The history and controversy surrounding depression

Tiny Matters

There's a whole lot of information (and misinformation) out there about depression, and debate surrounding how it's treated. In this episode, Sam and Deboki unpack this complex mood disorder that impacts over 300 million people across the globe as well as the effectiveness of SSRIs and the work being done to find better drugs.

Transcript of this Episode

Sam Jones: In 1953, chemists developed a drug called iproniazid. It was one of the first treatments for tuberculosis, a nasty bacteria-caused illness that mainly affects a person’s lungs and is passed through the air from one person to the next, just like COVID-19.

Now, if you saw the title of our episode, you know the topic for today is why am I kicking things off by talking about a tuberculosis drug? Well, it turns out iproniazid had some side effects like increased appetite and improved sleep. Some tuberculosis patients who took iproniazid even reported feeling euphoric. So although iproniazid continued to be marketed as an antitubercular compound under the name Marsilid, it soon became the first drug used to treat patients with depression.

Welcome to Tiny Matters. I’m Sam Jones and I’m joined by my co-host Deboki Chakravarti.

Deboki Chakravarti: Today Sam and I are going to tackle a very tricky disorder: depression. We should say now that in this episode there are a couple of references to self-harm, so if this episode is not for you there is a whole back catalog of topics to check out.

Today’s Tiny Matters was inspired by an email from our listener Kayla M. Kayla wrote in suggesting an episode about neurotransmitters, specifically the neurotransmitter serotonin which was first linked to depression many, many decades ago. Kayla told us that in their graduate work, they've come across a whole lot of misinformation and debate surrounding serotonin and depression and how well antidepressants work.

And depression is an incredibly complex topic, which is part why it can be difficult to navigate the information that’s already out there. So let’s start with the basics. Depression is a mood disorder that manifests in a variety of ways.

Gemma Lewis: It's defined really by a sustained period of low mood and also by something called anhedonia. And that refers to a loss of pleasure or enjoyment in things that the person once found enjoyable. There are also loads of other symptoms of depression, such as, such as changes in appetite, changes in sleep, reduced self-esteem, negative cognitions, negative thoughts, negative patterns of thinking about the person themselves, about the world, and about the future. And depression can often, in more severe cases happen at the same time as self-harm and thoughts about, and even suicide attempts and suicide itself, of course. So what really distinguishes depression that requires treatment or intervention from the low mood that we all recognize is that symptoms of depression mark a change in how a person was once functioning and once feeling, and it also leads to impairment. So it has detrimental effects on that person's daily functioning. And the symptoms need to have been present most of the day, every day for at least two weeks.

Sam: That was psychiatric epidemiologist Gemma Lewis at University College London. Epidemiologists like Gemma take a population perspective when looking at a condition or disease . They work to understand how common that condition or disease is, how it’s distributed throughout the population, and who is experiencing it. Epidemiologists also try to get at the root cause to hopefully inform treatments as well as measures for prevention.

Gemma Lewis: How we might prevent depression by using public health interventions that are available to the general population is a main focus of my research. Now prevention is not something that we are particularly good at for mental health problems, and that's across the whole range of mental health problems across all of the countries in the world.

So this is a really important challenge that we face as researchers, as policy makers and as a society. And this is a gap that we are really trying to address in order to advance primary prevention for mental health problems. To get it up to where the primary prevention of physical health problems such as cardiovascular disease or ulcers, cancers. One of the things that I'm interested in is that depression and anxiety, and also self-harm, they often begin during the teenage years. So an adult for example who has experienced several episodes of depression will often have experienced their first episode when they were a teenager. And that has pointed to the potential of schools as settings where we could locate preventative interventions for mental health problems. One of the things that I'm looking at at the moment is whether increases in the level of academic pressure that young people have been exposed to over the past few decades may have led to the increases in depression that we've also seen over the past decades. And whether we can modify the environment and culture of schools in order to make them more positive environments for young people's mental health.

Deboki: So in an ideal world, we would be able to prevent as many people as possible from ever developing depression. But right now that’s not possible, and there are a lot of people who have depression that are seeking out treatment.

One of the challenges of finding a treatment for any given patient is the lack of an obvious biomarker that can tell doctors: yes this person has depression and this is a drug that will treat it. If you compare this to cancer, for instance, tumors produce molecules that can serve as biomarkers for the type or stage of cancer, and that gives doctors insight into which specific treatment option would be the most effective.

Of course, it’s not always that straightforward with cancer either, and with any disease or disorder there will be patients who are more difficult to treat. And in the case of depression specifically, the lack of any kind of biomarker means that finding treatment is a case of trial and error.

