Aditi Singh ’28

In 2020, author Robert Kolker published Hidden Valley Road, detailing the tragic story of the Galvin family, in which six out of twelve children were diagnosed with schizophrenia, one of whom committed suicide. By the end of this family’s story, unspeakable tragedy befell them over and over again, and with a lack of existing research came a lack of closure. At the time when the 

Galvin children were born, schizophrenia was considered the product of poor mothering, despite the lack of scientific backing. Throughout their lifetimes, scientists began taking a more biological approach to understanding the disease, eventually even collaborating with the family to develop a genetic understanding of schizophrenia. Interestingly, several of the children in the Galvin family who were diagnosed with schizophrenia struggled with some sort of drug addiction, causing many scientists to question whether substance abuse was an outcome of schizophrenia or a cause of it.

Epigenetics, the study of how environmental factors alter gene expression, has become more involved in scientific analyses surrounding substance abuse and schizophrenia, producing more nuanced discussions. However, despite the progress made in the field, more research is undeniably necessary to better qualify this relationship and use our understanding to improve mental health outcomes. 

The comorbidity of substance abuse and schizophrenia was by no means unique to the Galvin family. Notably, experts estimate that nearly 47% of people with schizophrenia have struggled with drug and alcohol abuse compared to only 16% of the general population. Scientists are exploring several explanations for this comorbidity. According to the diathesis-stress model, an epigenetic proposal focusing on the interaction of environment and biology, the combination of genetic vulnerability to schizophrenia and an environmental stressor like substance abuse disorder causes the expression of schizophrenic traits.

Considering the relatively recent realization that schizophrenia patients who have experienced child abuse, another environmental stressor, typically experience worse displays of psychosis, this model is popular within the biopsychological community. Other research posits the cumulative risk factor hypothesis, which suggests that similar environmental factors result in both the development of schizophrenia and substance abuse– someone who is traumatized is likely to experience schizophrenia and is likely to use substances as a coping mechanism. 

Determining the direction of causality is incredibly difficult, but both theories rely on one idea: schizophrenia and substance abuse have some sort of related mechanism that causes one to influence the other. A 2015 study published by the National Institutes of Health (NIH) explored a potential mechanism through the lens of adolescent cannabis consumption, specifically focusing on cholecystokinin-expressing (CCK) basket cells. They contextualize that adolescent cannabis users developed psychotic symptoms nearly three years earlier than their non-psychotic counterparts and generally had increased risk for developing schizophrenia.

CCK basket cells are involved in inhibitory neuronal pathways that are involved in functions like mood regulation and working memory. In primates, activating cannabinoid 1 receptor (CB1R) G-protein coupled receptors in the prefrontal cortex by Δ9-tetrahydrocannabinol (THC) had a detrimental effect on working memory, and CB1Rs are almost exclusively expressed by CCK basket cells. Since previous research demonstrates that dysfunctional basket cells and impaired memory likely play a role in schizophrenia, researchers suggest that marijuana use is an interactive risk factor or mechanism for increased vulnerability to schizophrenia.

The prevalence of marijuana use among current adolescents necessitates further researchon its connection to schizophrenia. The NIH and NIDA report that nearly 30.7% of high school seniors and 15% of all teenagers report marijuana use in the last year. Among teenagers in the US specifically who had been hospitalized for psychotic disorders, 83% reported previous marijuana use. Thus, researching the connection between marijuana use and schizophrenia can help advance scientific understanding of schizophrenia’s mechanism of action and drive future preventative measures or treatment regimes. 

Future research can take three different approaches to understanding the environmental and genetic causes of schizophrenia: genetic testing, epidemiological studies, and adolescent-specific research. 

1) Genetic testing has already yielded promising advances, particularly in recent years. Prior to the Galvin family, a large set of genetic data for a family with schizophrenia was virtually impossible to acquire. A 2024 CU Boulder study directly linked a SHANK2 genetic mutation and CHRNA7 gene to schizophrenia and identified a chemical, choline, that protects against future mental illnesses in utero. Identifying at-risk populations is the first step to delaying onset of the disease and developing more effective treatments. 

2) Identifying at-risk populations also means understanding common environmental factors through epidemiological studies. Specifically, people in poverty are far more likely to have mental illness. Similar to substance abuse, understanding the direction of causality here is difficult. Perhaps other environmental factors, including chemical exposure during pregnancy, can create increased vulnerability as well. 

3) Adolescents are vulnerable to environmental circumstances. Considering the popularity of the diathesis-stress model, characterizing all of the different environmental factors that have particularly detrimental impacts on adolescents can help scientists understand how different stressors interact with one another to cause future onset of psychosis and schizophrenia. 

Gaining a comprehensive view of schizophrenia through these approaches will give scientists a much larger toolbox to understand its causes. After determining its driving factors, researchers can work to develop more effective treatments to alleviate the effects of schizophrenia.

Edited by Jack Ranani ’25

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