Abstract

Schizophrenia is a complex, polygenic disorder with prominent links to epigenetics, which may play a key role in its occurrence and effects and could thus serve as an avenue through which to approach its treatment. This paper seeks to understand existing literature on the disease and offer further insights to this link, presenting the central argument that epigenetics is a promising field with which to study and develop clinical treatments for schizophrenia. The methodology employed was an exhaustive literature review to present a holistic model of the relationship between schizophrenia and epigenetics. The genetics of schizophrenia was also analysed to improve the analysis of the factors leading to its occurrence. The literature review suggests that delineating how epigenetics contributes to the etiology, expression and heterogeneity of schizophrenia is essential to form new treatment options. From this, various potential treatments such as demethylating agents and epigenetic therapies were suggested. Additional questions, as well as recommendations for future studies, include discerning the epigenetic profile of schizophrenia and identifying novel biomarkers.

1. Introduction

1.1 Overview

Schizophrenia is a complex disorder with a variety of causes and serious effects on the lives of those affected. It is possible that there may be important links to analyse between this condition and the phenomenon of epigenetics, which may prove useful in understanding the disease and devising treatments accordingly.

1.2 Objectives

1. This article seeks to present a holistic analysis of the various aspects through which schizophrenia and epigenetics are related, evaluating existing literature on the topic to achieve a stronger understanding of the work already done in the field.
2. The article aims to suggest potential recommendations for the future treatment and study of schizophrenia to be considered after the in-depth analysis of the links between the disorder and epigenetics.

1.3 Epigenetics

Epigenetics refers to the study of changes in gene expression that occur without altering the underlying DNA sequence. These changes are often influenced by environmental factors and can affect how genes are turned on or off (Aboud et al, 2023). This regulation can be seen through epigenetic markers on the genome, which is often referred to as the ‘epigenome’. This epigenome is a non-static arrangement, and can show rapid and flexible modifications in response to environmental stressors (Moelling, 2023).

Examples of these modifications include: DNA methylation, histone modification and non-coding RNAs. 

DNA methylation describes the addition of methyl groups to DNA, typically to turn specific genes ‘off’, as well as demethylation to turn them back ‘on’ and resume expression to produce the corresponding protein. An example is H3-K9 methylation, also known as the ‘heterochromatin mark’, in repressing transcription (Yabe et al., 2024).

DNA molecules are wrapped around histone proteins during the formation of chromatin. This structure helps in packaging the long DNA molecules into a more compact and manageable form, which fits within the cell nucleus.  Histone modifications are another example of an epigenetic modification in response to the environment. For example, modification H3K4me3 for DNA-packing histone H3, which increases transcription of specific genes by making DNA in the chromatin more accessible (Zhang et al, 2015).

Finally, non-coding RNAs (ncRNAs) are important epigenetic modifications that are involved in the silencing of specific genes and interfere in the transcription process. An example is microRNA, which binds to a target mRNA molecule to halt protein production (Macfarlane and Murphy, 2010).

1.4 Epigenetic Inheritance

Epigenetic inheritance refers to the phenomenon of inheriting epigenetic markers across multiple generations (Utah.edu, 2009). This can occur due to epigenetic changes affecting the germline or parental gametes (some strands of ncRNA, for example, can escape alteration and be transmitted through sperm) in the case of transgenerational epigenetic inheritance (Heard and Martienssen, 2014). These changes are passed on across multiple generations through these mechanisms, or due to environmental factors such as exposures to chemicals.

Epigenetic modifications  are typically erased before passing on to offspring to avoid difficulties and errors in zygote formation, through the process of ‘reprogramming’. However, scientists theorise that some markers may escape this reprogramming and persist across generations through imprinting, where sex-specific gametes are epigenetically altered allowing for DNA marks to be inherited (Macdonald, 2012).

As a result, epigenetic characteristics might persist across generations and showcase inheritability. Thus, offspring show greater propensity to displaying the same traits.

1.5 Schizophrenia

Schizophrenia is a complex multifactorial chronic mental illness noted to cause a wide variety of severe symptoms including psychosis, extreme agitation and cognitive difficulties. It is noted to be of extreme detriment to the quality of life for those afflicted and usually develops during the late adolescence to twenties stage of development (Patel et al., 2014). Not only do affected cases face various medical concerns, but those with the disorder also face challenges with maintaining support systems and are frequently discriminated against (WHO, 2022).

The etiology of schizophrenia remains a mystery, although multiple potential reasons have been proposed. While genetics is noted to be a major risk factor overall, studies have indicated that individual genes, such as neuregulin 1, are typically not as significant alone in increasing the occurrence of schizophrenia, suggesting that it has a polygenic origin. Mutations involving the duplication or deletion of genes have also been suggested as a cause. Scientists place heavy emphasis on the significance of pre/perinatal environmental exposures to harmful chemicals or stresses in the developmental of the disorder. The combination of these two factors (genes, environment) increase the risk of schizophrenia; for example, in cases where the foetus is genetically predisposed to schizophrenia and the mother expresses depression or psychosis, the chances of the offspring gaining the disorder dramatically increases (Gilmore, 2010). Due to the complexity of the factors that must interact to cause the disorder, some also argue that it might be neurodevelopmental in nature, meaning that it is a multifactorial condition caused by abnormal brain development (Mullin et al, 2013). Environmental agents later in life such as exposure to trauma or illicit substances in conjunction with abnormal early brain development for those with genetic risk factors as a cause is one widespread aetiological model for the disorder.

