The Myth of Low-Serotonin & Antidepressants - Dr. Mark Horowitz

Welcome to another episode of Afterschool. My name is Mark Horowitz. I'm a trained psychiatrist and researcher, and today I'm going to be talking about common misconceptions that people have about depression and antidepressants. Without further ado, here we go. There are a number of myths about depression and antidepressants that are hard to dislodge. Most notable is the myth that depression is caused by a chemical imbalance in the brain. If you ask people in Western countries, about 80% to 90% of them will say they believe this to be true. The chemical imbalance theory is the colloquial description of the hypothesis that depression is caused by low serotonin, a chemical transmitter in the brain. This idea was first proposed by academics, but was propagated widely by drug companies as part of their marketing push for antidepressants that increase serotonin in the short term. The selective serotonin reuptake inhibitors, or SSRIs, that are so familiar to us today. These drugs became blockbusters and one of the most widely used classes of drugs in the world. Most people still don't know that there is no evidence that depression is caused by low serotonin, and researchers no longer think this is true. When people stop antidepressants, they can often experience low mood, anxiety, and a host of other symptoms. They can often conclude, or are told by doctors, that they are experiencing a return of their underlying condition, and therefore need to stay on these drugs, sometimes for life. However, we now know that withdrawal symptoms from these drugs can look very similar to anxiety and depression, and can be easily mistaken for them. So these symptoms are not a sign that people need to stay on the drug, but may indicate that they need to come off them more carefully and slowly. There has been new research in this field on hyperbolic tapering, a specific way of slowly reducing their dose, and an advance over old-fashioned ways of tapering that can help people to come off more safely. Before I talk much more about these ideas, I just want to say that many people feel that they have been helped by antidepressants, and I in no way want to take that away from them. That's the last thing I want to do, because aside from being a psychiatric researcher and training psychiatrist, I myself have used antidepressants for 20 years, although I am now stopping them. So I am in the same boat as lots of other people. My major aim is that people are more informed about what these drugs can and can't do. One of the most common ways of treating mental health conditions, like anxiety and depression, has become prescribing antidepressants. In the past, antidepressants were reserved for severe conditions, going back about 25 years ago, when they were given to about 3 in 100 people. Since then, rates of prescribing have been increasing every year in Western countries, and this trend only increased more sharply, in America especially, during the pandemic. Across the world, there are at least 100 million people on antidepressants. According to the CDC, over 43 million Americans are on an antidepressant, which is about 1 in 4 adults. Over 15 million Americans have been on the medication for more than 5 years. Rates are similar across the Western world, with about 1 in 6 to 1 in 8 adults using antidepressants in any given year in Europe, the UK and Australia. We also know from studies that a lot of these drugs are prescribed to people who don't have approved indications for taking the medication. That is, between a third and a half of people on antidepressants currently have, or never had, an evidence-based reason to be on the drugs. The role that medication plays in depression and anxiety is contested in academic circles. There are two main ways of thinking about what psychiatric drugs do, and this is from the work of Joanna Moncrief, a professor of psychiatry working in the public health system in Britain. One has been called the disease-centred model, which is borrowed from mainstream medicine. A good example would be antibiotics for a bacterial lung infection. The antibiotics target and kill the bacteria and so solve the underlying cause of the infection, relieving the symptoms of cough and cold. And for a long time, drugs like antidepressants have been marketed in just the same way, that in some way antidepressants are reversing the process of depression, like antibiotics kill bacteria. This way of thinking about antidepressants was tied into the story that most people believe about depression, that it is caused by a chemical imbalance or low serotonin. This idea was first conceived of as an academic hypothesis in the 1960s by academic psychiatrists, but it was only in the 1990s and 2000s that the idea became widely spread to the public through advertising by drug companies. A famous commercial showed a sad blob with low serotonin in its head that was made happy again when Zoloft was given to it and raised at serotonin levels. Drug companies have been incredibly effective at communicating this idea to the point it has entered popular discourse and taken on a life of its own, with people on social media talking about low serotonin days. The media has wholeheartedly embraced this explanation for depression. Of course, if you believe that depression is caused by low serotonin, then it seems perfectly sensible to take a drug that increases serotonin as the SSRIs do in the