





































Abstract
Schizophrenia is a neurological disorder that affects an individual’s perception of 
themselves and the world around them. In recent years, research on schizophrenia has 
plateaued, with much of the focus placed on post-onset treatments, such as the use of 
antipsychotic medications and psychotherapy. Although the disorder has been 
extensively studied, the prodromal stage—preceding the onset of psychosis—remains 
relatively underexplored. We assert in this scientific review that the prodromal stage 
offers significant promise in the prevention or strong reduction of schizophrenic 
symptoms and has been overlooked by previous research. Emerging studies 
suggest that both pharmacological and psychological interventions targeting 
epigenetic markers may offer promising new approaches for early-stage treatment.

Preventing Schizophrenia: Insights from 
Epigenetic Research
By: Cheyenne Fischer-Zimmermann, Khushi Shah, Laney Seligson and Noah Perazzo

Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
Cheyeneathome@gmail.com

Keywords:
Epienetics    
Schizophrenia
Prodrome
Psychosis

Published July 31, 2025

Full Open Access

Creative Commons Attribution 
License 4.0



1. Introduction

Schizophrenia is a highly debilitating neurodevelopmental disorder that 
significantly affects an individual's mental health, cognition, and behavior. 
Affecting nearly one percent of the U.S. population, the disorder currently 
has no known cure. Most research to date has focused on alleviating the 
severity of symptoms following the onset and formal diagnosis. Common 
symptoms of schizophrenia include hallucinations, delusions, and 
disorganized thinking, speech, and movement.1 

1.1 Background on Schizophrenia 

Globally, schizophrenia affects approximately 0.32% of the 
population—about 1 in 300 individuals. The disorder also exhibits a strong 
hereditary component, with genetic studies suggesting up to a 90% 
likelihood of heritability from one generation to the next. Schizophrenic 
symptoms are generally categorized into two broad groups: positive and 
negative symptoms. Both types are detrimental to an individual’s 
functioning and tend to worsen over time.1 

Positive symptoms are any change in behavior or thought that was not 
originally present. These include delusions, hallucinations, confused 
thinking, and confused speech. These symptoms can be managed by 
antipsychotic medications. On the contrary, negative symptoms are 
classified as a withdrawal from the world. Individuals with Schizophrenia 
experiencing these symptoms take no interest in the things they used to care 
about and essentially appear emotionless. Examples of these symptoms 
include apathy, little emotion, poor attention and concentration, and 
depression. Unlike positive symptoms, negative symptoms are more 
resistant to pharmacological treatment and often emerge months or even 
years before positive symptoms, making early detection and intervention 
particularly challenging.1 

1.2 Clinical Overview of Schizophrenia 

Schizophrenia is a chronic disorder that affects both men and women 
equally. As of 2022, it is estimated to impact around 1 in 222 adults 
globally.1 The typical age of onset falls within early adulthood, generally 

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between the late teens and early thirties, with men tending to exhibit 
symptoms earlier than women. While childhood-onset schizophrenia is rare, 
cases have been documented in individuals as young as thirteen.2 

Schizophrenic symptoms can range in severity from mild to disabling and 
are typically classified into three categories: positive, negative, and cognitive. 
Positive symptoms reflect the presence of abnormal thoughts or behaviors, 
such as auditory or visual hallucinations, persistent delusions, disorganized 
thinking, and incoherent speech. Negative symptoms represent a reduction 
or absence of normal emotional and behavioral functions. These include 
diminished motivation, anhedonia (lack of pleasure), flat affect, limited 
vocabulary and speech detail, and social withdrawal. Cognitive symptoms 
involve deficits in attention, memory, and executive functioning, which can 
impair decision-making, judgment, and problem-solving abilities.2 

According to the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5), a diagnosis of schizophrenia requires the presence of 
at least two of the following symptoms for a significant duration: delusions, 
hallucinations, disorganized speech, grossly disorganized or catatonic 
behavior, and negative symptoms. Crucially, at least one of the symptoms 
must be delusions, hallucinations, or disorganized speech. Additionally, 
other psychotic or schizotypal disorders must be ruled out in the diagnostic 
process.2 If left untreated, patients with schizophrenia may suffer 
psychological distress, relationship difficulties, employment issues, struggle 
with substance abuse, and self-harm. Schizophrenia is further associated 
with a variety of comorbidities, the most common of which being comorbid 
substance abuse and depression in about half of individuals with the 
condition.3 Additional psychiatric comorbidities include PTSD, OCD, and 
panic disorder. The addition of these psychiatric conditions can greatly 
hinder the proper diagnosis, and treatment of schizophrenia. This can be 
due to the possibility of an individual’s symptoms having crossover from 
both conditions, meaning it can be hard to pinpoint whether the individual 
has both conditions at the same time. Furthermore, there could be different 
medicinal treatment methods for schizophrenia and an additional condition 
that may have conflicts.3 

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The timeline of schizophrenia development has been insufficiently studied, 
largely due to the challenges in accurately identifying and tracking the early 
progression of symptoms. While a subset of individuals experience an acute 
onset of the disorder, approximately three out of four cases are preceded by 
a prodromal phase.4 This phase varies in duration but typically lasts between 
one and five years. During the prodrome, negative symptoms and some 
cognitive impairments often begin to emerge. In some cases, a first-episode 
psychosis (FEP) may occur later in the prodromal period, following the 
appearance of mild psychotic symptoms. 

