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How can you treat what you don’t understand? How can a medication’s side effects improve the lives of millions? And how can a chemical substance bring light to someone’s darkness?
This is Knowable. And I’m Adam Levy.
Mohamed Maoui: “It was something that completely changed my life.”
Becca: “I suppose I don’t know life without depression and anxiety.”
This podcast is about clinical depression, and science’s ongoing journey to find medications to treat it. A story of accidental discoveries, and unexpected twists. A story that’s still unfolding today. The episode will include candid descriptions of depression, as well as attempted suicide, so please do use your own discretion when listening further.
Becca: “It just feels like life is unbearable. That you are utterly pointless. You are a mistake.”
Mohamed Maoui: “So you don’t understand what’s going on, you are just crying. You feel alone even though you have the entire world with you.”
Becca: “Really, a lot of times it’s like you’re living permanently on the edge of a cliff, or that you’re actually falling from that cliff and yet you never reach the bottom and no one catches you. No one can catch you. You’re just falling. And it’s dark.”
That’s Becca, who lives in Ireland, and before her you heard from Mohamed Maoui, a bioengineer and creative writer who just graduated from McGill University in Canada. And as isolating as depression can feel, Mohamed and Becca are far from alone in their experiences. Philip Boyce, a psychiatrist at the University of Sydney in Australia, has treated people with depression since the 1970s.
Philip Boyce: “Generally we talk about 5 percent of the population suffering from significant clinical depression at any particular time. Depression is in the Top 5 causing disease burden across the world. So it is a really big and significant problem worldwide.”
People like Becca and Mohamed can tell us what depression is — their experiences, how it has affected their lives. But defining what depression is, physically, has long challenged scientists. In fact, around the middle of the 20th century, we were still completely in the dark.
Lace Riggs: “So we don’t necessarily know at that time that depression or other disorders really have a strong biological component or cause. And so that manifests in the type of approaches that were used to treat depression at that time, like psychotherapy, for instance.”
This is Lace Riggs, who’s based at the McGovern Institute for Brain Research at MIT in Cambridge, Massachusetts. So if we didn’t know whether depression had a biological element — never mind what that biological element was — how did we ever develop antidepressant drugs? Here’s Todd Hillhouse, a neuropharmacologist at the University of Wisconsin, Green Bay.
Todd Hillhouse: “But when the first antidepressants came out, it wasn’t based on mechanism or really hypotheses. A lot of it was driven by chemists developing drugs for other disorders.”
And when we talk about other disorders, we’re not talking about other psychiatric disorders, but completely unrelated problems. Here’s Philip again:
Philip Boyce: “There was some fortuitous circumstances happened in the early ’50s. Firstly in patients who were being treated with tuberculosis. They found to their surprise that some of the people being treated in tuberculosis wards would suddenly become quite cheerful and quite happy. And then they realized this drug was actually working as an antidepressant.”
This drug was iproniazid. This accidental antidepressant pointed the way. Not just to treat depression, but also to understand the underlying physical basis of it. So what exactly did this drug point to?
After the discovery that iproniazid acted as an antidepressant, it was shown to be a monoamine oxidase inhibitor — an MAOI. Monoamines are neurotransmitters, chemical messengers that play a key role in how signals are transmitted across connections — synapses — in the brain. MAOIs, like iproniazid, inhibit the rate at which monoamines are broken down, and so effectively act to increase levels of these neurotransmitters in the brain.
So a natural hypothesis was that a depletion of monoamines was driving depression. Evidence for this hypothesis grew with the arrival of tricyclic antidepressants. These also increase monoamine levels, but in a completely different way: by reducing their reabsorption rather than blocking their destruction. And they also alleviated depression. Meanwhile, another chance discovery showed that a medication for hypertension, which depleted monoamines, appeared to bring about depressive symptoms.
Todd Hillhouse: “We put the two together and said, well, we must have lower levels of monoamines in the brain, which is causing this depression.”
A 1968 article titled “Human Pharmacology of Antipsychotic and Antidepressant Drugs,” published in the Annual Review of Pharmacology, captures the mood of this “monoamine hypothesis” at the time, which was…
… currently one of the most exciting aspects of the chemistry of emotional disorders.