short term. Just as if someone with diabetes was told they lacked enough insulin in their body, of course they would be happy to take insulin. So this explanation has served the objectives of these companies well because it makes their products seem natural, sensible and safe. However, it turns out that this entire explanation was mostly a marketing lie. The hypothesis put forward by psychiatrists 50 years ago has not been borne out by subsequent research. Most psychiatrists now say that they had long ago given up this idea and that no informed psychiatrist would say such a thing. We recently published a large study looking at all the evidence linking serotonin and depression, whether you look in cerebral spinal fluid, blood, scan people's brains or look at their brains after they have died or look at their serotonin genes or even deprive them of serotonin by changing their diet. There is no evidence linking low serotonin level or activity with depression. Our paper dispelling this myth was widely covered in the media because this was news to most of the public who had been led to believe this. So, if there is no convincing evidence that depression is caused by low serotonin, then antidepressants can't be reversing this underlying chemical cause of depression They can't be said to be acting in the same way as antibiotics. There is now a whole range of other theories about what antidepressants might do, acting on inflammation, causing the growth of new neurons, etc. None of them proven in humans. Most derive from work in animals. So, if there is no proof that they fix an underlying chemical problem, then what could they be doing? There is another way of thinking about what psychiatric drugs do, particularly antidepressants, and that is what Professor Moncrief calls the drug-centred model. An example would be, we know that alcohol is very effective for social anxiety. If you drink alcohol, it will make you feel calm. It reduces anxiety. It will make you feel more at ease in social situations, whether you have a social anxiety disorder or not. We don't think that alcohol is reversing the underlying cause of social anxiety disorder, or that social anxiety disorder is caused by an alcohol deficiency. We know that alcohol is a drug that acts on the brain and causes certain changes to our emotions and thoughts that are superimposed on top of whatever anxiety you have underneath. And when the drug wears off, the anxiety will come back. And some people have suggested that this may be a more appropriate way to think about what psychiatric drugs are doing. So, what do antidepressants actually do to our thoughts and feelings? If you look at them through this lens, there are a wide variety of different compounds that are called antidepressants, and they have differing effects. Some of them are a bit energising, some are a bit sedating. Many of them cause emotional numbness. That's one of the most common effects that people will report when they're asked. In surveys of people on antidepressants, between 50% and 70% will report numbed emotions. Sometimes people claim that this is because of the depression itself, but a recent study found that even in healthy volunteers, without any depression, they cause blunting of emotions. This emotional numbing has also been linked to the genital numbing often experienced by people on antidepressants. In fact, if you crush up many antidepressants and swish them around your mouth with some water, they will numb your mouth. Numbing will reduce negative emotions. You can see why some people might welcome that. If they're in the depths of despair, if they're beside themselves with anxiety, the numbing effects might give them a reprieve from those symptoms. But antidepressants are not so targeted as just to affect negative emotions. They affect all emotions, including ones we enjoy. So there might be unforeseen consequences of such an approach. In the long term, numbing might affect relationships, quality of life, and the ability to experience positive emotions. So how effective are antidepressants? This has been explored in hundreds of randomized controlled trials. Study after study finds it very difficult to distinguish between antidepressants and placebo. There have been hundreds of studies conducted comparing antidepressants to sugar pills over about eight weeks. And in these studies, everybody gets better over eight weeks, whether they're given an antidepressant or a sugar pill. We know that depression tends to get better over time. When people turn up to their doctor's offices, they're often at the worst point in their lives. Over time, people tend to return to average. That's called regression to the mean. It applies to nausea, headache, and to mood like depression. Also, people tend to work through their problems. They get over the lost job or relationship, move on in some way, and that is called natural recovery. People also respond to the hope of being given a treatment, and that is what the placebo effect is. To briefly summarize hundreds of studies, on a 52-point depression scale, people given sugar pills improved by about eight points over eight weeks, and people given antidepressants improved by about 9.8 points over eight weeks. There is a difference of 1.8 points on a 52-point scale between the two. One large study found that it takes a 6- to 7-point difference on this scale to cause noticeable improvement, so that many people think that the difference between