Breaking Free from Depression
Depression is often mistaken for ordinary sadness, but clinically it is something profoundly different: a medical illness that can alter the way the brain processes emotion, motivation, and even hope itself.
In this episode of Road to Resilience, host Stephen Calabria speaks with James Murrough, MD, PhD, to discuss how groundbreaking neuroimaging research explains why depression may leave the brain "entrapped" in inefficient patterns of activity,
The conversation explores the difference between sadness and clinical depression, why chronic stress can reshape the brain, how behavioral therapy and medication help people break free from depression's grip, and why the brain's extraordinary capacity for change offers genuine reason for hope.
Stephen Calabria: [00:00:00] From the Mount Sinai Health System in New York City, this is Road to Resilience, a podcast about facing adversity. I'm your host Stephen Calabria, Mount Sinai's Director of Podcasting.
Depression affects hundreds of millions of people around the world, yet it remains one of the most misunderstood medical conditions. For many, it isn't simply sadness--it can feel like being trapped, disconnected from the world around you, and unable to imagine ever feeling like yourself again.
On this episode, we're joined by James Murrough, MD, PhD, to explore new and groundbreaking depression research about what may lie at the root of depression, what that means for treatment, and why--even in the darkest moments--the brain is remarkably capable of recovery.
We're honored to welcome Dr. James Murrough to the show.
Dr. James Murrough, welcome to Road to Resilience.
James Murrough: Thank you.
Stephen Calabria: Depression is one of the most common illnesses in the world, but it's also one of the [00:01:00] most misunderstood. When someone says they're depressed, what does that really mean?
James Murrough: So this is the challenge we have because the term depression, of course, is used in general in life.
I feel depressed, I feel sad. Maybe I lost something. Maybe I lost a job. Maybe there was a death in the family. So these are words we use-- happy, sad, depressed, to describe normal human experience.
In medicine, in psychiatry, when we use the term depression, we tend to mean something very different. Sometimes we use the term clinical depression.
The technical name for this illness we're talking about today is major depressive disorder, or MDD, the core of which is some type of negative mood state of sadness, hopelessness.
Even sometimes it's about lack of feeling, lack of responsiveness to positive things in their environment.
Full Episode Transcript
[00:00:00]
Depression and Hope
Stephen Calabria: From the Mount Sinai Health System in New York City, this is Road to Resilience, a podcast about facing adversity. I'm your host, Stephen Calabria, Mount Sinai's Director of Podcasting.
Depression affects hundreds of millions of people around the world, yet it remains one of the most misunderstood medical conditions. For many, it isn't simply sadness. It can feel like being trapped, disconnected from the world around you, and unable to imagine ever feeling like yourself again.
On this episode, we're joined by James Murrough, MD, PhD, to explore new and groundbreaking depression research about what may lie at the root of depression, what that means for treatment, and why, even in the darkest moments, the brain is remarkably capable of recovery
Dr. James Murrough, welcome to Road to Resilience.
James Murrough:Thank you.
Stephen Calabria: Depression is one of the most common illnesses in the world, but it's also one of the most misunderstood. When someone says they're depressed, what does that [00:01:00] really mean?
Clinical vs Everyday Sadness
James Murrough:So this is the challenge we have because the term depression, of course, is used in general in life.
I feel depressed, I feel sad. Maybe I lost something. Maybe I lost a job. Maybe there was a death in the family. So these are words we use-- happy, sad, depressed, to describe normal human experience.
In medicine, in psychiatry, when we use the term depression, we tend to mean something very different. Sometimes we use the term clinical depression.
The technical name for this illness we're talking about today is major depressive disorder, or MDD, the core of which is some type of negative mood state of sadness, hopelessness.
Even sometimes it's about lack of feeling, lack of responsiveness to positive things in their environment.
But it's very different than the way we use the term colloquially, depression, in a number of ways. One is, it doesn't respond to the environment. I'm not sad because I lost something. I just wake up and I'm [00:02:00] sad.
Also, the next day I'm still sad, and then the day after that. And I'm not just sad in the morning or at night, it's like most of the day.
So these are what characterizes the syndrome, the condition that we call clinical depression or major depression is sad, depressed mood most of the day, more days than not, for the big book of psychiatric diagnosis tells us at least two weeks.
Of course, unfortunately, it can last much, much, much longer than that, months or years, but that's kind of the official at least two weeks.
And one way I talk about it to patients or families or medical students is the mood state in the normal course of human experience is actually a really important source of information.
It helps tell people what's good, what's bad, what should I do with my time, what makes... you sort of go with your-- people might not even really notice, it's so automatic, but their [00:03:00] emotional state is guiding and giving them information, whether it's a good or bad.
And in illnesses like depression, clinical depression, that stops being the case. There's no correspondence or very little between the person's emotional state and their outside world.
It stops being what we say, we call adaptive. Typically, emotions have a very adaptive role in our mental economy. They give us information. That goes away when we're talking about depression.
Symptoms and Red Flags
James Murrough:And the last thing I'll say about that, the difference, is there's a host of cognitive, emotional, and physical changes that go along with this abnormal, sometimes what we'll call pathological mood state I described.
Again, in medicine we refer to it as pathological because it no longer is functioning. It's not adaptive for the person. It's just negative down all the time. But it's not just that. So the person that would have clinical depression is gonna have an array of changes in their physiology and behavior.
Sleep [00:04:00] disturbance is very common. They can only sleep sometimes for a few hours at a time. They keep waking up and there are reasons for that. Appetite, they might lose their appetite.
In more extreme cases, they may stop eating completely. In more severe forms of depression, they would need to come into the hospital.