During this phase, individuals might experience subtle changes in 
perception, thought patterns, or behavior that can precede the onset of 
more severe psychotic symptoms, such as delusions or hallucinations. 
Recognizing and understanding these early signs can be crucial for timely 
intervention and treatment. This is particularly relevant for clinical high-risk 
(CHR) individuals, who exhibit early signs or symptoms indicating a 
heightened likelihood of developing a psychotic disorder, such as 
schizophrenia, in the future. Several screening tools have been developed to 
identify CHR individuals, with varying degrees of success. The Early 
Detection, Intervention, and Prevention of Psychosis Program (EDIPPP) 
employed the Structured Interview for Prodromal Syndromes (SIPS) in 
conjunction with the Scale of Prodromal Symptoms (SOPS) to detect early 
signs of psychosis with notable accuracy.5 The Positive and Negative 
Syndrome Scale (PANSS), the Basel Screening Instrument for Psychosis 
(BSIP)6, and the Comprehensive Assessment of the At-Risk Mental State 
(CAARMS)7 have all proven to have valid and reliable methods of screening 
for individuals at risk for psychosis. However, despite the efficacy of these 
tools in detecting prodromal symptoms, their ability to accurately predict 
progression to a full psychotic disorder remains limited. This raises ethical 
and clinical concerns, as individuals labeled as CHR may never develop 
psychosis yet still face stigmatization due to their risk status. Although 
research on the prodromal phase remains limited, emerging evidence 
suggests that early intervention during this stage can significantly reduce the 
likelihood of transition to active psychosis.8 

 

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1.3 Environmental Risk Factors 

Environmental risk factors play a significant role in the development of 
schizophrenia, often interacting with underlying genetic predispositions. 
Key environmental contributors include prenatal complications, urban 
living conditions, and socioeconomic adversity. Prenatal exposure to 
maternal infections—particularly viral infections such as influenza, rubella, 
and toxoplasmosis—has been linked to an increased risk of schizophrenia in 
offspring. Furthermore, birth complications, including hypoxia (oxygen 
deprivation) and elevated maternal stress, may disrupt neurodevelopment 
and increase susceptibility to the disorder. Growing up in urban 
environments is also associated with a heightened risk of schizophrenia 
compared to rural areas. Contributing factors may include social isolation, 
environmental stress, pollution, and limited community cohesion, all of 
which are more prevalent in densely populated settings.8 

Additionally, socioeconomic disadvantage—characterized by poverty, low 
educational attainment, unemployment, and social marginalization—has 
consistently been linked to increased schizophrenia risk. Other relevant 
factors include exposure to chronic stress, inadequate access to healthcare, 
and systemic social inequalities, all of which may exacerbate vulnerability to 
psychosis.8 

1.4 Genetic Risk Factors 

Schizophrenia is highly hereditary, as several genetic risk factors have been 
implicated. Individually unique genomic variations, otherwise known as 
copy number variations, have been linked to an increased risk of 
schizophrenia. These variations can arise through genomic mechanisms 
such as deletions and duplications of chromosomal segments. Additionally, 
Single Nucleotide Polymorphisms (SNPs) are genetic variations that can 
also lead to mutations that are associated with a higher risk of schizophrenia. 
Among these, variations in the Neuregulin 1 (NRG1) gene have garnered 
attention due to the gene's role in neural development, synaptic plasticity, 
and signaling pathways related to schizophrenia. Moreover, genes encoding 
proteins involved in dopaminergic neurotransmission have been extensively 
studied, supporting the dopamine hypothesis of schizophrenia. This theory 

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posits that dysregulation of dopamine pathways contributes to the positive 
symptoms of the disorder, such as hallucinations and delusions.8 

1.4.1 Dopamine Hypothesis 

The dopamine hypothesis is a long-standing theory suggesting that 
dysregulated dopamine activity contributes significantly to the 
pathophysiology of schizophrenia. Research has particularly implicated 
dopamine D2 receptors in the subcortical and limbic regions of the brain, 
where hyperactivity is thought to underlie positive symptoms such as 
hallucinations and delusions. Additionally, dopamine D1 receptors have 
been associated not only with positive symptoms but also with negative and 
cognitive manifestations of the disorder.8 

The origins of the dopamine hypothesis stem from pharmacological 
evidence: antipsychotic medications such as haloperidol and clozapine 
reduce dopamine activity—especially by antagonizing D2 
receptors—leading to symptom relief. Conversely, substances that elevate 
dopamine levels, such as amphetamines and cocaine, can induce 
psychotic-like behaviors in otherwise healthy individuals, further 
supporting the link between dopamine dysregulation and psychosis.8 

