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Dr Maletic on Utilizing Neurobiology in Major Depressive Disorder Treatment

Dr Maletic on Utilizing Neurobiology in Major Depressive Disorder Treatment

July 21, 2022

Vladimir Maletic, MD, MS, clinical professor of neuropsychiatry and behavioral science, University of South Carolina School of Medicine, Greenville, discusses the role of understanding the neurobiology of major depressive disorder (MDD) in guiding treatment. Additionally, Dr Maletic who is also the ADHD section editor of Psych Congress Network, explores the patient experience with treatment failures and how neurobiology can calibrate treatment goals.

Dr. Maletic
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Hello. My name is Vladimir Maletic. I'm clinical professor of psychiatry and behavioral sciences at the University of South Carolina in Greenville, South Carolina. Let's talk a little about what kind of role understanding the neurobiology of major depressive disorder (MDD) has in guiding our treatment. 

I happen to believe that it is quite important; here's why.

When it comes to the diagnosis of major depressive disorder, it is purely descriptive if we follow DSM-5 nomenclature. Therefore, there are various symptoms and manifestations of major depressive disorder, which, together with functional impairment and duration criterion and rolling out bipolar disorder, help us define our patient’s mood disorders, major depressive disorder.

However, it neglects one cardinal factor. That factor is: major depressive disorder is not a single entity. It is not a single entity in terms of its clinical presentation, in a sense that there can be over a thousand different variations of symptom composition that can all lead us to MDD diagnosis.

Also, as we learn more about neurobiology of major depressive disorder, we quickly realized that from the level of genetics to changes in functional circuitry, to structural changes in the brain, all the way to changes in economic function, endocrine function, inflammatory signal, intracellular signaling cascades, neuroplasticity, there are multiple, multiple different biotypes associated with major depressive disorder.

Why is this problematic? For a very simple reason, key role of any diagnostic system is to guide our treatment. Once we establish that our patient is suffering from major depressive disorder, that is not the end of the road, it's not very clear what to do, it's just the beginning of our challenge.

Unfortunately, making a diagnosis gives us no idea whether we should start with let's say, exercise, prescribing socialization, dietary changes, psychotherapy, mindfulness meditation, an SSRI or SNRI, or any other pharmacologic treatment, for that matter. We don't know where to go. Therefore, treatment is trial and error, trial and error. It is a very expensive process when it comes to our patient's experience, because the more treatment failures they have, the less and less odds of them improving. 
More recent research has focused on attempting to make a connection between a relatively simple phenotype and biotype that would give us some kind of a treatment perspective. Let us cover 2 possible instances.

One is a feature commonly associated with something we used to call atypical depression. It was called atypical depression, because if we assume that depressed patients should have disturbance in their sleep pattern and loss of appetite, these are individuals who actually have increased appetite or at least increased food consumption and hypersomnolence.

They also have fatigue and increased emotional reactivity. They feel a little bit better in the morning but as the day goes on, they feel more and more depressed. Unfortunately, they tend not to respond well to antidepressants and have recurrent episodes. So, trying to have it phenotype to biotype, we have not succeeded very well because it still does not give us better odds of finding the right treatment.

More recently we have isolated one feature of atypical depression, which is the most common presentation of depression in women. And that is an increase in appetite and BMI. If we see the presence of this symptom, can that in any way help us understand the biotype, and will that biotype then guide our treatment?

There are a few things that we have learned. Patients who have major depressive disorder plus an increase in appetite and BMI have shared genes between MDD and genes that propagate the risk for high BMI or obesity.

They have 2 populations of a gene, so to say, that overlap with each other. The second part is these individuals have imaging characteristics and neuroendocrine characteristics. When it comes to reward circuitry, particularly insula, what we're finding out is that when viewing pictures of appetizing foods, they have very intense activity in these reward areas in the brain.

To make it an interesting peril, it is very similar to what one experiences when falling in love and looking at the photo of their loved one. I don't want to take it too far, I don't want to say they're falling in love with their food, but they definitely have very warm and positive emotional experience when viewing food. 

Well, food does bring them pleasure, but along with that, we're finding something else that is interesting, is these individuals will have increased inflammatory signaling. These individuals will have increased so-called adiponectins. Adiponectin is one of the adiponectins and it's an important one because it is not only involved in regulation of appetite, but adiponectin at some level acts as a neurotrophic factor, adiponectin has to do with the regulation of inflammatory signaling has to do with regulation of insulin receptor activity and therefore risk for diabetes. It also mitigates the risk for cardiovascular disease. 
Leptin is another one that is supposed to be a chemical message sent from adipose tissue that we have abundant stored calories, and then we can afford to eat less. Unfortunately, the message does not get delivered. These individuals have disrupted signaling between the periphery of their body adipose issue and the brain. They therefore continue to have an increase in appetite despite the signals that are supposed to help blunt the appetite. 
Now that we understand some of these things, we can understand the relationship with some of the other symptoms. 
Stay tuned for Part 2 to find out what Dr Maletic has found that literature has to say about these symptom relationships. 

Vladimir Maletic, MD, MS, is a clinical professor of psychiatry and behavioral science at the University of South Carolina School of Medicine in Greenville, and a consulting associate in the Division of Child and Adolescent Psychiatry, Department of Psychiatry, at Duke University in Durham, North Carolina. Dr Maletic is a member of several professional organizations, including the Southern Psychiatric Association and The American College of Psychiatrists. In 2013-2014 he has served as a program chair for the US Psychiatric and Mental Health Congress. In addition, he has published 3 books, including The New Mind-Body Science of Depression, numerous articles, and several book chapters. Dr Maletic is board certified in psychiatry and neurology.