And one of the things we'll probably get into later is if somebody starts experiencing or expressing thinking of death, dying, or a thought that maybe people would be just as well off if they weren't alive anymore.
Of course, that's a huge red flag, and clinically that's a way we can draw a red, a line in the sand and say, "Okay, now, there's really no example in the normal course of human experience in terms of emotion changes and responses that a healthy adaptive response is going to involve suicidal thinking."
There's nothing-
Stephen Calabria: Right.
James Murrough:You know what I mean? So that-
Stephen Calabria: Nobody would ever advise that.
James Murrough:So when we do see that, that tells us we're dealing with a condition that needs further evaluation and treatment and not [00:05:00] just sort of a normal variant of human experience.
But often this is what we're doing in psychiatry and mental health. We're trying to draw that line. You've got normal variation of human experience here, and then you've got what we call, illnesses i- in medicine. And that's always somewhat of an arbitrary line, right? Again, it's not just in psychiatry.
How many headaches is too much that now you have a headache disorder, et cetera, et cetera,
Stephen Calabria: So a lot of it is somewhat subjective still, on the part of the practitioner.
James Murrough:Yeah, and there has to-- You know, there's conventions. There's sort of agreed-upon standards. When do you call something major depression?
And it's spelled out so that at least if I'm making the diagnosis and someone in Kansas is making the diagnosis and someone over somewhere else, at least we're speaking the same language. It doesn't mean that it's fundamentally a ground truth. It's just it represents our accumulated knowledge over, oh, however many hundreds or of years that, [00:06:00] medicine has been practiced.
Subtypes and Biomarkers
James Murrough:We think it's probably unlikely that fundamentally depression is one thing, let's say at a biological or brain level. So we think a lot in psychiatry and in research about the idea of subtypes. A subtype could be clinical, biological, but what we usually mean is that fundamentally, there's a physiology to every disease, right?
Whether it's of the heart, the brain, et cetera. Psychiatric illnesses, of course, are brain illnesses. They're more about functional circuits rather than obvious things you can see on a standard brain scan.
But these are brain disorders, and we think eventually we're gonna learn enough to be able to reliably subtype and say, "You have this type of depression versus that type of depression that has a different biology."
There's a lot of roads to getting into a clinical depression. And if we know what that is for a given person, [00:07:00] then ideally we would know how to more effectively treat it.
Stephen Calabria: What are different subtypes of depression?
James Murrough:So we have a few subtypes that are clinical, meaning it's based on the symptoms that the patient presents with. I used the example of I mentioned that some people with depression have profound levels of anxiety, anxious distress.
They just feel knotted up inside. They just feel that anxious pit in their stomach all the time. It's a really nasty form of the illness. Not all people have that.
And when I go to make a diagnosis of major depression, I can indicate what's called a specifier with anxious distress. Which is all fine, but of course, if it doesn't help to understand the prognosis of the illness, what's the likely course?
How long is it gonna last? And probably most importantly, what treatment should I give them? It's not that useful. And that's kind of the place we've been in psychiatry.
We can find there are somewhat reliable, stable clinical subtypes, meaning based on symptoms and the way it [00:08:00] presents, but that has-- it's been disappointing. That doesn't seem to tell us that much information about the prognosis or the treatment of the illness.
But for example, there are current clinical trials and drug discovery efforts going on this specifically to recruit people that have a certain clinical type of depression, anxious depression, sometimes we call it, and to test a medicine that we think chemically the way it works in the brain may be particularly good for both depression and anxiety.
So there are efforts up to this point in the history of treatment development for depression. I don't believe there's any subtypes specified in any FDA label, right?
You're either approved for the treatment of MDD or you're not. I'll add one caveat to that. There is a few medicines that are labeled for what's called treatment-resistant depression, but that's not really a subtype.
It just means it's indicated for someone that has a history of non-response to multiple treatments. So that's not really what we're [00:09:00] talking about. But we are in desperate interest in identifying reliable biomarkers so that we can subtype so that we can get more patients better faster, and that also connects to this concept of like personalized treatment, right?
Right now we don't have that because I don't have any reliable measure to put you in a, smaller more nuanced label, right? To say, "Okay, actually these medicines are much more likely than these over here."
Right now we just have uh, do you have depression or not? And then I have a vast actually armamentarium of antidepressant medicines And many other treatment techniques, by the way.
Psychotherapy behavioral therapy, cognitive therapy, all these are forms of psychotherapy. So we have a range of options to treat this illness. And what we need now is a way to more quickly match what treatment is most likely to benefit a patient.
Right now, it's essentially trial and error, [00:10:00] which is the same as when I was in medical school. And we need to move beyond that.
Stephen Calabria: So much like treating other diseases where it's almost a one-size-fits-all type situation, folks come in, they get tested, and they determine what treatment they should take as opposed to getting your blood drawn and then immediately knowing what course you should take from there.
James Murrough:And to be fair to psychiatry, I always try to remind myself and other people, it's not that scenario you, you just described, which we want that-- We all want that in all fields, right? We know that oncology has made a lot of progress in this area. Several other fields.
But much of the practice of medicine doesn't look all that different from the way we treat depression. You go into your doctor's office, they take a measurement of your blood pressure and you have high blood pressure.
And they think, "Okay I'm gonna give you medicine." How do they decide which medicine to give you? Because how many antihypertensive drugs are on the market? It's gotta be probably even [00:11:00] more than there are antidepressants, if you can believe it.
And there's no special test. They're gonna prescribe something that's generic, cheap, has a good safety profile, available at your drugstore.
