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One of the topic that we've talked about the most is depression. It is a really complicated subject, so we’ve put together some of our episodes about depression to hopefully help you understand more about it.

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[SciShow Psych intro]

BRIT GARNER: From weird behavior to mental health, we talk about a lot here on SciShow Psych. But one topic that keeps coming up over and over again is depression. And there's a good reason for that. Depression affects millions of people around the world, and like many conditions, it's really complicated. Questions like "what does depression look like?" and "why does it happen?" aren't always easy ones to answer. But don't get me wrong: there's still a lot that psychologists can tell you.

In this compilation we've put together some of our episodes about depression to hopefully help you understand more about what's going on in the brain and in the research when it comes to this condition. So let's get started with an episode from Hank about what depression actually is. Because spoiler alert, despite what people say, it's not just a "chemical imbalance".


HANK GREEN: Chances are that you or someone you care about has experienced depression. It's one of the most common mental health problems in the US: around 16% of American adults will suffer from depression at some point in their life.

Given how much we talk about and treat depression, it might seem like we've got it figured out, from a scientific perspective. But we do not understand as much about it as you might think, especially what's actually going on in your brain when you're depressed.

Doctors have defined depression, or at least agree on a set of criteria to diagnose it. The Diagnostic and Statistical Manual for Mental Disorders, also known as the DSM, is the handbook healthcare professionals use to diagnose mental disorders. And the latest edition of the DSM lays out two key symptoms of depression. The first is feeling sad or depressed, but many depression sufferers experience this more as a lack of feeling or numbness rather than sadness. The second is a loss of interest or pleasure in activities that are normally enjoyable. You have to have at least one of these key symptoms, as well as three to four additional symptoms consistently to be diagnosed with depression. Additional symptoms can include unpleasant things like feeling worthless, difficulty sleeping or sleeping too much, difficulty concentrating and making decisions, or

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suicidal thoughts.

Not all of your symptoms need to be severe, but as a group they can make it harder for you to function at work or school, in your relationships, or just in life. We know that depression isn’t simply a bad mood that you can snap out of — something is not functioning correctly in your brain. The question is what?

One widespread impression among the public is that depression is caused by having too little serotonin. But that’s an oversimplification at best. Serotonin is a neurotransmitter — a chemical that neurons use to signal each other. When a neuron signals its neighbor, it releases a neurotransmitter, like serotonin, into the synapse — the space between itself and its neighbor. The serotonin molecules diffuse across the synapse and bind to their receptors on the neighboring neuron, transmitting the signal. Then the signalling neuron reabsorbs — or re-uptakes — its serotonin.

Some of the most commonly used medications for depression are selective serotonin reuptake inhibitors, or SSRIs. SSRIs reduce the reuptake of serotonin, which increases the amount of serotonin hanging around synapses. But how these medications work and sometimes don’t work show that a lack of serotonin isn’t the only thing happening in the depressive brain.

If that were true, you’d expect that SSRI medications would work pretty quickly, and to work for everyone with depression — but they don’t. Even though serotonin concentrations may go up right away when you take an SSRI, it can still take weeks for people to start feeling better. That is, if they even start feeling better at all. SSRIs simply don’t work for all patients.

Research has identified a few other potential factors that could help us better treat depression. First off, serotonin isn’t the only neurotransmitter that plays a role. Research has shown that at least 5 other neurotransmitters could be involved, all of which serve many different functions in the brain and elsewhere in the body — it’s complicated! And the structure of our brains  