The effects of schizophrenia are almost as varied as its causes. The changes that arise due to schizophrenia can be found in alterations of brain structure, such as reduced brain volumes and redistribution of grey matter, especially affecting the frontal and temporal lobes responsible for thinking and emotional processing. The positive (overly expressed) symptoms include paranoia and hallucinations, while the negative (underexpressed) symptoms include reduced socialisation and experience of pleasure (Picchioni and Murray, 2007). Those afflicted also tend to appear more disorganised as they may face difficulties in ordered thinking and movement, which often expresses itself in atypical behaviours that lead to stigmatisation. 

It is possible to treat and rehabilitate schizophrenic cases through programmes designed to support the development of life-management and social skills, as well as through the continued existence of a strong support system. In addition to psychotherapies, antipsychotic medication, such as with a focus on inhibiting dopamine reception (a neurotransmitter where abnormalities in its distribution are associated with schizophrenic symptoms, and excesses lead to expression of the positive symptoms), are also heavily prescribed and encouraged to mitigate symptoms (Seladi-Schulman, 2022).

1.6 Established Links Between Schizophrenia and Epigenetics

As mentioned in the analysis of the causes behind schizophrenia, the interaction of environmental and genetic factors mean that the study of epigenetics is key to understanding the disorder. This will be the main focus of this paper.

Previous researchers have collected evidence that supports the links between epigenetics and schizophrenia. For example, the risk loci – sections of genes associated with coding for these specific traits – on the genome typically associated with schizophrenia are noted to be very close to those responsible for DNA methylation, a key modification for epigenetic changes. Considering the control of many important proteins by this process (e.g. hypermethylation in schizophrenic cases for GAD-1 genes that are meant to code for the inhibitory neurotransmitter GABA, the close link between DNA cytosine methylation which interferes with transcription and schizophrenia) and that it is a commonly observed modification for environment exposures such as to viruses, this suggests that many causes of the disorder can be linked with epigenetic changes (Föcking et al. 2019).

Features of the chromatin, histone protein modifications (including increased H3K9me3 levels), and other signalling proteins are also closely associated with such genes, although deriving a direct link has been complicated due to the advanced technology needed to analyse it. Furthermore, as alterations in the HDAC level for animal models have proven successful in causing antidepressant effects (Bilecki et al, 2023), targeting the epigenome has some basis for being an important step to consider in combatting mental disorders.

2. Schizophrenia Disease Formation and Factors

There is an association (Alnaes et. al., 2019) between several brain abnormalities and schizophrenia. Schizophrenia is associated with widespread brain abnormalities, with most patients showing structural differences being ventricle enlargement, reduced thickness and area of frontotemporal cortices, and reduced hippocampal and amygdala volumes (Clark et. al., 2020). These homogeneities in the brain structure in most schizophrenia patients could help in understanding the underlying pathophysiology of schizophrenia. However, variability is seen across individual patients (Weinberg et. al., 2016), presenting a major challenge for achieving imaging-based diagnostic predictions. A recent meta-analysis reported increased interindividual volumetric variability (differences in the volume of one or more brain parts between members of a population) in several cortical and subcortical structures, including the temporal lobe, thalamus, hippocampus, and amygdala in schizophrenia, and lower variability in the anterior cingulate cortex (Brugger, Howes, 2017). These results point to the importance of modelling heterogeneity, as well as mean changes, as it reflects gene-environment interactions related to individual sensitivity to genetic and environmental perturbations. 

Similar meta-analysis of cortical thickness and surface area abnormalities in schizophrenia was conducted (Turner et. al., 2018). Data from 4,474 individuals with schizophrenia (mean age, 32.3 years; range, 11–78 years; 66% male) and 5,098 healthy volunteers (mean age, 32.8 years; range, 10–87 years; 53% male) was assessed with standardised methods at 39 centres worldwide. It was found that, compared with healthy volunteers, individuals with schizophrenia have a thinner cortex and smaller surface area, with the largest effect sizes for both in frontal and temporal lobe regions. They also found that regional group differences were observed in cortical thickness, suggesting regional specificity. In contrast, effects on cortical surface area appear global and uniform. They observed that cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals, and that negative correlations between age and bilateral temporal thickness were stronger in individuals with schizophrenia than in healthy volunteers. A similar study (Karlsgodt et. al., 2010) was done using imaging techniques to show that schizophrenia is associated with changes in the structure and functioning of a number of key brain systems, including prefrontal and medial temporal lobe regions involved in working memory and declarative memory, respectively. The MRI studies showed reduced gray matter volumes of the medial temporal, superior temporal, and prefrontal areas – regions associated with auditory information and short-term memory and decision making. Postmortem studies (Glantz, Lewis, 2000) reveal that the reduction in grey area reflects reduced dendritic complexity and synaptic density impacting interneuronal communication and integration. 

