Between the years of 1959 and 1991 my grandfather, William Sacks, published a series of neurochemistry papers in which he identified links between the pathophysiology of Schizophrenia, and alterations in the metabolism of glucose by brain cells. As is often the case with any scientist working with complex diseases, my grandfather was never able to finish his research. Due to the nature of the time period in which he worked, my grandfather had the unique opportunity to perform much of his research in vivo, using live human subjects. William, has always been an immense inspiration to me, and for this reason I have chosen to use this Capstone Project as an opportunity to connect his original research to literature that has been published since, particularly articles published within the last five years.
Current Schizophrenia research takes many different perspectives and approaches to understanding the illness, with the primary focuses being the dopamine hypothesis, neurotransmission, and genetic mutations. Despite this, there are still scientists who have continued to pursue the relationship between impaired glucose metabolism and schizophrenia. In searching through various databases, I was able to find a substantial number of articles tackling this relationship, dating all the way from 1968 to 2016. Consistently, this field of study has relied on Proteomic and Metabolomic studies in order to observe this relationship. What this means, is that researchers measure the levels of specific metabolites at specified times, and compare the levels to those obtained from healthy subjects. Some research has even been able to indicate relationships between Diabetes and Schizophrenia, another condition that is directly related to metabolism.
One thing I find interesting about the body of work I have unearthed, is that there appears to be a major conflict between the scientists investigating this avenue of Schizophrenia’s biochemical origin. Many current authors, like my grandfather, believe and have demonstrated that individuals afflicted with Schizophrenia display abnormalities in their brain’s metabolism of carbohydrates, and that these alterations are a causal factor for developing the disorder. However, another subset of authors believes that these alterations are the product of treatment with anti-psychotic drugs. Interestingly, neither of these perspectives seems to be definitive as on one hand, experiments have been performed assessing the impact of various antipsychotic medications on glucose metabolism. These experiments indicate that these medications do impact glucose metabolism, and that some have greater impacts than others. On the other hand, experiments have been performed using only drug-naïve or drug-free patients (those who have never been medically treated for their condition), and have still revealed abnormalities in their metabolism of carbohydrates in comparison to that of healthy subjects. Personally, I am somewhat biased towards the notion that impaired glucose metabolism is a causal factor for Schizophrenia, as this was my grandfather’s life’s work. However, I cannot ignore the evidence that anti-psychotics impact metabolism as well. For this reason, I find myself taking the perspective that maybe these arguments are two sides of the same coin. What I mean, is that I wonder if impaired glucose metabolism is important to the development of Schizophrenia, and that antipsychotic drugs simply exacerbate the measurable symptoms.
In organizing my sources for this project, Cerebral Glucose Metabolism in relation to Schizophrenia will serve as one of two primary categories. Due to the prevalence of the above controversy in the published literature, I have chosen to use it as a means of organizing my sources regarding glucose metabolism. I will begin by separating these references into two categories: 1.) those that assess the impact of anti-psychotic drugs on carbohydrate metabolism, and 2.) those that look at metabolic abnormalities as causal factors for Schizophrenia. I will then further separate the latter into two subcategories: Those that specifically work with Drug-Naïve/Free subjects, and those that do not. Within the second main category, I would also like to explore a notion discussed in the first article I obtained. Dean’s article indicated deficiencies in sugar metabolism only in non-MRDS subjects. I am very curious to see if I can collect other literature that makes this same delineation between the subtypes of Schizophrenia. Finally, I have also found a couple of articles which, while remaining in the vein of relating glucose metabolism to schizophrenia, have proposed alternative treatments from general antipsychotics. These articles such as Sacks’s study of Acetazolamide and Thiamine treatment, or Robson’s analysis of cannabinoids as potential treatments will be organized into their own category which will be discussed much more briefly, and towards the end of my literature review.
In my investigation of the literature on Schizophrenia, I also found article discussing the role of Glutamate Neurotransmission in the pathophysiology of Schizophrenia. Research has shown the antagonism of Glutamate receptors produces Schizophrenia-like symptoms in healthy subjects, and agonism of the receptors alleviates the symptoms in patients suffering from the disorder. One of the avenues of glutamate biosynthesis is conversion from intermediates of the TCA cycle, such as a-ketoglutarate (a-KG). Furthermore, much of the research regarding impaired glucose metabolism in Schizophrenia identifies low activities of enzymes that are involved in the production of a-KG. This notion led me to the hypothesis that there may be a connection between cerebral glucose metabolism and glutamate neurotransmission, and that this link could be a mechanism by which impaired glucose metabolism produces the symptoms of Schizophrenia. Interestingly, I was unable to find any articles that implied or refuted this connection. One of my grandfather’s papers briefly mentions this connection, but does not follow up on it. This hypothesis could also explain the effectiveness of his Thiamine treatment, as well as why impaired glucose metabolism is not observed in MRDS subjects (a different receptor is involved). Therefore, Glutamate Neurotransmission will serve as one of two primary categories, alongside glucose metabolism, by which I will organize my sources. Once I have collected more sources regarding this topic, I will attempt to separate them into two categories: those focusing on the theory itself, and those focusing on related treatments. As of now, I have not yet made this deliniation.
I recognize that my system of organization is somewhat complicated, and may be a little bit difficult to follow in reading this blog post. Therefore, I have chosen to include the following schematic diagram in order to provide a more clear and understandable visual representation.
When I take on large projects such as this one, I have a tendency to get a little bit over ambitious with my ultimate goals. Interestingly, much of the related, current literature does not reference his papers at all, and thus a primary goal of mine is to reintroduce his studies to the modern scientific community. Furthermore, I hope that in my analysis of this collection of literature, I will be able to support my hypothesis about the connection between impaired cerebral glucose metabolism and glutamate neurotransmission in the pathophysiology of Schizophrenia. While these goals may not be fully plausible within the scope of this project, I am going to hold onto them anyway, as they will motivate me to put out my best work.
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