Th- these are the sort of mundane data points that we use to decide which amongst a variety of options to give patients. Let's talk about neurology because that's the other field in medicine that deals with the brain besides psychiatry.
Let's think of common neurologic conditions. Maybe headache, right? Migraine, cluster headaches, The practice of the treatment, which can be disabling, looks very similar to how we approach in psychiatry.
I'm sure they want to-- They have many subtypes of headaches but there's no sort of test, right? It's just you ask the patient, "How bad is your headache on a scale of zero to 10?
How many times a week do you have it?" And then there's a variety of anti-headache medicines in migraines, and they try one, and if that doesn't work, they switch to another one.
That's how we treat depression and the [00:12:00] other common illnesses. We want to do better. I think we can. But also to remind ourselves not to get too down on ourselves in psychiatry. We're not that far behind some of our friends in other areas of medicine.
Brain Entrapment Study
Stephen Calabria: And to catch up presumably will take a substantial amount of research, and your team's recent research introduces the idea of the brain becoming entrapped.
James Murrough:Yes.
Stephen Calabria: That's a powerful word- Yes ... because it's also how many patients describe depression.
They feel stuck like they're in a hole.
James Murrough:Yes.
Stephen Calabria: What did your study discover?
James Murrough:Yeah. So we've used a tool called functional MRI, functional brain imaging. You know, I I mentioned you go to a neurologist. Actually, I'll use the example of headache, and they're probably gonna do a, a MRI of your brain, not because it's gonna tell them how to treat your headache, but to rule out.
That's what we talk a lot about in medicine, rule outs. Rule out the very small chance there's something going on, there's a tumor in your [00:13:00] brain.
Very low likelihood, but you wanna know if it's there. So they get a scan. It's probably normal. They're gonna start treatment for a patient. In psychiatry we might do the same thing, get a brain MRI to rule something out.
But on the research side, we can use specific types of imaging with an MRI to get estimates of the brain function in addition to the structure. And, for your listeners, sometimes you've seen these and they come out as sort of colorful rainbow-like maps that sort of indicates how much one part of the brain is active compared to another.
Generally, we'll have the patient lie in the scanner for 10 minutes, 15 minutes, 20 minutes. And sometimes we'll just have them not do anything in particular, but we're measuring every few seconds the brain is-- the, the, the machine is taking a picture that gives us a proxy of what parts of the brain are more or less active.
It's based on a something called the bold signal, where small fluctuations in the magnetization in blood can correlate with the brain [00:14:00] activity. So we use that as a proxy, and we can get these maps. Most of that research you can, for example-- I'll give you a maybe a simple example.
You could ask people to recall a sad memory And then you're taking-- imagine you're snapping photos of the brain and the way the subtle distribution of the way the blood is going to different parts of the brain, because it turns out when part of the brain is more active, it's more metabolically hungry.
The brain subtly shunts more blood to that area. That's what we're actually measuring with functional brain imaging. Then we can have them recall a positive memory picture, and neutral, and then you do statistical modeling.
You get these brain maps that say, "this is your brain when you're sad, and that's your brain when you're happy."
So this is just basic functional MRI, and then you can sum that up, and then you can do that in a group of people that have depression and don't have depression, and then you can get these group averages.
So this is how we know something about the functional brain basis of these illnesses, and we certainly do know a good amount.
The work that you're talking about that we recently did that was actually led by Dr. [00:15:00] Jacob, her lab, which is within our depression center, and she has a wonderful very smart postdoctoral fellow Dr. Killick.
So what they did was ask in some ways a, a very interesting but fundamentally different question. Instead of saying what state is the brain in, they asked how does the brain dynamically change states?
How many states over a period of time, let's say 15 minutes someone's lying in the scanner, how many different configurations are there, stable brain states? You could think about it like a moving a picture or even maybe like a weather pattern, a snapshot.
Things are in a certain place, but everything in the brain's always moving, and these fluctuations in brain states presumably underlie how we think, how we feel. In the past, we've had these, what we call static snapshots.
It's like an average of all the pictures I told you. Like it takes a picture, take a picture.
You can get a snapshot, a one statistical [00:16:00] average of what the brain was doing over that period of time. This study and other recent studies has taken a fundamentally different approach to what we call dynamic functional brain imaging and computed how many states, how does things move how do the different states transition?
How long does the brain spend in one state or another? So in our work, we found that on average, there were four brain states that people tended to move between when they were spending their 15 minutes in the scanner, and that's consistent with other findings.
It turns out there's these canonical large-scale brain states that are replicable that we see over time, and we even know a fair amount about them.
There's a famous one called the default mode network, and there's a lot of evidence to indicate when that brain state dominates, people are engaged in sort of internal introspective sensations, thinking.
Data has linked over [00:17:00] representation of the default mode as a correlate of depression. You imagine that. Then, there's another brain state called the frontoparietal network, which you could think of as more task-oriented, external.
If you've ever been, like, mind-wandering kinda in your own head, and then someone says, "Hey," and you orient to that thing, or you're driving and suddenly a car zips by you.
Now you've engaged your frontoparietal network. We identified four brain states, including those that people would move between.
And so in this study, we computed, we focused on things like, how many times does the brain state move between these four, and how long does it spend in each state? And we could do that for every person.
I think in this study, we had about 40 healthy adults without depression and a similar amount that were in a major depression. And for each person, we could compute how long they spent in those brain states, all these cool metrics that gives us a dynamic picture of what's going on versus the type of brain imaging that's been done before, which is, [00:18:00] again, you get an average.
Stephen Calabria: So the more reflective state, brain state, it makes sense that would be the one most perhaps correlated with depression, because when you're feeling depressed, I imagine a great many people are reflecting upon past traumas, past experiences.
