Transcript: Trial and Error in Treating Depression
From Abraham Lincoln’s untreatable melancholy to the serendipitous discovery of SSRIs, we have come a long way in understanding depression. Psychiatrist Conor Liston, MD, PhD, explains the diagnostic challenges psychiatrists face, and the trial-and-error process to finding the right medication that frustrates both doctors and their patients.
Dr. Stieg: We all go through depression at some point in our lives. It is part of the human condition, but there is more than one kind of depression. I'm pleased to welcome Dr. Conor Liston today to talk with us about some exciting advances in diagnosing and treating depression. Dr. Liston is an Associate Professor of Neuroscience and Psychiatry at Weill Cornell Medicine where he is also conducting research to advance our understanding of the neurobiology of depression and treating psychiatric disorders. Conor, welcome.
Dr. Liston: Well, thanks for having me. Glad to be here.
Dr. Stieg: Perhaps we could start off with what depression is so that everybody's on the same level.
Dr. Liston: Intuitively, we all know what depression is. You don't need a brain scan to diagnose depression, but in order to provide doctors with a language, a common means of communicating about depression, psychiatrists kind of came together and came up with a list of criteria that define what constitutes like a clinically meaningful depressive episode as opposed to what's just kind of a normal reaction to stress or adverse experiences in your life. And those criteria include things like changes in sleep, changes in appetites, a loss of pleasure and enjoyment and things you used to enjoy. There's a list of nine criteria and one of the most important things to emphasize I think is that you meet criteria for this diagnosis today when you have five or more of these symptoms, and that means that there are a lot of different ways, at least 256 unique different ways you can come to a doctor and still get this diagnosis there. There are many different kinds of depression.
Dr. Stieg: So your office is filled.
Dr. Liston: It is, it is indeed.
Dr. Stieg: I guess if somebody starts looking up online for what depression is, they're going to be led to the DSM, which is the Diagnostic and Statistical Manual of Mental Disorders. When I think about that, it seems to me that that's, that's it's a cataloging system and it's a system of just how patients present with symptoms, which is kind of vague. Correct?
Dr. Liston: That's right. That's absolutely right. It's, it's really, I remember, I remember encountering this as a trainee and kind of being struck by it. It's different the way we diagnose conditions in most other areas of medicine. In psychiatry, we're really reliant on patients’ self-report of their symptoms as opposed to blood tests or brain scans or physical exam.
Dr. Stieg: Depression gets broken down into four sub-categories?
Dr. Liston: That's right. Historically, there's been a lot of interest mainly among psychiatric scientists and investigators in figuring out subtypes of depression, and one way to do that is to look for groups of symptoms that patients tend to come in with, and there are examples of that that have been very influential. We've learned a lot from them. Maybe the best well-known is seasonal depression where some people experience changes in their mood or around the time like winter when, when the, when the exposure to sunlight tends to change. But the challenge with those clinical subtypes is that they haven't really changed the way we treat depression very much. There's not really a one-to-one correspondence between any of those subtypes and a biological marker I can measure in a patient's blood or very predictive treatments that I can give to that patient and know it's going to work well.
Dr. Stieg: I think personally I experienced the seasonal depression. I lived in Stockholm for a year and by the time March came around and the sun never came up, I sensed what was going on.
Dr. Liston: 03:38 Completely. I was in, I was in Sweden in November for about four days once and I could feel it as well. I think we can all relate to that.
Dr. Stieg: And the other, uh, of the four types, what is it? Atypical Melancholic, Seasonal and Agitated Depression. The one that is of most interest to me actually is the black dog. You know, Winston Churchill's melancholy and also Lincoln's melancholy. You can still be very functional and still have the diagnosis of a depressive subtype.
Dr. Liston: Yes. Some people are very functional, especially between their depressive episodes. That's one of the really satisfying things I think about being a psychiatrist is that people, they do get sick but you can get them better and they can be very high functioning in between — in between episodes… technically we usually only diagnose a depressive episode if a person is actually experiencing some kind of functional impairments, whether that's at work or in their home life, but that doesn't mean it's totally impairing. They can, they can still often be doing very well.
Dr. Liston: I always like to emphasize when we're talking about DSM and the ways it can be improved, that DSM has done a lot of good for patients and for doctors. It's ensured access to care, insurance coverage, a means of communicating, but the fact remains that DSM has also kind of become an obstacle to scientific progress because this is big catchall category doesn't correspond to just one thing in the brain or just one thing in terms of biology in the way that like a pneumococcal pneumonia or something very specific than an infectious disease doctor might treat that that says, you know, you should get this antibiotic. We don't have that in, in psychiatry and think that's the way the field is moving.
Dr. Stieg: So I guess that's an important thing for people to understand is that the importance of the this DSM manual is that the insurance companies use it as a way to figure out how they're going to reimburse. But you as a doctor don't necessarily use it so much because you're thinking more along the biological aspects of their disease.
