Epigenetic Influences on Depressed Mood: A Concise Review

Epigenetics: An Important New Paradigm in Medicine and Psychiatry

Epigenetics is a rapidly emerging area of medical research that examines changes in the biological structure of function related to heritable changes in the expression or activity of genes that do not involve changes in genes themselves. A large variety of factors are known to mediate epigenetic changes including chronic stress, exposure to toxins, and diet. Nutritional factors influencing epigenetics have been extensively investigated. Behavioral epigenetics has to do with epigenetic influences on both normal and pathological behavior.

Findings of animal studies and a few human trials suggest that epigenetic factors may play important roles in the risk of developing psychiatric disorders, as well as heritability of psychiatric disorders across generations. In this post, I briefly review research findings on epigenetic influences on depressed mood. In subsequent posts, I will review the clinical implications of research findings on epigenetic factors influencing bipolar disorder, drug addiction, and schizophrenia.

The reader is referred to two recent review articles (see references) for a more detailed discussion of epigenetics and research findings on the relationships between epigenetic factors and mental illness.

Epigenetic mechanisms of action underlying psychiatric disorders

Psychiatric disorders are influenced by complex biological, social, and cultural factors. Accumulating research findings support that epigenetic factors that influence interactions between the environment and genes lead to changes in brain function that increase the risk of developing specific psychiatric disorders including depressed mood, bipolar disorder, schizophrenia and others.

Even brief periods of exposure to stress or environmental toxins may result in modification of DNA, histones, and other molecules found in nucleotides (i.e. the structural units of nucleic acids that comprise DNA). Modifications of these molecules by environmental stresses are known to activate or down-regulate genes that code for neurotransmitters or influence development of neural circuits underlying emotional regulation and cognitive function.

Epigenetic influences on depressed mood--a very short review of research findings

It is estimated that roughly 40% of the risk of developing depressed mood is related to heritable genetic factors, and the remaining 60% of risk has to do with nongenetic factors some of which may be mediated by epigenetic effects of chronic stress, diet preferences and other environmental factors. Depending on specific epigenetic changes and when they occur (i.e. before birth, in early childhood or adulthood) life-time risk of developing depressed mood and other serious mental health problems may vary significantly.

Animal models of depression have found that rodents exposed to chronic stress exhibit behavioral changes such as ‘chronic social defeat’ that may be similar to depressed mood in humans, including listlessness, reduced spontaneous activity, changes in appetite, avoidant behavior and other so-called ‘neurovegetative’ symptoms. Findings of animal studies also suggest that drugs that reverse DNA methylation or other epigenetic alternations may mitigate the deleterious consequences of early maternal-infant separation possibly reducing the risk of developing depressed mood. Along these lines, the antidepressant efficacy of fluoxetine (Prozac) and imipramine may be partly due to alterations in histones or DNA in nucleotides induced by both drugs resulting in change in expression of one or more genes in parts of the limbic system and the prefrontal cortex that manifest as reductions in the severity of neurovegetative symptoms.

Prenatal stress—including acute stress resulting from physical abuse during pregnancy—may result in epigenetic changes that have deleterious consequences on the developing brain and increase the risk of developing a depressed mood. Findings of animal models support that chronic exposure to early life adversity such as early separation of the mother and newborn, and early child abuse, results in lasting epigenetic changes such as a reduction in normal DNA methylation, that in turn increase the risk of developing depressed mood later in life and may increase suicide risk.

Exposure to even brief periods of severe stress or social isolation during adolescence and adulthood may also result in epigenetic alternations that increase the risk of depressed mood later in life.

Poor nutrition during pregnancy may increase the risk of depressed mood in offspring

There is evidence that poor maternal nutrition during pregnancy may result in long-term epigenetic alterations that may significantly increase the risk of developing medical and psychiatric disorders throughout the lifespan, and that such acquired epigenetic changes are heritable across generations.

Finally, changes in the gut microbiome influenced by diet can result in epigenetic alterations that influence the “gut-brain axis” manifesting as psychiatric symptoms. Findings of animal studies suggest that consuming foods rich in methyl-rich nutrients such as folate and B-12 may reverse deleterious epigenetic changes and reduce the risk of developing depressed mood.

Epigenetics Essential Reads

Epigenetics and a Paintbrush: How Environment Affects Genes

Epigenetics and a Paintbrush

Bottom line

Epigenetic factors such as chronic stress and poor nutrition during critical stages of development may have long-term deleterious consequences on brain function and increase the risk of developing depressed mood. Large human trials are needed to elucidate specific epigenetic mechanisms that operate before birth, early childhood and adulthood and how such mechanisms increase the risk of developing depressed mood. Human studies are also needed to identify drugs, nutritional interventions and lifestyle changes that may help mitigate or reverse deleterious epigenetic alternations and add to current treatments of depressed mood.