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Shebani Sethi

Stanford University

Shebani Sethi is a psychiatrist and researcher affiliated with Stanford University. Her work focuses on metabolic psychiatry, specifically the relationship between metabolic health and psychiatric conditions. Her published research examines the use of ketogenic and low-carbohydrate dietary interventions to treat serious mental illnesses, including schizophrenia, bipolar disorder, psychosis, obsessive-compulsive disorder, and binge eating disorders.

24 claims checked on air: 1 context 1 contradicted 1 overstated 18 supported 3 unverified

What they said on air

0:00:00supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

One in three people in the United States have insulin resistance.

"One in three people have insulin resistance in the United States" (said at 0:00:00)

Nationally representative surveillance data from the National Health and Nutrition Examination Survey (NHANES) support the claim that approximately one in three people in the United States have insulin resistance. Among non-diabetic US adults, the age-standardized prevalence of insulin resistance (measured by HOMA-IR) was estimated to rise from 24.8% in 1999–2000 to 38.4% in 2017–2018, averaging around one in three adults (~33%) across recent survey cycles.

0:00:04unverifiedvery lowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Insulin resistance doubles the risk of developing depression, even in individuals with no psychiatric history.

"and that doubles your risk of developing depression even if you have had no psychiatric history." (said at 0:00:04)

No published record matching the claim that insulin resistance doubles the risk of developing depression in individuals with no psychiatric history was located; this does not prove the claim false.

0:03:24supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Levels of lactate were observed to be elevated in serious mental illness.

"100 years ago in psychiatry we had seen that there were levels of lactate that were elevated in serious mental illness" (said at 0:03:24)

Elevated lactate levels (particularly in the brain and cerebrospinal fluid) have been consistently documented in serious mental illnesses such as bipolar disorder and schizophrenia, reflecting abnormalities in mitochondrial function and brain energy metabolism. Systematic reviews of magnetic resonance spectroscopy (MRS) and CSF studies show increased cerebral lactate concentrations in bipolar disorder across multiple cohorts, with preliminary MRS evidence indicating similar elevations in schizophrenia.

0:03:42supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Glutathione levels are low in serious mental illness.

"and that there were levels of glutathione which were low—they were low and it is an antioxidant." (said at 0:03:42)

Glutathione is a primary cellular antioxidant, and meta-analyses confirm that peripheral and brain glutathione levels are reduced in patients with schizophrenia, a major serious mental illness. A 2019 systematic review and meta-analysis found lower peripheral glutathione and total glutathione levels in patients with schizophrenia compared to healthy controls. Magnetic resonance spectroscopy (MRS) studies also demonstrate small but statistically significant reductions in anterior cingulate cortex and brain glutathione in patients with established schizophrenia. However, findings can vary by specific diagnosis and region; for instance, anterior cingulate cortex glutathione levels have been reported as elevated in bipolar disorder.

0:13:41supportedhighHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Approximately 37% to 40% of people with bipolar illness have metabolic syndrome.

"So in bipolar illness about 37, almost 40% have metabolic syndrome." (said at 0:13:41)

The speaker's estimate is directly supported by published meta-analyses of individuals with bipolar disorder. A landmark 2013 meta-analysis published in The American Journal of Psychiatry evaluated 37 publications (N = 6,983) and found an overall metabolic syndrome prevalence of 37.3% (95% CI: 36.1%–39.0%) across standardized criteria. Subsequent meta-analyses have similarly reported pooled global prevalence rates in the range of ~33% to 37%, depending on geographic region, treatment status, and diagnostic criteria used.

0:15:18overstatedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Cerebral glucose hypometabolism is a central characteristic of neurodegenerative conditions and is present in schizophrenia and bipolar disorder before the diagnosis of psychosis or administration of medications.

