Thesis 1: Schizophrenia is #epigenetic in Nature: A psychotic “breakdown” is usually followed by a lifetime of mental illness and misery. This often permanent change in functioning results from altered chromatin bookmarks that regulate gene expression. Since the deviant marks are maintained during future cell divisions, the condition doesn’t “go away”.
Thesis 2: Weak Antioxidant Protection is a Distinctive Feature of Schizophrenia: Most schizophrenics exhibit a genetic or acquired weakness in antioxidant protection. Evidence from my extensive chemistry database includes generally low levels of glutathione, cysteine, selenium, zinc, polyunsaturated fats, together with high levels of non-ceruloplasmin copper.
Thesis 3: Oxidative Overload Produces Deviant Epigenetic Marks in Schizophrenia: Cancer researchers have identified cumulative oxidative stress as a trigger that can transform healthy cells into cancer cells by altering epigenetic marks that permanently change gene expression. Examples include (a) skin cancer developing after years of excessive sun exposure, and (b) lung cancer following years of cigarette smoking. It’s not a coincidence that nearly all schizophrenia patients exhibit excess oxidative stress. The onset of schizophrenia occurs when oxidative stresses exceed the threshold level needed to alter chromatin marks that regulate gene expression.
Thesis 4: #methylation Imbalances Promote Epigenetic Vulnerability to Oxidative Stress: Abnormal methylation of chromatin is a leading cause of epigenetic errors in gene expression. The combination of oxidative overload and a methyl imbalance can produce gene expression changes that result in a chronic schizophrenia condition. The two most prevalent forms of schizophrenia develop in persons who exhibit either (a) methyl overload or (b) methyl deficiency. The two resulting psychotic disorders exhibit very different brain chemistry and symptoms.
A. #overmethylation – About 46% of persons diagnosed with schizophrenia exhibit excessive methylation of chromatin along with weak antioxidant protection. Mental breakdowns generally occur during severe physical or emotional traumatic events that produce overwhelming oxidative stress and deviant gene marks. This schizophrenia biotype is a sensory disorder that generally involves auditory, tactile, or visual hallucinations. This condition is associated with elevated activity of dopamine and norepinephrine, and reduced glutamate activity at NMDA receptors. The most common DSM-4 diagnosis is paranoid schizophrenia.
B. Undermethylation – About 28% of persons diagnosed with schizophrenia exhibit low methylation of chromatin together with weak antioxidant protection. Mental breakdowns generally occur during severe physical or emotional traumatic events that produce a separate set of altered gene marks. This schizophrenia biotype essentially is a thought disorder with delusions and catatonic tendencies the primary symptoms. This condition is associated with low activity at serotonin, dopamine, and NMDA receptors. The most common DSM-4 diagnoses are Schizoaffective Disorder or Delusional Disorder.
Thesis 5: Extraordinary Weakness in Antioxidant Protection Can Produce Schizophrenia in the Absence of Methyl Imbalances: The third major schizophrenia phenotype develops in persons with an inborn severe deficit in antioxidant protection. This condition is arbitrarily termed “Pyrrole Disorder” due to the presence of excessive pyrrole levels in blood and urine. Mental breakdowns occur for these persons during periods of extreme physical or mental stress in which deviant epigenetic marks are established. This condition is characterized by extraordinary anxiety, rapid mood swings, and often involves both auditory hallucinations and delusional beliefs. Brain chemistry abnormalities include (a) depressed glutamate activity at NMDA receptors, and (b) very depressed GABA activity.
Thesis 6: Failure to Follow Classical Laws of Genetic Inheritance Results From the Epigenetic Nature of Schizophrenia: Schizophrenia is strongly heritable (runs in families) but fails to obey Mendel’s classic laws of genetic inheritance. There are countless examples of identical twins where one sibling develops the disorder and the other does not. In addition, intensive research efforts to identify the schizophrenia gene (or genes) have met with little success. #epigenetics provides two explanations for the non-Mendelian nature of schizophrenia: (a) Environmental insults are required to produce deviant epigenetic marks and environmental conditions are highly variable for different individuals, and (b) Transgenerational epigenetic inheritance (TEI) contributes to schizophrenia heritability by transmitting deviant epigenetic marks to one’s children and grandchildren.