Dr. Liston: Me, as a scientist, I'm definitely thinking about the biological aspects of the disease. I think the DSM does provide like a useful tool for doctors to help at least narrow down the right like range of treatments. But it doesn't tell you like that this drug, this particular antidepressant, is definitely going to be effective. Rather, it says like we should look at this whole class of drugs instead of this other class of drugs.
Dr. Stieg: Are you saying then that for the various types that you would treat melancholy versus agitated depression with a different set or class of drugs?
Dr. Liston: You treat them with similar drugs. Usually. Yes.
Dr. Stieg: It seems to me like everybody's on a serotonin reuptake inhibitor.
Dr. Liston: That's right. Oftentimes the considerations that go into picking a drug that, that subtype of depression might be one of them, but it's not definitive, right? Many other like side effects — and it just so happens that SSRI drugs have very tolerable side effect profiles.
Dr. Stieg: So SSRI is the serotonin reuptake inhibitor kinds of medications that are used to treat depression. Can you explain what that means or how that works?
Dr. Liston: So serotonin is a chemical in the brain that we think is important in mood. We don't really understand well how it works. It's actually kind of an interesting historical anachronism, how it came to be that we use these drugs. Many years ago, doctors were looking for an anti-tuberculosis drug and they, they came across a substance that seemed like it might be promising. They gave it to a lot of patients with tuberculosis. Those people, their tuberculosis didn't get better, but they were all isolated in these infectious disease wards and many of them had kind of low mood as a result and coincidentally they noticed that their moods tended to improve and with a little more investigation they figured out that it's probably got to do, at least in part with this chemical serotonin and many of our drugs today are just kind of cousins of that serendipitous discovery many years ago.
Dr. Stieg: As I understand it, you have found that there are different connections or different neuro networks that exist that correlate with these four different types of depression. Can you describe that?
Dr. Liston: Sure. I always think about it kind of with the analogy to our airport network, so anyone who flies a lot knows that our national airport network is set up into a system of hubs and kind of spokes and big airports like JFK or Chicago O’Hare, if you want to get to a small town in the United States, you're probably going to fly through one of those big airports. We call them hubs when we're dealing with airports. The brain is organized in a similar way. There are some areas of the brain that connect to many other smaller areas and when you have some kind of dysfunction in, in one of those hubs, that can kind of percolate out into the rest of the network. And we see that with airports as well. You can be sitting on a runway on a beautiful day like today, it's sunny and clear. We could be sitting on a runway and JFK waiting for hours to take off because of bad weather in Chicago that is affecting flights all over. Um, some, something similar probably happens in the brain and depression.
Dr. Stieg: What’s the other area of the brain that it's connected to that is also so important in this mood? Or, does depression fall into an affective disorder?
Dr. Liston: It does, yeah. Yes it does.
Dr. Stieg: And now I've used the new term affective disorder. Can you describe what that means?
Dr. Liston: Yes. Uh, affective disorders or are is just another term for any kind of psychiatric disorder that affects your mood. Common examples are, are depression and many people have heard of bipolar disorder as well where people go through periods of low mood but also periods of really elevated mood.
Dr. Stieg: And we were talking about the middle part of the frontal lobe that's connected with what other parts of the brain that are important in terms of depression?
Dr. Liston: So we know that there are a number of brain regions that are important in depression. One of them is the amygdala. It's the structure kind of at the base of the brain that's important in regulating fear and anxiety kind of responses. There are other parts kind of adjacent to the amygdala that are, that are important in regulating reward approached behaviors. When we see something we like, you can imagine how dysfunction in either of those circuits could lead to problems with anxiety or problems with enjoying pleasurable activities in life.
Dr. Stieg: What I've always found interesting about this is this is the most ancient part of the brain. It's called referred to as the limbic system. And, uh, obviously this whole set of emotional affect of problems has been around both in animals and in humans for a long time.
Dr. Liston: That's right. Uh, that's an important feature of depression that allows us to study at least some aspects of it in animals, which is really critical for developing treatments. These, these brain limbic brain regions, as you mentioned, they're conserved across many different species and that kind of makes sense. I mean, it's a, it's an important part of life no matter what animal you are, to be able to regulate fear, detect, um, fear inducing things in your environment and respond appropriately to them.
Dr. Stieg: Yeah. Again, as a peripheral person that sends patients to, to the psychiatrist and work with their depression, it seems to me that there's just this hierarchy of medicines, you know, and each psychiatrist has their own algorithm of their own flavor. Is that true? And does that make it, from your perspective as a clinician, also a clinician scientist, how hard is it to treat depression?