Internal- Yes ...
James Murrough:thoughts, memories. Yes.
Stephen Calabria: Whereas other folks who've talked about in their case, having overcome depression, many people threw themselves into their work, task-oriented. Folks are less likely to get stuck. Right ... And trapped in their own cyclical thinking. What were the other two brain states?
James Murrough:In this case, we just sort of labeled-- I mean, it was not that creative. We called them brain states one, two, three, four.
And then they mapped onto again, they're either depending on what nomenclature you use, there's either five or seven what we call large-scale brain networks that, again, that's been studied for many years in healthy people.
Trying to understand what role do they have in cognition? So internally directed versus external, that's one that's easy to understand. Another one that came up in our work that's also been found [00:19:00] before, we call the salience network. So salience, right?
A network that seems to be responsive to, goes back to our earlier discussions, it seems to carry information or represent information and help guide adaptive behavior because it it indicates or indexes how salient something is.
Not necessarily whether it's good or bad, but just is this something to pay attention to? So again, you're an animal foraging for food. You better have that system online because if you're a squirrel and you see a nut that's very salient to you, assuming you're hungry or maybe you're getting ready for the winter.
I don't know. One of our findings, which was very interesting and not expected, was that people with depression transitioned into the salience state, salience network configuration.
Think of like a three-dimensional, think of a map, but in three dimensions, right? So you got the map, but then you have the peaks and valleys. So that's how this data's kind of represented.
But now [00:20:00] imagine every second, it's moving, so it's fluctuating. The peaks are getting bigger, smaller. The, the continents are moving around. That's the type of dataset that is generated, and that's how we're representing brain activity.
And again, you can take all the variance in that and sort of identify these four states. So, imagine a map that's like moving between four states, and it can spend different times.
What we found in depression is that people with depression were much more frequently reconfiguring their brain states into the salience, spending more time with the salience network dominating the picture, if you wish.
Which was a little bit of a surprise because one of the hallmarks of depression is, again, they're disconnected from and not that responsive to, the environment.
But what we found was although the patients with depression, they kept entering the salience configuration over and over much more than healthy people, they spent much less time in it.
So imagine [00:21:00] rapidly the depressed brain was continually trying to take on a salience configuration, but never spending any time in it.
In and out, like basically quickly in and out, kept switching in and out of salience. So we interpreted that as It's unstable, and if it's an unstable configuration, then that could account for why people are disengaged.
If the squirrel in my example is depressed, they might just pass that nut even though, 'cause like whatever.
Stephen Calabria: So an example in the real world, let's say, and this is me just taking a stab at it. Let's say a depressed person enters a room at a party-
James Murrough:Yeah ...
Stephen Calabria: and they are trying to engage, and they're trying to find the salience here, but they immediately give up hope. They assume that everyone here is judging them or laughing at them. Yep. Yes. And then they leave the situation-
James Murrough:Yeah, what we would think is going on in terms of their brain states at that time, when they're in the room, is that while the brain is attempting to [00:22:00] configure them into a sort of salience positive state, which presumably corresponds to a mindset that I'm gonna enjoy this, and then you do enjoy it, right?
Social, our social network these are the most rewarding things to humans, besides water and food and stuff. But it's very salient, but not for the depressed person.
So our findings would suggest that person's brain state as they're at the party is trying but failing to configure into a stable, functional prosalience state that would correspond to " like, "I'm glad I'm here at the party."
So that's the type of thing , this is still early days, so this sort of dynamic and thinking about brain states in this, this way is relatively new so we have a lot more to learn. But I'm hopeful because it kinda gets away from, again, a more simplistic, very useful, but I think probably the field's gonna be moving away from just I'm in state A or B.
Like, it's can't be that simple. I mean, We know it's not that [00:23:00] simple. And this starts to get at the dynamics that we know is underlying brain function, but it's very hard to measure directly.
Stephen Calabria: And this is the entrapment-
James Murrough:The entrapment was the-- I guess it made it into the title of the paper. That was a actually a second finding. So far we've been talking about functional brain states, right?
A novel, but one of the very novel aspects, I'm not sure it's been done before, at least in depression, is that what we did is we, in addition to that- In the same patients from the same brain scan session, we can generate a totally different data set that essentially gives us the wiring diagram of the brain.
This is the physical connections. So you've got neurons, and the neurons sprout these long axons that are covered in myelin. People may have heard of this. This is what's called the white matter in the brain.
Think of them-- The gray matter is like the, the hubs. That's where the business is done, and the white matter are the roads connecting.
Okay. So we talked about distributed functional [00:24:00] brain states, the map. That's sitting on top of a set of roads, right? Connections. So what Dr. Kilic and Jacob did was to ask a very interesting question.
So it turns out , I think it's called network controller theory, you can impose this structural constraint and then ask questions about given the structural constraint, like there are more roads and they're wider between some areas of the brain and then you got like the narrow country back roads to others.
There's an expected correspondence between this sort of structure of the brain and its connections and the way the states reconfigure. So remember we talked about the peaks and valleys in the brain states.
The parts that have the largest roadways connected should be co-active together. And then you can interpret that in terms of energetics. You can say how much energy, in a computational sense, would it take to move from state one to two or two to three on average?"
And then you can ask in a given [00:25:00] individual, were their brain states changing in a way that would make sense. If you had the roadmap, that would be that's how you would travel.
In depression they did not follow the most economic energy efficient routes is one way to think of it. Again, we didn't expect this.