Despite its foundational role, the dopamine hypothesis does not fully 
account for the wide spectrum of symptoms observed in schizophrenia. 
Current understanding acknowledges that the disorder likely results from 
complex interactions between genetic and environmental factors, 
potentially affecting early brain development and leading to broader 
neurochemical and structural abnormalities beyond dopamine alone.8 

2. Background on Epigenetics 

Epigenetics is the study of heritable changes in gene expression that occur 
without alterations to a DNA sequence itself. These changes are mediated 
by chemical modifications to DNA or histone proteins, as well as through 
non-coding RNA molecules. Epigenetic mechanisms play a crucial role in 
regulating gene activity in response to environmental cues, developmental 
stages, and cellular differentiation. They contribute to diverse processes that 
function throughout an organism’s lifetime. Epigenetics provides insights 

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into how external factors influence genetic activity, offering profound 
implications for understanding disease susceptibility, evolution, and even 
personalized medicine. By unraveling the complexity of epigenetic marks, 
scientists are gaining new perspectives on human biology and the intricate 
ways in which our experiences leave lasting imprints on our genetic code.9 

Epigenetics overall is a relatively new concept that is being put more into 
practice each year. The term “epigenetics” was created in the human biology 
setting by the embryologist Conrad Waddington in 1942. The biggest 
advancements in epigenetics and the understanding of them have occurred 
in the 21st century. This includes but is not limited to, a better 
understanding of DNA methylation, further development of 
CRISPR/Cas9 skills, more knowledge of histone modifications, and the 
expansion of knowledge of epigenetics with disease treatment.9 

2.1 Epigenetic Mechanisms 

Epigenetic mechanisms refer to reversible modifications that regulate gene 
expression without altering the underlying DNA sequence. These 
mechanisms include DNA methylation, histone modifications, and the 
regulation of gene activity by non-coding RNAs. Epigenetic modifications 
play crucial roles in various biological processes, including development, 
where they regulate gene expression during cell differentiation; 
differentiation, by influencing how stem cells mature into specific cell types; 
and disease, as seen in conditions like cancer, where abnormal DNA 
methylation patterns can lead to the silencing of tumor suppressor genes. 
These modifications can also affect brain function and contribute to 
neurodevelopmental disorders such as schizophrenia. Dysregulation of 
epigenetic mechanisms has been implicated in numerous diseases, including 
cancer, neurodevelopmental disorders, and autoimmune diseases.9 

2.2 DNA Methylation 

DNA methylation involves the enzymatic addition of methyl groups 
(–CH₃) to the cytosine residues of DNA, typically at CpG islands, which 
are regions rich in cytosine and guanine nucleotides. This epigenetic mark 
generally acts to suppress gene transcription by reducing the accessibility of 
DNA to transcription factors and other regulatory proteins. When 

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methylation occurs in promoter regions of genes, it often leads to 
transcriptional silencing, effectively turning the gene "off." Aberrant DNA 
methylation patterns—either hypermethylation or hypomethylation—are 
implicated in a wide range of diseases, including schizophrenia, where they 
may alter the expression of genes critical for brain development and 
function.9 

2.1.1 Histone Modification 

Histone modifications are chemical changes to the histone proteins around 
which DNA is wrapped to form chromatin. These modifications affect how 
tightly or loosely DNA is packaged and thereby influence gene accessibility 
and expression. Acetylation causes the chromatin to relax by neutralizing 
the positive charge on histone proteins, which lessens their attraction to 
negatively charged DNA and, therefore can assist with gene activation. 
Phosphorylation acts in a similar capacity to altering the histone charges, 
but instead, it can make it either relaxed or compact. Methylation is most 
commonly used to promote gene silencing by enhancing the interaction 
between the DNA and histones. Ubiquitination can play a dual role and 
could both loosen or compact the chromatin. Histones are proteins around 
which DNA is wrapped to form chromatin. They play a fundamental role 
in packaging and organizing DNA into a compact and orderly structure 
which is essential for the regulation of gene expression, among other 
processes.9 

Additionally, non-coding RNAs—including microRNAs (miRNAs) and 
long non-coding RNAs (lncRNAs)—contribute to epigenetic regulation by 
interacting with chromatin remodeling complexes and transcription factors. 
These RNA species can modulate gene expression post-transcriptionally or 
by guiding epigenetic modifiers to specific genomic loci, further increasing 
the complexity of epigenetic regulation in health and disease.9 

2.1.2 Chromatin 

Chromatin is the complex of DNA and proteins found within the nucleus 
of cells helping to organize and compact DNA within the nucleus into a 
manageable structure. Specifically, chromatins condense into visible 
chromosomes during cell division. It is important to note that its structure 

