Beyond Neurotransmitters: Unraveling the Brain Circuitry of Mental Health

In his recent NEI Congress session, Vladimir Maletic, MD, MS, University of South Carolina, Greenville, explores the complexities of brain circuitry and the neurobiological basis of major psychiatric conditions. Through genome-wide association studies, it has become evident that numerous genes contribute in small ways to the risk of developing conditions like major depressive disorder (MDD). In this video, Dr Maletic discusses the overlap of risk genes between depression, schizophrenia, and ADHD affects symptom presentation and treatment response. Integrated treatment approaches can help to restore harmonious interactions between brain networks and balance neurotransmitter systems.

Watch the video or read the transcript to level up your clinical practice.

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Read the transcript:

Dr Vladimir Maletic: Hello, I'm Vlad Maletic. I'm a clinical professor of psychiatry in behavioral sciences at the University of South Carolina School of Medicine in Greenville, South Carolina.

Meagan Thistle, Managing Editor, Psychiatry & Behavioral Health Learning Network: What are the key takeaways from your NEI session, ‘Brain Network Circuits and Neurotransmitters: A Roadmap to Better Outcomes?’

Dr Maletic: This particular session, focusing on brain circuitry, but also the neurobiologic underpinning of major psychiatric conditions, at NEI has great complexity in multiple layers.

I would start at the foundation: What is new in our understanding of psychiatric conditions?

Well, something that may at the same time provide some relief from frustration in that we are not more efficient in helping our patients, but also open up paths for new thinking about psychiatric conditions. So, what am I exactly talking about? It's not going to be news to any of you that psychiatric conditions are in terms of their genetic mosaics. We do have a new genetic technology available to us, and therefore we're able to conduct huge genome-wide association studies that include thousands of patients in each cohort. What is it that we are finding out? Well, what we're finding out, number one, is that we can quantify genetic risk for psychiatric conditions.

The current understanding is there are about 100 to 120 genes that all provide small contribution toward the risk of acquiring major depressive disorder. If we count up those genes, it'll be translated into something that is called polygenic risk score.

Why would that be relevant to a clinician? Well, our patients, although we may not be aware of it, but those who have higher polygenic risk scores for major depressive disorder are the ones who will have an earlier onset of this condition. They will have more severe symptoms. Unfortunately, they will be less likely to respond to treatment and are more likely to have recurrent form of this disease; there are clear clinical implications. We can retrospectively speculate and say that 'maybe our patient has that pattern,' which means that they have a robust neurobiological underpinning. Therefore, we need to think about different approaches to treating their depression.

But the other thing that we're beginning to understand is that the individuals who have risk genes for major depressive disorder may also have risk dreams for schizophrenia, in which case they're more likely to have psychotic symptoms in conjunction with their other manifestations of MDD. They may have ADHD symptomatology, which will likely make them a little bit more treatment-resistant. If they have bipolar illness, we're now understanding that individuals who have bipolar I actually have a significant ad mix of schizophrenia genes, and individuals who have bipolar type II actually have more contribution of MDD-related genes.

If they're bipolar and have ADHD risk genes, they're more likely to be rapid cyclers. If they're bipolar I and they have a lot of schizophrenia risk genes, they're less likely to respond to mood stabilizing agents such as lithium. We do not have a way of directly translating into our practice, but at least at the level of understanding we have a better sense of why is it that we don't have one best treatment for depression, one best treatment for schizophrenia or bipolar disorder, and were ultimately the best solution will probably be some form of integrated treatment.

The other thing that we have understood through understanding better circuitry and neurobiology is that we really have little chance of translating one neurotransmitter disturbance into symptoms of any psychiatric condition or, for that matter, translating a single receptor action into a certain kind of clinical domain. What we're understanding better it is dysfunctional relationship between major brain networks that leads to symptomatic expression of these psychiatric conditions and that our goal will actually be to balance neurotransmitter systems that provide input into these major brain networks and therefore have more harmonious interactions between these major brain networks.

When I'm speaking about brain networks, I'm talking about the salience network, which provides emotional echo to the sensory experience in our internal and external environment. So, these are interrelated brain areas that generate our emotions. The central executive network, a network that is involved with problem-solving, organizing our adaptive responses includes parts of parietal cortex and dorsolateral prefrontal cortex, default mode network, which has to do with our ability to self reflex, contemplate, reminisce, process social information, and finally sensorimotor network which regulates our sensory experience as the name would suggest, but also our motor activity. Again, it is a disturbance in connectivity between these brain networks that ultimately generates some of the manifestations of major psychiatric disorders.

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 served as a program chair for the US Psychiatric and Mental Health Congress. His special areas of interest include the neurobiology of mood disorders, schizophrenia, pain, and the regulation of sleep and wakefulness. Dr Maletic is board-certified in psychiatry and neurology.