And in individuals with depression, the brain was continually making energetically inefficient decisions. And one consequence of that is that the states would tend to get stuck and constrained within these specific patterns.
And so the idea of entrapment we had as a way to describe the fact that the depressed brain was attempting to move between brain states inefficiently and therefore getting stuck.
As a consequence, it would get stuck in certain patterns. And you mentioned this before, and we don't know if there's a one-to-one correspondence, but [00:26:00] patients describe being stuck mentally, like whether it's not being able to get out of your own head, not getting-- not being able to get away from these sort of negative self-talk.
Brain Energy Inefficiency
James Murrough:I've had patients describe the experience of being in a depression as being like down in a hole and like looking up So there were aspects of what we saw in these sort of dynamic brain states transitions and sort of, abnormal energetics that was consistent with and maybe a sort of biological correlate of the subjective experience of being stuck, trapped.
Now, obviously, one of the big questions that raised is why would the brain not take the most efficient routes? It's all-- Imagine you're trying to get from point A to point B, and instead of taking the highway, you keep taking the back roads for no good reason. That we don't know. That's the, that's one of the biggest sort of next questions.
Because they seem to be-- The, the implication would [00:27:00] be the brain is using more energy and inefficiently than it needs to in a depression. Again, tempting. We haven't talked about the symptom of fatigue.
But it can be very-- If you've ever had depression or talked to people who've had it, they-- Again, some people, not everybody, but there's a subtype, if I dare say, of depression where they really have this profound physical lack of energy.
Some pe- you know, I say, "Well, why didn't you go to the party?" "Well, I didn't want to." Or "I thought people would judge me." You have other people that say, "I couldn't. I literally-- It felt like I was sitting on my couch," that the activation energy, the threshold, the, that hump you'd have to get over-
Stephen Calabria: Is
James Murrough:exhausting
to get up, it's like everything is exhausting. We don't really understand that. There's been attempts to measure energetic use directly. Again, it's not easy to do. It's been very hard to find objective correlates of, [00:28:00] why is it someone feels like they don't have any energy?
Presumably, if you do routine tests of how much, how many calories the body's using and things that all kinda is normal, and yet they have this profound subjective sensation of no energy.
Stephen Calabria: May I present a totally non-scientific, Please do. If your brain, which consumes a disproportionate amount of your body's energy, if your brain is making all of these inefficient decisions that tax your body, and we know from this very show there is such a thing as a mind-body connection, if your brain is using energy in all of these inefficient ways, could that not explain why, physically, a person might feel so exhausted?
James Murrough:I would say yes, I think that sets up-- That is exactly the hypothesis I would have. Then the challenge is, how do we actually test that? But that would be the hypothesis, or one hypothesis, that this inefficient navigation that the brain seems to be doing, I don't [00:29:00] think that's ever been reported before in depression, and again, we have to be careful. This was a study with less than 100 people, so can we replicate it, right?
That's always the first question in science. And then, what does it mean And most importantly, for doctors trying to treat patients and for a patient and their family, how does that tell us how to treat the person?
But I'm a strong believer, this is the fundamental tenet of medical science. We have to know the physiologic basis of these conditions. Like I said, in psychiatry maybe we're a little behind, but this is what's exciting to me about this type of work, that maybe we have a clue to the physical underpinning.
That's been hard to-- this was done with state-of-the-art ultra high field, systems. We've only been able to do this type of research relatively recently. There's always the hope that, with a bigger microscope or a bigger telescope, we're gonna discover something more about our universe or something.
I think often that, that is the case. It's the sort of similar here. The more powerful tools, in this [00:30:00] case, the more powerful magnets, the more powerful the analytic tools, the software to make sense of the data that we hope that's gonna, start to accelerate our understanding.
But ultimately I'm a firm believer we need a fundamental physiologic understanding of depression to really do rational treatment discovery, treatment testing, subtyping. There have been times in medicine, history of medicine where somebody stumbled upon a blood test that was super helpful to indicate something or to tell.
So, you could still have a very medically useful biomarker, subtype that you kinda just lucked into that's super helpful.
But so far we haven't been that lucky in psychiatry, and we probably just need to really understand the physical causes of these illnesses before we can really come up with useful and much better ways to treat patients.
Stephen Calabria: Sure.
Stress and Disconnection
Stephen Calabria: Getting back to the earlier point, many people describe depression as feeling [00:31:00] disconnected from themselves, as if they're watching life happen instead of participating in it.
And for many people who experience profound depression, it wasn't always that way. It was a gradual thing over time. And in your research, have you been able to track that sort of process?
And what takes place in the brain and how to counteract it, both from a pharmacologic level and a behavioral level on the part of the patient?
James Murrough:Yeah. So we do see that, and you're right about one thing I didn't mention before, when we're trying to evaluate depression, that's a very important thing we're looking for- is this a change from how things were and when did it start?
And you can imagine like anything else, people vary in their habits, in their both behavioral and physical traits, which is great. Everybody's different.
Some people may just be more engaged in the external world just by their nature, and other people a little bit more in their head, right? [00:32:00] But what we're really looking for is a change.
Like, when did this... and it's not one of our nine official symptoms of depression, like feeling disconnected. It's not that, but it is something we see.
It's interesting to note we haven't talked that much about the role of stress in causing or exacerbating depression, but there's a major role for that. We know about, in the natural predicted stress reaction to a significant stressor or trauma, is some level of that disconnection.
And you could think about why might that be, both from a biological or maybe even evolutionary what's useful about it?
It turns out that in, in under conditions of severe stress, some disconnection or some to say dissociation from the environment actually can be adaptive for ways we could talk about.
