Since we officially launched back in September, our researchers have been getting stuck into an array of exciting research activities. In this blog, Dr Iain Campbell, our PPIE co-lead and Baszucki Research Fellow in Metabolic Psychiatry, explores some of the key themes raised at the Baszucki Trials Meeting he attended in October, and shares some of his thoughts on how the voices of those with lived experience are impacting the research taking place within this growing field for the better.

As a researcher with lived experience of bipolar disorder, I have always admired the work of Emil Kraepelin (1856 - 1926), one of the founders of modern psychiatry, and someone who exemplified lived experience involvement in his work. He saw every interaction with patients as a valuable opportunity, a chance to learn some new insight into the condition, to gain some perspective and to find a new piece of the scientific puzzle.

His engagement with lived experience connected him to the reality of the condition and took him beyond his pre-conceived conceptualisations of it. By seeking insights from patients, he received feedback from minds (and neurons) directly affected by the condition, and in doing so he gained remarkably prescient insights which still inform the field of Psychiatry nearly 100 years later.

I think that this kind of scientist-patient engagement is the unique value of lived experience involvement which is driving Metabolic Psychiatry with such significant momentum. These interactions connect research to reality, concepts to biology, and the map to the territory. Many of the clean lines of conceptual distinction drawn in research between mental and physical health dissolve in the lived experience of patients who experience concomitant mental and physical health symptoms.

In 1921 Kraepelin concluded from his observations that “All these changes indicate that in manic depressive insanity, marked disorders of metabolism must take place” [emphasis Kraepelin’s]. (1) However, he lamented the lack of ability in his time to properly study the features of this metabolic dysfunction, noting in the next sentence: “Unfortunately the results of investigations carried out in regard to this have been up till now still rather unsatisfactory.” You can find on the subsequent pages of his foundational book Manic Depressive Insanity and Paranoia many diagrams and annotations noting changes in body weight, blood pressure and other available cardio-metabolic measures. Kraepelin was tracing the outlines of an undefined form of metabolic dysfunction which could only be viewed in low-resolution with the available tools at the time (see p.51 of Manic Depressive Insanity and Paranoia for example). I can only imagine what an opportunity he would have seen in the talent, resources and tools available in the Hub for Metabolic Psychiatry to better understand this metabolic aspect of the condition.

Manic Depression and Insanity was edited by a previous Chair of Psychiatry at Edinburgh University, Prof. George Robertson, and published in Teviot Place. It was a privilege therefore to attend a meeting in Florida recently with Prof. Danny Smith, Chair of Psychiatry at Edinburgh University, to view findings from the first wave of clinical trials in Metabolic Psychiatry. I can’t help but think how much Kraepelin would have enjoyed this meeting where researchers presented findings from the first wave of these metabolic investigations, driven directly by insights from the lived experience of patients.

These trials emerged from the insightful observations of Jan Baszucki and her son Matthew in their journey treating his bipolar disorder. Having unrestricted access to the best of the US healthcare system, they worked through over 30 treatment modalities, finding - like many patients - only temporary symptom suppression. The use of anti-seizure medications in treating bipolar disorder gave them some indication that other anti-seizure treatments may be worth investigating. And so, they decided to try a Ketogenic Diet, an anti-seizure intervention in epilepsy established through 13 randomised controlled trials (RCTs). Matthew has shared the unexpected relief of symptoms he has found while in ketosis, leading to the Baszucki family funding the first pilot studies in Metabolic Psychiatry including our pilot study here at Edinburgh.

In a parallel journey my father Harry Campbell and I began a fruitful collaboration with Prof. Daniel Smith after we shared our own lived experience of the effectiveness of ketosis in treating my bipolar symptoms. Upon entering ketosis accidentally, while trying to lose weight on a ketogenic diet, I found relief from decades of severe bipolar depression and suicidal ideation, and so I sought to research this to see if it could help others. We noted that similar reports were already common in the bipolar community and might be worthy of more detailed investigation. (2)

At the first Baszucki trials meeting in 2023, Matthew and myself among other patients shared our lived experience of the effects of ketosis, and Danny and I presented the first data from our pilot study. It sparked interest across many established bipolar research groups, several of whom Baszucki Group funded to carry out their own investigations.

At the 2nd meeting of the Baszucki trials group in Florida this year, early findings from these trials were presented and received with great interest. The meeting began with observations from lived experience. 10 patients shared their experiences on a video call and in-person. One was a doctor, another a psychiatric nurse of 16 years, another a college student, another a patient from our pilot study, all of them healthy, lucid, and talking about their future with a sense of grounded and genuine optimism. Each of them shared how improving their metabolic health through ketosis improved their mental health. Experiences of weight loss, improved energy and cognitive function were shared, along with a discussion of challenges of adhering to a ketogenic diet.