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The structure of our brains matters too, not just the chemicals inside them. Certain regions of the brain and the connections between them have been shown to be altered in depression. The amygdala, which helps us process emotions, and the hippocampus, which has a role in memory storage, are among the brain regions that undergo structural changes with some patients with depression. Changes like having a difference size compared to people without depression, though ? we're not sure what that means exactly, yet. And rather than merely changing the levels of certain neurotransmitters, studies have shown that antidepressants can actually help new neurons grow in certain parts of the brain, which may be one reason why SSRI medications typically take so long to work. Your brain could be growing new neurons, not just for responding to short-term changes and chemical messengers. There's likely a genetic component to depression as well. There is some evidence that depression can run in families, though the association isn't particularly strong. A 2018 genome-wide study sampled a huge pool of genes in people with and without depression. It found 44 variants that seem to be associated with depression. These so-called "genes of interest" included genes previously shown to have a role in the growth of neurons -- as well as some surprises, like genes previously shown to be involved in immune system function. But it's unlikely that a particular gene or genes cause depression on their own. More likely, it could be the result of how your personal set of genes interacts with your environment and your experiences. Some studies have found that variants in certain genes can interact with major stressful events in childhood to affect the rate of depression in adults. But not all studies find such strong links between our genes and our environment. It's still an active area of study. So depression is hard to figure out. There are so many factors involved, and they all interact with each other, from genetics to environment, to the chemistry and structure of the brain.

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- The good news is that even though we don't entirely understand how depression works, we still have ways to treat it that help lots of people. You don't have to know exactly how an existing medication or treatment works to know that it does work, that patients may respond to it and feel better.

Meanwhile, scientists are working to tease out the many intertwined causes of depression to develop new treatments, so there's hope on the horizon even if you can't see it.

[slide: "SciShow Psych"]

[Brit]: So depression is... messy. There's a lot of nuance in everything including how it happens to how it's treated. And to make things more complicated, as if they need to be, the symptoms of depression aren't always easy to recognize either. Because the symptoms people often talk about - like fatigue or sadness - aren't the only ones. Here's another one from Hank.

[slide: " The Lesser-Known Symptoms of Depression]

[Hank]: Hopefully, by now, we all know that depression is about more than sadness. But even if your idea of depression also includes things like hopelessness or apathy, what about irritability or anger? Does depression make you think of overwhelming guilt? What about memory loss? Because those are all symptoms, too.

There's a lot we still don't understand about depression, especially when it comes to what's happening on the cellular level. But we know that when it comes to the experience of depression, the disorder often shows itself in the form of unhealthy psychological processes. It turns out that some of those processes - specifically self-blame and rumination - can lead to symptoms people may not realize are signs of depression. And that's too bad, because the result is that we misunderstand those who are suffering from it, sometimes, including ourselves.

Freud, as wrong as he was about a lot of things, pointed out that, "Depression was different from simple sadness because it was associated with guilt," and today, Psychologists consider self-blame a key symptom of depression.

When something bad happens, depressed people tend to blame themselves and see it as a reflection of their self-worth as a whole. An example researchers sometimes use is that if you fail at a sports match, it means "you're a total failure." What's weird is that this only applies to yourself. Depressed people -

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- yourself.  Depressed people don't usually assign blame to others in the same way. Turns out, the unusual amount of guilt and the "only applying it to yourself" might come from two regions of the brain that don't activate together the way they should.

In a 2012 study, researchers scanned the brains of 25 people who'd previously had depression and 22 people who didn't. When the people who'd never been depressed read descriptions of themselves doing something wrong, it activated both the part of their brain associated with guilt and the part that deals with morality and what's socially appropriate. In people who'd been depressed, that second part wasn't activated as strongly. 

This was a small study, so we can't draw too many conclusions from it, but based on the results, the authors suggested that people who are more prone to depression don't get an accurate picture of what they did wrong, sos they just feel guilty about everything. So that's one unhealthy thought pattern that can cause symptoms beyond plain ol' sadness or apathy.

Another is "rumination," and it is a big one. Rumination is basically brooding, usually unintentionally. Part of problem solving involves analyzing the factors surrounding the problem, and that applies to negative emotional experiences, too, but rumination takes that way too far; it's getting stuck thinking about everything that led to - and resulted from - a negative experience, and it's strongly linked to both depression and anxiety.

It can also explain some of the less-straightforward signs of depression like memory problems. Of all the symptoms of depression, memory problems might be the most surprising, because we tend to classify depression as "emotional" and memory as a more "mechanical" part of the mind. But this is just a false dichotomy - that's not how the brain works. 

Depressive disorders often include problems with cognitive function: the ability to clearly understand, process, and respond to information. And researchers think that it has a lot to do with rumination eating up all your brainpower. 