When we deal with things like depression, what we tend to see is the stress, it's not like someone's walking along, then they undergo a stressor or trauma, and then there's this [00:33:00] reaction, a recovery period.
Depression seems to result from chronic stress that kind of just builds over time, and eventually there's some sort of balance and some tipping point where the resilience to stress gives way to depression.
That's one way to think of it. And then to compound matters further, being in a depression is stressful. So it's some kind of models of how this works. The episode of depression itself can be conceptualized as a stressor. So then you can imagine stuck in this, again, one of these feedback loops.
Stephen Calabria: Like I'm depressed. I am a depressed person. This is now a part of my life. This is a thing that exists, yet another thing that I have to get over, which is on top of all of the initial stressors.
James Murrough:Correct. You had to pay your bills, all that stuff. Now you have depression. So it's really has this sort of insidious way of inserting itself into people's lives.
But a consequence of that is people might feel a little bit in that stress reaction disconnection kind of all the [00:34:00] time.
And we also talked about kind of an overdominance of this sort of default mode way of being in the brain, which again is internally directed. So that also probably accounts for some subjective experience about not really being all there.
And what, or what, and what loved ones and family members will say like, " H e's just sitting there. He's not really doing anything."
So again, I think we've gotten to a point where we have a pretty good working knowledge of how this is happening in the brain, and now we just need to get to the point of what can we actually do about it.
CBT and Behavioral Activation
James Murrough:Again, you mentioned, a behavioral treatment that we would recommend for this type of thing is, and really for depression in general, is a form of CBT, cognitive behavioral therapy.
I mean, That's really kind of an umbrella, very, evidence-based kind of collection of different therapeutic approaches and techniques that are rooted in sort of fundamental cognitive behavioral therapy theory.
But and some of it's pretty straightforward, but in the case of depression just when the person is feeling and their depressed brain is telling them, "Stay home, stay on the [00:35:00] couch, don't go to the party," the job of the doctor and the therapist is like, "Nah, you gotta go."
So it's that coaching. It's that you gotta engage in life. You gotta get out of your head. Even if you feel disconnected, if you have to-- And this is what's so cruel about depression. It's you have to put even more effort in to do it.
And this is what I talk to a patient. I say, "Look, I'm gonna tell you right now, I get it, and I know you're gonna tell me you can't do it. You can do it. It feels terrible, and but now more than ever is when you need to do it."
You need to engage. You need to find things to do in the external world. And by doing that, again, that will switch those brain states into that more externally directed, probably more adaptive, Right style, right?
Stephen Calabria: It's never going to be as difficult as it is right now- ... to reenter these patterns of behavior. And then once you start doing it- ... the thinking, I imagine, goes over time, it's going to get easier and easier.
James Murrough:That's right.
Stephen Calabria: You push yourself the very first- [00:36:00] That's right ... time's the hardest.
James Murrough:That's right. And often , you bring the family in, 'cause they're saying, "What do we do? Do we leave him alone? He wants to stay or she wants to stay in their room with the door closed."
So this is complicated stuff, but the principle is, yeah, I know it's really hard, but you gotta do it. That's one of our jobs. And we think that, let's say this is a case where we might also be starting an antidepressant medication.
These things go together, 'cause one of the things antidepressant medicines probably do is, they help the brain through various ways to get into that more adaptive brain states.
But then that should synergize with the behavioral, what we call behavioral activation or these kind of, techniques getting out there. So that's one way we see how those things, synergize.
I always make the point that, same thing, there's a tendency to retreat in a depression for all kinds of reasons, fatigue, shame, right?
But also that, like you mentioned, being judged. And let's say I'm seeing them once a week or a couple times a month in follow-up, checking in and we'll make a [00:37:00] plan. "Okay, what are you gonna do? What's your plans for the weekend?"
"Oh, I'm not sure." "Okay, let's make that plan," right? You need something to do. And I'll ask about "So who are the most important people in their lives? Who do they reach out to when they're down?"
I have a good friend, but I haven't been taking her phone call recently." Oh, wrong answer. You gotta pick up that phone because more than ever, there's lots of research to show that the robustness and the extent of someone's social network protects them from depression, and also it's likely to speed recovery.
So again, we're in the same situation where just when they would like nothing more than to not take the phone call, shut out the outside world, that's the exact opposite.
And so we're in a position we have to be counseling, coaching, being the champion and holding patients accountable. Striking that balance of "I know it's hard. I know your brain states are stuck in energy states that don't make any sense. We did that study, but you still need to do it," right?
So there's still that agency and empowering people that you can do it.
Stephen Calabria: It can be incredibly [00:38:00] difficult on the one hand to show unceasing support, while on the other hand, what do you do when someone cannot be dislodged?
I imagine there are also folks listening now who have never experienced depression and who may simply see it as prolonged sadness. Mm-hmm. From the inside, how would you describe to those folks what the difference is?
James Murrough:Yeah. In some ways it's very understandable because we use the same language and feeling sad is an ubiquitous human experience. Why would they know?
But again, going back to where we started the conversation, when we say depression, we're talking about a medical condition where the mood state is stuck, not responsive to the environment, not adaptive, and no matter what's going on, they feel lousy, anxious, sad, or sort of nothing at all, or some combination of that.
And if [00:39:00] the person looks closely, they'll know, or the person wondering, or if they've met somebody, that we're not talking about feeling sad because the person with clinical depression is going to be at risk of, again, having major life disruptions.
They can't go to work they lose friends. In, in extreme forms of the illness they'll stop eating. In the most extreme forms of depression, of course, they need to come into the hospital because they're not eating, they're at risk of, if that goes on and on of dying.
