Swiss Re Ag · SIX:SREN
Swiss Re — Technical Presentation (October 2023)
42 slides from Swiss Re's technical presentation, October 2023
Slide 1: A Pilot Study of a Ketogenic Diet in Bipolar Disorder
Dr. Iain Campbell Baszucki Brain Research Fellow in Metabolic Psychiatry The University of Edinburgh A Pilot Study of a Ketogenic Diet in Bipolar Disorder: Clinical, Metabolomic and Magnetic Resonance Spectroscopy Outcomes Iain H Campbell, Nicole Needham, Helen Grossi, Ivana Kamenska, Saturnino Luz,
Slide 2: Disclosures
Disclosures Fellowship funded by the Baszucki Brain Research Fund. No other financial relationships to disclose.
Slide 3: Intro
Intro • Dr. Iain Campbell. Global Health PhD. Usher Institute. • Baszucki Brain Research Fellow in Metabolic Psychiatry. • Co-PI Ketogenic Diet for Bipolar Disorder Study. • Lived Experience of Bipolar Type 2.
Slide 4: Metabolism, Energy and Bipolar Disorder
Metabolism, Energy and Bipolar Disorder
Slide 5: Anti-seizure Medications and Bipolar Disorder
Anti-seizure Medications and Bipolar Disorder • A ketogenic diet is established as a metabolic therapy for refractory epilepsy, supported by data from 13 randomised controlled trials and over a century of clinical use. [PMID: 30403286] [PMID: 31786950] • Epilepsy and bipolar disorder may share some
Slide 6: A Pilot Study of a Ketogenic Diet for Bipolar Disorder
A Pilot Study of a Ketogenic Diet for Bipolar Disorder Can we recruit and retain • 27 recruited > 26 participants began the study > 20 completed the study study participants? • 93% completeness of daily mood measures Can people with Bipolar • 95% completeness of capillary sampling of glucose and ket
Slide 7: Summary of Adherence
Summary of Adherence • Patients in ketosis 91% of the time throughout the study (8 weeks; daily self-administered ketone measurements) • Mean daily blood ketone readings were 1.3 mmol/L (SD= 0.77, Median = 1.1) Ivana Kamenska Helen Grossi Master’s Student Studying NHS Ketogenic Diet Nutrition and Me
Slide 8: Cardiometabolic Outcomes: Context
Cardiometabolic Outcomes: Context • Bipolar disorder (BD) carries a substantial metabolic burden alongside increased cardiovascular risk and shortened life expectancy by over a decade [PMID: 35184778] • ~68% of people with BD are overweight or obese [PMID: 21379357] • People with BD have a two-fold
Slide 9: Cardiometabolic Outcomes
Cardiometabolic Outcomes Weight BMI Mean weight loss: 4.22 kg (9.3 lb) Mean BMI decreased by 5.31% Max: 10 kg 28.24 ± 4.24 kg/m2 to 26.74 ± 3.86 kg/m2 (p <0.001) Min: 0.2 kg 81.21 ± 13.21kg to 76.99 ± 11.69kg (p <0.001) 19 out of 20 participants lost weight.
Slide 10: Cardiometabolic Outcomes
Cardiometabolic Outcomes Systolic Blood Pressure Diastolic Blood Pressure Mean systolic blood pressure reduction 7.37mmHg Mean diastolic blood pressure decreased by 4.05mmHg (133.05 ± 16.16 mmHg to 125.68 ± 11.87 mmHg (p = 0.041)) (81.47 ± 12.20 mmHg to 77.42 ± 7.65 mmHg (p =0.162)) 57.89% of partic
Slide 11: Edinomics
Edinomics Metabolomics Facility Dr. Tessa Moses Dr. Karl Burgess Metabolomics Specialist and Scientific Director Edinomics Facility Manager Edinomics Core Facility
Slide 12: Metabolomics
Metabolomics All patients except one show an increase in beta-hydroxybutyric acid levels (p value = 8.84E-06) in follow up serum samples DL-beta-Hydroxybutyric Acid 700000. 525000. 350000. 175000. 0. 01B 01F 02B 02F 03B 03F 04B 04F 05B 05F 06B 06F 09B 09F 10B 10F 13B 13F 14B 14F 15B 15F 16B 16F 17B
Slide 13: Metabolomics
Metabolomics Most patients show a decrease in lactic acid levels (p = 0.017) in follow up serum samples. Marker associated with increased glycolysis and mitochondrial dysfunction. L-(+)-Lactic Acid 600000. 450000. 300000. 150000. 0. 01B 01F 02B 02F 03B 03F 04B 04F 05B 05F 06B 06F 09B 09F 10B 10F 13B
Slide 14: Metabolomics
Metabolomics Central carbon metabolism: citrate Box and whisker plot shows the Column chart shows the levels in individual patients at baseline (B) and follow up (F) average (yellow dot) and biological variation across the paired samples. 10 patients show an increase in citrate levels in follow up s
Slide 15: Systematic Review: Metabolomics
Systematic Review: Metabolomics [PMID: 30411484]
Slide 16: Systematic Review: Brain Imaging in BD
Systematic Review: Brain Imaging in BD [PMID: 30411484]
Slide 17: Ketones as an Alternative Fuel Source for Mitochondria
Ketones as an Alternative Fuel Source for Mitochondria Ketone bodies bypass glycolytic pathways. Lactate Image: Campbell I, Campbell H. Ketosis and bipolar disorder: controlled analytic study of online reports. BJPsych Open. 2019;5(4).
