Depression: A Killing Disease


Charles Nemeroff, MD, PhD argues for psychiatrists to consider obtaining inflammatory marker labs on every patient that they see.

Charles Nemeroff, MD, PhD

Charles Nemeroff, MD, PhD

with David Carreon, MD and Jessica A. Gold, MD, MS

Depression is a killing disease: the effects of depression on the body beyond suicide

In the first part of this interview, Dr. Charles Nemeroff, Director of the University of Miami Center on Aging and Chairman of the Department of Psychiatry and Behavioral Sciences at University of Miami, discusses depression, including its symptoms, epidemiology, and the link to other physical illnesses like cardiovascular disease and diabetes. In particular, he discusses the role of depression in clot formation and inflammation. He then looks ahead to future studies and treatments that might target inflammatory factors, including stem cells, and argues for psychiatrists to consider obtaining inflammatory marker labs on every patient that they see.

Part 2: Abuse, Attachment, and Resilience: Genes and the Environment


Welcome to Psyched, a podcast about psychiatry that covers everything from the foundational to the cutting edge, from the popular to the weird. Thanks for tuning in.

David Carreon: Hey, everybody. This is David Carreon.

Jessi Gold: This is Jessi Gold.

David Carreon: And this is Psyched, a psychiatry podcast. Today, we have Dr. Charles Nemeroff, the Leonard M. Miller Professor and Chairman of the Department of Psychiatry and Behavioral Sciences at the University of Miami. He was born in New York City and graduated from City College of New York in 1970. He earned his PhD in neurobiology and his MD from the University of North Carolina at Chapel Hill. Dr. Nemeroff has received numerous honors during his career, including the distinguished Menninger Prize from the American College of Physicians and the Research Award from the American Foundation for Suicide Prevention. He's published more than 1100 research reports and reviews. Dr. Nemeroff, thank you for joining us on the show.

Charles Nemeroff: It's a really pleasure to be here with both of you.

Jessi Gold: Thank you.

David Carreon: You've got an incredible body of work here. We'd like to start the conversation off about depression. For our audience that does have a pretty broad range, what is depression? What is its essence? What does it look like?

Charles Nemeroff: Depression is a syndrome, a collection of symptoms like any disease. It happens to be a very common disorder, so that about 11% of men and about 21% of women in their lifetime will suffer with what we call major depression. The constellation of symptoms, of which you have to have five of nine in the DSM-5 criteria, include such symptoms as sleep disturbance, difficulty falling asleep, having trouble staying asleep, waking up too early, although a small percentage of patients oversleep. A very clear decrease in appetite. Most people, a decrease with body weight loss. Some small number, an increase. Difficulty concentrating, thinking, making decisions.

Obviously, the symptom we worry about the most . . . is suicide. Suicide is the 10th leading cause of death in the United States. It's the only one of the top 10 causes of death that are increasing in number. All the others, including stroke, cancer, heart disease, are decreasing in number. And we can talk about that, if you'd like.

But depression is this terrible syndrome. Its cornerstone is the inability to experience pleasure. If you think about the worst day of your life, loss of a loved one, lost your job, breakup of a relationship, think about feeling that way every day and not knowing why. There's a feeling of hopelessness and helplessness associated with depression that, of course, then leads to suicidal thinking.

David Carreon: It's a pretty devastating condition and something that both Jessi and I have seen plenty of patients with. I guess, from your perspective as somebody who's done a lot of research in biological psychiatry, what does depression look like in the brain, from your perspective?

Charles Nemeroff: Well, before I answer that, let me just interject a couple of other things about depression for the audience. First, one of the really important facts to know is that depression is a systemic illness. It affects the whole body. Part of having depression is being very vulnerable for other medical disorders, including diabetes, heart disease, certain forms of cancer, stroke. Depression is a killing disease. Not only does it kill you by suicide, it kills you because your life expectancy is shorter because of the biology of the illness. What I mean by that is the biology of depression is not just in the brain. It's in the whole body.

David Carreon: I think that's an important thing to emphasize. Certainly, on some popular levels, it's all in your head, just snap out of it. But you're saying that it's something much more than that. It's not even just in your brain. It's a widespread disorder across the body.

Charles Nemeroff: Well, first, even if it was just in your brain, you couldn't just snap out of it. We don't generally tell patients with epilepsy, "You know, you just ought to stop having seizures." Right?

Jessi Gold: Right.