When it's very severe, sometimes they become what we call delusional or have psychosis, so actually believing things, typically they're very negative about the self. They may be things that they've done.
Maybe they've sinned and deserve what is happening to them to the point where it becomes what we call delusional, which is in psychiatry a technical term which means a fixed false belief they can't shake.
These are the more extreme, again, presumably the [00:40:00] more extreme the depression, the more obvious it is that we're not talking about feeling sad.
But again, the core, is the mood is fixed, unchanged, doesn't respond to the environment, and again, it's not useful anymore. The earliest terms I think for this disease that I think maybe Hippocrates was credited with the or some of the earliest was called melancholia.
Maybe we need a different word because it really, it uses depression it's like in name only right? It's really not that.
And again, it's been described for thousands of years. This is not are some people think.
Stephen Calabria: Yeah, Lincoln was described as melancholic.
James Murrough:Yeah. That's a term that we don't tend to u- It's just a historical-- We just, for whatever reason, we don't tend to use that term anymore.
But, throughout the centuries or the eons, we know that this is a biological illness which again can be life-threatening in extreme. And, we're still trying to figure out what the heck causes it.
Suicide Risk and Stigma
Stephen Calabria: In your dual role as both a researcher and a practitioner you also study and treat suicidal ideation [00:41:00] and thinking. For many families, that's the most frightening part of depression.
From a research standpoint, do we have any insight into when a person has reached suicidal ideation? And from a treatment standpoint, how do you recognize when someone has moved beyond hopelessness and into immediate danger?
James Murrough:Yeah. I'm glad you brought that up because we haven't mentioned suicidal thinking yet, although that's an important part of an answer to some of the things we were talking about, like what's the difference between normal sadness and clinical depression.
So although we haven't talked about it, that, every doctor is trained, that's like-- it sounds silly even saying it, but that's a major red flag, and that for us, if I'm evaluating a patient, very early In the interview, if I'm trying to suss out, again, normal sadness versus what we sometimes call pathological mood state, normal sadness versus clinical depression, I'm gonna ask if they've thought about killing themselves or they don't wanna be [00:42:00] alive anymore.
And of course, the key to getting a authentic answer is to ask it just the same way you'd ask, "When's the last time you-- When was your last meal?" 'Cause they-- people can feel very ashamed.
So it's very important for practitioners to-- And again, this is basic. This is like Psychiatry 101 medical school.
You learn how to ask this question. This is one of the symptoms of depression, and obviously it's one of the most concerning because depression, as I mentioned, can be fatal.
Depression, I think, is the most common medical diagnosis associated with suicide. Maybe not surprisingly. It's not specific people that have alcohol disorder, schizophrenia, or maybe for other reasons entirely could be at risk of having suicidal thinking and ultimately committing suicide.
But by and large, the vast majority of individuals who die by suicide will have a diagnosis of depression.
So [00:43:00] we have to take it very seriously. And , again, you bring in the family and help them understand , how do you detect it? What do you do about it?
You can imagine if someone's not professionally trained in mental health, they're not used to asking someone if they wanna die. That's just not something we were taught to do in polite company, right?
Stephen Calabria: I've never asked anybody that.
James Murrough:There you go. Yeah. And that's one of the things you have to ask, and there's sort of a misconception or fear that, if they ask, that will give someone the idea.
So one of the things we do in terms of education is to try to dissuade people from thinking that by asking about it, you're gonna somehow cause it or give someone the idea. There's lots of research to show that's not true. So it's hard to do.
Any medical professional, will do that. It's one of the first questions they'll ask, but it's important if a loved one, if you're worried about the best thing to do is ask in a gentle, direct way "Are you thinking about wanting to [00:44:00] die?"
And obviously, if you think someone in your orbit might be at risk, take action.
Stephen Calabria: One perennial topic of discussion is the fixation on the mentally ill as being violent.
While it is true that some acts of violence are committed by those who are mentally ill, and while it is also true that depression is considered a mental illness, and a disproportionate number of gun deaths per year are those who carry out suicide, there is no evidence, correct me if I'm wrong, that mentally ill people are more violent than the population. In fact, it is the opposite.
James Murrough:Yeah, that's true. Yeah, that's right. Exactly. And, It goes back to something we talked about before about stigma, shame. So, one of the things we're trying to do in medicine and psychiatry and sort of a public health vein is to, again, try to do education like podcasts like this and lots of other things.
Excellent organizations like NAMI, Brain Behavior Research Foundation. [00:45:00] Part of what they're doing is trying to get the word out that, mental illness is not something that you need to keep behind closed doors or that's some taboo thing or some other like,
"Oh, those people have those problems and they're violent and we should stay away from them."
So, to my mind, that all goes to the kind of continuing importance of public health education about what mental illness and psychiatry is and depression, things like that.
Recovery and Resources
Stephen Calabria: One message that runs through so much of your work is that the brain remains capable of change. For someone who's convinced they'll always feel this way, they're stuck, what would you want them to know about the brain's capacity to recover?
James Murrough:Yeah, that's a great question, and I can't tell you how many times I've had that exact conversation with a patient because when they're sitting in my office and they're in a depression, every fiber of their being is telling them it's never gonna change.
Stephen Calabria: It's just the way the world is. It's never gonna change. It'll never work.
James Murrough:And what's [00:46:00] interesting is, one of the things I've discovered-- I guess it's known, but to see it up close and then over and over with patients.
You know, if I have the privilege to follow patients over time and depression, we haven't really talked about this, but it for some people it's like there are relapses, okay? It recurs. Not always.
