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March 8, 2015
by Dr. C. Wayne Winkle,Phd

Schizophrenia: Seeking The Cause

March 8, 2015 05:55 by Dr. C. Wayne Winkle,Phd

New research from Columbia University’s Mailman School of Public Health takes one more step toward finding the causative factors behind the development of schizophrenia (Stansfield, et al., 2015). Studying the brains of rats exposed to lead brought more strong indications that this kind of exposure may be a precursor to schizophrenia.

Why do studies of rat brains pertain to humans? Because rat brains and human brains bear a great resemblance in many ways (Palmowski, et al., 2014). And study after study has revealed similarities in the way rats’ brains and human brains react to various stimuli. Thus, studying these cheap subjects which can be controlled almost totally is the most practical method of understanding how the human brain reacts.

This new research into schizophrenia and its causes showed cells in three areas of the brain react detrimentally to lead.These three brain areas are also implicated in schizophrenia. They are the medial prefrontal cortex, the hippocampus, and the striatum(Stansfield, et al., 2015). Brain cells known as Parvalbumin-Positive GABAergic interneurons (PVGI) decreased in density by about one-third in the rats exposed to lead. This is about the same amount of decline as seen in schizophrenics. Also, higher levels of a dopamine receptor called D2R; the amount of this increase was again about the same that has been seen in schizophrenics.

Prevalence of Schizophrenia

Research results like those referenced above and to follow in this article are important in the study of schizophrenia because of the number of people in the U.S. and around the world who suffer from this lifelong disease.

According to the Centers for Disease Control and Prevention (2013), between 0.5% and 1% of the population around the world has this illness at any given time. Approximately 1.1% of the U.S. population is estimated to have schizophrenia. This is about 3,432,000 people.

Impact of Schizophrenia

There are various ways to measure the impact of this sometimes devastating illness. The greatest impact, of course, is that suffered by the individuals who develop its symptoms.

Schizophrenia is a brain disease that can affect nearly every area of a sufferer’s life (Smith & Segal, 2015). It makes distinguishing between what is real and what is not real difficult. A schizophrenic can go through life not knowing what to respond to or responding to the wrong “reality”. It’s also difficult to think clearly and to communicate with others so that they can understand what the person with schizophrenia is trying to say. Emotions typically are dampened and are very difficult to express. Relating to others becomes so hard the person with schizophrenia withdraws from social contact.

Combine this with the alarming rate of attempted and completed suicide among schizophrenics, and the personal impact of the illness becomes clearer. Among schizophrenics, about one out of three will attempt suicide and one in ten will complete it (CDC, 2013).

The economic impact on the individual with schizophrenia and on society is great. The person with schizophrenia typically can’t work for a significant amount of time because he or she can’t comprehend instructions and can’t communicate that misunderstanding. Thus, many of those with this illness are on disability.

A study in Canada showed both direct and indirect health costs of schizophrenia to be 2.02 billion Canadian dollars in 2004. Adding productivity losses and mortality costs brought the total to 6.85 billion Canadian and U.S. dollars (CDC, 2013).

Seeking Causes of Schizophrenia

The above information helps to showcase the importance of finding causes of this illness. Once causes are found, mechanisms of progression of the disease will follow, along with more effective treatments.

An earlier study at Columbia University showed mice who had been grown with a human gene for schizophrenia and then exposed to lead early in their lives showed both behaviors and structural changes in the brain indicative of schizophrenia (Abazyan, et al., 2013). This research targeted the way lead might trigger the development of schizophrenia. It built on earlier research that suggested prenatal exposure to lead in humans increases the risk of schizophrenia later in life. Results of this research suggested lead inhibits a synaptic connection point, N-methyl-D-aspartate (NMDAR). An hypothesis about schizophrenia that said a decrease in glutamate dysfunction in schizophrenia combined with inhibition of NMDAR might explain much of the overall dysfunction seen in schizophrenia.