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is highly dynamic and can be altered by various epigenetic mechanisms such 
as DNA methylation, histone modifications, and non-coding RNA 
regulation. These epigenetic modifications regulate gene expression by 
controlling the accessibility of DNA to the transcriptional machinery. 
Essentially, chromatin structure and its modifications are central to the field 
of epigenetics, playing critical roles in the regulation of gene expression, 
cellular differentiation, development, and disease.9 

2.2 Prior utilization of epigenetics in medical research 

Although there has been slow progress in the implementation of epigenetic 
pharmaceuticals due to their low specificity, there are several medicinal 
drugs currently on the market for clinical use focused on modulating the 
epigenome. Controlling gene expression pre-transcriptionally is desirable in 
treating a variety of diseases. Epigenetic drugs targeting tumor and cancer 
growth have been approved by the FDA for oncological use.9 

Histone deacetylase (HDAC) inhibitors and DNA methyltransferase 
(DNMT) inhibitors have also been suggested as epigenetic drugs that may 
be relevant in combating schizophrenia. Histone deacetylases are enzymes 
that remove acetyl groups on histones. This allows chromatin to wrap more 
tightly around histone proteins and thus serve as an obstacle to restrict 
transcription, eventually permitting the chromatin structure to be more 
relaxed and accessible for transcription factors. Therefore, histone 
deacetylases can help restore the normal expression of genes which can assist 
in alleviating symptoms such as cognitive impairments and memory deficits 
which are common symptoms of schizophrenia. DNMT contributes to the 
abnormal methylation of regions of DNA. Additional second and 
third-generation epigenetic drugs have explored additional enzyme 
inhibitors, however, ensuring low toxicity and high specificity has thus far 
proved to be a major hurdle. The use of DNMT inhibitors in schizophrenia 
treatment would assist in reversing abnormal DNA methylation patterns 
that may have contributed to the onset of schizophrenia.9 

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Figure 1: Chromatin modifications mediated by methylation and 
acetylation. This figure illustrates the sequence of mechanisms that cause methylation–the 

addition of a methyl group on the DNA. It also shows the different effects of methylation in 
activating or inhibiting a gene’s expression. 

3. Previous exclusion of Epigenetics in Schizophrenia 
research 

Although schizophrenia is a disease with a known high heritability, and thus 
offers strong promise for early prevention through epigenetic treatment, 
there has been little to no high-quality research examining the potential for 
the use of drugs such as HDAC or DNMT inhibitors in responding to early 
psychotic symptoms. While the broader medical field has embraced the 
principle that prevention is the most effective form of treatment, and 
epigenetics has been extensively applied in oncology and other areas for 
identifying trauma-related and disease-specific biomarkers, the field of 
schizophrenia research has largely overlooked the potential of epigenetic 
approaches. This neglect may stem, in part, from the complex and 
multifactorial etiology of schizophrenia, which continues to resist simple 
genetic or biochemical explanations.9 

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Nevertheless, numerous well-characterized environmental and genetic risk 
factors—including prenatal infection, early-life stress, and gene 
variants—could serve as promising starting points for epigenetic 
investigation. Given that epigenetic modifications are reversible, unlike 
permanent gene-editing interventions, they offer a more flexible and 
potentially safer therapeutic avenue. This reversibility enables dynamic 
modulation of gene expression in response to treatment, positioning 
epigenetics as a compelling but underutilized frontier in schizophrenia 
research.9 

4. Current Models of Interventional Treatment 

The current treatment models for schizophrenia continue to rely 
predominantly on reactive interventions, initiated after the emergence of 
clinical symptoms, rather than on preemptive or preventive strategies. 

4.1 Psychological Intervention 

Psychological interventions, particularly psychosocial treatments, play an 
essential role in the comprehensive management of schizophrenia. 
Psychosocial treatment refers to a broad category of therapeutic approaches 
that involve not only the patient but also family members, caregivers, and 
support networks. These interventions may include individual or group 
therapy, family counseling, peer support groups, and community-based 
rehabilitation programs.10 

 Psychoeducation helps patients and their loved ones understand the 
condition and available treatment options. Additionally, psychosocial 
rehabilitation teaches patients skills to manage daily activities.10 Although 
therapy is often incorporated into treatment plans after a formal diagnosis, 
emerging evidence supports its early integration. Cognitive Behavioral 
Therapy (CBT), in particular, has demonstrated effectiveness in reducing 
symptom severity, improving medication adherence, and enhancing overall 
psychosocial functioning. When combined with pharmacological 
treatment, CBT can contribute to more favorable long-term outcomes for 
individuals living with schizophrenia.10 

 

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4.2 Pharmacological Intervention 

