Robert Naviaux, MD, PhD, on Metabolites May Predict Risk of Recurring Depression

In this video, Dr. Robert Naviaux, MD, PhD, discusses his research, in collaboration with Dutch scientists, that found the risk of future depression was determined in large part by a mitochondrial nexus in metabolism, which could be a new diagnostic tool. He also describes the study’s other major findings and how this research applies to clinicians treating patients with recurring major depression.

Reference

Mocking, RJT, Naviaux, JC, Li, Kefeng et al. Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence. Translational Psychiatry. 2021;11(37).

Dr. Naviaux is Professor of Genetics in the departments of Medicine, Pediatrics and Pathology at UCSD where he directs a core laboratory for metabolomics and exposomics. He is the co-founder and a former President of the Mitochondrial Medicine Society (MMS), and a founding associate editor of the journal Mitochondrion. Dr. Naviaux is the discoverer of POLG1 mutations as the cause of Alpers syndrome—the oldest Mendelian form of mitochondrial disease—and the developer of the first DNA test to diagnose it. He directed the first FDA-approved clinical trial to study the safety and efficacy of the antipurinergic drug suramin as a new treatment for the core symptoms of autism spectrum disorder (ASD). His lab has also developed new methods in metabolomics, exposomics, and environmental toxicology that have shown that many complex chronic disorders like primary mitochondrial disorders, ASD, chronic fatigue syndrome (ME/CFS), neuropsychiatric and neurodegenerative disorders have a metabolic signature that can be used in diagnosis and prognosis and guide new approaches to treatment. Information about Naviaux Lab research can be found on his website.

TRANSCRIPT:

I'm Dr. Robert Naviaux. I'm a professor of genetics in the Departments of Medicine, Pediatrics, and Pathology at the University of California San Diego. I'm delighted to talk to you about our recent paper published in Translational Psychiatry on the metabolomic evaluation of patients with recurrent major depressive disorder.

Q: What lead you and your colleagues to look into metabolites and their role in depression? (00:31)

A: All of our research is actually connected by mitochondria. Mitochondrial functions in health and illness, development, and aging have been an organizing theme for our research over the past 25 years.

We know that many adults with primary genetic forms of mitochondrial disease that are called MELAS or MERRF and others suffer with mental health disorders ranging from depression to schizophrenia.

In addition, one of the oldest findings from blood testing in patients with major depressive disorder is an increase in blood lactic acid, lactate. We know from all our mitochondrial work that that increase in lactate only happens when mitochondria in the body can't meet demands of normal metabolism, so we were very confident that we would be able to find a mitochondrial connection in depression.

Q: Please briefly describe the study method and your most significant findings. (1:30)

A: First and foremost, it's important to note that our study was an international collaboration that was led by Dr. Johanna Assies, MD, an internist and endocrinologist at the University of Amsterdam with a life-long interest in mental health disorders and metabolism, and a team of talented physician-scientists at both the University of Amsterdam and Radboud University in Nijmegen.

All of the patients and about half of the controls were enrolled in Amsterdam for the study. We enrolled the other half of controls at UC San Diego. Altogether, we had 127 participants.

My lab has developed new precision medicine methods that use mass spectrometry to study metabolomics. We measure over 400 natural chemicals from over 60 biochemical pathways from the equivalent of a drop of blood.

The way that we did the study is we collected a blood sample from all the participants and the patients, who had a past history of major depressive disorder but were at that time in remission. They didn't have any depressive symptoms at the time. Then, we followed them into the future for 2 and a half years.

We looked at the utility of metabolomics both as a diagnostic test and as a prognostic tool. The top 5 findings were one, interestingly, the chemistry of depression is different in males and females.

Two, depression is a whole‑body disease. It's not all in your head. The biomarkers in metabolism that were most useful for diagnosis were actually different than the biomarkers that predicted the future risk of recurrence of depression.

Number four, the mitochondrial dysfunction that we saw was found at the center of the web of lipid protein and purine metabolites that was associated with a risk of resilience and the risk of recurrence of depression. This has been called the mitochondrial nexus or this convergence of pathways controlled by mitochondria.

Then, five is by addressing the whole‑body nature of depression, these new clinical tools can lead to the design of new trials of specific foods, supplements, activity regimens, and new medicines that can be designed to target the systems identified by metabolomics that may prove to be even safer and more effective than current brain‑focused medications.

Q: Were there any outcomes that were different than you expected? (4:23)

A: Yes. We were surprised by how accurate the predictive power of metabolomics was for identifying the patients at greatest risk of future recurrence of depression even years into the future. We were also surprised by how different the chemistry of depression was in males and females.

Q: Are there any practical applications of your findings for clinicians treating depression? (4:45)

A: Right now, what we can say is metabolomics is not yet available for routine clinical use. Like many other ‘omics’ methods and precision medicine, metabolomics is still a research test that is expensive and time‑consuming to perform.

We believe that some of the biological insights from metabolomics can be put into practice immediately in the form of new clinical trials of completely new approaches to treatment of major depressive disorder.

One example that is gaining momentum from many other studies is the utility of certain antipurinergic drugs to help reset and reboot metabolism and rebalance inflammation that can block and slow healing and recovery.

Q: Can you elaborate on why you feel the initial findings require validation in a larger study? (5:31)

A: Yes. This question comes down to statistics. The statistical power of any study is proportional to the number of participants in that study. Small studies are weak. Large studies are strong.

We've learned, through experience with human metabolomic studies where we measure over 400 different chemicals, that we need a minimum of about 30 cases and 30 controls, for a total of 60 patients, from each sex, or about 120 participants total in a study of both males and females, to achieve the level of confidence we need for a discovery‑phase study.

This is what we call a pilot experiment. The goal is to discover the top biomarkers that make up a signature of health and disease. Then, to build confidence in the new biomarkers and the new biology found in the discovery‑phase study, larger independent studies are needed.

We calculated that validation studies in females with remitted recurrent major depressive disorder would require 100 patients and 100 controls, for a total of 200. Adding males would add another 200 participants. For both males and females, a validation study would be about 400 subjects.

Q: Are you conducting more research in this area, and are there any related studies you feel are needed? (6:58)

A: We are conducting new studies in this area. We have just completed a metabolomic study in an independent cohort of 203 patients with major depressive disorder and suicidal ideation and controls.

This new study has helped us validate the basic biological findings of our first study and is allowing us to apply metabolomics to better understand how we might be able to help patients with the severest forms of depression that can lead to thoughts of suicide.

As you know, it is a major healthcare problem in the United States, and it's around the world. It's something we're really dedicated to trying to help with.

Q: Any final notes or key takeaways? (7:49)

A: I'd say metabolomics is a new and emerging tool for precision medicine and that it's leading to insights that show us that depression is a whole‑body disease, and that in order to best treat it, we need to focus on the mind‑body/brain‑body system.


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