Other researchers at the University of Southern Denmark studied proteins in the brains of rats (Palmowski, et al., 2014).The researchers knew these proteins well. They studied the ways the proteins differed in brains that exhibited schizophrenic symptoms from those that didn’t. Developing more effective medications for the treatment of schizophrenia was the goal.

In 352 different proteins, changes suggestive of symptoms of schizophrenia were seen. Preventing these changes in the proteins could be a way to more successfully treat schizophrenia.

Phenocyclidine (PCP) was used to affect the rats’ brains in a way that produced symptoms similar to schizophrenia. The PCP made the proteins turn on or off when they should not turn on or off. This was comparable to the very significant negative changes in the brain of a person with schizophrenia.

Other research at Rutgers University studied protein, also (Carrel, et al., 2014). This research looked at the amount of protein expressed by a gene, NOS1AP, that had been connected with schizophrenia. Too much protein from this gene leads to changes in the structure of the brain and prevents nerve cells from communicating. The overabundance of protein from this gene kept the dendrites of nerve cells in the neocortex from emerging from the neocortex and growing connections with other nerve cells. This led to problems in spatial reasoning, conscious thought, motor commands, language, and sensory perception.

Yet other researchers have investigated the neurodevelopment issues seen in the brains of people with schizophrenia as being similar to advanced aging (Kochunov, et al., 2013). The brain structure and function changes seen in schizophrenia bear strong similarities to those seen in advanced aging. People with schizophrenia have shortened telomeres like those seen in significantly older people. Lower gray and white matter volumes and more cortical thinning are seen both in schizophrenics and people of advanced age. Knowing these similarities may lead to new ways to treat schizophrenia early.

Other research supports these findings. Indications of differences in the development of the cortex of people with schizophrenia were seen in this research (Alexander-Bloch, et al., 2014). Knowing this revealed important clues to the causes of schizophrenia. This research allowed scientists to focus future studies on specific areas of the brain affected by altered connectivity due to the schizophrenia process.

The ability of neurons to communicate adequately and accurately with one another is one hallmark of proper functioning of areas of the brain. When this communication is poor, thinking becomes difficult, perception is changed, understanding is skewed. Abnormalities in the myelin surrounding white matter in the brains of people with schizophrenia leads to this kind of poor communication among neurons (Du, et al., 2013). Problems with information processing and cognition were found in this research, likely caused by abnormalities in myelin and changes in diffusion of N-acetylaspartate, a metabolite usually found in nerve cells. The search for new ways to remedy this kind of abnormal functioning may ultimately lead to new medications or other forms of treatment for schizophrenia.

Maternal C-reactive protein levels have also been studied as a possible risk for later development of schizophrenia (Canetta, et al., 2914). The C-reactive protein levels in the blood of mothers is a biomarker for inflammation. Inflammation has been linked to increased risk of developing several mental health conditions, and now may be a risk factor for later emergence of schizophrenia symptoms. This research showed for every 1 mg/L increase in maternal C-reactive protein, risk for development of schizophrenia increased by 28%. The link appears to be developmental in nature, because inflammation has been shown to change brain development, and schizophrenia has been shown to be a neurodevelopmental disorder.

Vitamin D has been shown to be at low levels in people with schizophrenia (Valipour, et al., 2014). And people with deficient levels of vitamin D are two times more likely to be diagnosed with schizophrenia as those with good levels of the vitamin. That there is some connection between deficits in vitamin D and the development of schizophrenia is supported by the occurrence of schizophrenia being increased at high latitudes and cold climates where there is less opportunity for the body to make vitamin D from exposure to the sun. Much more research is needed for this kind of connection to be certain.