Danny gave a presentation on the Hub for Metabolic Psychiatry, and it struck me how much the field has developed since the previous year’s meeting. To see this emerging field recognised by UKRI Medical Research Council was a sign that the voices of the patient community were being heard. Next, there were presentations of early metabolic psychiatry trial findings from researchers from Harvard, Stanford, UC San Diego, Ohio State and James Cook university among others. Several remarkable, if preliminary, findings were shared and it is unfortunate that these are unpublished so I cannot yet share them here. However, I did identify a number of emerging research trajectories from the meeting which will be of interest to those planning research in Metabolic Psychiatry. I think that the detailed investigations of metabolic biomarkers through brain imaging and metabolomics paired with psychiatric evaluations are the kind of metabolic studies Kraepelin would have liked to have seen in his time, and so I felt fortunate to witness these presentations.

Here are some of the areas of research discussed at the meeting which I hope will be helpful to ongoing Metabolic Psychiatry research:

There were some indications at the meeting, that the effects of ketosis may be related to counteracting insulin resistance and dysregulation of glucose metabolism. Dysregulation of glucose metabolism has gradually become established as important feature of the pathophysiology of bipolar disorder indicated by meta-analysis of brain imaging studies (3) and meta-analysis of prevalence rates of metabolic syndrome in bipolar disorder patients (4).
A feature of ketone body metabolism that I have found to be of interest, is the role of ketone bodies as an alternative substrate to glucose in neuronal mitochondria. Ketones may provide an alternative and stable fuel source for the brain when glucose metabolism and insulin signalling are disrupted. I have discussed these ideas in more depth in this publication . (5)
Many of the targets of Lithium participate in the insulin signalling pathway which we have highlighted in a paper in Nature - Translational Psychiatry proposing that Lithium acts via PI3K/Akt insulin signalling (6) and there have recently been several studies and publications in Lancet and Nature press journals supporting this perspective (7, 8, 9, 10, 11).
Mitochondrial dysfunction is implicated in bipolar disorder through brain imaging, metabolomics and genetic data alongside comorbidity of bipolar disorder with mitochondrial disorders. (12) These observations align with the patient perspective that energy regulation is central to bipolar disorder pathophysiology. (13) In addition to serving as an alternative metabolic substrate to glucose, ketone bodies also produce significantly more energy per molecule than glucose, generating 31% more ATP per molecule of oxygen than pyruvate, the end product of glycolysis. (14)
Elevated cerebral glutamate is a consistent finding in bipolar disorder research, indicated by meta-analysis of findings from brain imaging studies. (15) The most consistent effect of ketone bodies in synaptosomes, cultured astrocytes, animal studies and brain imaging in humans is a reduction in glutamate (15, 16) We observed this effect in Michael Thrippleton’s brain imaging work in our ketogenic diet pilot study in bipolar disorder patients.
A significant proportion of brain glutamate is derived from glucose in astrocytes. It is possible that the metabolic shift from glucose to ketone body metabolism may down-regulate cerebral glutamate metabolism, thereby reducing excitotoxicity in the brain. I have proposed testable mechanisms for this metabolic adaptation in a recent paper in Nature - Molecular Psychiatry (17).

We are just entering into the early phases of Metabolic Psychiatry research, but the intersection of established features of bipolar pathophysiology with the effects of metabolic interventions highlighted by lived experience, are interesting areas of convergence for further investigation.

It was a privilege to see the early findings of the first trials in Metabolic Psychiatry. However, the clear highlight of the meeting for me was seeing a participant from our pilot study in the lived experience group looking healthy and clearly thriving and hopeful about his future. Perhaps such people, myself included, only represent a distinct and relatively rare phenotype of bipolar which responds to ketosis, or perhaps there are other factors underlying our improvement which we are not aware of. Metabolic Psychiatry aims to answer these questions through the scientific process and robust research methodology in an endeavour to investigate a clear patient priority.

Tackling the prevalence of metabolic dysfunction in the form of insulin resistance, type 2 diabetes and other cardio-metabolic conditions which contribute to 70% of deaths of people with SMI in the UK is a worthy goal for Metabolic Psychiatry, in and of itself. However, if such metabolic dysfunction extends to the brain and central nervous system, and is implicated in the pathophysiology serious mental illness, there may be unique opportunities for the development of disease modifying treatments which go beyond symptom suppression, and have implications for early intervention.

Below are just a handful of the many sketches Kraepelin made outlining the metabolic dysfunction he supposed to play a role in the aetiology of bipolar disorder. Looking at the effort he put into these time-worn sketches, I’m all the more grateful for the opportunity we have in the Hub for Metabolic Psychiatry to investigate these issues in the depth Kraeplin would have valued so greatly in his time.