The hypothesis posited that monoamines — and, crucially, levels of monoamines — were an essential biochemical component of how the brain regulates mood. And that raising the levels of monoamines was key to treating clinical depression. The monoamine hypothesis, which debuted over half a century ago, is still central to scientists’ understanding of depression and to its treatment.
Todd Hillhouse: “It almost seems like how we’re talking about the monoamine hypothesis hasn’t changed much.”
And that’s not the only thing that hasn’t changed much in the last 54 years. Then, as now, the possibility of figuring out shortcuts for finding the right drug for the right person — for example, through EEG scans to measure brain waves — is raised, though not very optimistically:
Desirable as it might be to have a physiological predictor of clinical response as simple to obtain as an EEG, this hope is still not realistic.
But, as you might expect, some discussions of depression and its treatment in that 1968 review are substantially different from what you’d hear today. The review suggests, for example, that:
Responses to psychotropic drugs are considerably modified by the personality of the recipients.
In other words, the effectiveness of a particular drug was thought to depend on the patient’s personality.
Lace Riggs: “So we’d definitely say that that’s debunked now.”
Time ticked on, and more and more antidepressants became available — still focused on increasing the levels of monoamines in the brain. Almost two decades later, and another review by the same author, titled “Current Antidepressants” in the Annual Review of Pharmacology and Toxicology, updates progress. The review relates how antidepressants had already profoundly changed medicine’s approach to depression.
Prior to the late 1950s, depression was treated primarily with electroconvulsive therapy and psychotherapy. The advent of effective antidepressants changed practice, so that presently drug therapy is the main modality of treatment.
There were still plenty of open questions as to what depression was. In 1986, it seemed that new drugs could help us answer these questions. Back to front from many diseases, where it’s often our understanding that helps inform new drugs.
As we learn more about how drugs act in treating depression, we can postulate new theories about the condition’s biological bases.
At this time, many of the antidepressants that were available had debilitating side effects. For example, “the cheese reaction” of MAOIs. Taking these drugs could make certain foods, such as cheeses, fatal to consume. This is thanks to a chemical — tyramine — which is found in various foods, which can cause dangerous increases in blood pressure and potentially strokes for patients on MAOI drugs.
What’s more, powerful medications present a serious risk of overdose when prescribed to patients who may be thinking about suicide.
But antidepressants were about to change forever. Previous drugs had affected levels of all the monoamines in the brain, but it was hypothesized that a more selective drug would still alleviate depression, without causing so many unwanted effects. And, in 1986 — the same year as the review we just heard from — a drug that did exactly that became available to the first patients. This was fluoxetine. Or perhaps you know it better by its brand name: Prozac. Here’s Lace again.
Lace Riggs: “Instead of affecting dopamine, histamine, norepinephrine and serotonin, how about we just block the reuptake of serotonin?”
What Lace is describing is a selective serotonin reuptake inhibitor — an SSRI. Serotonin was an attractive target, because research had indicated that it could be particularly implicated in depression. For example, one post-mortem study in 1967 found lower levels of serotonin in the brains of people who had died by depressive suicide. And now, here was a drug that aimed to increase serotonin levels, without affecting all the other monoamines in the brain. SSRIs do this by blocking the serotonin transporter, which limits the rate at which serotonin is reabsorbed into cells.
Lace Riggs: “I think that the introduction of an SSRI like fluoxetine, Prozac, was a huge game changer.”
Here’s Philip again, who saw the changes SSRIs brought to the treatment of depression.
Philip Boyce: “Here was a medication, it was very easy to treat. You used one tablet per day and it was thought that it had no side effects. So it made a huge difference, the introduction of the SSRIs, and the availability. And they’re now one of the most commonly prescribed drugs around the world.”
And they truly are commonly prescribed. In the UK alone, over 70 million prescriptions were written for antidepressants in 2018. And for some people, SSRIs have had dramatic effects. In 2018, Mohamed, who we heard from at the beginning of the podcast, was struggling to prepare for exams, was struggling in general, as a result of his depression. He risked losing his scholarship and so his ability to stay in Canada. And although he’d tried counselling twice, nothing seemed to make a difference. That is, until he — reluctantly — started to take antidepressants.