Andrea Cipriani: In mental health, we have guidelines about average effect, average treatment, which we start with first line treatments without knowing whether this treatment is the best treatment for you. And then if it doesn't work, we go to a second option and a third option and fourth option. So my big problem as a patient and as a clinician is not treatment resistance itself, but also how long it takes to find the right intervention.

Sam: That’s Andrea Cipriani, a psychiatrist and professor at Oxford. Most of the patients he treats have depression and other mood disorders and his work focuses on personalized mental health care.

Right now Andrea and his colleagues are running a trial called PETRUSHKA that aims to personalize pharmacological treatment for adults with major depressive disorder. To do this, they’re using an evidence-based clinical decision making tool. The algorithm behind the tool was created using data from 40,000 patients from randomized control trials plus data from 700,000 real world patients in the UK.

So here’s how it looks in practice: a person can log on to a webpage that has this tool and then provide demographic information like gender and age as well as the symptoms they’re experiencing, the severity of those symptoms, the number of episodes they’ve had previously, and a bunch of other info including their preferences in terms of the types of treatment they’d be open to.

Andrea Cipriani: We combine all this information and give a recommendation to the clinician and the patient about what is the best treatment for that specific individual they can discuss and then agree about the prescription. So I think this is the first step towards a real world, evidence-based second generation of treatment for patients.

Deboki: The PETRUSHKA project is expected to run until this fall, 2023. Other researchers we spoke with for this episode, including Gemma, would love to see a personalized approach when it comes to depression.

Gemma Lewis: So personalized medicine, being able to predict which treatments an individual will respond best to, is sort of a holy grail across the whole of medicine, and something that is not practiced at all or, you know, something people aren't able to practice at the moment for mental health. And that is certainly something that we would all like to see happen. So personalized medicine and also stratified medicine, knowing which medications are more effective or which subgroups within the population that would help to personalize and individualize treatment programs so people get treated more effectively more quickly.

Deboki: OK so to recap: early intervention during childhood and highly personalized treatment are ideal. They’re the goal. But where are things at right now? And how were they before?

To answer those questions, Sam called up David Hellerstein, who is a professor of clinical psychiatry at Columbia and the director of the Depression Evaluation Service which is a research program at New York State Psychiatric Institute. David also has a book coming out called The Couch, the Clinic, and the Scanner: Stories from Three Revolutionary Eras of the Mind.

Sam with David: What are a couple of ways that doctors no longer treat depression that they used to?

David Hellerstein: When people talk about outmoded treatments of depression, we usually think of horrific treatments like lobotomy, which was putting the equivalent of an ice pick into someone's brain and muddling it around and destroying brain circuits. Obviously that's not done anymore. Insulin coma—people would be given insulin and put into a prolonged coma and hopefully would not die—would come out and possibly not be depressed. But I think that the actual most common kind of treatment that's not done for depression is putting someone in an asylum, removing them from society, locking them away, or putting them in a hospital for a long time.

Sam: And beyond lobotomies, induced comas, and asylums, there are pharmacological treatments that are no longer used for depression. For example, the tuberculosis drug iproniazid I mentioned at the top of the episode.

Iproniazid is what’s called a monoamine oxidase inhibitor or MAO inhibitor, and MAO inhibitors work by blocking the activity of an enzyme that removes certain neurotransmitters, like dopamine and serotonin. These are chemical messengers between brain cells.

When you give a patient an MAO inhibitor, those neurotransmitters can stick around and they affect our mood. But they can also have a bunch of side effects, and overdose and death are possible. Because of that, MAO inhibitors are rarely used to treat people with depression today. Instead, drugs that only target serotonin have become more common.

Deboki: A link between lower serotonin levels and depression was first suggested in the 1960s, and in the 80s and 90s it really took off with the creation of selective serotonin reuptake inhibitors or SSRIs, which includes drugs like Prozac.

David Hellerstein: Prozac came out in 1988. And then Zoloft and Paxil and some of the other SSRIs came out in the subsequent years. So we've had really several decades now of those medicines as the primary antidepressant treatment medications. And we've seen their limits. We've seen that we need newer and more effective treatments. But they are currently still the standard of care.

Deboki: The development of SSRIs was a big step forward because although they of course have side effects that can vary a lot based on the person, they were much safer than MAO inhibitors and a lot of initial studies pointed to their effectiveness. We should note that serotonin also plays an important role in sleep, digestion, wound healing, bone health, blood clotting and more. And, when it comes to the brain and mood, there were—and still are—big question marks.

