Ernst Strüngmann Forum

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Metabolic Neuropsychiatry

May 12–17, 2024

Frankfurt am Main, Germany

Dost Öngür and Judith Ford, Chairs

Program Advisory Committee

Kim Q. Do, Judith Ford, Julia Lupp, Lilianne R. Mujica-Parodi, Dost Öngür, Zoltan Sarnyai, and Rachel Upthegrove

Goals of the Forum

To leverage the new field of metabolic neuropsychiatry, this Forum aims to identify (a) basic research progress needed to support translation of findings, (b) tractable clinical interventions aligned with the basic research findings, and (c) strategies to be deployed to test these interventions.

Background

Energy metabolism and related processes play a critical role in supporting and regulating brain function. Much of the energy generated in the brain is used to support action potential generation and synaptic transmission—the basic mechanisms of nerve cell communication. This realization has led to renewed interest in the role that energy metabolism plays in both healthy brain function and in the emergence of brain disorders, with the hope that improving energy metabolism may lead to treatments for brain conditions for which existing treatments are unsatisfactory.

Several lines of research provide converging evidence that neuropsychiatric disorders (schizophrenia, neurodegenerative disorders, and autism) are characterized by abnormal brain bioenergetics—evidence from GWAS of neuropsychiatric disorders, abnormal energy metabolism in patient-derived samples, reduced expression of mitochondrial markers in patient-derived postmortem brain tissue, and in vivo neuroimaging studies indicating reduction in the synthesis and utilization of ATP coupled with a shift from high-efficiency oxidative phosphorylation to inefficient glycolysis for energy production. These bioenergetic abnormalities are best conceptualized as part of a set of interconnected biochemical processes, including abnormal redox biology and neuroinflammation, which together impair brain function in various ways. Although the exact mechanisms linking abnormal brain bioenergetics to neuropsychiatric dysfunction are not well delineated, spatial and temporal aberrations in availability of energy supply may lead to abnormal neural signaling. Depending on the details of bioenergetic dysfunction in subcellular location, affected cell-types, and available compensatory mechanisms, this basic theme may manifest itself in deviation from expected developmental trajectories in early life, abnormal information processing in midlife, and accelerated neurodegeneration in late life.

Abnormal brain bioenergetics is receiving increased attention because of the potential for developing new treatment interventions. A large body of research in diabetes and other metabolic disorders has led to a deep understanding of energy metabolism and to effective diet/exercise and medication treatments to correct metabolic abnormalities, but until now has not been studied systematically in neuropsychiatry.

Reports of clinical improvement in response to the ketogenic diet in individuals with severe mental illnesses become relevant in this context. The ketogenic diet is an FDA-approved treatment for childhood epilepsy in the U.S., and several reports have linked it with positive outcomes in other brain disorders. Several large-scale studies are currently underway to test the effect of this diet and various other metabolic interventions in neuropsychiatric disorders, and more are expected. These developments provide hope that it may be possible to leverage metabolic interventions to improve outcomes in neuropsychiatric disorders. Greater focus on brain metabolism may also lead to the development of new treatments that are easier to administer, more efficacious, and associated with fewer adverse effects.

Are metabolic abnormalities seen in neuropsychiatric disorders restricted to the brain or are they systemic? Most evidence would suggest the latter, a point further highlighted by the well-known propensity of patients with neuropsychiatric disorders to develop metabolic syndrome. Since the same factors that contribute to the emergence of abnormal brain function may also contribute to a higher burden of medical conditions such as diabetes, obesity, and hypertension, this is an important area of focus in neuropsychiatric disorders not only to improve psychiatric outcomes but also to prevent medical morbidity and mortality.

This Forum is supported by the Deutsche Forschungsgemeinschaft

The German Research Foundation

Group 1: Role of Metabolism in Brain Function?

Where are the promising areas of basic research to support clinical translation? The group will review examples of neuroscience discoveries that have stimulated neuropsychiatric research and identify other discoveries which can follow the same path. Guiding questions include:

How do neurons and glia work together to optimize brain energy metabolism for the ever-changing demand?
How is brain energy metabolism linked to intra- and intercellular signaling (neurotransmission) in the brain?
How can we best integrate fundamental neuroscience findings of brain energy metabolism into systems neuroscience and human behavior?
How do metabolic substrates fuel energy production and structural plasticity during the life course?
Can we identify specific metabolic pathways or mechanisms that are particularly vulnerable to insults to give rise to pathological changes in the brain?

Group 2: Metabolic Abnormalities in Neuropsychiatric Disorders

Utilizing the expertise of patient-oriented researchers, this group will review the current state of evidence for metabolic abnormalities in neuropsychiatric disorders to delineate a research agenda going forward. Key domains for discussion:

Based on findings from genetic/metabolomic/postmortem/induced stem cell studies, can we say we have a coherent picture of bioenergetic abnormalities in neuropsychiatric disorders?
In what ways are these metabolic abnormalities expected to impact brain function? What about related processes such as circadian rhythms? Can these findings offer clues about the emergence of neuropsychiatric disorders?
What is the current state of our knowledge regarding how metabolism is differentially impacted in different neuropsychiatric disorders such as seizure disorders, neurodegenerative disorders, psychotic disorders, and mood disorders?
What are the best candidates for applying our existing knowledge of brain bioenergetics for studying neuropsychiatric disorders? Which biomarkers in this domain are promising for use in clinical studies?

Group 3: Systemic Metabolic Aspects of Neuropsychiatric Disorders

This group brings together researchers who work at the intersection of psychiatry and systemic metabolic factors. Individuals with neuropsychiatric disorders are at high risk of developing metabolic syndrome and this risk appears at least partially independent of the well-known medication effects. This group is charged with delineating potential connections between neuropsychiatric disorders and the “rest of the body,” including microbiome, autonomic, endocrine, and inflammatory factors to develop a research agenda for addressing these connections. Domains for discussion include:

What is the role of insulin resistance, elevated body mass index, and systemic metabolic abnormalities as risk factors for morbidity/morality in neuropsychiatric disorders?
Is there a bidirectional connection between brain function and metabolism, whereby metabolism affects brain function and brain function affects metabolism?
Can systemic metabolic factors be identified and targeted for intervention during child/adolescent development to reduce severity of neuropsychiatric disorders?
How can clinical care for metabolic syndrome and other medical conditions in people with neuropsychiatric disorders be integrated into a broader “metabolic psychiatry” approach to care?

Group 4: Metabolism-Based Therapies for Neuropsychiatric Disorders

This group will focus on addressing the analytical/methodological challenges associated with assessing therapeutic approaches, relating to both efficacy and interpretability. Key questions include:

What would “success look like”? What biomarkers should we be focusing on as key mechanistic and clinical outcome measures? What steps can we take to avoid confirmation bias?
Given the multiple causal pathways affected by fundamental interventions like metabolism, can we identify a reasonably complete set of competing hypotheses for distinguishing between driving mechanisms vs. downstream effects?
Given the key role of feedback across multiple affected systems, how do we assess causality?
For dietary approaches, what key factors do we need to control for in achieving the rigor and reproducibility of clinical trials within the field of nutrition? Are there innovative strategies for achieving randomized double-blind placebo-controlled designs?
For pharmacological approaches, what are the challenges associated with targeting a key mechanism in isolation? Are there candidate pharmaceuticals used in other metabolic disorders that are well-motivated in terms of being repurposed? How would strategic use of pharmacological/targeted approaches advance our understanding of disease processes?

This Forum is supported by the Deutsche Forschungsgemeinschaft

The German Research Foundation