Mohamed Maoui: “It saved me, too. I think I wouldn’t have been able to finish my degree. There was even a high chance I could have gotten worse if I didn’t take the pills.”
Philip Boyce: “For people who’ve been severely depressed, who can’t do anything — they’re almost bedridden, they feel hopeless — to suddenly have the light come back in their eyes, it’s an amazing thing to see happen.”
Following the release of Prozac in 1986, a number of different SSRIs were released. These had a variety of different properties. But all worked on the assumption that increasing the monoamine serotonin in the space between synapses — that’s the connection within our brains — could alleviate depression. Here’s Todd.
Todd Hillhouse: “So if they took Prozac, and they had side effects on that, they can change and go to a different SSRI that might be a little bit better, so there’s much more hope for the patient.”
And if SSRIs didn’t work, other drugs — that aim to raise levels of a different combination of monoamines — could be tried out. But finding the right medication for the right patient isn’t always easy. And that’s if there is a right medication for the patient. Plus it takes time for the effects of each drug to kick in, and to establish whether the drug is beneficial. What’s more, many patients do experience side effects from SSRIs, ranging from nausea to sexual dysfunction.
Philip Boyce: “It can take a while to get the right medication for the particular patient. Basically they are in this terrible state. And to be with someone like that and try to find the right treatment for them over weeks or months can be very, very difficult. It’s a painful process for both you and for the patient, more importantly.”
Becca, who we heard from at the beginning of the podcast, experienced this painful process firsthand.
Becca: “It was only after having a complete breakdown in my late 20s. I mean, I basically made multiple attempts on my life — it was a complete collapse. And I went through various different SSRIs. Well, I certainly didn’t notice any positives, I didn’t notice any changes in my mood. I still felt incredibly depressed, incredibly anxious.”
The challenges and frustrations of this process are exacerbated by the withdrawal effects that many experience on modern antidepressants. Becca remembers one particular antidepressant which she struggled with.
Becca: “And coming off that one — when I eventually did — however gradually we did it, I remember once sitting in a cold bath for two hours staring at the wall and not even realizing that time had passed. It was awful.”
In the end, Becca decided to stop using medication. She now structures her life in a way that helps her manage her depression and other issues. And interventions from mindfulness to art therapy have had a profoundly positive impact on her life.
Todd Hillhouse: “And there’s anywhere from 30 to 50 percent of patients that do not respond to any antidepressant treatment.”
But, wait. All of this is based on one single, fairly simple idea. That depression is caused by decreased levels of monoamines — serotonin in particular. But then why are 30 to 50 percent of patients not improving when their serotonin levels are raised? And why do these drugs — when they do work — take weeks to improve mental health? After all, they inhibit the serotonin transporter — that protein responsible for cells’ absorption of serotonin — within a matter of hours. Gradually, it has become clearer and clearer that depression is more complex than the monoamine hypothesis suggests.
Lace Riggs: “The efficacy of MAOIs and tricyclic antidepressants has really shaped our worldview of what depression is. Do I believe, though, that that at times has prevented us from seeing drugs that could have been effective? Yes. And I would love to give you an example of ketamine.”
Yes, you heard correctly: ketamine. This is a drug, which today is famous — or perhaps I should say infamous — for its recreational use. Often used as a club drug, it can have hallucinogenic as well as dissociative effects, where the user’s experiences become detached from the environment. But ketamine has long had profound medical uses as an anesthetic. It was extensively used in the 1950s and 1960s, particularly during the Vietnam War, and to this day is included in the World Health Organization’s List of Essential Medicines as an anesthetic.
But what does this have to do with depression?
Lace Riggs: “Use as an antidepressant is, again, very similar to what we’ve seen with traditional antidepressants — it was really discovered serendipitously.”
The antidepressant effects of ketamine were first suggested in the year 2000 by researchers who’d been using the drug for something else entirely during the ’90s — as a way of modeling the symptoms of schizophrenia in otherwise healthy patients. Then, in 2006 psychiatrist Carlos Zarate and colleagues conducted a randomized trial on 18 patients in National Institute of Mental Health clinical research center in Bethesda, Maryland. Zarate and colleagues showed that low doses of ketamine could alleviate depressive symptoms within two hours — effects that lasted for many days. Even more astounding was that these patients were “treatment resistant,” having previously tried several antidepressant treatments without success. In the study’s conclusion, the authors note:
To our knowledge, there has never been a report of any other drug or somatic treatment… that results in such a dramatic rapid and prolonged response with a single administration.