antidepressants and placebo is not big enough to make a meaningful difference to people, even before adverse effects from the drugs are brought into the picture. And even that difference might be exaggerated by the way the studies are done, mostly by drug companies who are evaluating their own products. People will know they're on an antidepressant in these studies because of the side effects, dry mouth, nausea, et cetera, and we know that this can lead to expectations of improvement, what is called the amplified placebo effect, which can make people in the drug group do better. And these studies are done very short term. Depression can last for long periods, months or years, and the vast majority of these studies go for six to 12 weeks. The duration of these studies is a far cry from how long the drugs are taken in the real world, with nearly half of American adults who are on antidepressants taking them for more than five years. Moreover, drugs tend to wear off over time, and so differences from placebo tend to become smaller. This is true for benzodiazepine drugs like Valium and opioid drugs like OxyContin, which look effective at six weeks, but their effects wear off over time. What works to start with is a raise by the process of tolerance. We know this also occurs for antidepressants because they give you withdrawal effects when you stop them, the flip side of tolerance. Americans refer to this colourfully as antidepressant poop out. And the few studies that have gone for long periods of time, like a study from the American government called the STAR-D study, after 12 months of treatment with antidepressants, only 5% of people were free of depression and had not dropped out of the study. So we really don't have very good evidence that these drugs are useful in the long term. We know lots of people think about coming off their antidepressants. Some of the most common reasons people give is the numbing effects that people experience, or other side effects, also called adverse effects, like sexual problems, weight gain, daytime tiredness, trouble with memory and concentration. Other people are more concerned about the long term physical health risks, which can include increased risk of osteoporosis, heart disease, strokes, falls, and even an early death. Others feel that whatever was causing stress in their life has passed, or they have developed other ways of coping, and they would like to try coming off their drugs. The first thing to say to anyone considering stopping antidepressants is they should absolutely not stop these drugs cold turkey. This can be a dangerous thing to do for some people. We know now that there are withdrawal symptoms from antidepressants, and that for some people these can be severe, can last for long periods, and can sometimes be life threatening. Like lots of drugs taken long term, being on antidepressants causes physical dependence. That's different from addiction. These terms are often confused. Addiction involves people who are craving a drug, they become fixated. Some people break the law to get more of the drug. That, of course, doesn't happen with antidepressants. But you don't need that to become physically dependent on a drug. For example, probably most people, myself included, are physically dependent on caffeine. We're not craving it, not thinking about it all day, we're not stealing from our neighbours to get it, but if we stop caffeine, we'll get withdrawal symptoms. And similarly, antidepressants cause physical dependence, and when you stop them, you're at risk of getting withdrawal symptoms. This occurs simply because the body has become accustomed to a certain level of the drug, and misses it when it's reduced. As antidepressants affect almost every system in the body, the brain, the gut, the hormonal system, the muscular system, the effects of stopping them are very wide ranging. So, there's physical symptoms, dizziness, perhaps the most common symptom, brain fog, difficulty concentrating and remembering things, headache, unsteadiness on your feet. People also have a strange sensation that things around them are not real. They become dreamlike, called depersonalisation and derealisation. Some people have these very particular electric shocks in their head, which they describe as either their brain being shut off for a second, or a little zap in their heads, sometimes on moving their arches. People can get muscle tremors or spasms, they can have nightmares. Doctors are often poorly informed about these withdrawal symptoms, which means the diagnosis is often missed. The second category of withdrawal symptoms are probably the ones that cause the most confusion and trouble, and that is emotional withdrawal symptoms. This is not to say that these are symptoms in someone's head. These are physiological symptoms of withdrawal that are expressed through emotions, because, of course, antidepressants affect the brain, they affect the way we think and feel. And so some very common withdrawal symptoms are depressed mood, anxiety, panic attacks, crying, fear, trouble sleeping. Some people can become very agitated when coming off antidepressants. We know that these symptoms are symptoms of withdrawal, and not just a return of an underlying condition, because even people who have no underlying condition experience them when they stop. For example, people who have put on antidepressants for pain or the menopause can experience for the first time in their lives some of these