Pharmacological treatment for schizophrenia has been largely guided by the 
dopamine hypothesis, which attributes positive symptoms—such as 
hallucinations and delusions—to dopaminergic hyperactivity, particularly 
in the mesolimbic pathway. This model led to the development and 
widespread use of first-generation (typical) antipsychotics, such as 
chlorpromazine, which alleviate positive symptoms by blocking dopamine 
D2 receptors.11, 12 However, this narrow pharmacological focus has several 
limitations. While effective for positive symptoms, D2 antagonists provide 
limited benefit for negative symptoms (e.g., lack of motivation, social 
withdrawal) and cognitive deficits, which often appear earlier and more 
persistently impair daily functioning. Moreover, excessive D2 receptor 
blockade is associated with significant side effects, including extrapyramidal 
symptoms and tardive dyskinesia, which may hinder long-term adherence. 
Current pharmacological strategies, therefore, risk overlooking core 
domains of the disorder that are critical to long-term recovery, highlighting 
the need for more holistic and targeted treatments—potentially including 
non-dopaminergic and epigenetic approaches.12 

4.3 Limitations and Complications 

Current schizophrenia treatment models often overemphasize the 
dopamine hypothesis, primarily targeting positive symptoms while 
overlooking the full spectrum of the disorder. Additionally, treatment 
typically begins after the onset of schizophrenia, despite evidence that early 
intervention during the prodromal phase may significantly reduce symptom 
severity or prevent full disease progression. Unfortunately, the prodromal 
stage remains under-researched and underutilized in preventative treatment 
approaches. 

Psychological interventions, though beneficial, are commonly introduced 
only after initial symptom onset. Yet research indicates that earlier 
implementation may yield better outcomes. These interventions are often 
combined with pharmacological treatment, but their effectiveness depends 
heavily on patient engagement. A major barrier to treatment is 
anosognosia—a condition in which individuals are unaware of their own 
illness, often due to delusions, hallucinations, or disorganized thinking. 

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Anosognosia complicates medication adherence and therapy participation, 
as patients may not recognize their need for treatment. Furthermore, 
individuals with schizophrenia often score low on conscientiousness, a 
personality trait linked to routine and self-discipline. As a result, they may 
struggle to follow structured treatment regimens, such as attending therapy 
or taking medication consistently. When treatment is delayed until later 
stages of illness, these challenges can become even more pronounced. 

There is also the risk of the affected individual developing anosognosia if 
treatment isn’t sought out before the full onset of symptoms. Anosognosia 
affects individuals who do not believe they have a disability and therefore do 
not seek out treatment. They often actively avoid any assistance offered. 
Therefore, the current models of interventional treatment will not be 
effective due to needing participation from the individual. Potentially, their 
symptoms could have been first eased by preventative treatment, so they 
lessen their chances of developing anosognosia by the time of the onset of 
symptoms.13 

Cultural and socioeconomic barriers also contribute to delayed or avoided 
treatment. In some contexts, individuals may fear discrimination, 
stigmatization, or the loss of legal and social rights following a psychiatric 
diagnosis. In many countries, limited access to affordable mental health 
care—including psychiatric evaluations and follow-up services—remains a 
significant obstacle, particularly in low-income or rural areas.13 

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Figure 2: The Consequences of Anosognosia in Schizophrenic 
Individuals13 

 

 

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5. Epigenetic Regulation in Preventative Treatment 

5.1 Psychological Potential 

Therapy and broad psychological intervention are already an established 
part of schizophrenic intervention plans; however, the connection between 
psychological stress and its epigenetic impact on an individual’s risk for 
developing schizophrenia has not been greatly explored as a means of early 
prevention. Awareness about the transgenerational effects of prenatal 
maternal stress and the promotion of cognitive behavioral therapy in at-risk 
individuals are promising as early responses to pre-psychosis.13 

5.1.1 Prenatal Sensitivity to Stress 

Prenatal maternal stress (PNMS) is defined by a pregnant woman 
experiencing stress during her pregnancy whether it is physical or 
psychological. The fetus can sense stress stimuli through elevated levels of 
maternal stress hormones, such as cortisol, which can cross the placenta. 
This exposure may trigger physiological adaptations, potentially altering 
gene expression. During development, the fetus takes cues from its 
environment to optimize its growth and function, but excessive stress 
exposure can lead to long-term changes in brain structure and function. 
This can alter the expression of the fetus’ genes because, during 
development, the fetus takes cues from its environment on how best to 
develop.14 

It has been shown that PNMS in combination with other factors such as 
genetic disposition and childhood trauma increases the risk of 
schizophrenia. It has been shown that individually, PNMS does not have a 
statistically significant effect on the fetus in developing schizophrenia. 
However, it is important to acknowledge PNMS’ role in combination with 
other factors that influence schizophrenia to help identify high-risk 
individuals and be able to create an early intervention plan. PNMS has also 
been shown to affect sleep, diet, and inflammation which could also 
contribute to schizophrenia development. Identifying PNMS’ role in 
affecting other factors that could contribute to schizophrenia, is crucial in 
order for more research to be conducted on PNMS’ indirect effect on the 
development of schizophrenia.14 

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5.1.2 Individual Therapy and Psychoeducation 

