Summary of a pilot study (clinical trial NCT03935854) by Stanford University on humans for metabolic psychiatry giving promise for the keto diet on metabolic and mental health
This story does not include health advice. It is for information, inspiration, and awareness purposes.
For more than three decades, I have tried keto diets as a lifestyle choice. In all my explorations, nothing has left as profound an impact on my physical and mental well-being as the state of ketosis through nutritional interventions, fasting, and physical exercise.
I firmly believe that keto diets and fasting might be valuable interventions for Hyperlipidemia/Inflammation and dyslipoproteinemia leading to type II diabetes, type III diabetes, and cardiometabolic disorders, including heart disease and stroke for some metabolically vulnerable people.
Everyone is unique. What works for one may not work for another. Therefore, governments preaching just one diet is not a viable solution. I acknowledge and respect that my approaches may not suit everyone’s needs or circumstances.
Last year, I wrote an inspiring story titled A New Clinical Trial Found a Low-Carb Diet Better Than the Dash. It created awareness among my followers and subscribers, who shared their remarkable experiences with keto diets. It inspired many of my readers to experiment with it safely with guidance from their health consultants.
In this post, I want to summarize the critical points of a new research pilot (clinical trial NCT03935854) at Standford University conducted on humans and published the peer-reviewed paper in Elsevier’s Journal of Psychiatry Research for the May 2024 issue, which is publicly available now.
Why These Researchers Conducted This Pilot Study
Many people worldwide suffer from severe mental illnesses like schizophrenia and bipolar disorder, which can be hard to treat with standard therapies due to resistance or side effects.
Traditional medications may even reduce life expectancy. The ketogenic diet, used mainly for epilepsy and obesity for decades, offers a different approach by providing an alternative brain fuel source (ketone bodies), potentially improving symptoms without harmful side effects.
Mental illness often coincides with metabolic issues, leading to a higher risk of health conditions like type II diabetes and cardiovascular disease. Medications used to treat mental illness can worsen these problems due to multiple side effects.
Ketogenic diets have shown promise in improving metabolic health and may benefit those with mental illness. While research on ketogenic diets for mental illness is still limited, it is a promising area for further investigation through clinical trials.
How They Designed the Study
These researchers (Shebani Sethi, Diane Wakeham, Terence Ketter, Farnaz Hooshmand, Julia Bjornstad, Blair Richards, Eric Westman, Ronald M Krauss, and Laura Saslow) designed a nationwide pilot study in the US to assess the effects of a ketogenic diet on metabolic and psychiatric health in participants diagnosed with schizophrenia or bipolar disorder according to DSM 5 criteria.
The Stanford University Institutional Review Board approved the trial, registered with ClinicalTrials.gov (NCT03935854). Participants, primarily recruited through physician referrals or responses to ClinicalTrials.gov, continued their standard psychiatric treatment during the trial without restrictions on medication adjustments.
Eligibility criteria included being aged between 18 and 75, current use of psychotropic medications, and being overweight (BMI of 25 kg/m2 or above) with weight gain while on psychotropic medications or having at least one metabolic abnormality.
Exclusion criteria included acute psychiatric instability, medical conditions like anorexia or pregnancy, and severe renal or hepatic insufficiency. Informed consent was obtained from all eligible participants.
23 participants were recruited, but two withdrew from the study before completion — one due to dietary restrictions and the other due to relocation. Of the 21 who completed the trial, five were diagnosed with schizophrenia, and 16 were diagnosed with bipolar disorder.
How They Approached and Conducted the Study
Participants underwent initial screening for eligibility based on their medical and psychiatric history, prior laboratory tests, and consent. They underwent a comprehensive medical and psychiatric evaluation, including fasting blood tests, and attended a one-hour teaching session on implementing the ketogenic diet if eligible.
The researchers provided educational materials and cookbooks and assigned a personal coach for support. They had regular medical visits with the study physician and underwent psychiatric assessments at baseline, midpoint (two months), and endpoint (four months).
The assessments included mood ratings and overall functioning. Health coaches were available for weekly check-ins, primarily to discuss dietary adherence. Participants followed a keto diet with specific macronutrient proportions and were taught to monitor blood ketone levels.
The researchers assessed compliance with the diet based on the percentage of time in nutritional ketosis, with adherence defined by specific ketone levels measured over time.
How They Made the Study Assessment Qualitatively
They obtained fasting blood specimens and measured assays of a comprehensive metabolic panel, hemoglobin A1c (HbA1c), fatty acid profile, high sensitivity C-reactive protein (hs-CRP), a homeostatic model for insulin resistance (HOMA-IR), and advanced lipid testing (LDL subfractions, ApoB, Lip (a)) at baseline and final visits.
Tests were performed by a commercial CLIA-certified laboratory (Quest Diagnostics, Madison, NJ), which was unaware of the study design or assigned conditions.