emotional withdrawal symptoms on stopping. Of course, we all know all sorts of drugs that cause emotional withdrawal symptoms on stopping, like caffeine, nicotine, amongst others. If you don't know what to look for, then these emotional symptoms of withdrawal can look a lot like the underlying condition that people were first given the antidepressants for, like anxiety or depression. This can confuse a lot of people, so doctors can jump to the conclusion that this must be a relapse, that is, a return of an underlying condition, rather than withdrawal symptoms. If someone walks into a doctor's office and says they've stopped their antidepressant, they can't sleep, and they feel awful, it is very likely that the diagnosis of relapse will be made on the spot by the doctor. This leads to people being put back on antidepressants and sometimes told that they need the drugs, perhaps even lifelong. This is very unfortunate, because a more sensible approach to withdrawal symptoms would be to conclude that the person just needs to come off the drug in a more careful way, not that they need to stay on it. We have learned over the last few years from large studies that withdrawal symptoms from antidepressants are much more common, can be more severe and longer-lasting than official guidance has said for many years. If you look at these studies, about half of patients will experience withdrawal effects when they stop their drugs. In surveys of patients, about half of those with withdrawal symptoms will say the symptoms are severe. So perhaps one in four people will have severe symptoms when they stop antidepressants. Because there are so many people on these drugs, that is a lot of people. These symptoms, which drug companies used to say would only last a week or two, we now know can last for months, and in some people for more than a year, and sometimes even longer. At the moment, knowledge on how to safely stop antidepressants is a major blind spot in psychiatric and medical education. There is much greater attention paid to starting these drugs than stopping them. So on the one hand, there have been 1,000 studies on starting antidepressants. There has only been about a dozen on stopping them, mostly because this hasn't been in the interest of the major funder of these studies, the drug companies that make the drugs. And it is these studies that inform what is then taught in medical schools and ends up in guidelines. So what do we know about stopping antidepressants? The worst possible way to stop antidepressants is to stop them in one day, i.e. throw them in the bin. Your brain has gotten used to a certain level of effect from the drugs, and going to zero straight away is the neurobiological equivalent of jumping from the top of the 10th storey of a building. And the consequences can sometimes be very unpleasant. What makes more sense is coming down floor by floor so that your body and brain have time to readjust to lower levels of the drug. This will cause less of a jolt to your system. Even better is to come down step by step so that the worst that could happen is you bang your knees a little. And that is what gradually tapering off a drug is all about. But at the moment, the most common approach to stopping antidepressants by most prescribers is to halve the dose for a couple of weeks and then to halve the dose again for another couple of weeks, often by giving a tablet on every second day, and then stop. For some people, that seems to be OK. But for a large proportion of people, they can get terrible withdrawal symptoms from this approach. Their doctors mostly diagnose relapse, and patients often get put back on the drugs. Some of them end up going elsewhere, like social media or peer support sites for advice on how to stop their drugs as they lose faith in their doctors. There's a reason for this misalignment in clinical practice and patient experience. In the late 1990s, drug companies worked with some academics to minimise the risk posed to their product by knowledge of withdrawal. They coined the term discontinuation symptoms, a euphemism for withdrawal symptoms that makes them sound benign. They arranged the writing and printing of several academic articles that described them as brief and mild, and they sent these articles out to doctors in America and Europe. And that became the mantra. Stopping antidepressants, you get a few discontinuation symptoms, and they're brief and mild. That was what the guidelines said for many years in England, and it is what it still says in North America today. And if that is what's in your mind as a doctor, then there's no big deal in stopping these drugs. So if you stop them, and you do have trouble, and you turn up to your doctor with severe symptoms that are long-lasting, the doctor thinks it can't be withdrawal effects because, after all, these are mild and brief. It must be the underlying condition coming back. And that becomes the medical education that junior doctors are exposed to. This misunderstanding has helped fuel the widespread prescribing and long-term continuation of these drugs. But there has been some green shoots recently. Some healthcare professionals have caught onto what patients have had to figure out on their own, a better way of coming off these drugs. In the last few years, there has been a technique called hyperbolic tapering that has become better known. This is a science-based approach to tapering antidepressants built on an understanding