A 2017 study (Kelly et. al., 2017) showed that people with schizophrenia have a reduction in white matter throughout the brain compared with those without the condition. White matter is essential for the proper functioning of the brain, as it helps the body process information, connecting regions that send and receive signals, affecting the ability to focus and learn, commonly noted in patients with schizophrenia. Furthermore, white matter genetic variants have been found to overlap with genes associated with liability for schizophrenia (Bohlken et. al 2016). Abnormalities have been linked to cognitive deficits and symptoms in schizophrenia, including memory impairment and auditory hallucinations (Kubicki et. al., 2005). Studies using neuroimaging techniques such as MRI and PET have revealed various structural abnormalities in the brains of schizophrenia patients often observed in regions critical for cognitive and emotional processing, including the prefrontal cortex, temporal lobes, hippocampus, and thalamus. A study in 2022 (Constantinides et. al., 2022) compared brain imaging data from almost 3,000 people with schizophrenia with around 2,500 people without the condition. It was found that the brains of people with schizophrenia appeared to be around 3.5 years older than those without. 

Schizophrenia has a complex etiology, influenced by both genetic and non-genetic factors. It is highly heritable (Sullivan et. al., 2003) prompting the identification of intermediate brain phenotypes and explains the pathway from genes to illness manifestation. A genetic epidemiologic study has shown that schizophrenia is highly heritable (~80%) with evidence of both common and rare genetic variants, as well as diverse environmental factors contributing to its etiology (Owen et al. 2016).

2.1 Genetic and epigenetic control of  inheritance of schizophrenia

The polygenic risk score (PRS) for schizophrenia, which represents a weighted sum of common genetic schizophrenia risk alleles, has been proposed to account for the polygenic nature of disease risk (Allardyce et. al., 2018). PRS has also been linked to a thinner cortex, to prefrontal working memory, and hippocampal related activation and connectivity in patients and healthy participants (Kauppi et. al., 2014), thus in line with the frontal cortex and hippocampus as core regions in the pathophysiological process of schizophrenia. Risk alleles could also affect individuals’ environmental sensitivity, which could be reflected in the phenotypic variability between individuals. Grey matter abnormalities in schizophrenia are partially hereditary, as shown in twin gene studies, and are partially modulated by intrauterine risk exposures such as foetal hypoxia (Cannon et al., 2003). 

Factors such as prenatal stress, maternal infections, malnutrition, and early life adversity have been implicated in the development of schizophrenia (Merikangas et. al 2022). These environmental stressors can lead to epigenetic modifications that affect brain development and function, potentially exacerbating the structural abnormalities associated with the disorder. Neurocognitive dysfunction in schizophrenia was studied (Lewandowski et al. 2010) and reveal that patients with schizophrenia exhibit dysfunction preceding the onset of illness, which becomes more pronounced in the preliminary and early years following diagnosis, then settles into a stable pattern. Sometimes the structural and functional changes may not become clinically apparent until adolescence or early adulthood, when the brain undergoes significant maturation.

The identification of genes associated with schizophrenia, including those involved in synaptic function, neurotransmitter regulation, and neural development, indicate their fundamental role in brain function. Mutations or variations in these genes can disrupt neural processes, leading to the manifestation of schizophrenia. Copy number variants (CNVs or structural rearrangements to chromosomes and represent a major source of genetic variation) at specific loci have also been identified as important risk factors for several neuropsychiatric disorders, such as schizophrenia (Rees, Kirov, 2021). They involve gains and losses of DNA segments, respectively known as duplications and deletions, such as the 22q11.2 deletions, which were first associated with increased risk for schizophrenia (Murphy et. al., 1999). For schizophrenia, strong statistical evidence has been found for up to 12 risk CNVs (Marshall et. al., 2017).

Dopamine has been shown to be critical in the pathophysiology of schizophrenia. One of the most studied genes in the context of schizophrenia is the Disrupted-In-Schizophrenia 1 (DISC1) involved in neuronal development and function crucial for neurite outgrowth and axonal guidance – processes essential for proper brain development (Miyoshi et. al 2003). Mutation of DISC1 can lead to dopaminergic abnormalities observed in schizophrenia (Dahoun et. al 2017). Alterations in the aforementioned gene expression have been associated with increased dopamine levels and higher susceptibility to schizophrenia over three generations. Collectively, a picture is emerging of how DISC1, through a multiplicity of protein-protein interactions, including with other known risk genes, regulates two core etiological concepts in schizophrenia, namely neurodevelopment and neurotransmission. Further studies in both humans and rodents of defined genetic status for DISC1 and its many partners are likely to improve our understanding of schizophrenia etiology at the molecular and systems level, a requirement for the diagnosis of patients, the design of new and more effective drug therapies, and the ability to predict the course of illness and treatment responses (Johnstone et al., 2011).