You need cognitive resources to pay attention and remember things, and when people with depression -

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- with depression are using those resources to brood, they have trouble redirecting them toward the task at hand. They end up struggling with episodic memory, which is the recollection of specific events that happened to you, and working memory, which is how you hold onto information that you're currently using to process other information.

Those are both... pretty important??

It becomes a vicious cycle where the only way to break out of this pattern of rumination is to redirect your mental resources towards something that might make you feel better. But that's exactly what rumination makes it so much harder to do. So people get stuck.

Rumination can also lead to another symptom of depression - anger and irritability - which appears in more than half of patients, although it's only used to diagnose the disorder in kids and teens. But it can be a sign of particularly severe depression. At it's core, rumination is a coping strategy people use to help regulate their emotions, it's just not a very good one.

Instead of feeling better, when people brood on something that made them angry, they tend to spend more time angry. We still have more to learn on how unhealthy thought patterns like self-blame and rumination could contribute to depression and its symptoms, but as we study them, we're discovering that they can explain a lot. And there are some good news here, too.

Self-blame may have to do with brain regions not activating the way they should, and rumination may feel like getting stuck, but researchers point out that unhealthy thought patterns like these are exactly what psychotherapy is meant to help with. Cognitive behavioral therapy, especially, is designed to identify the connections between thought patterns and behaviors and reshape those thought patterns in a healthier way.

So yes, depression is a complicated, difficult illness, but there are therapies and treatments that can help. And recognizing the different ways depression manifests itself is an important step toward getting that help and doing this research.

[slide: "SciShow Psych"]

[Brit]: So, depression isn't a thing you can put in a box. The good news though is that there are plenty of treatments for it. Although, unfortunately, some get a pretty bad rep. Like antidepressants. We've got some myths to debunk.

[slide: "4 Common Misconceptions About Antidepressants, Debunked"]

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[Brit]: Honestly, there's nothing clever or funny to say about depression. If you've ever known someone who's depressed or experienced it yourself, you know how hard and all-consuming it can be. The good news is that depression can be treated with therapy and medication, but antidepressants can also be kind of complicated, and there are a lot of misconceptions that only increase the stigma around them.

So, let's set the record straight.

One common misconceptions is that "antidepressants don't actually do anything" - but that's not true. They DO help. This idea mostly came from a 2008 study published in PLOS Medicine. The study was a meta-analysis, meaning that it analyzed a bunch of other studies - in this case, 47 of them -  and looked for a measurable effect across all of their results. 

It suggested that for people with mild to moderate depression, antidepressants don't work much better than a placebo, a treatment that makes you think you're being treated but doesn't actually do anything. Instead, the study found out antidepressants worked better for people with more severe symptoms.

There was another meta-analysis in 2011 that found antidepressants WERE more effective than placebos in treating mild long-term depression called "dysthymia" or "persistent depressive disorder." But that didn't stop the controversy of the first study. It turns out, that if you didn't look at the methods for that first meta-analysis, it was easy to misinterpret the findings. 

For one thing, the average length of the treatment in those studies was just 4-8 weeks, whereas most people take antidepressants for months. Research subjects were also selected and treated differently than they would be as patients. In real life, a patient and their doctor will work to find the best dose and kind of medicine because the same medication doesn't work for everyone, especially when it comes to mental illness. But in a study, everyone is given the same prescription.

So, if you're just looking at whether one antidepressant is better than a placebo if you give it to everybody, then yeah. You'll find it's not that helpful for mild to moderate depression because a bunch of the subjects won't respond well to that particular medication. But that doesn't mean antidepressants as a WHOLE aren't effective - as long as you're taking the right medicine for you. 

Which brings us to another misconception that "all antidepressants do the same thing, so if one -

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- same thing, so if one doesn't work for you, none of them will." But that's also not true, because different antidepressants do different things. To understand why, it helps to know a little bit about neuroscience. 

Your brain is full of neurons which have tiny gaps between them called "synapses," and neurons communicate by sending chemicals called "neurotransmitters" across synapses to each other. Researchers aren't entirely sure why, but having more neurotransmitters in your synapses seems to ease depression, possibly because it helps your neurons transmit information. 

