Learning About Schizophrenia, Part III: Cause

What are the potential causes of schizophrenia? Is there always a genetic neurological component present, or can environmental factors trigger schizophrenia's onset? Here's some of what we've learned about what may cause schizophrenia.

In the previous two blog posts, we discussed the symptoms, diagnostic criteria, and treatment options for patients with schizophrenia. Our third post explores some of the potential causes of schizophrenia. Let's dive in.

The current conversation about schizophrenia's cause revolves around epigenetics, which is the study of how our environment influences our genes by changing the chemicals attached to them (Cleveland Clinic). But the lack of definitiveness in terms of its precise causality leaves those with schizophrenia (and their loved ones) in the dark about what could have triggered, or possibly prevented, this disorder. As Sandra Luckow says in her 2017 documentary about her brother, Duanne, who struggles with late-onset schizophrenia, "What happened to Duanne?" and "Why didn't we see this coming?"

Technically speaking, schizophrenia itself is caused by a chemical imbalance in the brain (Johns Hopkins Medicine). Neuroimaging studies reveal changes in the brain structure and central nervous systems of schizophrenic patients (Mayo Clinic), thereby solidifying the illness as a brain disorder (not a personality disorder). But what exactly are these neurological changes, and how do they arise?

In terms of the hereditary nature of schizophrenia, pioneering schizophrenia researcher David Rosenthal, who studied the Genain quadruplets (all of whom had schizophrenia), was one of the first to theorize that a person's genetic predisposition and their environment may interact with each other to produce the symptoms of schizophrenia. A patient's genetic predisposition refers to an increased likelihood of developing a particular disease or trait due to inherited genetic variations (VeryWell Health).

The assortment of genetic irregularities associated with schizophrenia includes mutations of the SHANK-2, C4, and CHRNA-7 genes. Respective differences of the aforementioned genetic mutations may explain the wide variety (and severity) of symptoms that schizophrenia patients present. The chromosome housing CHRNA-7 mutations has been definitively associated with schizophrenia and affects a specific cell in the hippocampus, a part of the brain's temporal lobe involved with memory consolidation. Profilic schizophrenia researcher and University of Colorado Professor Robert Freedman identified the alpha-7 nicotinic receptor as the source of the brain's malfunctioning "inhibitory interneurons" that cause a person to process the same information over and over again, leading to disorientation, delusions, and paranoia (PubMed). The alpha-7 nicotinic receptor controls the on/off switch for inhibitory interneurons, but requires a neurotransmitter called acetylcholine to function properly. Variations in the CHRNA-7 gene can lead to the brain producing fewer alpha-7 receptors (compared to a neurotypical brain), and therefore less acetylcholine to support the receptors' functionality (National Library of Medicine). These findings may explain why recreational nicotine use has reportedly helped some schizophrenia patients self-medicate, as well as why medication including the compound "DMXBA" (which mimics nicotine's effect on the brain) showed promise in improving schizophrenia patients' cognitive function during experimental trials ("Schizophrenia and the alpha7 nicotinic acetylcholine receptor").

Professor Robert Freedman has supported the vulnerability hypothesis about schizophrenia, which says "Certain genetic traits directly compromise the brain's sensory and information-processing functions" (Kolker, R. (2020). Hidden Valley Road: Inside the mind of an American family, p. 179), making a schizophrenia patient's brain more vulnerable to environmental stressors than a neurotypical brain. Perhaps due to the genetic variability of CHRNA-7 (and subsequent lack of alpha-7 nicotinic receptors), schizophrenia patients often struggle with sensory gating. Sensory gating refers to the brain's ability to filter irrelevant sensory input. Auditory sensory gating deficit is considered a marker of schizophrenia (National Library of Medicine). Freedman's theory about schizophrenia boils down to the idea that having a genetic predisposition makes a patient more vulnerable to certain environmental stressors that could ultimately trigger schizophrenia.

According to the Mayo Clinic, certain environmental stressors or risk factors that increase the likelihood of a person developing schizophrenia may include:

• Genetics: A family history of schizophrenia

  • Studies have shown that family history is present in 10-15% of schizophrenia patients (Curr Opin Psychiatry, 2014)

• Environment: Traumatic life experiences (e.g. Poverty, stress, danger, etc.)

• Brain Chemistry Issues (notably during pregnancy (in utero) and childbirth)

  • This can result from a lack of nutrition, low birth weight, or exposure to toxins and/or viruses that affect a baby's brain development before birth

• Substance Use: Taking psychoactive or psychotropic drugs as a teen or young adult

  • "Heavy use of cannabis is associated with an elevated risk of the disorder" (WHO)

In the 1987 paper "Implications of normal brain development for the pathogenesis of schizophrenia," Johns Hopkins University School of Medicine Professor of Psychiatry, Neurology, Neuroscience, and Genetic Medicine, Daniel R. Weinberger stated that schizophrenia's neurodevelopmental origin was, in and of itself, "not a sufficient explanation" for what causes the illness. Professor Weinberger suggested that the unique characteristic of what causes schizophrenia is how a person's pathology interacts with the "normal course of maturation of the brain systems affected by it" ("The neurodevelopmental origins of schizophrenia in the penumbra of genomic medicine"). One such brain system is called synaptic pruning, the brain's process of eliminating unnecessary neural connections, which could potentially contribute to the timing of schizophrenia's onset. Though most active in early childhood and adolescence, synaptic pruning continues into a person's 20s, specifically in the prefrontal cortex region of the brain. This is significant because the window of schizophrenia's typical onset occurs during a person's late adolescence until their late 20s, and some studies cite the brain's excessive synaptic pruning in late adolescence/early adulthood as the source of what may uncover a person's latent genetic predisposition to schizophrenia (National Library of Medicine, Harvard Medical School).

But the synaptic pruning theory of schizophrenia may not explain what causes late-onset schizophrenia. Late-onset schizophrenia (LOS) is when a person begins experiencing symptoms of schizophrenia after the age of 40, and accounts for approximately 15-20% of all cases of schizophrenia ("Schizophrenia in late life: emerging issues"). For female patients, there is some speculation and research about menopause and how its reduced estrogen protection may be a trigger for late-onset schizophrenia in middle-aged women (sometimes diagnosed as "menopause-associated psychosis"). However, a 2023 scholarly article about menopause and schizophrenia stops short of making any definitive conclusions about a causal interaction ("Understanding the Impact of Menopause on Women With Schizophrenia-Spectrum Disorders: A Comprehensive Review"). The study does, however, appear to certify that menopause renders women more vulnerable to developing late-onset schizophrenia, especially if there are risk factors present: "Genetic predisposition, medication use, lifestyle factors, and social determinants of health may contribute to this heightened risk."

In conclusion, research and scholarly studies conducted over the past 40 years appear to have settled the classic, black-and-white 'nature versus nurture' debate regarding schizophrenia's cause, concluding that components of both nature (genetic/hereditary) and nurture (environmental) interact, collectively spawning the disorder. It is possible that a person's latent genetic vulnerability can remain dormant during a person's lifespan until certain behavioral tendencies (such as substance abuse) and/or life events (including hormonal disturbances like menopause, postpartum, or enduring severe physical or emotional trauma) trigger schizophrenia's onset. But the persisting ambiguity about schizophrenia's cause continues to complicate its prevention. We will explore potential theories and mechanisms for preventing schizophrenia in our next blog post.