Since genetics factors play a significant role in the development of schizophrenia, studies have shown that the risk of schizophrenia is substantially higher in individuals with a family history of the disorder. For instance, the risk to first-degree relatives is approximately nine times greater than in the general population. Twin studies further support this, with monozygotic twins showing a 53% concordance rate compared to 15% in dizygotic twins, indicating a heritability estimate of 68% (Walton et. al., 2014). 

2.2 Environmental Factors

Factors such as prenatal stress, maternal infections, malnutrition, and early life adversity have been implicated in the development of schizophrenia (Merikangas et al., 2022). These environmental stressors can lead to epigenetic modifications that affect brain development and function, potentially exacerbating the structural abnormalities associated with the disorder. 

Neurocognitive dysfunction in schizophrenia was studied by Lewandowski et al. (2010). Their study revealed that patients with schizophrenia exhibit dysfunction preceding the onset of illness, which becomes more pronounced in the preliminary and early years following diagnosis, then settles into a stable pattern. Sometimes the structural and functional changes may not become clinically apparent until adolescence or early adulthood, when the brain undergoes significant maturation.

Other epidemiological studies have reported a relationship between maternal psychological stress and an elevated risk of schizophrenia in the adult offspring, for instance, Malaspina and colleagues reported a raised incidence of schizophrenia in offspring whose mothers were pregnant during the Arab-Israeli war of 1967 (Malaspina et al., 2008). A more recent population-based study by (Khashan et al. 2011) showed that the risk of schizophrenia was elevated in offspring whose mothers were exposed to the death of a relative during the first trimester, thus showing the epigenetic nature of schizophrenia (Khashan et al., 2011). Hence, certain schizophrenia risk loci can influence gene expression through epigenetic processes, highlighting the interaction between genetic and epigenetic control of neurodevelopmental trajectories. A retrospective epidemiological study by (Huttunen, Niskanen, 1978) suggested for the first time that children whose fathers had died before their birth had higher risks of developing schizophrenia than those children whose fathers died during the first year of their lives, thus showing that the risk of developing schizophrenia may be influenced by the timing of adverse experiences in relation to critical periods of brain development (Huttunen, Niskanen, 1978). In addition, a substantial portion of epigenetic alterations in schizophrenia may be acquired through environmental factors and may be manifested as molecular “scars.” Some of these scars can influence brain functions throughout the entire lifespan and may even be transmitted across generations via epigenetic germline inheritance.

3. Specific Epigenetic Mechanisms in Schizophrenia

Despite extensive research, scientists have not yet identified a single definitive cause for schizophrenia. However, factors such as environmental changes are commonly associated with the disorder, suggesting that epigenetics play a significant role in the manifestation of schizophrenia. Environmental changes, DNA methylation, and histone modifications are discussed in this section.

One known factor leading to schizophrenia includes environmental changes. Environmental changes include diet, alcohol consumption, pollution, trauma, and drug use. Should these changes occur in utero, the epigenome may be modified and regulate the genome irregularly, leading to the development of schizophrenia later in life. Likewise, such modifications can be inherited, potentially leading to schizophrenia across three generations. 

Three specific epigenetic mechanisms sourced from the environment are discussed in the paper: DNA methylation, non-coding RNA action, and histone modification. DNA methylation is the addition of methyl groups to DNA, typically inhibiting gene transcription. If this process occurs on genes that promote brain development, it can cause social, emotional, and behavioural disorders, especially during foetal development. Studies have found that schizophrenia patients tend to have more methylated DNA in their cells (Chen et al. 2021). Hypermethylated DNA has also been found in the brain tissue of post-mortem schizophrenia patients.

Another process suspected to cause schizophrenia is the action of non-coding RNAs (ncRNAs). ncRNAs are functional RNA molecules not translated into proteins, instead aiding in gene expression, transcription, and translation. The ncRNA most closely associated with schizophrenia is microRNA (miRNA), a small strand of ncRNA spanning about 21-25 nucleotides involved in gene transcription and regulation. The study of Chen et al. (2021) showed that schizophrenic patients had higher levels of miRNA in their blood, suggesting a potential link to the disorder. Abnormal miRNA levels have been shown to affect cognitive development and performance, and may play a crucial role in explaining the symptoms and etiology of schizophrenia.

The final process contributing to schizophrenia is histone modification. Histones provide structure to chromosomes and can be modified through various chemical reactions, including acetylation and methylation. Acetylation of histone H3 causes the histone to drift away from DNA, allowing transcriptional processes to occur. This can destabilise chromatin; such destabilisation is readily observed in schizophrenia patients (Chen et al., 2024). Furthermore, histone methylation, the addition of methyl groups to H3 and H4 histones, can repress or regulate gene transcription and is related to cognitive impairment. Increased methylation of histone H3 is a key biomarker in post-mortem schizophrenia patients and can produce antidepressant-like symptoms recognised in schizophrenia.