Charles Nemeroff: So, this notion that you could snap out of it is just . . . One of the cardinal features of depression is incredible fatigue. I'm always wondering, when people say to severely depressed patients, "You need exercise." Well, yeah, it's hard enough to exercise when you're not depressed, right?

Jessi Gold: Yeah.

Charles Nemeroff: But if you're morbidly depressed, if you have a Hamilton score of 35, and you're not sleeping, and you can't concentrate, and nothing feels good, you think you're going to go out and run? No. Yes, you're absolutely right. The notion that you can just get over it, it just doesn't make any sense.

David Carreon: What are some of the key things? I think we don't talk as much about the increased risks of dying with depression. We talk a lot about suicide, at least in psychiatry. We don't talk a lot about some of these other things, things that primary care has to deal with. Do you think that that's been a perspective that's been . . . How do you think we got into that way of thinking?

Charles Nemeroff: For many years, I conducted research on trying to understand why depressed patients were at risk for heart disease, myocardial infarction, and stroke. It took almost 20 years of negotiating with the American Heart Association before they were willing to actually list depression as a risk factor for heart disease on their website.

Jessi Gold: Twenty years.

Charles Nemeroff: And the conversation, I wish I had recorded the conversations with leadership of American Cardiology because one of the issues that came up is we were almost there, like 15 years ago, and the then-president of the AHA, who will remain nameless, said to me, "Well, you know, actually, the reason we can't list it as a risk factor is because you have not demonstrated yet that, if you effectively treat depression, then you can actually obviate the risk." I said, "Wait a minute, you have genetic risk factors on your website. We haven't shown that you can modify genetic risk factors, and therefore change risk." And that was sort of the end of the conversation.

But, in the end, long after I was president of the American College of Psychiatrists, in the end, we managed to get this listed as a risk factor. But there is a general bias about the notion that psychiatric disorders are biological illnesses, and that they have alterations in the body, as well as in the brain.

Jessi Gold: Would you say that the risk factor is just physiologic? Like I have depression, I'm tired, I'm not exercising. Or is there actually something going on in the body and the brain because of depression that's leading to-

Charles Nemeroff: Oh, there's no question about it. Many years ago, when you were in elementary school, we published a report showing that drug-free depressed patients have a clotting diathesis.

They have a fundamental abnormality in the platelet clotting cascade, in several steps in the cascade, in the initial platelet activation phase, but also in the final clot formation stage, so that depressed patients simply have a diathesis for forming clots. They're much more likely to form a thrombus than non-depressed patients.

That's one abnormality. There are five or six others in terms of oxidative mechanisms. Then the big factor right now, which we and others have spent, now, several years focusing on, is the fact that a very sizable percent of depressed patients exhibit marked increases in markers of inflammation. And inflammation is involved in the pathophysiology of all of the diseases we talked about, right? Diabetes, stroke, heart attacks.

There have been many meta-analyses done that have looked at this already, but the fact of the matter is depressed patients have markedly abnormal inflammatory markers, C-reactive protein, Interleukin-6, tumor necrosis factor. Not all, but clearly a sizable percent.

Jessi Gold: And at a level that somebody who might not understand all those markers would understand what does inflammation ... How does inflammation work for depression?

Charles Nemeroff: Well, so the American Heart Association has a cut-off of three for C-reactive protein as a risk for myocardial infarction. A substantial percent of depressed patients have levels of three and above.

Jessi Gold: That makes sense.

Charles Nemeroff: Very clear.

Jessi Gold: Yeah.

David Carreon: I think there's a lot of popular conceptions and a lot of popular misconceptions about inflammation and anti-inflammatory foods or anti-inflammatory dietary supplements or things like that. What is inflammation at its core level? Why might the body be doing this in depression? What is its purpose or intended outcome?

Charles Nemeroff: We have to remember that inflammation is an evolutionarily important adaption. It's there because it fights bacterial and viral invaders. It's there, fighting against certain kinds of cancer. The immune system is an extraordinarily component evolutionarily, and it's probably partly responsible for the increased survival of our species.

We also know there are a number of inflammatory diseases. The classic ones are sarcoid, Sjogren's disease, rheumatoid arthritis, lupus, …. We know that these diseases are in fact diseases of inflammation. We also know that Alzheimer disease, stroke, heart disease, certain forms of cancer are unfortunately accompanied by increases in inflammation.