"So cerebral glucose hypometabolism in the brain globally is a central pathological characteristic of neurodegenerative conditions and also present in schizophrenia and bipolar in particular. And that's really when certain areas of the brain cannot use glucose for energy. Even though glucose is present, it can't process the glucose well, and you develop insulin resistance as well. And when you have insulin resistance centrally, there's a problem with insulin signaling and glucose signaling in the brain, and we see this even before the diagnosis of psychosis, before medications are given and before the diagnosis it's present." (said at 0:15:18)

While cerebral glucose hypometabolism is a well-established feature of neurodegenerative diseases such as Alzheimer's disease, and peripheral insulin resistance is frequently observed in drug-naïve psychiatric patients, the claim that global brain glucose hypometabolism is present in schizophrenia prior to medication or diagnosis overstates the evidence. A systematic review and meta-analysis of 36 FDG-PET imaging studies (PMID 35730361) found that glucose hypometabolism in schizophrenia is regional (confined primarily to the frontal cortex, termed hypofrontality) rather than global. Critically, absolute frontal metabolism was significantly reduced in chronic and medicated patients, whereas drug-free and first-episode psychosis patients did not differ significantly from healthy controls.

0:17:02supportedvery lowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Lithium improves insulin signaling in the brain.

"And I'll give you an example is lithium. It also improves insulin signaling in the brain." (said at 0:17:02)

Preclinical and mechanistic literature supports the claim that lithium acts on and enhances downstream insulin signaling pathways in the brain. Lithium inhibits glycogen synthase kinase-3beta (GSK-3β)—a major downstream node in the canonical PI3K/Akt insulin signaling cascade—and has been shown in rodent models to restore central insulin-related kinase activation (including Akt, mTOR, and phospho-GSK3β). However, evidence is currently limited to preclinical animal models, in vitro experiments, and mechanistic reviews, with direct clinical trial evidence in human brains remaining preliminary.

0:17:25supportedlowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Peripheral insulin resistance leads to degeneration and atrophy of hippocampal neurons.

"When you have insulin resistance peripherally—so outside the brain—it leads to degeneration and atrophy of some of the hippocampal neurons as well." (said at 0:17:25)

Preclinical and clinical neuroimaging studies support the link between insulin resistance and hippocampal neurodegeneration. In human observational studies, measures of peripheral insulin resistance (such as HOMA-IR) are inversely correlated with total and regional hippocampal volume and grey matter integrity on MRI. In animal models, experimental insulin resistance directly induces dendritic atrophy and structural deficits in hippocampal CA3 pyramidal and dentate gyrus neurons. Because human evidence relies primarily on observational MRI proxies and causal cellular mechanisms are established mainly in animal models, the certainty is graded as low.

0:23:16contradictedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Metformin crosses the blood-brain barrier, supports the TCA cycle in mitochondria, and reduces inflammatory cytokines such as TNF-alpha and interleukin-6 in studies.

"For example, you could take metformin. A lot of us know metformin improves glucose, it improves insulin sensitivity, but it also crosses the blood-brain barrier and it has a neuroprotective effect. It helps in the TCA cycle. Within the mitochondria we have machinery to produce energy, to produce ATP, and there are deficits in that energy pathway, whether they're enzymes or co-factors they're not present. Metformin helps support that to some degree and it also does decrease inflammation. So in some studies it's been shown to reduce TNF-alpha, reduce interleukin-6, reduce other cytokines." (said at 0:23:16)

The claim bundles accurate and inaccurate assertions. Published evidence supports that metformin crosses the blood-brain barrier and exerts neuroprotective and anti-inflammatory effects, including suppressing microglial activation and reducing pro-inflammatory cytokines. However, the assertion that metformin supports the TCA cycle to produce ATP when mitochondrial machinery is deficient misstates its mitochondrial mechanism: metformin acts primarily as a mild inhibitor of mitochondrial complex I (NADH:ubiquinone oxidoreductase). This inhibition reduces ATP generation and alters the cellular AMP/ATP ratio to activate AMP-activated protein kinase (AMPK), rather than enhancing the TCA cycle or replacing missing enzymes to boost ATP production.

0:24:38supportedhighHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Pro-inflammatory cytokines affect tryptophan metabolism and serotonin synthesis.