Cognitive Behavioral Therapy (CBT) is a widely practiced, evidence-based 
psychotherapy that targets maladaptive thoughts, emotions, and behaviors 
to improve overall mental health. When applied during the prodromal 
phase of schizophrenia, CBT has been shown to reduce the risk of transition 
to active psychosis, making it a promising early intervention strategy15. 
Additionally, enrolling at-risk individuals in psychoeducational programs 
may help prevent behaviors linked to schizophrenia through epigenetic 
pathways.15 

One notable comorbidity of schizophrenia is substance abuse, particularly 
the high prevalence of tobacco use among individuals with the disorder. A 
leading theory suggests that tobacco may serve a self-medicating function, 
offering short-term cognitive benefits for patients by interacting with 
epigenetic mechanisms. Animal studies have demonstrated that nicotine 
exposure reduces levels of DNA methyltransferase 1 (DNMT1) in 
telencephalic GABAergic neurons in the frontal cortex—a brain region 
critical to cognition. DNMT1 is an enzyme responsible for methylating 
CpG islands, which suppresses gene transcription and plays a vital role in 
maintaining epigenomic stability. Notably, elevated DNMT1 levels have 
been observed in the GABAergic neurons of patients with schizophrenia16. 
This suggests that nicotine’s ability to lower DNMT1 expression may 
temporarily improve cognitive function, potentially explaining the high 
rates of tobacco use in this population.16 

However, despite these cognitive effects, the long-term consequences of 
tobacco use remain profoundly harmful. Integrating psychoeducation into 
early intervention programs could help at-risk individuals understand the 
biological basis of their susceptibility to tobacco use and inform more 
tailored, health-conscious treatment plans. This approach may enhance 
both the prevention and management of schizophrenia by addressing 
underlying epigenetic vulnerabilities.16 

5.2 Pharmacological Potential 

As the majority of schizophrenia treatments have focused on treating the 
dopaminergic pathway and the subsequent positive symptoms, the 

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pharmacological potential of epigenetically adjusting abnormal levels of 
other neurotransmitter pathways has been overlooked. In the prodrome, 
where negative and cognitive symptoms take precedence over positive 
symptoms, epigenetically regulating other neurotransmitter pathways that 
are imbalanced through pharmaceuticals could prove to be a powerful 
preventative measure against full schizophrenic onset.17 

 

Figure 3: A chart depicting the contributors to each kind of 
schizophrenic symptom category. Figure 3 shows the relevant neurotransmitters 

and their connections to each of the three symptom categories of Schizophrenia. Certain 
neurotransmitters play little to no role in contributing to certain symptoms, so this serves as a 
means of narrowing what is worth researching for treatments for specific symptoms.  

 

 

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5.2.1 DNA Methylation Focused Pharmacologic Treatment 

Multiple post-mortem studies of patients with schizophrenia have identified 
hypermethylation in the promoter regions of genes in GABAergic neurons, 
leading to reduced GABA neurotransmission—a key inhibitory process in 
the brain.17 This epigenetic suppression results in the downregulation of 
mRNA for glutamic acid decarboxylase 67 (GAD67) and reelin (RELN), 
both of which are crucial for normal synaptic function. GAD67, encoded 
by the GAD1 gene, catalyzes the conversion of glutamate to GABA, and its 
reduced expression in the prefrontal and temporal cortices has been 
associated with cognitive impairments, particularly deficits in working 
memory and executive function, seen in individuals during the prodromal 
phase of schizophrenia.18 

Another promising molecular target is the neural cell adhesion molecule 
(NCAM), a glycoprotein involved in axon growth, synaptic plasticity, and 
neuronal migration. NCAM is found to be overexpressed in the prefrontal 
cortex and hippocampus of individuals with schizophrenia. In animal 
studies, the presence of anti-NCAM1 autoantibodies has induced 
schizophrenia-like behaviors, suggesting that such antibodies could serve as 
a biomarker for the disease.18 

The elevated levels of DNA methyltransferase 1 (DNMT1) found in 
patients with schizophrenia can potentially be normalized through the use 
of DNMT inhibitors or DNA demethylation inducers. DNMT inhibitors 
prevent the addition of methyl groups to DNA, while demethylating agents 
remove existing methyl marks. Both strategies may restore GAD67 and 
RELN expression, thereby enhancing GABAergic signaling and potentially 
ameliorating cognitive and synaptic deficits associated with the disorder. As 
epigenetic regulators, these agents offer a promising route to reverse 
transcriptional repression of key genes implicated in schizophrenia.18 

5.2.2 Histone Modification-Focused Pharmacologic Treatment 

Previous epigenetic research has found that schizophrenic-like symptoms 
can be replicated by administering mitotoxin (a cytotoxic molecule that 
causes cell death by interfering with protein or DNA synthesis) on day 17 of 
the embryonic prenatal stage. The mitotoxin administration had several 

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effects on various epigenetic mechanisms, including decreased methylation 
in certain promoter zones of cannabinoid receptor 1.19-23 