We were the first group to report in the '90s that depressed patients and depressed patients with cancer showed an increase in inflammatory markers. This has now been confirmed time and time and time again. Why this is the case is a great question. I wish I could answer that. But any more than I can answer why inflammation's involved in the pathophysiology of Alzheimer's Disease or epilepsy or stroke or diabetes. We really don't know why some patients and some diseases are affected with it or not.

What we do know is that patients with inflammatory diseases have high rates of depression, and people with depression have high rates of inflammation. If you give somebody a treatment to increase their inflammatory response, for example, treating someone with malignant melanoma with interferon in order to create an inflammatory response to fight the cancer, one of the major side effects is robust and severe depression in a sizable subset of patients. There is this link.

Jessi Gold: I bet originally when that was determined, people just said that was a drug side effect or something like that, instead of thinking more about the mechanism.

Charles Nemeroff: It was first noted . . . it was really interesting. David Rubinow, who's the Chair of Psychiatry at the University of North Carolina, was in charge of consult psychiatry at the National Cancer Institute. When they started using interferon for treating certain cancers, he started getting called to come to the clinical center to see these patients who suddenly became severely depressed and suicidal.

I was in a meeting in Luxembourg, of all places, or in Germany right proximal to Luxembourg. There were two suicides of patients given interferon for the treatment of cancer there on the same day. It made it to the front page of the paper.

David Carreon: Wow.

Charles Nemeroff: I looked at it, and I thought, "What is going on here?" That led to our New England Journal of Medicine article on characterizing depression associated with inflammation that was produced by interferon, and then learned that we could pre-treat patients with SSRIs, beginning two weeks before the interferon and ameliorate the depression.

David Carreon: Do SSRIs affect the inflammatory state of the body in non-interferon patients?

Charles Nemeroff: This is a great question, of which there's very little data. SSRIs have multiple effects, one of which is to inhibit platelet aggregation and coagulation. We've always wanted to do a study, giving incredibly doses of SSRIs, like maybe a milligram of escitalopram, to see it if would work better than aspirin at preventing myocardial infarction in the general population because it wouldn't have much of a side effect, sort of a Framingham-like study. We could never find anybody that was willing to fund such a study.

But it also begs the issue that you asked me that I sort of avoided earlier, which is what about many of the lay public, who believe in anti-inflammatory agents, natural foods, fish oil, etc. and are they effective? It begs the question of whether anti-inflammatories are effective antidepressants, right?

David Carreon: Yeah.

Charles Nemeroff: First, I'm completely agnostic, as far as treatments. I'm just insistent on science.

David Carreon: Mm-hmm.

Charles Nemeroff: I'm willing to test any hypothesis that sounds reasonable, whether it's an integrative medicine approach, a psychotherapy, pharmacotherapy, food, diet, exercise, as long as it's a well-powered study, and we can get the answer to the question. And remember that the plural of anecdote is not data. Just because you treated a patient with some regiment and they got better doesn't mean that this is a controlled study or even a case series, right?

David Carreon: Sure.

Charles Nemeroff: I'm open-minded about this. I'd love to see more studies in this area. We're embarking on a very novel approach in this area, and that has to do with the following. There have been a few studies of anti-inflammatory agents that were very targeted, in particular, tumor necrosis factor inhibitors. A reasonable hypothesis, because tumor necrosis factor is one of the inflammatory markers that has repeatedly been shown to be abnormal in depressed patients. There are a few tumor necrosis factor antagonists that are on the market approved for other indications-namely, rheumatoid arthritis, for example, and treatment-resistant psoriasis.

There was a study done by Ranga Krishnan at Duke many years ago. Etanercept is a drug that's used to treat psoriasis. It's a tumor necrosis factor monoclonal antibody. He infused it to patients with psoriasis and depression, who had failed antibiotic therapy. In a placebo-controlled study, he found that it had anti-depressant properties. It's pretty exciting.

There was a second study done by Andy Miller, Chuck Raison, and their colleagues at Emory, in which they looked at different TNF Alpha antagonist called infliximab. Interestingly, in the patients with elevated CRP levels, indicative of inflammation, the drug did have anti-depressant properties.

My approach has been that, because multiple inflammatory markers have been shown to be abnormal in depression, I was looking for a more pan-inhibition kind of strategy, one that would quiet inflammation down in a broader way because I was concerned, if you block TNF Alpha, what about aisle 6? What about CRP? What about the inflammatory markers?

