How your metabolism could alter your mental health

In 2009, medical student Shebani Sethi https://med.stanford.edu/profiles/shebani-sethi watched a patient in a weight loss program make a remarkable recovery. The dietary intervention she underwent alleviated her schizophrenia symptoms, something the woman had tried – and failed – to treat with medication for years. That experience sent Shebani down a medical path that would lead her to treating mental health in a radically different way. Today host Emily Kwong https://www.npr.org/people/767284140/emily-kwong talks to Shebani about the emerging field of metabolic psychiatry and how ketogenic metabolic therapy may treat schizophrenia, bipolar disorder and depression. Read Shebani’s article on metabolic psychiatry here https://www.nature.com/articles/s44220-026-00609-5. Interested in more lifestyle science? Email us your question at [email protected] mailto:[email protected]. Listen to every episode of Short Wave sponsor-free and support our work at NPR by signing up for Short Wave+ at plus.npr.org http://plus.npr.org/ See pcm.adswizz.com https://pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences. NPR Privacy Policy https://www.npr.org/about-npr/179878450/privacy-policy

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  In 2009, when Shabani Sethi was in medical school, she met a patient who changed the rest of her career. At the time, Shabani was working at an obesity clinic in North Carolina, and this patient, who wanted to lose weight, was also taking medication for schizophrenia.

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  It's something that she had struggled with for over 20 years, and she had tried every single psychiatric medication that was available. And ultimately, when she underwent a dietary intervention, she lost weight and her symptoms of schizophrenia improved.

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  Shabani was curious. She looked into the patient's charts, previous medications, and whether there were any recent changes that could explain the patient's schizophrenia symptoms improving.

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  Because I didn't quite believe that a dietary intervention was the reason that this change was occurring for her.

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  But as Shabani kept digging through historical medical records, she found hints of this basic idea. A century ago, people understood there was a connection between metabolism, which is how the body turns food into energy, and brain health, two specialties that modern medicine largely keeps apart.

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  For decades, we've treated psychiatric conditions and physical conditions separately, like diabetes or obesity as separate problems, that happened to occur in the same patient.

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  So today, Shabani is deepening that understanding by formally combining them into a discipline that she calls metabolic psychiatry.

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  I saw this overlap with patients that had diabetes or insulin resistance or obesity, with food addiction, schizophrenia, bipolar illness, eating disorders. There's a lot to do in this intersection, and there are a lot of patients that can benefit from having treatment that addresses both.

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  Today on the show, what might metabolism have to do with mental health? We talk about three conditions that may have metabolic connections and uncover what scientists are doing to tease apart the details. I'm Emily Kwong, and you're listening to Short Wave, the science podcast from NPR.

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  Okay, Shabani, so I want to start with research. Studies have started to link an out-of-balance metabolism to a few different mental health conditions, specifically schizophrenia, depression, and bipolar disorder. And I want to go through each of them, starting with schizophrenia. Since meeting that patient over 15 years ago, what have you learned?

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  So before a diagnosis is made of schizophrenia, or even before the first episode of psychosis, there is both glucose and insulin signaling issues, which basically means that you have cells in the brain that do not get glucose. There is glucose basically surrounding the cell. It just cannot get into the cell. And so they're bathing in it. They're bathed, the cells, these neurons are bathing in the glucose and insulin, but cannot use it. And so they're essentially starving, and they can't create the energy. And this becomes far before medication is even prescribed. So it's not like just a metabolic side effect

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  of a medication. It's inherent in the illness itself. And this is called cerebral glucose hypometabolism.

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  Okay.

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  Fancy word for basically you cannot use the glucose around you. And this is something that we see in Alzheimer's disease, we see in other neurodegenerative conditions, and we see it in mental health conditions.

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  What about depression and bipolar disorder?

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  It's actually quite similar in the sense that, so with bipolar illness, there's also altered glucose utilization and insulin signaling issues, just like in schizophrenia. There's a GABA and glutamate imbalance.

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  Ah, yes.

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  You can kind of think of that as like the gas versus the brake.

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  Yep.

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  For our system. And with bipolar illness specifically, we use medications that are pretty commonly used in the treatment of seizures and epilepsy. And these medications work in part by rebalancing that GABA and glutamate. It increases GABA, so you have more of the brakes, to help with mania, for example, so mood stabilization. But with depression, there's a connection between insulin resistance and just developing depression.

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  One in three people have insulin resistance in our country. And if you have insulin resistance, you are double the likelihood of developing major depression.

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  And insulin resistance, of course, that's the condition where the cells fail to respond effectively to insulin.

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  Yeah.

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  So are you saying that insulin resistance and depression are connected because the cells in the brain have insulin resistance?