Using MAM-E17 has replicated schizophrenic symptoms and has also been 
used as a method to examine the impact on histones. Tri-methylated histone 
H3 at lysine (K) (H3K4me3) facilitates gene transcription by opening 
chromatin. The opening of chromatin, allows transcriptional mechanisms 
such as RNA polymerase and transcription factors to have better access to 
the DNA, which means the genes are more likely to be activated. 
MAM-E17 experimentation has found lower levels of H3K4me3 near 
GAD1 promoters, thereby hindering the production of GABA23. Adjusting 
the expression of the SETD1A gene may be an epigenetic point of interest, 
as this gene regulates the downstream levels of H3K4me3.23 

 

 

Figure 4: A chart detailing the inhibitory or excitatory effects of 
various pharmaceuticals targeting histones. This figure shows the way in 

which epigenetic therapeutics target transcription, when DNA gets copied into RNA. When 
transcription is inhibited and inactive, proteins are not produced, and the gene is not 
expressed. 

 

5.3 Epigenetic biomarkers 

In identifying individuals at risk for schizophrenia, an accurate and reliable 
screening method is necessary. H3K4me3 deficits near GAD1 promoters 
have been noted in people with schizophrenia23. Brain-derived neurotrophic 

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factor (BDNF) levels were found to be frequently elevated along with 
C-reactive protein (CRP) elevation24. These may both contribute to 
lowered cognitive function or dysregulation in patients suffering from 
schizophrenia. Unfortunately, there are very few identified reliable 
biomarkers for the prodromal period of schizophrenia. This may be 
influenced by the difficulty of enrolling prodromal individuals into invasive 
trials to reliably determine prodromal biomarkers. However, biomarkers 
already associated with schizophrenia are suggested to be prodromal 
biomarkers as well. A deletion of a piece of chromosome 22 (22q11.2), 
noted in about 1% of all individuals with schizophrenia, is also theorized to 
be a genetic risk factor and subsequent biomarker of schizophrenia.25 
Certain biomarkers also suggest the role of prenatal stress in the potential 
for developing schizophrenia. DNMT1 and TET1 were found to be higher 
in prenatally stressed mice and are promising early biomarkers as well.26 

5.4 Methods for Screening for Epigenetic abnormalities and 
markers 

Since biomarkers are relatively unreliable for early detection of prodromal 
schizophrenia on their own, additional screening measures should be used. 
Individuals with a reported familial history of schizophrenia may be 
recommended to partake in regular annual screenings to catch early 
identifiers due to the high heritability of schizophrenia. The medical field 
already often suggests annual check-ups and screenings such as pap smears 
during certain years of life. This is less common regarding mental health and 
neurodevelopmental disorder prevention, likely contributed to by 
significant historical stigma regarding psychiatric disorders and mental 
illness. Recently, similar propositions for recommended mental health 
check-ups have been suggested by psychologists and psychiatrists alike, 
although little progress has been made as of yet.27 

There are a variety of symptom screening tests to identify early prodromal 
symptoms. The Structured Interview for the Prodromal Syndrome (SIPS), 
paired with the Scale of Prodromal Symptoms (SOPS), has been reliable and 
used in many clinical trials to determine individuals at high risk of 
developing psychosis. In SIPS, a clinician performs a lengthy interview with 
the patient examining their psychological, social, and health history. Using 

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SOPS, the patient’s responses are ranked on a four-item scale based on 
positive, negative, disorganized, or general symptoms. Individuals may be 
classified as being already psychotic, at high risk for psychosis, or not at risk 
for psychosis.27 

The third syndrome diagnosis is the least common, but highly relevant to 
those with schizophrenia, being the Genetic Risk and Deterioration 
Prodromal Syndrome (GRDS)27. Individuals with a general decline or 
deterioration in their well-being who have a first-degree relative with a 
history of a psychotic disorder or who may have a schizotypal personality 
disorder may be diagnosed with GRDS.27 

The Positive and Negative Syndrome Scale (PANSS) also utilizes a 
clinician-based interview and has been used since the 1980s to measure the 
severity of symptoms in affected individuals. It has use in screening for early 
psychosis as well, although its interview questions are less focused on 
identifying prodromal individuals similar to the Basel Screening Instrument 
for Psychosis (BSIP).27 

The Comprehensive Assessment of the At-Risk Mental State (CAARMS), 
is often used alongside SIPS/SOPS to determine prodromal individuals for 
early psychosis. It is reliable in tracking the development of psychosis and 
the onset of the FEP. CAARMS includes many subscales that measure the 
well-being of various aspects of the individual’s life and includes many 
interview questions across seven domains of interest in order to 
appropriately gauge the individual’s risk. Questions may explore the 
individual’s psychopathology, positive and negative symptoms, changes in 
their cognition, emotions, behavior, and physiology. CAARMS uses the 
Social and Occupational Functioning Assessment Scale (SOFAS), which 
rates individuals similarly to SOPS and determines if they meet the criteria 
for full onset psychosis, BIPS, or APS.27 

