The Walsh Theory Of Schizophrenia

A Novel Theory Of Schizophrenia

A flaw in existing theories has been the failure to recognize that schizophrenia is an umbrella term that includes at least three very different disorders, each presenting a distinctive set of symptoms and traits. It seems most unlikely that these disparate mental illnesses arise from the same underlying cause. I believe a proper theory of schizophrenia must include the following elements:

  • Separate causation for the major phenotypes,
  • Explanation for the “mental-breakdown” event that usually occurs in late adolescence or young adulthood,
  • Explanation for the life-long persistence of schizophrenia after the mental breakdown, and
  • Explanation why this familial (heritable) disorder violates classical laws of Mendelian genetics.

Common features of the different types of schizophrenia include (a) relative normalcy prior to the mental breakdown, (b) psychosis, (c) cognitive deficits, (d) loss of social skills, (e) high anxiety, (f) enlarged brain ventricles and smaller volumes in cortex and other brain areas, and (g) benefits often achieved using atypical antipsychotic medications. There is a common thread in these disorders, despite their very great differences in biochemistry. Eventually I realized that the three major schizophrenia phenotypes shared the following important features: (1) vulnerability to epigenetic errors that can alter gene expression, and (2) weakened protection against oxidative stress. These insights led to my theory of schizophrenia which is presented below:

Walsh Theory Of Schizophrenia

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.

Purchase Nutrient Power by William J Walsh from The Walsh Research Institute


Books | Schizophrenia

Book Review of Nutrient Power by Dr Judith Pentz International Network Integrative Mental Health Board Member

Book Review by Judith E. Pentz, MD (Board Member of INIMH)


NUTRIENT POWER is a synthesis of the science/research that was started by Abram Hoffer and Carl Pfeiffer. The book is a synopsis of William Walsh’s life work that led to the formation of the Pfeiffer Clinic located near Chicago. The clinic recently closed their doors but the legacy and the research that it generated are finally being shared with clinicians and the public. There are different laboratories around the world offering the testing described in the book, with the largest concentration here and in Australia. 

The collaboration with different researchers, including Carl Pfeiffer and Dr Walsh’s colleagues at Argonne National Laboratory, started with Dr Walsh being curious as to why there was such high recidivism in the prisons where he volunteered. He spent time with the families and noticed a pattern of one person from the family being ‘different’ from early on, compared to siblings that were more able to be part of an ordinary, non-criminal life. He decided to study their blood and urine samples as well as other lab studies. This led to small pilot studies as well as field studies with a blinded aspect to them. There were 12 outcome studies done. An open label study was done in 2004. The clinic found that the earlier the intervention (< 14y.o.) the better the outcome, so their focus switched to children and teens in 1985.

The patterns he saw were also seen by Abram Hoffer and Carl Pfeiffer. Notably, the interventions they proposed were correct but the hypotheses they put forth were inaccurate. With the help of basic biochemistry and epigenetics, there is an interesting convergence happening that may assist us in understanding patterns of behavioral/emotional challenges across all diagnostic categories in the DSM.

The awareness of environment, lifestyle, diet, and toxins having adverse impact on gene expression is growing. There is increased research noting that micronutrients may play a role. Nutrient overload is seen ‘to create more havoc on mental state’ than nutrient deficiency. The research has found that specific nutrient interventions can assist in creating balance in the blood and urine. The end results lead to: optimizing concentration of nutrients needed for neurotransmitter synthesis, epigenetic regulation of neurotransmitter activity, reduced oxidative stress. 

One main biochemical pathway that is often adversely affected is the methylation cycle with undermethyl-ation and overmethylation being great contributors to mental illness, depending on the variables of nature and nurture. The strength of the expression of the defect varies for each individual with the defect. 

DNA and histones involve a winding and unwinding process, via adding either a methyl group or acetyl group. Methylation tends to put the brakes on the process and acetylation speeds up the process. 

The use of nutrients and modifying oxidative stress impacts this process on the number of transporters at the cell membrane. The transporters aid in the passage of neurotransmitters across the cell membrane.

A discovery in 2009 aided in understanding some of the puzzling findings. The methyl (CH3) group and folic acid ratio have an inverse relationship from an epigenetic point of view on norepinephrine. Folates tend to enhance histone demethylation. Methionine increases histone methylation. With this information, more specific nutrient interventions were possible. 

This may also help us to better understand why certain people with depression who are overmethylated respond poorly to SSRIs but those who are undermethylated respond nicely to SSRIs.

Other specific interventions address what are referred to as biotypes: 

  • copper overload with zinc deficiency; 
  • vitamin B6 deficiency; 
  • Zinc deficiency due to dietary issues; 
  • amino acid imbalances; 
  • fatty acid imbalances; 
  • oxidative stress; 
  • toxic overload; 
  • glucose dysregulation; and 
  • malabsorption.

The details of various studies that were conducted during the 20 years are reviewed. The response time depended on the type of imbalance with the challenge of pyrrole overload being the easiest and quickest to remedy. Positive impact can be seen in days. There is also a breakdown by disorder with the specific biotypes that are noted above.

Schizophrenia is a focus, with two expanded views/hypotheses: glutamate theory, with a discussion of the role of NMDA being modified with glycine, noting that the NMDA receptor has the unique role of simultaneous docking of glutamate and glycine. The second theory has to do with oxidative stress being a primary cause of the disorder. He notes that, with the reduction of glutathione, this allows for reduced glutamate. This leads to delusions and hallucinations.

Time is spent reviewing the strengths and the challenges of the nutrient interventions. Looking at non-responders, the majority were due to noncompliance with the protocols. Other setbacks were growth spurts, injuries, illness, emotional stress, Type A blood and malabsorption. Substance abuse, anoxia at birth, and head injuries would lead to poor outcomes. The only exception with substance abuse was if the person was using marijuana, they would still respond.

He is hopeful that the field of epigenetics  will further the future of nutrient therapies rather than ‘introducing more foreign molecules to the brain’.

It is a promising approach that is summarized relatively well. There is a level of repetition that can be a bit tedious but it drives home the point that there is a pattern present and yet there are very different expressions that occur at the physical/mental/emotional level. Interestingly, the nutrient therapies are still specific to the biotype, regardless of the DSM diagnosis. Further research to replicate this body of research would be good to consider but should not deter the clinician from considering exploring this nutrient intervention in a clinical setting.