As you probably know, there is a huge, burgeoning database on the use of stem cell therapy in regenerative medicine, that you can give intravenous infusions of mesenchymal stem cells derived from bone marrow. These cells travel to sites of inflammation, where they quite down inflammation locally. At Miami, our stem cell institute director, Josh Hare, has done this post-MI. He's done it in congestive heart failure. He's done it in frail elderly. He's done it in COPD. He's done it in arthritis. You infuse these cells, and they literally go to the hot spots, your knee, your chest.

We've done a study in frail elderly. In the study in frail elderly, we saw a six-month reduction in tumor necrosis factor levels after a single infusion of 200 mesenchymal stem cells. No side effects of the treatment at all. And an increase in a sort of crude measure of well-being. They weren't depressed. And an increase in their capacity in terms of frailty.

The Stanley Foundation has just agreed to fund a pilot study for us, looking at treatment-resistant depression, looking at these patients who are treatment-resistant to, say, SSRIs and have elevated inflammatory markers. We're going to do that, and I have an NIH application in to look at a very unique population of patients who ought to have robust inflammation, which are patients with comorbid alcohol abuse and depression because both alcohol abuse and depression are associated with robust increases in inflammation. I'm pretty excited about this.

David Carreon: That's a fascinating approach. Just to kind of think about this more concretely, where do you expect, hope, predict, imagine them to go? If I've got an aching knee, it's going to go to my knee. What is inflamed? Where?

Charles Nemeroff: First of all, we know that peripheral inflammation increases depressive symptoms, both from the interferon studies I've told you, but then from a variety of other studies that have been done by Janet Kiecolt-Glaser at Ohio State. She's shown that artificially increasing inflammation by giving, say, LPS, lipopolysaccharide to college students causes a robust inflammatory response, and their mood plummets.

Stress can do it, as well. I think, by blocking information peripherally, we should, in fact, see a bonafide improvement in depressive symptoms, particularly the cardinal vegetative symptoms. Think about what you feel like when you have the flu. You're at home, you feel terrible, but you're not working, but you can't concentrate. You can't read, you can't watch TV, you're lethargic, you're listless. That's sort of part of the depressive syndrome. There may be some cardinal symptoms of depression that respond to this kind of treatment. A big issue, which was cloaked in your question, is is there a direct effect on the brain?

David Carreon: Mm-hmm.

Charles Nemeroff: There's a huge amount of controversy about this. There's an investigator at the University of Virginia named Daniel Kipnis that, this year, for the first time, discovered a direct link between the periphery and the brain, as far as the immune system, which had hithertofore not been understood.

It looks like there is a tremendous amount of communication between the periphery and the brain and the immune system. Secondly, you'll remember from your basic neuroanatomy . . . that there are seven circumventricular organs in the brain that have leaky blood/brain barrier passages that do not have tight junctions separating the brain from the periphery. They are, just to remind you from the Latin, they are the median eminence, the subfornical organ, the area postrema, which controls vomiting, for example. That's why you vomit when something in the periphery is upsetting you. The organ laminosum, the lamina terminalis. I know you'd like that.

David Carreon: Thank you.

Charles Nemeroff: These areas allow immune cells to enter. Then, lastly, the brain has its own immune system, which is the equivalent of macrophages in the brain, or microglial cells. They also make inflammatory markers.

Jessi Gold: Do you envision that like, I'm working in a hospital, someone comes in with depression, I would be looking at their inflammatory markers to decide treatment in the future?

Charles Nemeroff: First, because a third of your patients don't have another doctor, you should be doing it anyway because our patients are at risk for heart disease and stroke. I get CRPs on all my patients, just to make sure. And you'd be stunned at how many of them are in the risk range and don't know it.

But yes, I think this will end up being sort of part of personalized medicine in psychiatry. I think, in psychiatry, we had this notion that monotherapy was good. Then, when the treatment studies like STAR*D came out, we discovered that only 28% of patients treated with citalopram actually got into remission. That's not a good number.

If you go to an oncology clinic, nobody's on monotherapy, right? Everybody's on triple-drug chemotherapy, radiotherapy, whatever. Why would the brain, as complicated an organ as it is, with a syndrome like depression that affects certainly different brain areas, circuits, neurotransmitter systems, why would we think that one antidepressant would bring people into remission?

I think we're going to see patients show up, you're going to evaluate them, you're going to end up getting inflammatory markers, maybe one of these anti-inflammatory treatments will be part of the depression regimen. We'll find out better whether psychotherapy affects inflammation. It's not out of the bound of reason that maybe effective CBT maybe helps patients reduce their inflammatory markers. These are all active and important avenues of investigation.

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