"And we know cytokines also are pro-inflammatory, right? And they end up also affecting serotonin synthesis. It affects tryptophan metabolism." (said at 0:24:38)

Pro-inflammatory cytokines (such as interferons, TNF-α, and interleukins) induce the enzyme indoleamine 2,3-dioxygenase (IDO). IDO catabolizes tryptophan along the kynurenine pathway, reducing the availability of tryptophan for the synthesis of serotonin (5-HT).

0:24:41supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

A study showed that metformin adjunctively improved outcomes in patients with treatment-resistant bipolar depression.

"And so there was a study a colleague of mine did looking at metformin and treatment-resistant bipolar depression and that showed an improvement in those who were treated with metformin and also had psychiatric medication on board." (said at 0:24:41)

In a randomized, quadruple-masked, placebo-controlled clinical trial by Calkin et al. (the TRIO-BD study, n=45), adjunctive metformin was evaluated in patients with treatment-resistant bipolar depression and comorbid insulin resistance. The trial found that patients who reversed their insulin resistance on metformin (10 of 20 on metformin vs 1 of 25 on placebo) experienced statistically significant and sustained improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores, functioning (GAF), anxiety (HAM-A), and global clinical impressions (CGI-BP) compared to non-converters.

0:26:32supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Exercise has been shown to increase BDNF (brain-derived neurotrophic factor) levels and improve cognition.

"And, you know, increasing BDNF, which you and I talked about last time, I think on your show like now five years ago, the time has flown. But you described it as Miracle-Gro. And I really love the way you described it because it's exactly what it is. That was one with exercise that is shown to improve those levels and improve cognition and so forth." (said at 0:26:32)

A substantial body of randomized controlled trials and meta-analyses demonstrates that structured physical exercise (including aerobic, resistance, and combined training) significantly increases circulating brain-derived neurotrophic factor (BDNF) levels and improves various domains of cognitive performance across healthy individuals, older adults, and clinical populations.

0:27:44supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Supplementation with at least 1 gram of omega-3 containing EPA per day for 8 to 12 weeks showed modest benefit for early-phase psychosis and schizophrenia, but did not have the same effect for chronic schizophrenia.

"Give an example of research that's been done in our field by colleagues who looked at omega-3 supplementation, at least one gram including EPA per day, for I think it was a total of 8 to 12 weeks period, which significantly had a good—it was modest evidence that showed benefit for psychosis, early-phase schizophrenia, early-phase psychosis, and it's also been an adjunctive treatment for depression. Things like this are helpful for us to know about. It unfortunately didn't have the same effect for chronic schizophrenia" (said at 0:27:44)

The speaker accurately describes the findings of landmark trials and stage-specific meta-analyses. A prominent randomized controlled trial by Amminger et al. (2010) tested 1.2 g/day of omega-3 polyunsaturated fatty acids (containing 700 mg EPA) for 12 weeks in individuals at ultra-high risk for psychosis, finding a significant reduction in transition to psychotic disorder and symptom improvement. Subsequent meta-analyses (e.g., Chen et al., 2015; Fusar-Poli & Berger, 2012) confirmed stage-specific trends showing modest symptom reductions in prodromal and early-phase schizophrenia, whereas trials in chronic/established schizophrenia consistently failed to demonstrate symptomatic benefit.

0:31:34supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Depression severity and chronicity are significantly associated with the triglyceride-to-HDL ratio, which is directly related to insulin resistance.

"looking at triglyceride/HDL ratio, for example. That's been something that has been shown with a lot of good data that depression severity and chronicity is associated with that marker, and that's directly related to insulin resistance." (said at 0:31:34)

The triglyceride-to-HDL (TG/HDL) ratio is an established clinical surrogate marker of insulin resistance. Longitudinal observational studies, such as the Netherlands Study of Depression and Anxiety (NESDA), have confirmed that elevated TG/HDL ratio and other markers of insulin resistance significantly predict the development and course of major depressive disorder. Additional cohort and clinical studies have similarly observed relationships between lipid dysregulation and depression severity.