A major obstacle with prodromal screening is that they often require highly 
trained clinicians who can offer appropriate interviews. The interviews 
themselves can also be quite lengthy and inaccessible to individuals who 
have significant life obligations.27 

 

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6. Discussion 

Developing pharmaceuticals that target the epigenome has historically 
proven to be a challenging endeavor, which has discouraged widespread 
research into their therapeutic potential. Compounding this difficulty are 
ethical concerns related to privacy and genetic data, which have further 
hindered funding and institutional support for epigenetics research. As a 
result, the application of epigenetic therapeutics in schizophrenia treatment 
remains limited, despite substantial evidence supporting its promise. 
Currently available epigenetic drugs often suffer from issues such as low 
target specificity, off-target effects, and high toxicity, reducing their viability 
in clinical settings. Furthermore, many research institutions prioritize areas 
with higher academic prestige or more secure funding, creating a significant 
opportunity cost for pursuing epigenetics-based research. These factors have 
collectively slowed progress in exploring how epigenetic interventions could 
be used to prevent schizophrenia and other neurodevelopmental disorders. 

Nonetheless, recent advances in developmental psychology and genetics 
have contributed to the reframing of the nature vs. nurture debate, now 
widely accepted as an interactionist model. The consensus among 
psychologists is that both genetic predispositions and environmental 
exposures influence developmental outcomes, including disease 
susceptibility. This evolving perspective has opened the door for greater 
exploration of epigenetics in medicine, as it accounts for how environmental 
factors can modulate gene expression without altering the DNA sequence. 
In the case of schizophrenia, while heritability remains high, growing 
evidence indicates a significant interplay between epigenetic modifications 
and environmental influences in shaping the onset and progression of the 
disorder. 

As discussed in Section 4.2, pharmacological intervention — particularly 
the use of antipsychotic medications—remains the most common 
treatment model for schizophrenia. These medications have proven effective 
in reducing positive symptoms such as hallucinations, delusions, and 
disorganized thinking by modulating dopaminergic activity 21. However, 
research also shows that pharmacological treatments are most effective when 
combined with psychological therapies, such as Cognitive Behavioral 

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Therapy (CBT), which equip patients with coping strategies and cognitive 
restructuring tools. 

Despite the therapeutic utility of antipsychotics, there is a growing need to 
shift the focus toward prevention. Early-stage, non-pharmacological 
interventions may help delay symptom onset, reduce severity, and lessen 
reliance on medication. Preventative treatment is particularly important for 
individuals who cannot tolerate antipsychotic medications due to severe side 
effects or treatment-resistant schizophrenia22. Given the unpredictability of 
medication efficacy and tolerability, alternative or complementary 
preventative strategies are critical to improving outcomes. 

Another vital consideration is the social stigma historically associated with 
schizophrenia and other psychotic disorders. Being labeled as “at risk” for 
psychosis can significantly impact a person’s self-perception, social standing, 
and mental health, even if symptoms never manifest. Stigma may lead to 
ostracization, bullying, or discrimination, particularly if peers or family 
members are unfamiliar with the disorder. These social pressures may 
contribute to the development of comorbid conditions, such as depression, 
anxiety, or panic disorders. 

Therefore, any preventative framework for schizophrenia must be 
implemented with cultural sensitivity and clinical precision. Accurate 
screening tools are essential to avoid false positives and mislabeling, which 
may do more harm than good. Furthermore, public education is a key 
component of reducing stigma. Increasing awareness and understanding of 
mental disorders among the general population can foster a more 
supportive and inclusive environment for those identified as at risk. 
Building such a community is vital—not only for the effectiveness of 
treatment but also for maintaining morale, social integration, and overall 
mental well-being. 

7. Conclusion 

The field of schizophrenia research has historically underemphasized 
prevention, despite mounting evidence supporting the efficacy of 
standardized preventative measures, including psychoeducation, therapy, 
early detection, and epigenetic interventions. As a result, many individuals 

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continue to suffer from lifelong, severe symptoms that might have been 
mitigated—or even prevented—through early response strategies. Stigma 
surrounding schizophrenia further delays diagnosis and treatment, 
exacerbating the burden on affected individuals. Emerging research suggests 
that epigenetics may offer a powerful avenue for early intervention by 
enabling reversible modifications to gene expression. These interventions 
have the potential to reduce symptom severity or prevent the onset of 
psychosis altogether. To fully realize this potential, greater investment is 
needed from pharmaceutical and biotechnology companies, as well as from 
clinical psychologists, to explore the interplay between epigenetic regulation 
and schizophrenia pathophysiology. 

Though still a developing field, epigenetics presents transformative 
possibilities not only for schizophrenia but also for a broad spectrum of 
conditions, including neurological disorders, autoimmune diseases, 
metabolic syndromes, and cardiovascular conditions. Continued 
exploration and application of epigenetic science stand to advance both 
preventive medicine and precision therapeutics, reshaping the future of 
healthcare.  

 

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