In summary, DNA methylation, ncRNA activity, and histone modification are critical factors associated with the development of schizophrenia. Understanding these epigenetic processes provides valuable insights into the complex nature of this mental disorder.

4. Research Methodology

This section will explore a laboratory technique that is used to investigate the epigenetic associations, causes and influences for schizophrenia. A key methodology to study epigenetics is mass spectrometry, which is a tool used to measure the mass-to-charge ratio of one or more molecules that are present (Föcking et al., 2019). 

Mass spectrometry uses an ionisation source, a mass analyser, and an ion detection system to analyse its data (What is Mass Spectrometry?, 2010). Firstly, in the ionisation source, molecules are changed into gas-phase ions in order to allow it to be manipulated by electric and magnetic fields externally. One technique that can be used is called nanoelectrospray ionisation, and it allows the molecules to create positively charged ions or negatively charged ions. This technique can allow a tiny chromatography column to separate compounds that are passing through it directly to a mass spectrometer, which enables the efficient analysis of the molecules. Secondly, the mass analyser is used to sort the molecules of ions by separating according to mass-to-charge ratios. Lastly, the ion detection system is used to measure and send the ions to a data system where the mass-to-charge ratios are stored. These three methods all work together to allow mass spectrometry to function and allow it to be a useful tool in analysing the epigenetic causes behind schizophrenia.

The type of  epigenetic changes analysed by mass spectrometry in relation to schizophrenia are histone modifications. According to the Research Progress on the Correlation Between Epigenetics and Schizophrenia, histones are highly conserved structural proteins that are involved in the composition of eukaryotic chromosomes, which are divided into five types. These five types are H1, H2A, H2B, H3, and H4 (Chen et al., 2021). Histone N-terminal tails are post-transcriptional modifications sites, and they can undergo chemical modifications including methylation, acetylation, phosphorylation, adenylylation, ubiquitination, and adenosine diphosphate ribosylation, which affects the genes functions such as gene transcription, repair, replication, and recombination. Histone methylation normally occurs on lysine and arginine residues. Lysine positions K4, K9, K27, L36, and K79 of histone H3 and K20 of H4 can be methylated. By studying these histone modifications related to schizophrenia, it can be seen how it associates with the expression of several metabolic-related genes in schizophrenia and how mass spectrometry can be used to analyse them. 

Two different types of mass spectrometry used in histone modifications analysis in relation to schizophrenia are (1) top-down whole protein analysis and (2) bottom-up peptide analysis after digestion. Top-down mass spectrometry is used to analyse intact proteins that are directly in the mass spectrometer, and it measures both intact and fragmented ions (Catherman et al., 2014). This method allows for complete sequence coverage, which is the number of unique readings that contain a given nucleotide in the sequence, and characterisation of proteoforms, which are specific forms of proteins resulting from genetic variations, post-translational modifications, and alternative splicing. On the other hand, in the bottom-up method, proteins are broken down into peptides before the introduction into the mass spectrometer, where the peptides are then detected and fragmented (Boccaletto, Siddique and Cosson, 2018). It is widely used as a methodology for histone modification analysis in schizophrenia because of its ability to analyse many peptides at once because of its advancements in nanoscale separation techniques and high-performance mass spectrometry instruments. In conclusion, these methods allow a clear view of histone modifications in schizophrenia, including insights into protein and its forms and modifications, along with a detailed characterisation of post-translational modifications.

4.1 Strengths and Limitations 

Mass spectrometry has high sensitivity and selectivity, meaning it can detect and quantify compounds with low concentrations and distinguish between compounds with masses that are similar, which makes it suitable for the analysis of histones related to epigenetics in schizophrenia. In addition, it covers a wide range of molecular weights and is able to provide structural information on molecules by looking at fragmentation patterns which helps with identification and characterisation. It allows for precise measurement of concentrations, and it can be coupled with many different separation techniques in order to enhance separation and resolution of complex mixtures. Although mass spectrometry has many advantages, it comes along with disadvantages as well. It is quite complex and requires expertise in instrumentation and data analysis. The preparation of samples to be used for mass spectrometry is time-consuming and requires precise work in order to preserve analytes and avoid contamination. Additionally, not all compounds are able to ionise efficiently, which can lead to sensitivity and detection limit errors for certain analytes. 

Top-down whole protein analysis allows for the direct analysis of intact histone proteins, including their modifications without the need of enzymatic digestion beforehand. It allows us to understand the full scope of modifications present on histones, including the complex combinations of post-translational modifications across the protein sequences, and it preserves the quality of the protein’s modifications. The proteins in top-down mass spectrometry are directly ionised, which allows for improved sequence coverage. However, it may be hard to handle large proteins and interpret complex data. Proteins that are being analysed can be large, which makes it challenging because it would require specialised instrumentation. Its complex data can also be hard to interpret because it contains multiple charge states and overlapping signals which makes data analysis and interpretation more complicated.