And since 2006, these startling results have seemed to stand up.
Lace Riggs: “It’s been replicated by many different groups independently. It’s really quite amazing.”
It isn’t just ketamine’s fast effects for treatment-resistant patients that has astounded researchers. The compound’s effects appear completely unrelated to levels of monoamines in the brain. The fact that it left these neurotransmitters untouched was one reason that ketamine was used in medical contexts for half a century before its antidepressant properties were uncovered.
Lace Riggs: “We kind of missed that ketamine had antidepressant effects because it didn’t alter monoamines.”
Researchers generally now accept that monoamines — whether that’s serotonin or another common target of antidepressants, norepinephrine — aren’t the biological root cause of depression, despite playing a role.
Lace Riggs: “Maybe there’s something downstream of serotonin or norepinephrine signaling that’s then triggering antidepressant response in the long term.”
So if depression isn’t caused by levels of serotonin or other monoamines, like norepinephrine, what is it caused by? And what is ketamine doing that our other antidepressants can’t?
Evidence has grown — for example, from animal studies — that the biological cause of depression isn’t about levels of chemicals in our brains, but about connections. Studies in rodents have shown that depressed animals have fewer connections between neurons in key parts of the brain, for example. And ketamine may affect these connections. Not by altering monoamines, but with an entirely different neurotransmitter: glutamate.
Glutamate is responsible for a host of functions in the brain. By strengthening connections, it plays a role in everything from mood to memory. And ketamine triggers a release of glutamate in key regions of the brain associated with emotion, potentially causing better connections right where they’re needed.
Lace coauthored a 2021 review titled “Ketamine and the Future of Rapid-Acting Antidepressants” in the Annual Review of Clinical Psychology. The review states that:
… ketamine may exert its antidepressant actions by strengthening the efficacy of synaptic transmission… Alternatively, it is possible that ketamine exerts its effects by decreasing excitation in regions whose activity promotes depressive-like phenotypes …
In other words, it’s still very unclear what’s going on here. It’s also not clear how ketamine triggers these effects. Ketamine binds to receptors on the surface of neurons called NMDA receptors. Many believed this could be key to understanding the drug’s antidepressant properties. But tests with other drugs have muddied that picture. Drugs that bind to NMDA receptors just as well as ketamine fail to act as antidepressants. So perhaps this binding…
… accounts for the anesthetic properties of ketamine but not its antidepressant effects.
For Todd, the buzz around ketamine and the rush to understand results is reminiscent of how scientists grappled to understand the very first antidepressants.
Todd Hillhouse: “I think what we’ve done, it’s kind of similar to what happened in the ’50s. We found an antidepressant drug that works really well and now we’re going back to the bench science and trying to figure out why it works.”
This bench science may help us uncover more about the root causes of depression and, hopefully, how to treat it. The 2021 review points out that these ketamine effects have prompted advances across the board.
Without question, the robust rapid and sustained antidepressant effects of ketamine have initiated significant theoretical, scientific, and clinical advancements with regard to depression treatment, which have been long overdue.
But as promising as the ketamine results have been, there are limitations. For the antidepressant effects to last, ketamine may need to be taken regularly, but some scientists aren’t convinced that taking the drug repeatedly over long time periods of time is safe. Clinics that provide ketamine infusions are inaccessible to many, and often have long waiting lists. A nasal spray provides a more accessible alternative, but many psychiatrists fear that there’s a potential for it to be misused. After all, many people do take ketamine illegally for recreational reasons. These recreational reasons also make the drug less appealing as an antidepressant, since its dissociative and hallucinogenic effects can be disruptive in daily life. And for Todd, it’s important we keep a healthy dose of skepticism about the results seen so far.
Todd Hillhouse: “The majority of the patients do have some hallucinogenic or dissociative anesthetic effects. Meaning they know they got the drug, because their perception has been changed.”