of the relationship between the dose of the drug and its effect on the brain. That is, blocking their main target, the serotonin transporter, and also the other receptor targets. Put simply, very tiny doses of antidepressants have outsized effects on the brain. When there is not much drug in the brain, every extra milligram has a large effect. But when you get to the larger doses that are often used in clinical practice, every extra milligram has less and less additive effect because most of the receptors are already occupied by the drug. This leads to a pattern called a hyperbola to describe the relationship between the dose of drug and the effect on the brain. The relationship is very steep at low doses and flattens out at higher doses, an example of the law of diminishing returns. This relationship can help us to understand why people get into so much trouble coming off antidepressants in the way most doctors recommend. The usual approach is called linear tapering, and it involves reducing by the same amount of medication each time, for example, 5 milligrams. So you might go from 20 milligrams to 15 milligrams to 10 milligrams to 5 milligrams to nothing. The first reduction does not cause much change at all in terms of effects on receptors. Each subsequent change will have a larger and larger effect on the brain because of the hyperbolic shape of the curve. So when you go down from 5 milligrams to 0 milligrams, it sounds like the same size reduction in terms of dose as going from 20 milligrams to 15 milligrams, 5 milligrams. But actually, it can have almost 20 times as large an effect on the brain as going from 20 milligrams to 15 milligrams because the changes are so steep at lower doses. This exactly matches what patients report, that reducing their dose at the beginning is not too difficult, but when they get down to lower doses, it becomes harder and harder to make reductions. And doctors are mostly unaware of this relationship and so often conclude that because people have trouble at the ends, they must need the medication. Imagine walking down a flight of stairs in the dark, but the final steps are several metres high rather than just a few centimetres. This is the trap that traditional approaches to tapering these drugs have missed, and people conclude that those stairs are just too dangerous to walk down. Hyperbolic tapering takes into account the shape of this curve. You make smaller and smaller reductions as you get down to lower doses so that each step causes the same sized effect on the brain, like carefully climbing down a steep cliff rather than jumping off of it. There needs to be a fundamental shift in the way in which we understand what causes mental health challenges. The main thing that people should understand is that research points to the fact that depression and anxiety largely arises from the things we experience in life, those stresses like job loss, relationship breakdown, illness, not from faulty biology. In fact, studies show that by the age of 40, 86% of people will experience clinical levels of depression or anxiety, so this is a common part of the human experience. It's from this perspective, understanding the specific problems and challenges that an individual faces, rather than lumping everyone in the same bucket of chemical problems, that we can best understand what might help each person best manage their problems. Studies show that if people understand their mental health problems in terms of what is going on in their lives, they feel more hopeful for the future, more empowered to help themselves, and less likely to use medications. On the other hand, people who are told that they have a chemical problem in their brain that only medications can fix, what has sometimes been referred to as the broken brain explanation, feel more hopeless, less able to help themselves, and, of course, more willing to take medication, a fact that can hardly be lost on the marketing departments that ran these campaigns. At a societal level, the main drivers of mental health problems are poverty, job insecurity, relationship conflict and loneliness, physical illnesses and other things that threaten people's basic emotional and physical needs. So, perhaps, rather than there being a renewed call for more research into genetics and brain imaging every time there is a tragic suicide or a celebrity comes forward with their tale of mental health problems, what we need to do is to address the social drivers of despair and hopelessness. In some ways, trying to change the brain to fix these problems is like opening up the back of a computer to solder the circuit board when a piece of software crashes. On an individual level, people can take steps to manage and improve their own mental well-being through practices like mindfulness, exercise, nurturing relationships, getting better sleep, and learning about nutrition. Small changes to our habits can produce large results. And finally, I'm not saying that medication plays no role in managing mental health problems, but that we should be better informed about what medication can and can't do. Thanks for listening to another episode of Afterschool. I hope what you heard was informative. If you want to learn more about my work or about Jonah Moncrief's work or learn more about how we're helping people in Canada and the US to safely stop antidepressants without drug, you can check the links in the description. Otherwise, stay safe and have a good day.