Bipolar Disorder

Epigenetic Influences on Schizophrenia and Bipolar Disorder

A concise review of research highlights and clinical implications.

Posted Dec 17, 2019

This post is the second in a series on the relationship between epigenetic factors and the risk of developing psychiatric disorders. In the previous post I reviewed epigenetic mechanisms that may result in pathological changes in brain function that increase the risk of developing depressed mood. In this post I review findings on epigenetic influences on schizophrenia and bipolar disorder. In the final post in this series I will review research on epigenetic influences on addiction.

Limited efficacy and safety problems of antipsychotics 

Research findings on epigenetic influences that increase risk of developing schizophrenia are leading to new understandings of the causes of schizophrenia and have important implications for innovations in treatment. Schizophrenia is a severe psychiatric disorder characterized by ‘positive’ symptoms such as hallucinations, delusions, disorganized thinking, and ‘negative’ symptoms such as apathy, paucity of thought and social withdrawal. Currently available antipsychotics work by antagonizing dopamine (D2) receptors and serotonin receptors. While antipsychotics mitigate the severity of positive symptoms in some cases, they have limited efficacy against negative symptoms. The result is that most individuals treated with antipsychotics have a partial response.

The limited efficacy of available antipsychotics is complicated by the fact that many antipsychotics cause potentially serious side effects including metabolic syndrome—which increases risk of diabetes and heart disease—and permanent neurologic disorders.

Epigenetic factors influence risk of developing schizophrenia and bipolar disorder

Findings of animal studies and post-mortem analysis of the brains of individuals diagnosed with schizophrenia suggest that epigenetic factors may lead to alterations in gene function that increase risk of developing schizophrenia. Epigenetic-induced alterations in methylation of DNA or histones in the nucleotides (i.e. the essential components of DNA) are associated with increased or decreased expression of several genes in the prefrontal cortex and other brain regions resulting in abnormalities in brain function or structure manifesting as schizophrenia. As is the case in depression (see previous post) there is evidence that maternal stress during pregnancy may result in epigenetic alterations in DNA methylation resulting in cortical abnormalities that manifest as schizophrenia.

Currently available treatments of bipolar disorder also have limited efficacy suggesting that current understandings of the causes of bipolar disorder are not well understood. Advances in epigenetic research are resulting in important new insights about non-genetic factors that influence risk of developing bipolar disorder that may lead to important innovations in treatment. Similarities between genetic factors and the neurobiology of bipolar disorder and schizophrenia may be related to the fact that both disorders respond to the same drugs. Analyses of post-mortem brains of individuals diagnosed with schizophrenia or bipolar disorder revealed similar epigenetically induced changes in many of the same genes.

Nutritional psychiatry approaches mental illness from an integrative perspective

The emerging field of nutritional psychiatry studies the relationships between diet and mental illness and approaches the multi-factorial causes of psychiatric disorders from an integrative perspective.

Accumulating research findings from animal and human studies supports that select nutrients have beneficial effects on psychiatric disorders by reducing inflammation and oxidative stress, changing the gut microbiome, mitigating deleterious consequences of epigenetic alterations, and promoting greater neuroplasticity. Exposure to stress stimulates increased secretion of hormones called glucocorticoids that induce epigenetic alterations in genes linked to increased risk of developing schizophrenia, bipolar disorder and degenerative neuropsychiatric disorders such as Alzheimer’s disease and Parkinson’s disease.

Interactions between stress and nutritional status influence mental health

Complex interactions between nutritional status and stress add another important dimension to epigenetic influences on mental health. For example, the deleterious consequences of stress on different brain regions are modified by nutritional factors that may differ depending on the chronicity and severity of stress and age. It has been established that Individuals diagnosed with schizophrenia or other psychotic disorders have higher rates of childhood trauma or undernutrition, and are more likely to have mothers who were undernourished during pregnancy, compared to healthy adults.

Select nutrients may lessen the deleterious effects of epigenetic alterations on mental health

Dietary interventions that mitigate the deleterious consequences of epigenetic alterations on mental health may play a role in preventing or reducing the severity of psychiatric disorders. The clinical use of select nutrients to reverse damaging epigenetic consequences of stress, poor nutrition, exposure to toxins or other environmental factors is called nutri-epigenetics

Findings of animal studies suggest that maternal intake of choline (a methyl donor) during pregnancy may help reverse deleterious consequences of epigenetic alterations in the fetus caused by prenatal stress, possibly reducing the risk of developing neuropsychiatric disorders in adulthood. Folate, vitamin B-12, methionine and betaine are examples of nutrients that may help reverse DNA methylation potentially lessening the risk of developing depression, schizophrenia, bipolar disorder and neurodegenerative disorders .

Bottom line

Limitations of available treatments of schizophrenia  and bipolar disorder suggest that current understandings of the causes of these disorders are not well understood and call for new models of disease causation and innovations in treatment. Epigenetics research is helping to clarify the complex underlying causes of schizophrenia and bipolar disorder and may result in novel treatment approaches. 

An important goal of epigenetic research is to elucidate complex relationships between genetic vulnerability to psychiatric disorders and environmental factors such as chronic stress, poor nutrition and exposure to toxins and how these relationships affect each individual’s vulnerability to specific psychiatric disorders over the lifespan. Accumulating findings from animal and human studies are providing important clues about specific epigenetic mechanisms underlying the pathogenesis of severe psychiatric disorders.

Choline, folate, vitamin B-12 and other supplements may reverse damage induced by epigenetic alterations of the genome, potentially reducing the risk of developing  schizophrenia and bipolar disorder. More studies are needed to determine how epigenetic mechanisms influence risk of developing schizophrenia, bipolar disorder (as well as degenerative neurologic disorders), to identify periods of greatest vulnerability to epigenetic-induced alterations before birth and during early development, and to evaluate the efficacy of drugs and nutraceuticals as candidates for reversing deleterious consequences of epigenetic changes. The interested reader is referred to recent review articles in the references. 


Horowitz, S. (2015) Epigenetics and its clinical applications. Alt and Comp Therapies; 21:6; 269-275.