At each in-person visit, participants had their weight, blood pressure, heart rate, waist circumference, blood ketone levels, and body composition measurements recorded by a specialized SECA™ machine in the Stanford metabolic psychiatry® research clinic operated by study staff.
Body composition measurements included visceral fat measurements, lean muscle mass, and absolute body fat. If a participant was remote or unable to attend in person, they provided a blood pressure monitor and self-reported vital signs.
Psychiatric measurements gathered at specific visits included Generalized Anxiety Disorder, Patient Health Questionnaire Depression Scale, Pittsburgh Sleep Quality Index, Clinical Mood Monitoring Forms, Clinical Global Impression-Schizophrenia Scale, Clinical Global Impression for Bipolar Disorder-Overall Severity, Global Assessment of Functioning, Manchester Short Assessment of Quality of Life, Brief Psychiatric Rating Scale for Schizophrenia, and screening for suicidality.
Medical visits included side effects screening, which was evaluated and specifically asked about at each clinical visit. Throughout the study, they systematically evaluated potential side effects associated with the keto diet during each medical visit compared to those arising from psychiatric medication.
How They Analyzed the Results Statistically (Quantitatively)
These researchers performed statistical analyses using standard methods in Microsoft Excel, with data recorded within REdCap. Participants’ repeated measures outcomes were compared between baseline and final measurements.
The researchers reported data as mean (+/- stdev). They conducted paired t-tests for each participant between baseline and final quantitative data with confidence intervals of p = 0.001** and p = 0.05*, with asterisks indicating statistically significant differences.
They calculated the average difference and determined each participant's squared deviation of the observed change. Percent change was calculated as the average difference divided by the average initial value.
They also calculated the average percent change of each category (adherent, semi-adherent) and determined the standard deviation of the observed change and the standard error of the difference.
Using these values, they calculated t and assessed the probability of obtaining the results by chance. They performed McNemar’s Test for nominal data and conducted a Chi-squared analysis with confidence intervals of p = 0.001** and p = 0.05*.
For differences in demographics of adherent versus non-adherent participants, they calculated a two-tailed t-test for unequal group sizes. HOMA-IR was calculated using a specific formula, and visceral adipose tissue volume was reported in liters or converted from Visceral Fat Area using a correlation equation.
Summary of The Metabolic Research Results
The results include data from twenty-three participants, consisting of 5 participants with schizophrenia and 16 with bipolar illness. Fourteen participants were fully adherent to the diet, meaning their ketone measures were higher than 0.5 over 80%.
Six participants were semi-adherent, with ketones >0.5 between 60% and 80% of the time, and one participant was non-adherent, with ketones higher than 0.5 less than 50% of the time.
Initially, 29% of the total cohort met the criteria for metabolic syndrome, defined as having three of the following factors:
- abdominal obesity (waist circumference >40″ in men; >35″ in women),
- Elevated triglyceride levels (>=150 mg/dL),
- Low HDL Cholesterol (<40 mg/dL men, <50 mg/dL women),
- Elevated blood pressure (>= 130/85 mmHg), and
- Elevated fasting glucose levels (>=110 mg/dL).
Inspiringly and notably, by the end of the study period, none of the participants met the criteria for metabolic syndrome (p < 0.05).
Researchers analyzed all participants' data for LDL, total cholesterol, small dense LDL, triglycerides, visceral adipose tissue, omega-3 index, HOMA–IR, weight, and BMI.
Overall, they observed a 10% decrease in average weight, an 11% reduction in waist circumference, a 6.4% decrease in systolic blood pressure, a 17% reduction in fat mass index, and a 10% decrease in BMI.
Metabolic biomarker changes included a 27% reduction in visceral adipose tissue, a 23% reduction in hs-CRP, a 20% reduction in triglycerides, a 21% increase in LDL, a 2.7% increase in HDL, and a 1.3% reduction in small dense LDL.
They also observed a 3.6% reduction in HbA1c and a 17% reduction in HOMA-IR. There was no significant change in the 10-year ASCVD risk score among the whole cohort. However, among adherent participants, they noted a statistical improvement of −11%.
Summary of The Psychiatric Research Results
Among the full cohort, researchers observed an average improvement of 31 % in Clinical Global Impressions severity of mental illness assessments.
The proportion of participants in the recovery state increased from 33 % to 75 % by the end of the study. In the adherent group, 100 % were in the recovery state by the study’s end.
Overall, 43 % of participants achieved recovery during the study, with 50 % for adherent participants and 33 % for semi–adherent participants. Among participants with baseline symptoms, 79 % achieved a marked improvement, with 92 % for adherent participants and 50 % for semi–adherent participants.
For bipolar participants, the severity of mental illness showed improvements of >1 point in 69 % of participants. The proportion of participants in the recovered state increased from 38 % at baseline to 81 % at the end of the study.