So, antidepressants increase the availability of certain neurotransmitters in your brain but in different ways. "Reuptake inhibitors," for example, prevent neurotransmitters from being reabsorbed into neurons, so they stay in the synapse longer. The most common kinds are SSRIs or "Selective Serotonin Reuptake Inhibitors," which affect the neurotransmitters serotonin. They're the more famous ones, like Prozac and Zoloft.

There are other reuptake inhibitors that effect other neurotransmitters, like SNRIs [Serotonin/Norepinephrine Reuptake Inhibitorss], which work on serotonin AND norepinephrine. And there's another class of antidepressant called "tricyclics,"
 which also reuptake of serotonin and norepinephrine but slightly differently than SNRIs do. Then, there are antidepressants that work TOTALLY differently, like "Monoamine Oxidase Inhibitors" [MAOIs], which prevent neurotransmitters in the synapse from being broken down.

Plus a whole bunch of others that I didn't even mention.

So not all antidepressants are identical, and doctors have plenty of options for figuring out what's best for different people. Most of the antidepressants we use these days are really safe, but like a lot of medicines, they still have some side effects.

For example, people who start taking SSRIs often experience digestive side effects - like constipation, diarrhea, and bloating - which might seem confusing, because when you think "serotonin," you probably think "brain." But that's our third misconception - that "antidepressants only affect your brain." Because they can effect your gut, too.

About 95% of your serotonin actually goes to your digestive tract, where it controls smooth muscle function, regulates stomach acid, and controls mucus production. Increasing the amount of serotonin in your brain can lead to a shortage in your gut, -

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- in your gut, which causes those unpleasant symptoms. Antidepressants can have such a big effect on the digestive tract that doctors prescribe them to treat Irritable Bowel Syndrome, too. Thankfully, most of these side effects do go away after a few weeks and aren't anything to worry about.

It can also take a few weeks, usually 4-6, for antidepressants to start working AT ALL. And that's the last misconception on this list - that "antidepressants start working right away." It's still unclear why there's this delay. Antidepressants start impacting those neurotransmitters right away, even if you can't feel it.

One possibility is that instead of directly improving your mood, the extra neurotransmitters help by gradually affecting the way you process thoughts. The delay might also have to do with other signaling molecules in your cells that could be involved in depression but take longer to respond to the meds. But either way, even if you don't notice a change at first, that doesn't mean the medicine isn't going to work.

So, there's a LOT of misinformation and confusion about antidepressants out there, but for many people, they make a huge difference, so figuring out what's true and what's not is definitely worth it.

[slide: "SciShow Psych"]

[Brit]: Of course, the fact that certain antidepressants don't always work immediately or don't work as well for everyone can be kind of discouraging. Like, I know depression is complicated, but why is it so hard to match people to the right medication right away? Turns out, it's something doctors and researchers are working on. There's a lot we have left to learn, but we're also making progress thanks to a few big studies. 

So, to wrap up this compilation, let's look ahead at the future of depression treatments. Here's Hank with one more.

[slide: "The Future of Depression Treatment"]

[Hank]: Dealing with depression is not easy, and it doesn't help that it is really difficult to find effective treatments for it. Your genetics, your environment, and various factors in your brain all seem to play a role in whether you develop depression and how you experience it. So the most common treatments don't work for everyone.

Some researchers think that the solution to this is "personalized medicine," using information about a patient's symptoms or even their genome to match them to drugs that actually help. Personalized medicine sometimes sounds like a futuristic buzzword, -

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- futuristic buzzword, but there are already big projects looking into it, and they're making some progress.

So for depression, these kind of treatments might actually not be that far off. One of these projects is spearheaded by a group called "CAN-BIND" short for "Canadian Biomarker Integration Network in Depression." This team has already published a handful of studies and is working on many more, and they're mainly searching for biomarkers for depression. 

"Biomarkers" are defined pretty broadly by the larger scientific community, but they're basically something a doctor or a lab can reliably measure that tells them about your illness; anything from your pulse to a specific hormone in your blood is fair game. So doctors can use biomarkers to learn how well a patient is responding to a specific treatment, or they can use them to predict how likely a patient is to respond to treatments in general.