0:32:04supportedlowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

In clinical research, insulin sensitivity was associated with depression severity but not chronicity, whereas the triglyceride-to-HDL ratio was associated with both severity and chronicity.

"What was interesting about that study is that insulin sensitivity wasn't associated with the chronicity of depression, but it was for the severity, but the triglyceride/HDL ratio was associated with both." (said at 0:32:04)

The speaker accurately describes the findings from a clinical cohort study (Watson et al., JAMA Psychiatry 2021) investigating metabolic endophenotypes in the Netherlands Study of Depression and Anxiety (NESDA). In that study, standard insulin resistance/sensitivity measures (such as HOMA-IR) were significantly associated with depression symptom severity but not depression chronicity, whereas dyslipidemic insulin resistance markers, specifically the triglyceride-to-HDL ratio, showed significant associations with both depression severity and chronicity/remission status.

0:32:35supportedlowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

In patients with bipolar disorder, insulin resistance is associated with increased rapid cycling, greater treatment resistance, and higher suicidality.

"when we look at insulin resistance, we see that even with bipolar disorder, you have more rapid cycling, you have more treatment resistance, and you have more suicidality." (said at 0:32:35)

Published observational studies and systematic reviews indicate that insulin resistance (and broader impaired glucose metabolism) in bipolar disorder is significantly associated with an unfavorable illness course, including higher rates of rapid cycling (odds ratio ~2.9-3.1), poor response or resistance to mood stabilizers such as lithium (odds ratio ~6.7-8.4), and higher overall clinical morbidity. However, because the available evidence is largely derived from cross-sectional and observational cohort studies with relatively modest sample sizes, the GRADE certainty of the evidence is low.

0:36:07supportedhighHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

The human brain constitutes approximately 2% of body weight but consumes 20% of the body's energy.

"the brain—it makes up 2% of our body, but it consumes 20% of our energy." (said at 0:36:07)

Established physiological literature confirms that the adult human brain comprises approximately 2% of total body weight while accounting for roughly 20% to 25% of the body's total basal energy (glucose and oxygen) consumption.

0:37:49supportedvery lowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Conjugation of the ketone body beta-hydroxybutyrate with the amino acid phenylalanine mediates downstream appetite suppression and weight loss effects.

"downstream of ketone metabolism there may be, say, an amino acid called phenylalanine attached to beta-hydroxybutyrate, which is what ketones will break down into. And if you have that, the end effect of appetite reduction or weight loss is present." (said at 0:37:49)

Preclinical research demonstrates that beta-hydroxybutyrate (BHB) is enzymatically conjugated with free amino acids by the enzyme CNDP2, forming BHB-amino acids. The most abundant conjugate, BHB-phenylalanine (BHB-Phe), acts as a signaling metabolite that activates hypothalamic and brainstem neurons, suppressing food intake and reducing body weight in obese mice. Furthermore, CNDP2-knockout mice fail to produce BHB-Phe and display increased food intake and body weight despite ketosis. Subsequent human trials confirm that circulating BHB-Phe is induced during ketogenic diets and following exogenous ketone supplementation, although direct behavioral and weight-loss effects have only been causally tested in animal models (leading to a very low GRADE certainty rating).

0:46:22unverifiedvery lowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

The United States Senate Appropriations Committee issued a recommendation directing the National Institute of Mental Health (NIMH) to fund research on nutritional science and nutritional ketosis for serious mental illness.

"the Senate Appropriations Committee came out with a recommendation for the NIMH to put more money and funding into—guess what—nutritional science or nutritional ketosis work in serious mental illness specifically." (said at 0:46:22)

No published record matching the claim that the United States Senate Appropriations Committee issued a recommendation directing the National Institute of Mental Health (NIMH) to fund research on nutritional science or nutritional ketosis in serious mental illness was located; this does not prove the claim false.

0:58:35supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Eating disorders involve disruptions across serotonin, dopamine, and opioid signaling pathways.