The bottom-up method has shown significant progress and development in the improvements of peptide enrichment, the availability of high-resolution mass spectrometers, and innovative data obtaining. This enables extensive peptide identifications and strong analyses. It allows a precise analysis of peptides and the identification of post-translational modifications on histone tails which are an important factor for understanding the epigenetics behind schizophrenia. Although it has shown advantages, it has faced challenges in fully mapping the multifarious number of protein modifications due to the fragmented nature of peptide analysis, which can conceal the comprehensive context of the modifications. 

Despite these challenges, mass spectrometry is still used as an effective tool in histone modification analysis in schizophrenia, and it is an important tool in other fields as well due to its capabilities in molecular analysis and characterisation.

5. Existing Treatment Options for Schizophrenia

The highly heterogeneous manifestation of schizophrenia poses itself as a layered problem for clinicians (Rubio and Kane, 2022). Due to the variable nature of disease expression and etiology, treatment options are best effective when tailored to the patient.

However, a genre of pharmaceuticals known as antipsychotics have become a cornerstone for treatment. Antipsychotics are antagonist drugs, i.e. cell receptor blockers, that specifically target dopamine receptors in the brain. Such alleviates the symptoms of psychosis – a hallmark of schizophrenia – and prime the patient for recovery. Direct evidence shows that the psychotic symptoms of the disease are marked by hyperactivity of Dopamine Receptor 2 in the mesolimbic area of the brain (Abi-Dargham et al., 2000). Current generation antipsychotics have now been tailored to block this biochemical pathway.

That being said, some 20% of patients display ‘early nonresponse’ (ENR) to the effects of such drugs, which indicates a minimal response to antipsychotic treatment in the early phases of treatment (Rubio and Kane, 2022). This is referred to as treatment-resistant schizophrenia (TRS). These findings also suggest that the dopaminergic system in the mesolimbic region is not the sole cause of schizophrenia-related psychosis (Lowe et al., 2017). To address this, stratified approaches for treatment have been adopted – albeit underutilised – where modifying original treatment plans to include other pharmacological or psychodynamic means of symptom treatment are utilised. Here, clinical markers (e.g. ENR, worsening symptoms) are used as the basis for modifying treatment. For example, the use of clozapine, a serotonin receptor blocker, after displaying ENR to non-clozapine antipsychotics has been shown to increase response rate by 75% after two weeks (Kane and Correll, 2016). 

However, a substantial subset (40 to 70%) of TRS patients display ultra-treatment-resistant schizophrenia (UTRS), which also happens to be resistant to clozapine (Peitl et al., 2023). From thereon, critiques about the unidimensional inhibitory mechanism of antipsychotics have been voiced out due to the lack of novel mechanisms uncovered (Rubio and Kane, 2022). Since then, two pharmaceuticals have been tested clinically, including SEP-363856 and xanomeline. Notably, both are partial agonists; instead of inhibiting biochemical pathways, they activate it partially. Both are currently undergoing preliminary clinical trials, where a xanomeline-tropsin (a muscular agonist) mixture was shown to alleviate symptoms of schizophrenia without having any adverse effects (Singh, 2022).

Beyond pharmaceuticals, the highly genetic link of schizophrenia also enables the possibility of precision medicine, where treatment is bespoke to the needs of the person. Correcting the defective genes of a schizophrenic person, especially with its polygenic nature, proves to be a promising treatment option within the next decade (Nakamura and Takata, 2023). Currently, however, knowledge translation from basic biological research to clinical psychiatry is insufficient, posing a high risk for clinical application. Exorbitant costs also make gene therapy unfeasible from an economic perspective. 

The case is similar for epigenetic treatment options. Although progress has been made in identifying the epigenetic profile of schizophrenia, the mechanistic links remain unpronounced (Richetto and Meyer, 2021). Separating genetics from epigenetics is the idea of molecular scars that are obtained due to environmental adversity during the course of one’s lifetime, especially during developmental periods. Examples of environmental factors leading to these scars include cannabis and tobacco usage, pre- and postnatal stress, and postpartum nutritional deficits. Some epigenetic scars, including irregular methylation levels of the GAD1 gene, are implicated in long-term brain dysfunctions associated with schizophrenia. Just as with gene therapy, epigenetic therapies for schizophrenia have yet to exist, with much data on the topic coming from animal models that are difficult to clinically translate (Wawrzczak-Bargieła, Bilecki, and Maćkowiak, 2023). Nonetheless, the reversibility of epigenetic modifications makes it a promising option for total recovery-oriented treatment as compared to purely genetic and pharmaceutical treatment. Before this, the pronouncement of the interplay between epigenetic mechanisms and the expression of schizophrenia — especially on how these contribute to phenotypic variability — is first needed before personalised treatment can be realised.