So there are periods where they're well, and then they fall into depression, and then we try our darndest, they come out of a depression, et cetera. And I've actually seen this in a number of patients.
Not only when someone's in a depression do they feel that it'll never change, they'll never get better, they actually have significant trouble remembering and being convinced that there was a time when they weren't depressed, as crazy as that sounds.
The patient will be in my office, and they'd be accompanied by what? A spouse, family members. And the spouse or the fam- They're saying, "What are you talking about? You love doing XYZ. This has all changed in the last year."
And you can tell they're really struggling, and there's theories about this that, you know, when [00:47:00] we remember something, in some ways the brain is reconfiguring to what it was in part when you had that experience, if that makes sense.
The brain can't do that when they're in a depression, so they literally can't remember. You can imagine this is a setup for risk of suicide because in their brain, they've never been well and they're never going to, even though objectively it's not true.
Stephen Calabria: But they cannot channel the feeling of happiness.
James Murrough:That's right. That's right. So they can't recall. It doesn't feel real. They feel disconnected from their prior self and not even sure. I've had so many patients say, "No I, I think I've always been like this."
And again it used to be if I see someone and let's say I don't have family or other people to jump in and say, "Actually, that's not true," okay, then maybe some people have a chronic low-grade type depression for most of their life.
And then what I found was when we've been able to get them better and out of the depression, they're like a different person, completely different. Like you can see it [00:48:00] on their face.
And we chat, we check in, and then unfortunately I've seen where then months or years later the depression recurs, and they're telling me again they've never felt well. But this time I can say, " no. I have the data. I've known you for X number of years.
This is not you." But it is striking that it literally, they somehow cannot remember. They don't believe it. So that contributes to feeling trapped.
Back to your question what can you do? Again, as the doctor, and it-- you can there's some sort of sense in which there's a feeling that you're not sure you're getting through. But what I do is I just keep-- I'm just a broken record.
I just tell the patients and their family you're gonna get better. You're just gonna have to hang in there." One of the challenges we have is that most of the medicines we use do take a while to start working: days, weeks, months.
Particularly if the first one doesn't work, you're making changes, you're adding. It can be a long process, and people can start to lose hope.
So [00:49:00] as a psychiatrist who's focused on if my role is to focus on sort of the medication piece, which is often the case with psychiatry whereas hopefully they're getting good CBT or psychotherapy from a psychologist, a psychotherapist in parallel, right?
Part of the treatment team. But if I'm focused on the medicine, I'm trying to make smart, efficient choices with what medicine I'm using, what dose, how quickly can I push the dose up to try to get them better but not give them side effects that's gonna be like, two steps forward, one step backwards.
But what I'm mostly doing is, I'm being their kind of coach, cheerleader, "You're gonna get through this. Hang in there. Give me two weeks before this medicine starts working." So it's kinda that versus kind of the idea of just, "Oh, here, here's your prescription. I'll see you in a month."
And that, of course, happens, but that's really the role of the psychopharmacologist is the fancy word we would refer to what we do, is it's really a lot of patient education and cheerleading.
Stephen Calabria: This podcast is called "Road to Resilience". [00:50:00] What gives you hope that people, even after profound depression, can find their way forward?
James Murrough:Oh, yeah. I've been impressed over and over again on people's resilience in the sense that they hang in there through the tough times, through the depressions.
Again, with a little bit of luck, the vast majority of patients are gonna make a full recovery and they're gonna bounce back, and they're gonna be able to live their lives.
It turns out people are just very resilient, whether you're talking about going through major mental illnesses, trauma, it's just amazing whether it's the plasticity and adaptability of the brain, the body. We've evolved this body over millions of years.
It's been through a lot, right? So it's pretty good at bouncing back, continuing on. You know, When talking to patients and their families, it's very important as their doctor to, to help them keep their spirits up when it's difficult and encourage them, and then to see when they actually come through the other side.
It's very gratifying. You get to see that kind of [00:51:00] resilience shine through, right? Finally, after the dark clouds of the depression have receded.
Stephen Calabria: And the map is clear.
James Murrough:There you go.
Stephen Calabria: If someone is suffering from depression or someone they know is suffering from depression, what resources are here at Mount Sinai that they could find?
James Murrough:That's the good thing is that depression is eminently treatable, and the majority of depression is effectively treated by in primary care.
You don't necessarily need to come to a fancy depression center. Obviously, like anything else, there's more severe, there's tertiary care , but at Mount Sinai, you go all the way from the clinics, the general practitioners, primary care.
So tell your doctor, if you're having these things. I think most if you're having... And people know sometimes it takes a while or in hindsight, but they know when things aren't right. Their spouse knows. Their kids know.
Somehow they're just not themselves, but they don't know what to call it. So if you feel like this is happening to you or you [00:52:00] know somebody just really encourage them br- talk to their doctor about it because there are treatments.
Often there can be effective and they don't need specialty care. But if they do, we have a very a large mental health-focused set of clinics and practitioners, so there's lots of lots of opportunity to get treatment.
Stephen Calabria: Dr. James Murrough, thank you so much for your time, sir.
James Murrough:Thank you.
Stephen Calabria: Thanks again to Dr. James Murrough for his time and expertise. That's all for this episode of Road to Resilience.
If you enjoyed it, please rate, review, and subscribe to our podcast on your favorite podcast platform.
Want to get in touch with the show or suggest an idea for a future episode? Email us at podcasts@mountsinai.org.
Road to Resilience is a production of the Mount Sinai Health System. It's produced by me, Stephen Calabria, and our executive producer, Lucia Lee. From all of us here at Mount Sinai, thanks for listening, and we'll catch you next time.