This would make a truly controlled clinical study challenging, since hallucinations, for example, would allow a subject to know when they have received ketamine, rather than the control substance.
If ketamine teaches us anything, it’s that we still have a huge amount to learn about depression and its treatments. But we’ve come a long way since doctors first noticed a tuberculosis drug’s effects on depression.
Philip Boyce: “Look, I think it’s been extraordinary. I think from the second half of the last century there were dramatic changes.”
The accidental discoveries have helped us treat and understand depression in ways that no one could have predicted. Today, our understanding of the disorder allows doctors to provide medications that improve the lives of millions of people around the world.
Lace Riggs: “I’m really grateful that there is such a thing as this serendipitous discovery of traditional antidepressants. Because without it, who knows where we’d be? And it completely changed the way we look at depression: how to study it, how to treat it.”
But learning about depression by uncovering new drugs has also held us back. It has limited our understanding of what the disease is and, as a result, what avenues we should explore to treat it.
Todd Hillhouse: “Just relying on our old hypotheses really stifled us in the attempt to move forward.”
Still, research has moved forward. Our understanding has allowed many patients who had lost hope find a path out of the darkness that is clinical depression.
Philip Boyce: “Look, I think the most rewarding ones are where the patient comes back after they’ve been depressed and says, ‘Thank you,’ because they’ve just gone through hell. And then suddenly their life is enjoyable, they can get pleasure from things. And seeing that come back to people is incredibly rewarding.”
Improving our treatments of depression isn’t just about improving antidepressants, but also how psychiatrists prescribe antidepressants. That idea we first heard about in the 1968 review — the possibility of somehow measuring some property of a patient to work out which drug they would respond to — is very much an active area of research to this day. Scans of brain waves with EEG could be coupled with information from blood or genetic tests to accelerate the speed of the treatment process — something Lace very much hopes will come to fruition in the future.
Lace Riggs: “So that way patients can go in, maybe undergo EEG, and say, OK, they’re a good candidate for an SSRI or they’re a good candidate for ketamine. That would be a great situation to be in, because then patients wouldn’t have to spend months or even years troubleshooting their own treatment.”
Other treatments have also been shown to have profound impacts for many. That includes forms of psychotherapy such as cognitive behavioral therapy, where patients are encouraged to change their patterns of thoughts and actions. Exercise has also long been known to help alleviate depression, and there is evidence that it may achieve this by helping promote connections in key brain regions.
And despite falling out of favor for many years, electroconvulsive therapy has been shown to be effective as an antidepressive treatment. Research has shown, for example, that it may do this by promoting the growth of new neurons in parts of the brain associated with depression.
But despite its devastating impacts — on individuals and on society — mental health is often pushed to the side, even in wealthier countries. Many struggle to find the support that they need. What’s more, Philip argues that for a great number of patients, depression itself can’t be treated without addressing its societal causes.
Philip Boyce: “It would be lovely if we had something that would fix depression, but we’ve also got huge issues in fixing society to fix all depression. Social disadvantage is one of the drivers for people to get depressed. And we have to fix that as much as we need to give them tablets.”
We can’t know where the next half-century will take us in our treatment of clinical depression. But every step of progress is vitally important for the millions around the world suffering from this debilitating disorder.
Becca: “And you reach a sort of point of acceptance. And you learn that it’s part of you. There’s still more to life, and there are still things that I could do, like the writing, the drawing, seeing the boys grow up. And you have to learn to make yourself focus on those positives. And not keep beating yourself up about the stuff that you weren’t able to do.”
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In this episode you heard from Becca, Mohamed Maoui, Philip Boyce, Lace Riggs and Todd Hillhouse. The episode also featured quotes from three articles published by Annual Reviews. They are: Hollister, 1968; Hollister, 1986; and Riggs & Gould, 2021. You can find links to those papers and more in the show notes on our website: knowablemagazine.org/podcast.
This podcast was produced by Knowable Magazine, a nonprofit publication that seeks to make scientific knowledge accessible to all. Knowable Magazine is an editorially independent initiative from Annual Reviews. Explore more sound science and smart stories at knowablemagazine.org.
I’m Adam Levy and this has been Knowable.