Plots and graphs from the work of Emile Kraeplin showing metabolic dysfunction

References

Kraepelin E. Manic-depressive Insanity and Paranoia. Edinburgh: Livingstone; 1921.
Campbell I.H., Campbell H. Ketosis and bipolar disorder: controlled analytic study of online reports. BJPsych Open. 2019;5(4).
Wu, C., Ren, C., Teng, Z., Li, S., Silva, F., Wu, H., & Chen, J. (2021). Cerebral glucose metabolism in bipolar disorder: A voxel-based meta-analysis of positron emission tomography studies. Brain and behavior, 11(5), e02117. https://doi.org/10.1002/brb3.2117
Vancampfort, D., Vansteelandt, K., Correll, C. U., Mitchell, A. J., De Herdt, A., Sienaert, P., Probst, M., & De Hert, M. (2013). Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators. The American journal of psychiatry, 170(3), 265–274. https://doi.org/10.1176/appi.ajp.2012.12050620
Campbell I, Campbell H. Mechanisms of insulin resistance, mitochondrial dysfunction and the action of the ketogenic diet in bipolar disorder. Focus on the PI3K/AKT/HIF1-a pathway. Med Hypotheses. 2020;145(110299).
Campbell, I. H., Campbell, H., & Smith, D. J. (2022). Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder. Translational psychiatry, 12(1), 350. https://doi.org/10.1038/s41398-022-02122-6
Khayachi, A., Abuzgaya, M., Liu, Y., Jiao, C., Dejgaard, K., Schorova, L., Kamesh, A., He, Q., Cousineau, Y., Pietrantonio, A., Farhangdoost, N., Castonguay, C. E., Chaumette, B., Alda, M., Rouleau, G. A., & Milnerwood, A. J. (2024). Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder. EBioMedicine, 104, 105161. https://doi.org/10.1016/j.ebiom.2024.105161
Kelsoe, J., Ou, A., Rosenthal, S., Adli, M., Akiyama, K., Akula, N., Alda, M., Amare, A. T., Ardau, R., Arias, B., Aubry, J. M., Backlund, L., Banzato, C., Bauer, M., Baune, B., Bellivier, F., Benabarre, A., Bengesser, S., Abesh, B., Biernacka, J., … Zompo, M. D. (2023). Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study. Research square, rs.3.rs-3258813. https://doi.org/10.21203/rs.3.rs-3258813/v1
Dwyer D. S. (2024). Converging evidence for functional connections between the lithium response and PI3K-Akt signaling. Translational psychiatry, 14(1), 458. https://doi.org/10.1038/s41398-024-03160-y
Niemsiri, V., Rosenthal, S. B., Nievergelt, C. M., Maihofer, A. X., Marchetto, M. C., Santos, R., Shekhtman, T., Alliey-Rodriguez, N., Anand, A., Balaraman, Y., Berrettini, W. H., Bertram, H., Burdick, K. E., Calabrese, J. R., Calkin, C. V., Conroy, C., Coryell, W. H., DeModena, A., Eyler, L. T., Feeder, S., … Kelsoe, J. R. (2024). Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis. Molecular psychiatry, 29(1), 6–19. https://doi.org/10.1038/s41380-022-01909-9
Ni, R. J., Gao, T. H., Wang, Y. Y., Tian, Y., Wei, J. X., Zhao, L. S., Ni, P. Y., Ma, X. H., & Li, T. (2022). Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway. Zoological research, 43(6), 989–1004. https://doi.org/10.24272/j.issn.2095-8137.2022.278
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McNally, R. J., Robinaugh, D. J., Deckersbach, T., Sylvia, L. G., & Nierenberg, A. A. (2022). Estimating the symptom structure of bipolar disorder via network analysis: Energy dysregulation as a central symptom. Journal of psychopathology and clinical science, 131(1), 86–97. https://doi.org/10.1037/abn0000715
Veech R. L. (2004). The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins, leukotrienes, and essential fatty acids, 70(3), 309–319. https://doi.org/10.1016/j.plefa.2003.09.007
Yildiz-Yesiloglu, A., & Ankerst, D. P. (2006). Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Progress in neuro-psychopharmacology & biological psychiatry, 30(6), 969–995. https://doi.org/10.1016/j.pnpbp.2006.03.012
Hone-Blanchet, A., Antal, B., McMahon, L., Lithen, A., Smith, N. A., Stufflebeam, S., Yen, Y. F., Lin, A., Jenkins, B. G., Mujica-Parodi, L. R., & Ratai, E. M. (2023). Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48(5), 797–805. https://doi.org/10.1038/s41386-022-01364-8
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Baszucki Trials Meeting 2024: The Impact of Lived Experience in Metabolic Psychiatry Research

Here are some of the areas of research discussed at the meeting which I hope will be helpful to ongoing Metabolic Psychiatry research:

1. Interactions between ketosis, dysregulation of glucose metabolism and insulin resistance.

2. Indicators of mitochondrial dysfunction and the action of ketosis as an alternative mitochondrial fuel source to glucose.

3. Interactions between ketosis and cerebral glutamate/GABA.

In Conversation with Christina Steyn

In Conversation with Dr Joanne Kenney