6. Discussion

6.1 Potential Avenues for Treatment Formulation

I) Demethylating Agents

One potential avenue to explore in the treatment of schizophrenia could be the prescription of demethylating agents. Demethylating agents are drugs that act upon epigenetic methylation markers to remove their silencing effect and increase the expression of those genes (Charette et al, 2016). They are often used in cancer treatment, with some common examples including azacitidine and decitabine (Derissen et al, 2013). There exist two main classes of these: nucleosides, which incorporate into the DNA, and non-nucleosides, which act through alternate methods. Both of these inhibit DNA methyltransferases, a class of enzymes that catalyse the transfer of methyl groups onto genetic material, and as a result prevent DNA methylation from occurring (Gallimore and Fandy, 2023). 

As the hypermethylation of specific genes, such as BDNF and FOXP2 responsible for functions including the growth of neurons, is a key aspect of schizophrenia (Delphin et al, 2024), demethylation might effectively combat an integral contributing factor to the disorder. This paper would thus suggest the use of demethylating agents in cases with high risk factors for schizophrenia (especially those with genetic vulnerability to developing the disorder). 

Such a route may also serve as treatment for those that have already acquired the illness, as DNA methylation is noted to be reversible through the actions of enzymes such as Ten-Eleven Translocation Dioxygenases (Recillas-Targa, 2022). Additionally, some studies, such as Gudotti and Grayson (2014), suggest that traditional medications such as clozapine used for schizophrenia may also act to demethylate some regions, thus indicating that this is an area worth more analysis to devise treatment methods.

II) Epigenetic Gene Editing

CRISPR-Cas9 is a gene-editing method that involves editing parts of the genome by removing, adding, or altering certain parts of the DNA sequence, and this method allows epigenetic editing to occur. The mutations to turn off the schizophrenia marker are introduced in the embryo stage, and that DNA sequence stays inside the organism as it grows (What is CRISPR-Cas9?, n.d.).

NcRNAs such as microRNAs and long non-coding RNAs are involved in schizophrenia with multiple genetic alterations, so CRISPR/Cas9 allows the role of these ncRNAs to be studied by editing the genome or modifying the expression levels (Özulu and Erbaş, 2021). The CRISPR/Cas9 gene editing allows the ncRNAs to be broken down and analysed to determine whether the disruption of ncRNA genes causes schizophrenia. This gene-editing method can deliver components that are regulatory to target genes and activate or increase the rate of target gene expression. It can be used as a possible treatment because it can allow or disable a gene’s transcription and turn off the targeted gene that causes schizophrenia. Additionally, this method can also be used for drug discovery and therapeutic development. The edited gene models can be used to screen and look for potential therapeutic compounds that may help reduce symptoms or reverse any health deficits that are caused by schizophrenia. In summary, CRISPR/Cas9 gene editing can be used to target the gene that causes schizophrenia and it can be used for drug discovery.

6.2 Questions to be Addressed

This section identifies broad knowledge gaps in the field that are crucial for understanding the link between schizophrenia and epigenetics, but are outside the scope of the paper.

I. Epigenetic Profile of Schizophrenia

This remains relatively unknown. Delineating the epigenetic profile of the disease is a crucial stepping-stone for formulating future therapies. The range of this can vary: identifying chromosome loci most epigenetically vulnerable to environmental factors; discerning how irregular epigenetic mechanisms lead to schizophrenia development and its link, if any, with the disease’s heterogeneity; and determining how the epigenome contributes to the regulation of the neural regions (e.g. dopaminergic complexes, mesolimbic system) relevant to schizophrenia. 

6.3 Recommendations for Future Studies

I. Biomarker Identification

Biomarkers refer to precise biological characteristics, which can consist of processes, substances, structures etc. that can indicate the medical conditions of patients (Strimbu and Travel, 2010). As their quantifiable characteristics may correlate to observable traits, they are often used as an additional tool in diagnosis. 

Analysis of these biomarkers has previously been employed for the study of the disease and to predict responses to treatments. The focus has historically been on blood-based biomarker analysis due to the ease of collection and application of available technologies, with examples pertaining to schizophrenia including neurotrophin levels in blood. With special regard to epigenetics, methylation pattern analysis such as of CpG sites and studies into miRNA levels in blood plasma have been explored, although the field still needs further study to mitigate discrepancies in results (Lai et al, 2016). 

Deeper analysis of potential biomarkers in schizophrenia’s earliest (prodrome) stage also remains a source of scientific curiosity (Bilecki et al, 2023). Biomarkers in the brain have historically received insufficient research due to ethical considerations and difficulties in obtaining samples for study. However, due to the extreme impact of schizophrenia on brain structure, as discussed previously, as well as due to how epigenetic factors can further alter the expression of schizophrenia, analysis of patient or genetically vulnerable samples and their comparison to typical non-case samples might offer further insights into the specific changes that arise as a result of the affliction in this key organ.

