Excellent discussion, Awais--thank you! I would like to shift figure and ground for a moment, and note the importance of epigenetic factors. As Dr. Joe Coyle et al point out in a seminal paper on schizophrenia (I thank Dr. Manuel Mota for this reference):
"...adults who experienced abuse as children have altered epigenetic states and decreased expression of the glucocorticoid receptor gene NR3C1 in the hippocampus as compared with control subjects without a history of childhood abuse (61, 62). Epigenetic mechanisms are especially important in the complex pathophysiology of psychiatric disorders, including schizophrenia, where they mediate the emergence of molecular pathologies in specific populations of cells in specific brain regions stemming from nonspecific genetic and environmental risk factors. Fetal viral infections, famine during pregnancy, and complicated birth (63) as well as childhood abuse and neglect (64) are established environmental risk factors for schizophrenia."
And finally, as Bleuler pointed out in 1911, we are almost certainly dealing with a group of related disease processes (hence, Bleuler's term, "schizophrenias"). Accordingly, it may be more useful to inquire about the genetic and epigenetic factors (not to mention the psychosocial ones!) in the etiology and pathogenesis of the schizophrenias (plural).
Regards,
Ron
Ronald W. Pies, MD
1. Coyle J. Fifty Years of Research on Schizophrenia: The Ascendance of the Glutamatergic
Journal articles and books I have read by some of these authors and others, including Surviving Schizophrenia by E. Fuller Torrey, The Developing Genome by David S. Moore, and Innate by Kevin J. Mitchell suggests to me that many authors begin with preconceived beliefs about the etiology of schizophrenia and then seek evidence in support of those beliefs that is often unrepresentative of what really is a broad lack of consensus in academia. For example, Torrey cites what are tiny studies to question genetics before arguing for toxoplasmosis as a cause for schizophrenia, a position that has been questioned by other researchers who find less compelling results. Moore does a nice job of explaining heritability and epigenetics. But he also writes extensively about problematic beliefs in genetic determinism that may be rarer than he suggests among geneticists and biochemists: While teaching genetic determinism may be a problem among faculty members who either have not kept current in their field or are trying to simplify a topic for undergraduate students, I found when reading Emery and Rimoin's Principles and Practices of Medical Genetics and Genomics that not a single one of the many geneticists and biochemists who authored chapters of that book believe in genetic determinism--in fact, most of them explicitly reject the idea while explaining that genes and the proteins they encode do not exist in a vacuum but interact with their environments. On the other hand, authors of recent studies of adverse childhood experiences (ACEs) find those studies may often overemphasize the role of environment: One published as "Population vs individual prediction of poor health from results of adverse childhood experiences screening" (2021) in the Journal of the American Medical Association (JAMA) and another titled "Poor individual risk classification from adverse childhood experiences screening" (2022) in the American Journal of Preventive Medicine concluded that ACEs are only useful on a population level and not at the individual patient level where a careful assessment of a patient's entire family history is necessary. So wrong-headed thinking about genetic determinism may also apply to weakly supported thinking about infectious agents, trauma, and other purported causes of schizophrenia with each of those also identifying only a tiny amount of risk associated with (i.e., not causative of) schizophrenia. For these reasons, and because most researchers know a lot more than I do about these topics, I take no position.
A really clear follow-up article. Heritability, a bit like schizophrenia really, is a term that seems to cause so much confusion and argument, particularly in the academic literature around psychiatry and psychology. I do wonder whether other medical specialities get into the same difficulties when investigating aetiology?
Excellent discussion, Awais--thank you! I would like to shift figure and ground for a moment, and note the importance of epigenetic factors. As Dr. Joe Coyle et al point out in a seminal paper on schizophrenia (I thank Dr. Manuel Mota for this reference):
"...adults who experienced abuse as children have altered epigenetic states and decreased expression of the glucocorticoid receptor gene NR3C1 in the hippocampus as compared with control subjects without a history of childhood abuse (61, 62). Epigenetic mechanisms are especially important in the complex pathophysiology of psychiatric disorders, including schizophrenia, where they mediate the emergence of molecular pathologies in specific populations of cells in specific brain regions stemming from nonspecific genetic and environmental risk factors. Fetal viral infections, famine during pregnancy, and complicated birth (63) as well as childhood abuse and neglect (64) are established environmental risk factors for schizophrenia."
And finally, as Bleuler pointed out in 1911, we are almost certainly dealing with a group of related disease processes (hence, Bleuler's term, "schizophrenias"). Accordingly, it may be more useful to inquire about the genetic and epigenetic factors (not to mention the psychosocial ones!) in the etiology and pathogenesis of the schizophrenias (plural).
Regards,
Ron
Ronald W. Pies, MD
1. Coyle J. Fifty Years of Research on Schizophrenia: The Ascendance of the Glutamatergic
Synapse. https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2020.20101481
Journal articles and books I have read by some of these authors and others, including Surviving Schizophrenia by E. Fuller Torrey, The Developing Genome by David S. Moore, and Innate by Kevin J. Mitchell suggests to me that many authors begin with preconceived beliefs about the etiology of schizophrenia and then seek evidence in support of those beliefs that is often unrepresentative of what really is a broad lack of consensus in academia. For example, Torrey cites what are tiny studies to question genetics before arguing for toxoplasmosis as a cause for schizophrenia, a position that has been questioned by other researchers who find less compelling results. Moore does a nice job of explaining heritability and epigenetics. But he also writes extensively about problematic beliefs in genetic determinism that may be rarer than he suggests among geneticists and biochemists: While teaching genetic determinism may be a problem among faculty members who either have not kept current in their field or are trying to simplify a topic for undergraduate students, I found when reading Emery and Rimoin's Principles and Practices of Medical Genetics and Genomics that not a single one of the many geneticists and biochemists who authored chapters of that book believe in genetic determinism--in fact, most of them explicitly reject the idea while explaining that genes and the proteins they encode do not exist in a vacuum but interact with their environments. On the other hand, authors of recent studies of adverse childhood experiences (ACEs) find those studies may often overemphasize the role of environment: One published as "Population vs individual prediction of poor health from results of adverse childhood experiences screening" (2021) in the Journal of the American Medical Association (JAMA) and another titled "Poor individual risk classification from adverse childhood experiences screening" (2022) in the American Journal of Preventive Medicine concluded that ACEs are only useful on a population level and not at the individual patient level where a careful assessment of a patient's entire family history is necessary. So wrong-headed thinking about genetic determinism may also apply to weakly supported thinking about infectious agents, trauma, and other purported causes of schizophrenia with each of those also identifying only a tiny amount of risk associated with (i.e., not causative of) schizophrenia. For these reasons, and because most researchers know a lot more than I do about these topics, I take no position.
A really clear follow-up article. Heritability, a bit like schizophrenia really, is a term that seems to cause so much confusion and argument, particularly in the academic literature around psychiatry and psychology. I do wonder whether other medical specialities get into the same difficulties when investigating aetiology?