One issue in the study of schizophrenia seems to be certain. New, effective medications that don’t have the side effects of current medications for the treatment of schizophrenia are needed. People with schizophrenia often take medications that have significant side effects. Stiffness, tremor, and slow gait are among the most noticeable and uncomfortable of those side effects. This leads people with schizophrenia to stop taking their medications, sometimes before they even receive the most benefit from them. If medications without these side effects can be developed, treatment of the symptoms of schizophrenia would be dramatically improved and more people would experience a significant lessening of the devastating effects of schizophrenia.

To that end, researchers at the Centre for Addiction and Mental Health have sought and found a new target for medical intervention in the treatment of schizophrenia (Su, et al., 2014). The binding of two proteins in the brain, dopamine D2 receptors and the Disrupted-in-Schizophrenia (DISC1) protein, seems to lead to the development of the unwanted side effects so often seen. By developing a peptide to prevent this binding, researchers showed the antipsychotic effects wanted without the disruptive side effects. Further development of this peptide could lead to new medications for treating schizophrenia.

Other research from Monash University is looking at “dialing down” the effects of dopamine rather than totally blocking it (Lane, et al., 2014). This direction in research into treating schizophrenia could potentially lead to a completely new class of medications that are effective and without uncomfortable side effects.


That the kind of research ongoing into the causes of and into new treatments for schizophrenia is needed clearly is also obvious when examining the prevalence of the illness. Looking at the impacts of the illness further strengthens the need. Millions of people in the U.S. and around the world suffer from this devastating, lifelong illness. Their friends and loved ones likewise suffer.

Finding causes for the development of schizophrenia will lead to more and better treatments. Can prevention be far behind? It is important to cast the net of research far and wide, to investigate all possible causes and potential treatments in order to find the one or ones that will be most effective to relieve the suffering of those millions of victims of this illness.


Abazyan, B., et al. (2013). Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study. Schizophrenia Bulletin. DOI: 10. 1093/schbul/sbt071.

Alexander-Bloch, A. F., et al. (2014). Abnormal cortical growth in schizophrenia targets normative modules of synchronized development. Biological Psychiatry. 76(6):438.

Canetta, S., et al. (2014). Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. American Journal of Psychiatry. DOI: 10. 1176/appi.ajp.2014.13121579.

Carrel, D., et al. (2014). NOS1AP, a protein implicated in schizophrenia, controls radial migration of cortical neurons. Biological Psychiatry. DOI: 10. 1016/j.biopsych.2014.10.016.

Centers for Disease Control and Prevention. (2013). Schizophrenia Facts and Figures. Retrieved from

Du, F., et al. (2013). Myelin and axon abnormalities in schizophrenia measured with magnetic resonance imaging techniques. Biological Psychiatry; 74(6):451.

Kochunov, P., et al. (2013). Testing the hypothesis of accelerated cerebral white matter aging in schizophrenia and major depression. Biological Psychiatry; 73(5): 482.

Lane, J. R., et al. (2014). A new mechanism of allostery in a G protein-coupled receptor dimmer. Nature Chemical Biology. DOI: 10. 1038/nchembio.1593.

Palmowski, P., et al. (2014). Acute phencyclidine treatment induces extensive and distinct protein phosphorylation in rat frontal cortex. Journal of Proteome Research; 13(3):1578.

Smith, M., & Segal, J. (2015). Schizophrenia, signs, types, and causes. Retrieved from

Stansfield, K. H., et al. (2015). Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopaminesystem hyperactivity present in schizophrenia. Translational Psychiatry; 5(3):e522.

Su, P., et al. (2014). A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects. Neuron. DOI: 10. 1016/j.neuron.2014.11.007.

Valipour, G., et al. (2014). Serum vitamin D levels in relations to schizophrenia: a systematic review and meta-analysis of observational studies. The Journal of Clinical Endocrinology & Metabolism; jc.2014-1887.

About the Author

C. Wayne Winkle C. Wayne Winkle

I have over 30 years experience as a psychologist. My current 'day job' involves writing job descriptions, policy and procedure manual entries, and other writing activities for a mental health center.

C. Wayne Winkle can be found at
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