Andrea Cipriani: We still don't know the mechanism. So we know that they increase the level of serotonin in the brain, but what we know now is not the real effect of the medication. So at some point with the idea of the serotonin hypothesis, people thought if I boost the level of serotonin, I will feel better. Which is not true.

Deboki: So when someone takes an SSRI like Prozac their serotonin level will go up right away, but Andrea told us that people often don't see an effect on mood or other aspects of their depression for weeks, which means it’s not just the serotonin—there’s something else going on downstream—but it’s unclear what that is.

Sam: In a 2022 review analyzing 17 different studies, researchers didn’t find support for the hypothesis that depression is caused by lower serotonin activity or concentrations.

So it’s safe to say that depression is a whole lot more complicated than low levels of serotonin. But does that actually mean SSRIs are completely useless?

David Hellerstein: Do they work and how well do they work? Those are really key questions. And it's complicated because it's often hard to find a signal amidst the noise of actually doing clinical trials. And so reasonable people can disagree about how effective they are versus not. But I’d say most psychiatrists and most psychiatric researchers believe that they are effective, but there are certainly some studies, including some large sort of meta-analyses, that suggest that the effects are relatively low or or less than we would hope.

Deboki: David told us that, in his work with people who have mild or severe chronic depression, some of those people find existing medications including SSRIs to be extremely effective, even life-changing. He told us he has seen patients go back to work and develop relationships after many years of being disabled by depression.

The problem, he says, is that it’s unclear how to identify people who will respond right up front, so a lot of time can be spent seeking out medication and therapy options. He agrees that personalized medicine really is the ideal, but for that to work there need to be more drug options that are effective for a greater number of people.

David Hellerstein:To my mind, the real challenge is finding treatments that are more effective, work more quickly, have fewer side effects or toxicities. And that can treat the really high level of psychiatric suffering that we see in our current society. There's a lot of essentially rehashing of how well were those studies done in the 1980s and nineties, and how many negative studies were there? … To me that's sort of a rear guard action and I'm really more interested, as a researcher and as a clinician, in how do you make medications that are more effective? How do you use existing medicines to the optimal degree possible? And how can we really make progress in something that is really a devastating, really almost epidemic condition. If you look at depression rates, especially with the covid epidemic, suicide rates, and other kinds of impairment, it’s just such a common and increasing problem that we're facing in our society, I think rather than hashing out how well these medicines work, let's find better ones.

Gemma Lewis: SSRIs not being effective is not a viewpoint or an interpretation of the evidence that I agree with. There is a lot of evidence, a lot of strong and convincing evidence that SSRIs can reduce depressive symptoms for people who use them. They do not work for everybody. They do not work for the same people every time they take them.

To be honest, within medicine, few medications do work for everyone. SSRIs and other antidepressants are often life-changing for the people who take them. But saying that they are not a magic cure for depression and other mental health problems, lots of people don't experience a response to them and will need to try a different antidepressant or another medication with their antidepressant. The other thing we know is that antidepressants are just one available treatment for depression. And of course they don't alter or cure the psychological environmental and social causes of a person's illness, but they were never meant to. So what we know and what we have evidence on is that the most effective form of treatment, particularly for treatment resistant depression, is an antidepressant in conjunction with a psychological therapy such as cognitive behavioral therapy.

Deboki: Andrea agrees with David and Gemma in that although SSRIs don’t work for everyone, for some people they really do work. He also believes that extremes are not productive when it comes to mental health.

Andrea Cipriani: There are people who take one side and say, drugs work for everybody, or drugs don't work for anyone. And that’s, again, an extreme we need to avoid because there's a lot of stigma around mental health. And if we give the message that drugs are ineffective, that's terrible for people who take drugs and they benefit from the medication. So we need to balance the position. And as a clinician, I'm a big pragmatist, so I think what really needs to inform our decision making is patient benefits, nothing else.

Deboki: SSRIs are obviously not a cure-all. We need something better. Part of finding what’s ‘better’ means going back to the drawing board, at least to some degree, and trying to understand depression on a more basic level.

David is interested in understanding how treatment changes the structure and function of a person’s brain. In one study, he and colleagues looked at patients who’d had depression for two or more years and hadn’t responded to previous medication or psychotherapy treatments.

What they found was that people had increased activity in regions of the brain that become more active when you’re resting. The brain circuit of these regions is referred to as the default mode network.

David Hellerstein: If you close your eyes and you let your mind wander, then the default mode network activates. Whereas if you open your eyes and you are attending to some task it decreases its activity.