By the study's end, 100% of adherent bipolar participants were in the recovered or recovering state. Among subpopulations according to adherence level, a marked improvement was observed in 88 % of adherent participants and 60 % of semi–adherent participants.
Psychiatric outcomes for the full cohort include a 17 % improvement in life satisfaction, a 17 % improvement in the Global Assessment of Functioning, and a 19 % improvement in the Pittsburgh Sleep Quality Index. Among schizophrenia participants, there was a 32 % reduction in the Brief Psychiatric Rating Scale.
Were there any side effects?
Yes. Researchers initially documented common side effects of a ketogenic diet, including headache, fatigue, and constipation, in this study.
Not to my surprise as a keto dieter, notably, these side effects substantially diminished, reaching minimal to negligible levels beyond the third week of the study.
I wrote several articles about effectively dealing with keto-flu from ketogenic diets or intermittent/prolonged fasting before.
How did these researchers interpret the outcomes of the study?
The researchers observed and reported on the psychiatric and metabolic outcomes in the first group of participants with schizophrenia and bipolar disorder who underwent a specific ketogenic diet treatment along with psychiatric medication.
They found that, on average, the severity of mental illness improved by 31% as assessed by the Clinical Global Impressions scale. Additionally, 79% of participants with baseline symptoms experienced clinically meaningful improvement, with higher rates observed in the adherent group.
Other psychiatric outcomes, like life satisfaction, overall functioning, and sleep quality also showed improvement. These results suggest that the intervention positively impacted the mental health and well-being of the participants.
A significant proportion of participants adhered to the treatment, indicating the feasibility and potential implementation of this regimen in an outpatient population.
Regarding metabolic outcomes, the study demonstrated improvements in various metabolic biomarkers and overall health parameters. All participants who initially met the criteria for metabolic syndrome experienced its reversal by the end of the four-month study.
The cohort exhibited significant reductions in weight, waist circumference, systolic blood pressure, fat mass index, and BMI. Metabolic biomarkers like visceral adipose tissue, HbA1c, and triglycerides also showed notable reductions.
Although the 10-year ASCVD risk score in the overall cohort did not significantly change, it did change significantly among adherent participants.
Reductions in HbA1c by 3.6% and HOMA–IR by 17.2% reflected improved glycemic control and insulin sensitivity. These results collectively suggest that the intervention positively changed weight, body composition, and metabolic markers in a metabolically vulnerable population.
The researchers noted that while some participants experienced increased LDL cholesterol levels, none reached levels, qualifying them as lean mass hyperresponders (LMHRs).
Since saturated fat intake was not limited in the intervention, participants with greater LDL increases could benefit from reducing dietary saturated fat. Overall, the lipid profiles did not suggest worsening cardiovascular risk.
However, the increase in LDL cholesterol with higher saturated fat intake is usually due to large buoyant LDL particles, which are less strongly associated with coronary heart disease risk than small dense particles, the levels of which did not significantly increase in the study participants.
The study also highlighted that common side effects of the ketogenic diet, such as headache, fatigue, and constipation, were reported only in the initial three weeks of the study and resolved thereafter.
However, the short-term nature of the assessments limited the understanding of potential longer-term side effects compared to other treatment options.
While lifestyle changes like exercise have been reported to improve cognition and mood in psychiatric disorders, a randomized controlled trial examining the metabolic impact of exercise in participants with schizophrenia did not show significant improvement in the equivalent time period to this study.
The ketogenic diet intervention, with its multiple mechanisms of action beyond blood glucose, showed promising results in improving metabolic and psychiatric outcomes.
Did the study have any limitations?
Yes, the study had limitations, including a small sample size, potential selection bias, and lack of a control arm, which limited the generalizability of the findings.
The short duration of the trial and the impact of the COVID-19 pandemic on adherence and outcomes were also acknowledged.
However, the results suggest that the ketogenic diet intervention could be a feasible and acceptable supplemental treatment to neuroleptic medications in outpatient settings, with improvements observed in psychiatric and metabolic health.
Final Conclusion of this Valuable Study
These findings emphasize the importance of addressing metabolic issues in people with serious mental illness to enhance overall well-being and inform the development of more effective interventions in psychiatry.
Further research, including randomized controlled trials, is needed to assess the intervention’s efficacy and long-term effects in this population.
This study is truly remarkable, shedding light on the immense potential and health benefits of ketogenic diets for mental health. Its findings are not only illuminating but also incredibly encouraging.
Personally, I am not surprised by the results, as I have experienced firsthand the transformative effects of a ketogenic diet on both my physical and mental well-being over the past 30 years.
Through this dietary approach, I have witnessed significant improvements in cognitive and neurological function, hormonal balance, and immune health. It is incredibly gratifying to see scientific research aligning with personal experiences, reaffirming the value of ketogenic diets in promoting overall health and wellness.
Thank you for reading my perspectives. I wish you a healthy and happy life.
If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.