But when it comes to depression, the most sought-after biomarkers - by far - are those that tie a specific drug to a patient's response. Basically, markers that take out the guesswork and say, "If you take this, here is what you can probably expect." If we could find a marker like this for depression, doctors could do something like a blood test, look for a certain result, and then match someone to an effective antidepressant based on that.

Of course, we are nowhere near that yet, but the CAN-BIND group is working on it, and even though there's a long way to go, they are learning a lot. For example, they've investigated whether or not people have gene expression markers that can predict how they will respond to medication. These markers would be things like messenger RNAs that tell a scientist how much protein is being made by a cell, which could, in turn, affect how the body processes or responds to a drug.

Scientists have studied a ton of potential markers, but unfortunately, the CAN-BIND team concluded in a 2017 review that none of them are ready for primetime just yet. The results are too inconclusive, maybe because we don't know enough about -

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- know enough about our genetic material.

But that doesn't mean that we should give up on this method yet; its just means there's likely more to learn. In the meantime though, the CAN-BIND team has also been looking at other kinds of biomarkers.

In 2018, they published a review that looked at brain imaging rather than molecular markers. This time, they looked at how all kinds of treatments - including psychotherapy - could affect the brain, not just drugs. And this time, they found some promising results. In this review, the team found studies that suggested that things like size and shape changes in several brain regions could be tied to specific treatments.

For example, they cited previous research where both increased activity in the prefrontal cortex, and decreased activity in a handful of other regions, were associated with better symptom improvement in patients who went cognitive behavioral therapy. In other words, there were specific brain features that predicted how well someone would respond to treatment.

These results do need to be validated, but if they're true, this essentially means a doctor could look at someone's brain for things like increased prefrontal cortex activity, and if they found it, they could use that knowledge to recommend someone for therapy.

At the end of the day, CAN-BIND still has a lot to do, but they're paving the way for some major advances in medicine.

Looking for biomarkers is not the only way to approach personalized medicine though. Another approach is to look for actual differences in the gene sequences among people; we're talking differences in those famous four DNA bases that make up someone's genetic code.

This approach has become more feasible in recent years as personal gene sequencing has become widely available, and as we've begun to understand how these gene variants function. For example, there's a liver enzyme that processes certain medications, including some used to treat depression, before they ever reach the brain. It's called CYP2D6 - I'm sure you'll remember that - and the gene that codes for it has over a hundred different variants which might make chemical changes to medications -

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-  changes to medications that render them more or less effective.

If we could track down all of these genetic changes, we could start to figure out how to tailor medications to someone's personal genetic code.

And another major research effort called the "GUIDED" study ["Genomics Used to Improve DEpression Decisions"] was a big step forward in that. The study was published online in January 2019, and it split over a thousand patients with depression into two groups.

In one group, doctors were allowed to use the results of a genetic test to look for potential drug interactions, ones that could make those drugs either more or less effective. In the other group, doctors could NOT use that knowledge, and made their drug choices the old-fashioned way.

In the genetic testing group, both patients' response to treatment and the number of people who experienced remission of their depression symptoms were significantly higher than in the business-as-usual group. And partway through the study, if patients were allowed to switch to a drug supported by their genetic tests, they also showed better rates of symptom improvement, treatment response, and remission.

Which is potentially awesome news, especially since this was a large, carefully controlled study. Scientists will always call for more research, but the GUIDED trial shows that knowledge of a patient's genes can potentially help them get better, especially if their depression has been otherwise tough to treat.

So there's a lot of reason to be hopeful about the future of depression treatments even if a lot more research is still needed. Whether it's through biomarkers or our actual genes, we're working on ways to know whether specific treatments will help specific people. So maybe in the future, no one will never need to go through three, four, or a dozen treatments to find something that works - we might figure out how to do it on the first try, and that is worth celebrating.

[slide: "SciShow Psych"]

[Brit]: If we can say anything about depression, it's that there's no "one rule fits all" scenario. Symptoms and responses to treatment vary a lot from person to person, but at the end of the day, it's important to seek help if you need it.

If you're struggling with depression, -

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If you're struggling with depression, we've left some resources in the description. There's no shame in asking for help if you need it.

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