Dr. Liston: It's hard. It's often very hard. So you've kind of described a conundrum that many psychiatrists and many patients experienced too. As we said at the beginning, depression is very common. So we, the statistics that we all know, people who have either been depressed or, or will be depressed at some point in their lives. And I think many of them can probably relate to this experience where it's really frustrating. You go to a doctor, you discuss different options, you try one. And there's this kind of trial and error approach to treatments. We see if it works, if it doesn't work, we try something else. There are algorithms I should emphasize, so it's not totally kind of random, but for the most part, trial and error is a big part of it. And again, the statistics tell us that many people, first drug you try, they're, they're just, it's not going to work and you're gonna need to try something else. And another really frustrating aspect of it is that, uh, that you often need to wait a couple of months to know whether it works. So I don't mean to be discouraging to people who are, who are, who need treatments are treatments do work. But I think as psychiatrists in the future, we hope we'll be able to do better in finding the right treatment faster.
Dr. Stieg: In addition to that, there are pros to taking antidepressant medications. Can you enumerate those?
Dr. Liston: Absolutely. So we know that antidepressants have a number of beneficial effects on the brain. They help facilitate the formation of new connections between brain cells, which we call synapses. We also know that they form new brain cells in certain brain regions, and that might be important in mediating some of the effects on mood and also possibly enhancing different kinds of cognitive functions like learning and memory and attention so they can have a variety of, of beneficial effects on the brain.
Dr. Stieg: And what about the negative effects?
Dr. Liston: Many people experience side effects, not directly related to their, their impact on the brain, but to their impact elsewhere in the body. For example, our gut, we know that many people experience upset stomach indigestion, things like that, that can, that can actually become a big obstacle to taking the treatments for some people. So again, it's another kind of motivation to look for new drugs that might be more effective and better tolerated.
Dr. Stieg: You know, when you go to the pharmacist and you pick up your drug and you get the list of all the potential side effects, I mean, how seriously does one have to worry about weight gain, suicide and loss of libido when they're taking these kinds of medications?
Dr. Liston: That's a really important question that is kind of best addressed on a one on one basis with your doctor because, um, some people need to worry about them more than others. Take suicide, for example, that's obviously a really serious consequence of psychiatric illness that we all take very, very cautiously. And some people are probably more at risk from suicide than others. For example, adolescents, we know we need to be especially cautious and uh, keep a close eye on them when they're taking these drugs when they first start them to make sure that they don't experience any suicidal thoughts. But I should emphasize like for the most part, most people can tolerate these medications really well. They're on the whole really beneficial for them, but we need to, we need to keep close tabs on side effects like that.
Dr. Stieg: What are the effects that that antidepressants can have on your memory?
Dr. Liston: Effects on memory are being studied and for most people they're probably not going to have any major effects on memory that they're gonna notice either beneficial or detrimental. But for some people, especially people who have problems with memory associated with their depression, with their low mood, for those people in particular, antidepressants can be really helpful for memory.
Dr. Stieg: When a patient comes in to see you, are you optimistic about being able to help them? I want to give the people hope.
Dr. Liston: I'm very optimistic when someone comes in with depression, we know that we're going to be able to get them better with time. The question is just like, how fast can we get them better and ideally we'd love to make them, make them go home the same day and feel great. Realistically, that doesn't always happen cause we have to remember depression is a problem with the brain, but it also has to do with many other aspects of your life that we can't control as doctors. So even if we can fix what's going wrong in the brain, sometimes it takes a while to get back into your kind of normal routine at work or at home with family.
Dr. Stieg: There an example, it'd be when someone, a loved one dies, you just go into a quote, a funk.
Dr. Liston: Right.
Dr. Stieg: You know, that's a normal funk.
Dr. Liston: Right.
Dr. Stieg: And eventually, over time you'll get out of it.
Dr. Liston: That's right. Exactly.
Dr. Stieg: Yeah. You as a psychiatrist can help them with that if they need it?
Dr. Liston: We can definitely help them with that if they need it. That's another kind of important and sometimes difficult thing to distinguish whether someone is depressed in the context of losing a loved one or just normally grieving, and I think grief can look a lot like depression sometimes and oftentimes that doesn't need any psychiatric treatments, but sometimes it does.
Dr. Stieg: Other common question is, is depression genetic?
Dr. Liston: Depression is genetic. Bipolar depression is especially genetic. It's quite heritable. So we know from twin studies, for example, if you have a twin with depression, you're much more likely to develop bipolar depression as well. The more kind of run of the mill depression. What we all think of when we, when we hear the word depression...
Dr. Stieg: Melancholy.
Dr. Liston: That is also genetic. It runs in families, but it's not as strong. So we often, the statistic you hear cited is something like 30-40% of it is heritable, but it makes sense intuitively, right? Many things impact our mood. You might inherit like a vulnerability to becoming depressed and if you experienced a lot of adversity in your life, perhaps you're more likely to actually become depressed than someone else who doesn't experience that adversity.
Dr. Stieg: Conor, thank you for helping us understand what depression is, the subtypes of depression, and the fact that there is a hopeful outcome for the treatment of depression. I look forward to talking with you about new innovative ways that we're going to treat depression in the future.