Slide 18: Magnetic Resonance Spectroscopy (MRS): Context
Magnetic Resonance Spectroscopy (MRS): Context • Systematic review indicates that brain glutamate level is increased in BD (Chabert et al., 2022) • Reduction in glutamate, glutamine, and Glx (glutamate+glutamine) in BD patients is considered a marker of response to pharmacological treatment (Dong et
Slide 19: Magnetic Resonance Spectroscopy (MRS)
Magnetic Resonance Spectroscopy (MRS) Mellissa Gibbs Edinburgh Clinical Research Facility Image Analysis Core Dr. Michael Thrippleton Research Fellow. Edinburgh Clinical Research Facility Image Analysis Core Dr Gerard Thompson Clinical Research Facility Image Analysis Core
Slide 20: Magnetic Resonance Spectroscopy (MRS)
Magnetic Resonance Spectroscopy (MRS) ACC Metabolite Concentration Change Pre- and Post-KD • Glx decreased from baseline by 9.22% in the ACC (p<0.02) • Glx decreased from baseline by 13.13% in the PCC (p<0.001)
Slide 21: Glutamate as a Metabolic Fuel Source
Glutamate as a Metabolic Fuel Source
Slide 22: Magnetic Resonance Spectroscopy (MRS)
Magnetic Resonance Spectroscopy (MRS) Campbell (2023). Hyperglycolysis and Glutaminolysis in Bipolar Mania. Molecular Psychiatry (In Revision)
Slide 23: Magnetic Resonance Spectroscopy (MRS)
Magnetic Resonance Spectroscopy (MRS) Campbell (2023). Hyperglycolysis and Glutaminolysis in Bipolar Mania. Molecular Psychiatry (In Revision)
Slide 24: Psychiatric Outcomes in Euthymic Patients
Psychiatric Outcomes in Euthymic Patients Dr. Nicole Needham Research Coordinator • Professor Saturnino Luz • Professor of Digital Biomarkers and Precision Medicine
Slide 25: Correlation between ketone levels and clinical outcomes
Correlation between ketone levels and clinical outcomes Mood Impulsivity r= 0.21 (p<0.001) r = -0.32 (p<0.001) Anxiety Energy r=-0.18 (p<0.001) r = 0.19 (p=<0.001)
Slide 26: Time Series: EMA Measures and Ketone Level
Time Series: EMA Measures and Ketone Level • Covariation and granger causality was observed for ketone level and mood (Z = 3.19 p<0.01) and anxiety (Z = 2.29, p<0.05).
Slide 27: Time Series: EMA Measures and Ketone Level
Time Series: EMA Measures and Ketone Level • >1/3 of participants who reached the wash- out period opted out to continue on ketogenic diet beyond the study. • Granger causality test for these participants had clearer patterns of significance for Mood (Z = 4.45 p<0.001) and Anxiety (Z = 3.37, p<0.001
Slide 28: Time Series: EMA Measures and GKI
Time Series: EMA Measures and GKI • Epilepsy research indicates that glucose ketone index (GKI) may be more strongly correlated to seizure control than either ketone or glucose level alone. [PMID: 35527506] [PMID: 34802897] • GKI and Granger Causality Mood (Z = 2.32, p<0.05), energy (Z = 2.28, p < 0
Slide 29: Time Series: EMA Measures and GKI
Time Series: EMA Measures and GKI • Granger Causality was more more significant in those remaining on diet. Mood (Z = 3.11 p <0.01), Energy (Z = 3.60 p <0.001) and Anxiety (Z = 55.14 p <0.001).
