression cases were considered treatment resistant. But in the early 2010s, this had dramatically risen to about 30 to 50%. Honestly, it's probably higher at this point. And if I think about my clinical practice and what I saw as a training psychiatrist, I was always seeing patients on multiple combinations of anti-depressants, sometimes three or four of them at a time. And this dramatic rise in treatment resistant depression, it's often attributed to some mysterious biological condition that has no clear scientific basis or no like biology behind it or like imaging behind it. And this has just conveniently allowed clinicians to kind of sidestep the whole idea of a drug induced worsening and just blame patients. You know, you can just blame their genetics or their brain chemistry and eventually you just end up prescribing more drugs or using more invasive treatments and this just creates this vicious cycle of using medications and interventions that don't actually work and it just kind of locks a person into being like a chronic mental health patient. And so what I really think is going on these days, and it's a real sad reality, and that is that a significant portion of so-called treatment resistant cases out there, they actually reflect long-term like anti-depressant induced neurotoxicity.
Okay, so where does all this leave us? So here's what I'm going to say. I'm not going to say that anti-depressants don't work because I I know they do, at least in the short term. I've taken them myself. I felt the effects. And but what I'm saying is that the evidence around their long-term use, you know, whether they actually help people in the long run is so much shakier than you've been led to believe. As you've seen today, there are safer and more effective options out there. Things like therapy, exercise, dietary changes, which do not come with risks like drug tolerance, where the medications gradually lose their effect over time. On top of that, there are also very real concerns that anti-depressants might even worsen depression, especially if used chronically, essentially causing tardive dysphoria. And like I said, in my own practice, I've seen this a lot. Sometimes this happens after 5 years. Sometimes this happens after 20 years. And there's simply no way to predict who is going to experience issues like tolerance or tardive dysphoria and who might be the fortunate few where the medications just seem to work well for them indefinitely. Having looked deeply into the evidence and having practiced as a psychiatrist for 10 years, I have to tell you it generally feels like playing Russian roulette when you take these medications long term because we have no data. We have no research that allows us to predict ahead of time what your experience is going to be like.
And so to wrap what I want to say is if you are currently taking anti-depressants and you're considering stopping them, please don't stop suddenly. That can be really dangerous. Always taper carefully and slowly. And if you need help or guidance, I've created a playlist. It's called the tapering tips playlist on this YouTube channel and it's filled with a lots of safe and practical tips to help you taper with your