"when we look at eating disorders, whether it's anorexia or bulimia or binge eating, there are disruptions in several different pathways: there's serotonin, dopamine, and opioid pathways as well." (said at 0:58:35)

Extensive neurobiological and clinical research indicates that eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder) involve alterations and dysregulation across multiple neurotransmitter and neuromodulator systems, prominently including the serotonin (mood, satiety, impulse control), dopamine (reward processing, reinforcement), and endogenous opioid (hedonic evaluation, palatability) signaling pathways.

0:59:06supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

A clinical trial evaluating Qsymia in patients with binge eating disorder and bulimia demonstrated a 63% abstinence rate in the treatment group compared to approximately 6% in the control group.

"I did a trial in the past with a colleague of mine, Deborah Safer, at Stanford, in which we looked at an FDA-approved obesity drug called Qsymia, and we looked at that in binge eating disorder and bulimia and achieved abstinence rates of 63% while on the drug versus the control group was about 6%." (said at 0:59:06)

A randomized, double-blind, placebo-controlled crossover trial led by Deborah Safer and colleagues at Stanford evaluated phentermine-topiramate extended-release (Qsymia) in 22 adults with binge-eating disorder (n=18) and bulimia nervosa (n=4). The trial found that binge abstinence rates reached 63.6% while receiving phentermine-topiramate ER compared to 9.1% while receiving placebo (p < 0.0001).

1:08:44unverifiedvery lowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

A 9-year-old pediatric patient presenting with severe aggression and disruptive behavior had elevated gut bacterial and fungal metabolites on a urine test and experienced rapid symptom resolution following treatment with an antibiotic, an antifungal, and probiotics.

"I remember this little girl I had who was a beautiful 9-year-old little girl who was just a terror, and she was kicked out of her class like routinely in school, on the bus ride home they'd have to stop the bus 15 times to deal with her disruptive behavior and violence, aggression. I did a urine test which looked at metabolites of bacteria and yeast in the gut, and she just was off the chart with fungal metabolites and bacterial metabolites. And so like, "I'm just going to go back to first principles and reset her gut and give her an antibiotic and an antifungal and give her some probiotics." It was like the lights just came on in this girl overnight. She went from like this terror to being this sweet little girl." (said at 1:08:44)

No published record matching this clinical case report—of a 9-year-old child presenting with severe behavioral disruption and aggression who was evaluated via urinary microbial metabolites and treated with an antibiotic, antifungal, and probiotics—was located; this does not prove the claim false.

1:08:44needs contextlowHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

In autoimmune conditions like PANS and PANDAS that manifest with OCD and depression, antibiotics are effective in improving psychiatric symptoms.

"Actually, the PANS autoimmune with OCD and depression, PANDAS—... It's a—call it PANS clinic at Stanford, but I've seen a lot of cases there where antibiotics are really helpful for the psychiatric symptoms." (said at 1:08:44)

Antibiotics (such as azithromycin) are widely used in specialized clinics for pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Clinical trials and reviews offer preliminary support for their role in improving psychiatric symptoms (notably obsessive-compulsive symptoms), but the overall evidence base remains limited. A double-blind pilot randomized controlled trial found significant improvements on the Clinical Global Impressions severity scale (CGI-S) and higher responder rates with azithromycin compared to placebo, though differences on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) were not statistically significant.

1:08:44supportedmoderateHow To Use Metabolic Psychiatry To Heal Your Anxiety & Depre

Acetyl-L-carnitine is low in patients with depression and increases or resolves in association with antidepressant treatment response.

"There was another biomarker, like L-acetylcarnitine, that my colleague actually at Stanford had looked at as a marker of depression. And it's low in depression, and so with antidepressants it resolved the marker, really with treatment response." (said at 1:08:44)

Clinical studies support the claim. Blood levels of acetyl-L-carnitine (ALC/LAC) are significantly lower in patients with major depressive disorder compared to healthy control subjects. Furthermore, patients who respond effectively to antidepressant treatment or achieve clinical remission demonstrate a significant increase/normalization in acetyl-L-carnitine levels, whereas treatment non-responders do not.

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