II. Longitudinal Studies

Despite several decades of research, our knowledge of the long-term course of schizophrenia is hampered by a lack of homogeneity of both research methods and phenotypic definitions of schizophrenia. It is clear that a range of factors, including genotype, age, and sex, are correlated with epigenetic variation and so including these as covariates in analysis is important (Boks et al., 2009). The analysis of schizophrenia-discordant monozygotic (MZ) twins represents a powerful strategy for overcoming many of these issues as both twins have their genomes, parents, birth date, and gender in common and are likely to have been exposed to a highly similar pre- and perinatal environment. A longitudinal study of epigenetic variation in 46 MZ twin-pairs and 45 DZ twin-pairs (total n=182) (Wong el.al., 2010) suggested that DNA methylation differences are apparent already in early childhood, even between genetically identical individuals, and that individual differences in methylation are not stable over time. Their longitudinal-developmental study suggests that environmental influences are important factors accounting for interindividual DNA methylation differences, and that these influences differ across the genome. These observations highlight the importance of longitudinal research designs for epigenetic research.

Importantly, longer follow-up durations may allow for the investigation of long-term effects of antipsychotics on brain structure, given that their long-term antipsychotic efficacy has recently been challenged (Harrow et. al., 2014). The MUFUSSAD study reassessed a sample of schizophrenia patients after a period of 15 years and observed rather stable negative symptomatology together with a considerable reduction in paranoid-hallucinatory symptomatology (Moller et al., 2010). The majority of patients (57%) had a chronic illness course, and 39% an episodic-remitting course. Similarly, 35 human studies were reviewed focusing on a narrow schizophrenia phenotype, employing a follow-up duration of six months or more and consistent methodology at the different measurement points to reduce the heterogeneity (Heilbroner et. al., 2016). For the meta-analysis on global cognitive change, eight and four studies were used to compare schizophrenia to healthy and psychiatric controls, respectively. They found that the course of schizophrenia is characterised by a constancy or even improvement of positive and negative symptoms and by fairly stable cognitive impairment, reflecting structural frontal and temporal cortical pathology. Two and 4.5 years after admission, almost half of the patients with schizophrenia (44%) experienced first-rank symptoms, but these values declined to 30% at the ten-year follow-up and rose again to 44% at the 20-year follow-up. When hallucinations were investigated separately over time, roughly 80% of schizophrenia patients experienced symptoms of this kind at index hospitalisation (Goghari et al., 2012). This value continually declined to approximately 30% at the 15-year follow-up, and showed only a slight increase at the last measurement point (20 years). The results suggest that medication can be an important modulator of the short-term decline of executive functions, which appears to be absent in patients treated with atypical antipsychotic medication. Because many psychotropic drugs have been shown to alter the epigenome, (Boks et al., 2012) such longitudinal study designs would allow us to determine whether epigenetic changes are independent of, or are mediated by, medication.

These findings also indicate that age is an important modulator of heterogeneity and therefore interactions of time and disease progression need to be further investigated (Heilbroner et. al., 2016). For future longitudinal research studies, it is important to analyse the longer follow-up intervals and more measurement points, diagnostic consistency, focus on schizophrenia progression in later life stages and a combination of cross-sectional and longitudinal research to distinguish between age and birth-cohort effects (effects of different medication or other environmental variables that are differentially effective in particular age groups).

7. Conclusion

Covered in this article is a brief introduction of epigenetics, including specific mechanisms for epigenome modification, before transitioning to an analysis of schizophrenia, particularly the nuances of its etiology and expression. Following this, the links between epigenetics and schizophrenia are briefly elaborated upon, a focus which guides the remainder of the paper. The connection of DNA methylation, non-coding RNA action, and histone modification to schizophrenia was briefly explained. This was supplemented by explaining the effects of schizophrenia on brain structure and function, where it was found that those afflicted had reduced brain matter, as well as displaying older brain levels (three and a half years older) relative to those non-afflicted. Genetic and environmental factors contributing to disease development were also discussed. Two different techniques of mass spectrometry for gauging the molecular bases of schizophrenia were also discussed, as well as their strengths and limitations: top-down whole protein analysis and bottom-up peptide analysis. Lastly, existing treatment options for the disease were discussed. It was found therein that antipsychotic use is a fundamental part of treatment for treating symptoms. However, this generalised approach to treatment was found to be ineffective for about 20% of patients, owing to the highly heterogeneous expression of schizophrenia. However, personalised (stratified treatment) and precision medicine (both genetic and epigenetic) was found to be scarcely used due to knowledge gaps and economic constraints. 

Upon further discussion, the paper derived potential contributions to the field through the suggestion of possible treatments for schizophrenia based on its relationship with epigenetics, such as the use of demethylating agents and epigenetic gene editing. Consequently, the remaining questions pertaining to epigenetics and schizophrenia, as well as further recommendations for future studies to explore through the collection of primary data, are suggested in the hopes that this paper’s analysis of existing literature will be able to provide insight into modes of treatment that may prove successful in the management of this disorder.

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