So one of the thoughts with depression is that the default mode network may be overactive, and that people may essentially have an inability to stop mind wandering, especially around ruminations and worries. So we found that the default mode network has increased activity in depression and also that medication, but not placebo, decreases the activity of the default mode network to the normal level.

Sam: So getting out of that default network seems to be important, and like David said, there are current medications that could help. But another possibility for breaking through that network has popped up in recent years.

David Hellerstein: We're involved in several studies with psychedelic drugs, and we were part of a large phase two study that was published last fall in the New England Journal of Medicine looking at psilocybin for treatment resistant depression.

Sam: Psilocybin is a naturally occurring psychedelic compound. You’ve maybe heard psilocybin-containing fungi casually referred to as “magic mushrooms.”

David Hellerstein: That study showed that a single dose of psilocybin seemed to lead to very rapid, within a few days to a week, and then sustained, over a course of three weeks, and then 12 weeks and longer response for a significant number of people with treatment resistant depression. So to me, it's really interesting, that's one tiny little piece in a new, whole new line of research that's gonna be very exciting.

One of the cool things about the psychedelic experiences people have, they'll hear colors, they'll see sounds, they'll talk to God, they'll see the beginning and end of the universe. They'll have these intense personal experiences that they can often perceive as really life changing and highly significant. And then if you do the MRI studies of these people pre- and post-treatment, you can see that there's significant changes in the brain connection activity, probably brain structure as well. So the sort of stuckness of depression and the stuckness of anxiety disorders, people are in these loops that it's really hard to get out of.

And I would say that some of the new treatments that we're looking at are things that can essentially break the loop, break the cycle, and then allow more plasticity of the brain, which is the ability for the brain to change based on experience, learning and, and other kinds of interactions with the world. And so the new treatments that we're looking for would actually potentially enhance, renew the brain's neuroplasticity in hopefully a positive way.

Deboki: David also told us that now there are a number of research groups studying versions of psychedelics that aren’t hallucinogenic. So psychedelics minus the trip. But he says maybe the trip aspect of psychedelics will turn out to be essential to effectively treating people with chronic depression.

David Hellerstein: Maybe the effect of the psychedelic drug is not only on the brain circuits, but also it's a radical, profound psychological experience that one is helped through with an expert therapist. To  me, that's kind of fun because when I was in medical school, we never talked about mystical experiences as being part of effective treatments. So that would be so cool if that played out as a potential component of these treatments.

Deboki: Psychedelics hold a lot of promise, but a lot of work still needs to be done.

David Hellerstein: There's hundreds of studies ongoing or being planned. And we want to bring kind of order and sanity to a process that can be very chaotic. Let's do really good studies, let's figure out how they work, how they can be improved upon, how to best use them, their availability if they become FDA approved.

Sam: The psychedelic research wave is here and seems to only be building. But this is not the first time. Part of why David really stressed the importance of doing rigorous studies to show safety and define efficacy and dosage of these drugs is because we’ve been here before. In the 1950s and 60s, and even earlier, scientists were studying mind-altering drugs to see if they could cure different mood disorders. But by 1970, poof! That research was pretty much gone. Why? Well, that’s a story for the next episode of Tiny Matters.

Sam: Tiny Show and Tell. It's time.

Deboki: It sure is.

Sam: Do you want to kick things off?

Deboki: Yes. I will start off. This is a very short one, but it was just a lot of fun. So, this was an article in The Atlantic called How I Got Bamboozled by Baby Clothes by Sarah Zhang. And this is just about bamboo clothes. That's why the Bamboozled, it's a fun on bamboo. Just to explain it out loud, which is always good for a joke to explain it.

Sam: That's how you make them land. That's good.

Deboki: Yeah. Yeah. So, this article is about bamboo clothes, which I don't know how you think of them, but I hear bamboo clothes and I'm like, I think of soft. I think of airy. I think it sounds really nice. It sounds comfy.

Sam: Sounds like natural or something.

Deboki: Yeah, exactly. So in this article, Sarah Zhang is talking about bamboo clothes and how a lot of us have this association with them. And in particular, I guess it's a really big thing for people to do this with everything that you can buy for your baby.

And in this case, she was talking about how she, one day she took a look at the actual tag of the clothes that she had for her baby, these bamboo clothes, and realized that actually these clothes are largely made of rayon, which is a fabric that a lot of times does not get a whole lot of love or respect because we just kind of associate it with cheap clothes.

