Epigenetic Therapies for Treatment of Mental Disorders

Mental health disorders range from anxiety and depression to schizophrenia and dementia, affecting a significant number of people worldwide. Current treatments tend to be short-term and carry high risks of withdrawal symptoms, among other adverse side effects. Epigenetic therapies are relatively recent and novel treatments being studied for their use against mental disorders, targeting illnesses at the source: the genetic code.

What is Epigenetics?

Genetics is the study of heredity, in which parents pass their genes to their offspring. These are located in the nucleus of each cell in the organism, providing the instructions for building proteins. In turn, they govern the way our bodies work, so defects in our genes are the cause of a variety of diseases.

However the incidence of certain disorders that ‘run’ in families cannot be fully explained by the genome alone². The most suitable biological mechanism proposed to explain this is epigenetics, originally described by C. H. Waddington, a British evolutionary biologist, in 1942.

Epigenetics (‘epi-‘ is Greek for ‘above’) presents a mechanism in which chemical compounds are added to genes, affecting the way they code for proteins. These natural processes are crucial for normal development, especially in cell differentiation, where different proteins are expressed based on the same genome³.

This regulation does not involve changes in the genetic code, so it is not a form of mutation. While epigenetic changes affect an individual’s phenotype (the result of gene expression), it does not change the genotype (the DNA responsible for that particular characteristic).

In addition, the environment is able to influence epigenetic changes, changes that may even be passed down to later generations⁴. Studies have shown that depriving the mother of food during early pregnancy increases the risk of coronary heart disease, obesity and schizophrenia later in the child’s life^5,6.

Maternal stress has been shown to also affect epigenetics in the fetal brain, contributing to mental health issues⁷. Other epigenetic mechanisms may also result in illnesses such as cancer⁸.

Effects of Epigenetic Modification

From as far back as 1969, DNA methylation has been linked with affecting long-term memory function¹⁰. New studies provide further evidence that epigenetic mechanisms are able to regulate long-term neuronal changes. In addition, these changes also affect neuroplasticity, learning capacity, memory and other related functions^11-14.

It is thought that handedness could be the result of epigenetic factors, with genome-wide association studies showing no single influential gene in handedness preference. ‘Handedness‘ in an individual could be the result of epigenetic changes brought about by environmental factors³¹.

DNA methylation involves inserting a methyl group – a small molecule – into DNA. This occurs at the 5′ position of cytosine in DNA, by an enzyme known as DNA methyltransferases (DNMT). DNMTs are usually active during development, cell division, and differentiation. Therefore it was believed that methylation patterns were stable in differentiated cells.

However, new studies show that the mammalian adult nervous system cells undergo significant methylation, contradicting this claim^15,16. Inhibiting the DNMT enzyme—and thereby preventing methylation—slows the formation of long-term memories¹⁴.

Epigenetic Therapies

On the back of these results, researchers are starting to examine the role of epigenetics in psychiatric diseases. Faulty epigenetic mechanisms are thought to contribute to depression, psychosis, Alzheimer’s, autism, addiction, etc^17-19. Therefore, the development of epigenetic therapies to counteract this is of great value.

But a major obstacle in brain drug design is the blood-brain barrier, limiting the number of drug candidates that target the brain. Due to the nature of this barrier, only molecules with high lipid solubility and low molecular size are able to cross it. Other drug delivery systems are also able to bypass this protective layer surrounding the brain.

Epigenetic therapies are not exactly new; a number are already approved for the treatment of various cancers²⁰. The problem facing current epigenetic drugs is high toxicity and severe side effects. This is acceptable in the case of life-threatening conditions such as aggressive forms of cancer, but not viable for diseases requiring a more subtle approach.

A few studies show possible therapeutic effects of drug candidate RG108 for the treatment of mental health illnesses, which will be discussed in greater detail.

RG108 – A Promising Drug Candidate

One promising drug candidate that fits the bill is RG108, a compound exhibiting high selectivity and low toxicity. RG108 is also able to cross the blood-brain barrier and bind to the active site of DNA methyltransferase. This blocks the activity of the enzyme and prevents DNA methylation in the brain²¹.

Addiction

Abnormal learning and memory patterns have links to individuals with drug addiction, such as those who are reliant on opioids. Synaptic plasticity causes neurons to ‘fire’ too much or too little, changing the strength of such impulses. Drugs like cocaine can override mechanisms that regulate this, and one such mechanism is the increase in DNA methylation in the brain23. Administration of RG108 and blocking of the DNA methyltransferase enzymes significantly reduced drug-seeking behavior in rats, with the effects persisting for up to 1 month²⁴.

Depression

In depression, stress is thought to have the biggest contributing factor. Recent studies show that depression increases the rate of DNA methylation while decreasing the expression of genes involved in neural plasticity. Researchers were able to modulate stress-induced changes in DNA methylation with RG108, which induced antidepressant-like effects in animal models²⁵.

OCD

In another study focusing on obsessive-compulsive disorders (OCD), researchers treated OCD-like behavior (obsessive grooming) in the 3 different mice models with a subcutaneous injection of one dose of RG108. RG108 reduced OCD-like behavior in all 3 mice models⁶. They also studied the role of DNMT methylation on memory and showed direct evidence of altered DNA methylation in a memory-related gene²⁶.

Future Direction

Based on these results, it is clear that mental health outcomes can benefit from epigenetic therapies such as RG108. Other areas where epigenetic drugs could have a large impact are in disorders characterized by memory dysfunction. These include PTSD (overactive recall of traumatic memories) and Alzheimer’s (impaired short-term and eventually long-term memory).

Schizophrenia and mood disorders also show links to epigenetic modifications, where the DNMT1 enzyme is selectively overexpressed in neurons. Brain tissue obtained from individuals who suffered from schizophrenia, bipolar disorder and psychosis exhibited hyper-methylation that decreased the expression of Reelin – a protein involved in normal neurotransmission, memory formation and synaptic plasticity^27,28.

Novel research shows that epigenetic mechanisms can even play a role in developmental disorders such as autism³⁰. These results support the hypothesis that mental health disorders can arise from faulty neural processes resulting from epigenetic changes. Further studies are required to better understand these mechanisms, as well as to identify epigenetic biomarkers that represent these diseases.

Technology such as genome-wide detection of epigenetic modifications will allow researchers to design safer, more specific and more effective epigenetic therapies. The design and development of these novel therapies provide exciting prospects for the future of mental health management.

This article was written by Catarina Cunha via Write For Us.

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