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  Well, we think so. But there's a lot of markers and pathways that are involved in these conditions, whether it's depression, or bipolar, or schizophrenia. And that's really where the field is moving. It's moving beyond, you know, depression is not just a brain chemistry issue, but also through the lens of whole-body energy metabolism, really, we're looking at how it's connected and how the body is producing and using energy because it's an extremely important concept.

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  Now, one of the big interventions you prescribe for these disorders is ketogenic metabolic therapy, KMT. In pop culture, it's known as the keto diet, and it is a high-fat, low- or no-carb, moderate-protein diet. But actual ketogenic metabolic therapy, that is a strictly monitored medical intervention, which causes your body to go into ketosis. What is that?

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  So instead of your body primarily breaking down carbohydrates into glucose, you are breaking down fat into ketone bodies. And those ketone bodies are small molecules that then cross the blood-brain barrier, and your brain uses that as fuel. So it's kind of like unlocking, you know, the key to breaking down the fat, which has shown benefits in, you know, certain conditions. It's improved with blood glucose, it's an anti-inflammatory diet. And I wouldn't want patients to do this on their own. It's not safe to do like a ketogenic metabolic therapy on your own. It's not a fad diet. It's a

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  dietary pattern that has been around for over 100 years. So the point is that people should not get off their medications and just do a metabolic treatment without monitoring, one. And two, it should be something that is done in conjunction to prevent any, you know, to prevent any harm. Because at the end of the day, every medication is really a risk-benefit equation. But we should also be thinking about lifestyle interventions that can also help with side effects, or even treat the illness itself, or help treat

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  the illness itself, even if it's adjunctive. So I'm optimistic and hopeful that things will move in a positive direction.

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  And in that state of ketogenesis, what do we know about what happens to the brain?

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  So there are lots of things that we think are happening in the brain. We know it's anti-inflammatory. We look at epigenetics and the changes there. We want to know who's responding and who's not responding, and why, and what levels make sense for, you know, these outcomes and improvement. We have trials that have shown improvements in both metabolic markers with this intervention and also psychiatric markers. So whether it's mood, whether it's energy, and whether it's cognition, in these conditions, there are improvements. And the more data that we gather, the more things we can measure.

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  And that's what's exciting, to be able to see in real time what's happening in this intervention just from food.

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  Yeah. I'm hearing you, and you're saying every person's body is so different, and so every person's body is going to respond differently to something like ketogenic metabolic therapy? There was a recent study done in mice out of the University of Utah, which found that a very high-fat, low-carb ketogenic diet, long-term, was associated with fatty liver disease and harmed blood sugar regulation, with some changes happening within a few days. Is there data on the long-term impacts of a ketogenic diet?

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  Yeah. So what I would say to that, you know, I can't comment on details of that study, but what is our long-term data for our current standard diet? We don't have really good outcomes. We have high elevated rates of obesity, metabolic syndrome, insulin resistance. It's really an epidemic now in this country. We have very poor metabolic health. As far as the study, one, it's in mice, right? And two,

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  The ketogenic diet that was fed to them wasn't a true ketogenic diet, from what I remember. And I think that's also part of the problem, is that things get misnamed. And then they get associated with it in a way that may not be completely accurate. It's not the whole picture. And I think we have to take a step back and really look and analyze at the real data. And when we're treating patients, that's real data to me. In this pilot study that we published, everyone that met criteria for metabolic syndrome

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  at the start of the study, to the end of the study, four months later, they no longer had metabolic syndrome.

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  Metabolic syndrome, that is a group of conditions, including high blood pressure, high cholesterol, that increase your risk for heart disease, stroke, and type 2 diabetes. So you're saying just in four months, folks no longer had metabolic syndrome?

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  Just in four months. The science is real and exciting. Overstating it does a disservice to patients and families who deserve an honest assessment of what we know and what we're still learning. And that's why I wrote the paper that was in Nature Mental Health, to really distill what we know, what we don't know, and what we are focusing on as a field moving forward. And there's something real, evidence-based, and increasingly accessible to consider.

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  What is your number one piece of advice for people who, listening to this, who want to better support their mental health?

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  I would say that metabolism is one of the biggest levers that we can use in improving our mental health. It is something that we can do something about, which is good news. And so I just want to instill some hope for people that this is something that can be used for improving our health.

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  Well, thank you for sharing what's on the horizon for metabolic psychiatry and for your work. Thanks so much for coming on Short Wave.

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  Thank you. Thank you for having me.

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  If you want to learn more about metabolic psychiatry, Shabani wrote an article for Nature Mental Health. We have linked it in our show notes. This episode was produced by Burleigh McCoy and was edited by Rebecca Ramirez. Tyler Jones checked the facts. The audio engineer was Jimmy Keely. I'm Emily Kwong. Thanks for listening to Short Wave from NPR.

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