And so what this article actually then is about is how do clothes go from bamboo to the actual fabric? I just always find fabric so fascinating and how it gets made, how it affects the design of clothing. And so it's about basically, how do we get from things that are sort of natural like bamboo, to this fabric that we don't really think of as natural, the way we might think of other fabrics as being natural. And also just how did that then make the leap to this thing that is marketed as so essential and so important for babies, I guess. But also why we're able to upsell rayon through this labeling. I just thought it was really interesting.

Sam: That is really interesting. Yeah. This feels like a greenwashing situation. Kind of.

Deboki: I think that's part of it. Yeah, for sure.

Sam: Okay, so Deboki, question for you. Do you know Balto the dog?

Deboki: Yeah.

Sam: All right. So my Tiny Show and Tell is about him. A bit of a backstory, before the science. Balto was a Siberian Husky that was part of a dog sled team that, in 1925, delivered lifesaving diphtheria antitoxin to a remote Alaskan town.

Diptheria is a disease that's caused by a bacteria. In the US as kids, we are all, or we should all, be vaccinated to prevent diphtheria because it's super dangerous. It causes inflammation that makes it hard to breathe and swallow, plus it causes nerve damage. It can be fatal. It's nasty. Vaccinate your children. But I digress. Balto.

Okay. So delivering this antitoxin in 1925 was no small feat. It was a 674 mile relay from Nenana, Alaska, to this remote village and the conditions were harsh. You had wind chill temperatures of negative 85 degrees Fahrenheit, which is... I can't.

Deboki: Very cold.

Sam: I can't understand that. I cannot compute. So, it's cold. It's way colder than anything I have ever, or ever hoped to experience in my life.

So, Balto is the inspiration behind the 1995 animated film that's aptly named, Balto. Balto the dog is voiced by Kevin Bacon. I had no idea who Kevin Bacon was at the time. I was six. I love dogs, as much as I love them now. I have two dogs, so I've loved dogs a long time. Loved Balto.
Watched this movie a bazillion times.

So when I came across some science related to Balto, I was like, this is perfect. This is my niche. So, this dog sled team that delivered this lifesaving diphtheria antitoxin, that was in 1925. It's 2023, and scientists just analyzed Balto's DNA. So, apparently Balto lived till he was 13 or 14, and then he was taxidermied. Didn't know that. And laid to rest or propped up. I don't know what you would say for something taxidermied, at the Cleveland Museum of Natural History.

Researchers were able to collect a sample from taxidermy Balto, and they compared it... It's so sad. I should just say Balto. From Balto and compared it to current living dog breeds, including three 21st century sled dogs that ran in the Iditarod, which is a modern annual dogsled race and it follows some of the trails that would've been included in the 1925 run with the medicine that Balto did.

So, these researchers found that Balto's ancestry is not so different from today's Alaskan sled dogs, but he also shares some ancestry with Asian dog lineages, which I thought was really interesting.

Oh, sorry. My sister's trying to call me. Caroline, I'm doing my Tiny Show and Tell!

Okay. Balto's genetics showed a bunch of positive adaptations, including the ability to digest starch, which is not a given with all dogs. Didn't know that but that's really important because sled dogs use around 10,000 calories a day during the Iditarod. So, being able to consume starch as well, would be an advantage because if you're trying to get all those calories from meat, it would probably give even a dog diarrhea.

So this is what a vet who was interviewed for this article that I read said, which I thought was interesting. Didn't think about that. With this article, there's also this very cool visual that shows a breakdown of Balto's ancestry, compared to modern day sled dogs. And I think the big takeaway is that he was a total mutt.

This is really a story about genomic diversity. And so genome diversity, it's generally considered a good thing in terms of species fitness and I'm talking about humans as well, because it makes it less likely that you might harbor a disease-causing genetic mutation.

So, I just really like the story. I love Balto. I didn't know he was taxidermied. That's kind of weird but I'm glad he is because we just learned something new about him, almost a century after this thing that he and these other sled dogs did. So, had to be my tiny show and tell. Just had to be.

Deboki: I love that. I'm so glad that we were able to make good use of taxidermied Balto.

Thanks for tuning in to this week’s episode of Tiny Matters, a production of the American Chemical Society. This week’s script was written by Sam and was edited by me and by Michael David. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team. Our artwork was created by Derek Bressler.

Sam: Thanks so much to Andrea Cipriani, David Hellerstein and Gemma Lewis for joining us. If you have thoughts, questions, ideas about future Tiny Matters episodes, send us an email at We have coffee mugs! I’ve put a link to where you can purchase one in the episode’s description. Find me on social at samjscience.

Deboki: And you can find me at okidoki_boki. See you next time.