Slide 30: Time Series: EMA Measures and Ketone Level
Time Series: EMA Measures and Ketone Level
Slide 31: Qualitative Feedback From Daughter of Study Participant
Qualitative Feedback From 15 y/o Daughter of Study Participant
Slide 32: Comparison of Baseline Readings Responders and Non-Responders
Comparison of Baseline Readings Responders and Non-Responders Discontinued Diet Remained on Diet % Difference • HOMA-IR (+27.19% in Weight 79.31 ± 15.66 83.6 ± 15.07 5.41 responders). BM I 27.71 ± 4.24 30.60 ± 6.55 10.44 Systolic Blood Pressure 129.05 ± 16.93 131.00 ± 11.35 1.51 • Insulin (+19.25% i
Slide 33: Case Study: Ketones correlating with better mood, more energy, less anxiety
Case Study: Ketones correlating with better mood, more energy, less anxiety Weight: 223lbs – 200.6lbs (-22lbs) HOMA-IR: 4.5 - 1.3 BMI: 34.5 – 31.1 Blood Pressure: 131/82 – 103/65 BDI: 17 – 11 ALS: 14 – 8 YMRS: 0 - 1
Slide 34: Energy Mood
‘THE UNIVERSITY of EDINBURGH Edinburgh Neuroscience FP Unew -0257 Mood oe 0 100 | te a sa = sa = ra Fy 10 2 3 00 sm Ketones Ketones 5 { Granger causality test (PID=16) b= 5 Granger causality st PID=16) <7, 4 ‘Energy ~ Ketones, F= 1.70. ma Mood ~ Ketones, F = 1.16 0 “p60 ® Bs Will m $3 Me c WW then z
Slide 35: Anxiety
‘THE UNIVERSITY of EDINBURGH Edinburgh Neuroscience Anxiety 60 w > e = g 40%. 2 < 20 Diet continued i) 20 40 60
Slide 36: Summary
Summary • Adherence to the diet was excellent (>91%). • Ketone level was correlated with improved daily measures of mental health throughout the study. The level of ketones, measured daily, correlated to improved mood (p <0.001) and energy scores (p <0.05) and to reduced impulsivity (p <0.001) and a
Slide 37: Summary
Summary • Changes in ketone levels show co-variation and evidence of a possible causal relationship to changes in mood (p<0.01) and anxiety (p<0.05) measured by Granger Causality Test. Similarly glucose-ketone index showed significant granger causality with mood (Z = 2.32, p<0.05), energy (Z = 2.28,
Slide 38: Team
Team Professor Harry Campbell Professor Daniel Smith Dr. Nicole Needham Helen Grossi Dr. Michael Thrippleton Joint Director of the Centre for Chair of Psychiatry and Head of the Global Health, University of Division of Psychiatry, University of Research Coordinator Edinburgh Edinburgh. NHS Ketogenic
Slide 39: Team
Team Dr Gerard Thompson Dr Ben Meadowcroft Maja Mitchell Professor Sharon Simpson Dr Rachel Brown Delivery and Development NHS Psychiatrist Clinical Research Facility Image NHS Psychiatrist Manager. Bipolar Scotland Professor of Behavioural Sciences. Analysis Core University of Glasgow Professor Emm
Slide 40: Questionnaire Study (n=94)
Questionnaire Study (n=94) THE UNIVERSITY of EDINBURGH Edinburgh Neuroscience Before Ketogenic Diet: 29.3, Depressive episodes Ver 5 A 22 (29.5%) oe TT 29 (25%) Moet TT 22 265%) Mid 7 (7.4%), Very mid M1 (13%) Not resent II 6 (6.48) ‘cant remember | 0 ‘Mutt answer Prcetageof respondents who selected
Slide 41: Questionnaire Study (n=94)
THE UNIVERSITY of EDINBURGH Edinburgh Neuroscience Questionnaire Study (n=94) Before Ketogenic Diet: 31.16 Suicidal thoughts 5 TT (7) 5 22 0%) oT 1° (025) a_i 1 2° (13°) cart remember M1 0.1%) Muti answer: Percentage of respondents who selected each answer option (29 10% woud represent that lf he qu
Slide 42: Thank you
Thank you Becky, Skye and Atholl Jan, Dave, Matthew and the Baszucki Brain Research Fund John Schoonbee. Andreas Obrist. Swiss Re. Nicole Needham, Helen Grossi, Ivana Kamenska, Saturnino Luz, Shane Sheehan, Gerard Thompson, Michael J Thrippleton, Melissa C Gibbs, Joana Leitao, Tessa Moses, Karl Burg