Anxiety and depression, the two most globally common mental disorders, have detrimental effects on an individual’s ability to enjoy life and successfully navigate it. Anxiety is severe worry or fear and umbrellas other disorders like post-traumatic stress disorder, panic disorder, or generalized anxiety. Depression is marked by a large decrease in enjoyment, thoughts of doom, lethargy, and a decreased capacity for learning. Like other mental disorders, the basal cause of anxiety and depression are manifold: environment, genetics, neurobiology, cultural influence, stress, and epigenetics all play a part in the etiology and progression of these conditions. Epigenetics, meaning “above the genome”, describes the events and molecules which regulate gene expression. Many of these factors can be readily modified with behavior, diet, exercise, or changes to stress levels, even though the DNA itself cannot. Even with genetic predisposition for depression or anxiety, treatment and prevention options can take advantage of epigenetics both pharmacologically and through lifestyle changes.
Our complexly-wired brains are great at pondering and imagining, but this comes with a curse; the ability to ruminate has also given us the ability to have these conditions. As Robert Sapolsky, a prominent stress researcher eloquently said, “On an incredibly simplistic level, you can think of depression [and anxiety] as occurring when your cortex thinks an abstract thought and manages to convince the rest of the brain that this is as real as a physical stressor.” The anxious brain learns to associate neutral or only slightly negative stimuli as scary as being chased by a lion, while the depressed brain’s reward and learning systems malfunction and get stuck in a loop of anhedonia and hopelessness. In both disorders, the brain’s architecture for learning and processing is unintentionally commandeered for negativity.
With the advancements of modern research, scientists have uncovered fundamental biological origins for both disorders. Anxiety and depression show several genetic links between specific genes and the increased likelihood of developing either disorder, and the affected body and brain systems are the same. In both conditions, the amygdala, associated with fear & strong emotion, shows greater activity, while the limbic system, the brain’s centre for reward, seems to be impaired or at least abnormal in both. Both conditions also see changes to the hypothalamus-pituitary-adrenal axis, a group of systems which help coordinate the “fight or flight” response, circadian rhythms, and stress. However, these two conditions are not identical. Although the differences in behavior can be vast, the gross biological differences can be subtle; hippocampal changes occur in both, but depression has been shown to be connected strongly to dysfunction in the hippocampus, which plays an important role in memory. A depressed hippocampus shrinks and shows signs of reduced neurogenesis, which suggests an impaired ability to learn or create connections between ideas or memories. Contrastingly, in anxious brains the hippocampus often appears normal in volume in imaging studies. Other parts of the brain such as a part of the reward system called the striatum seems to be hyperactive in anxiety, but not as strongly affected in depression. These two disorders often hijack the same systems, but in different ways and with different outcomes.
Zooming in, research points to a surge of detailed molecular differences. The field of epigenetics has exploded in recent years and introduced depression and anxiety researchers to a whole new world of molecules and mechanisms. Since 2010, research on epigenetics and depression has increased about 25-fold. Likewise, there were next to zero articles on epigenetics and anxiety before 2006, and several hundred now. Epigenetics describes a variety of mechanisms. Virtually any change in the body that occurs outside of the DNA itself can be attributed to changes in how genes are expressed. When a cell responds to a stimulus, it often produces more or less of a specific molecule. In order to do this, certain genes must be accessible and easily transcribed. For example, when two neurons need to forge a strong synapse between them, a certain signal cascade within the cell needs to occur, eventually resulting in transcriptional changes which recruit the right kind of receptor. When epigenetic elements are added, they can prevent, delay, or enhance that process and modulate the overall outcome. Epigenetics act as a modulator for increasing or decreasing the likelihood of a gene being transcribed. The three most-studied mechanisms include chromatin remodeling, DNA methylation, and non-coding RNA. We understand small snippets for each of these, but the complexity is so vast and these processes are so interconnected that the bigger subway map of connections is still unclear.
Chromatin contains the cell’s DNA, and histone proteins hold DNA like thread on a spool within chromatin. Under certain conditions, the histone proteins will loosen or tighten, thus restricting or enhancing DNA transcription. Generally, acetylated histones represent easier to open DNA, while deactylation has the opposite effect. Histone deacetylase (HDAC) proteins are widely studied and can act both broadly and specifically. Histone modifications act on a smaller scale by enhancing or inhibiting genes involved in serotonin production, learning, or neurogenesis. More broadly, inhibiting histone deacetylation indiscriminately has been implicated as a possible route of treatment for depression , and using HDAC inhibitors in conjunction with cognitive therapy has been shown to be a potential anxiety treatment, but the exact reason why is not clear yet.
Another common mechanism is DNA methylation, where DNA becomes harder to access due to methyl groups added directly to the DNA itself. DNA methylation is mediated by DNA methyltransferases. For example, a specific DNA methyltransferase was shown to be decreased in human adults treated with antidepressants, while it is normally increased in the brains of a mouse depression model. This epigenetic perspective has also deepened the knowledge of well-established mechanisms underlying the two conditions, like brain-derived neurotrophic factor (BDNF). BDNF has been shown to be a major player in alleviating or preventing both depression and anxiety by encouraging neurogenesis, and recent research has linked specific DNA methylation of the BDNF gene to increased depressive symptoms.
In addition to DNA methylation, non-coding RNA (ncRNA) can elicit epigenetic changes. Classically, RNA acts as the guide for amino acid sequences in protein production. However, RNA is not only used in protein translation: it is also found as a disruptor or modifier for many biological processes. Currently, there is limited research into the role of ncRNAs in anxiety and depression specifically. A few studies have linked early-life stress to changes in ncRNA expression, and a certain class of non-coding RNA called micro RNA (miRNA) has been implicated in learning, memory, and neuronal connections. Since both anxiety and depression have strong links to these processes, future research may reveal more detailed roles of ncRNA.
Perhaps unsurprisingly, manipulating transcription mechanisms globally does not always result in useful changes in all brain systems. Of the few studies where broad epigenetic interventions in a mouse or rat model were implemented, most showed that there were off-target effects even if the behavioral effects were net positive. As previously discussed, the most hopeful mechanism so far is using HDAC inhibitors, but the research is still in the beginning stages and has a long way to go before it reaches wide availability.
Beyond using epigenetic means directly for treatment, research reveals that other treatments suddenly have explanations. Anxiety and depression are often treated using lifestyle changes such as exercise, diet, or verbal therapy strategies. Epigenetics connect the efficacy of established therapies to the biological foundations of anxiety and depression. Just a year ago, a paper showed that exercise induces BDNF transitively through specific histone modifications. Additionally, specific dietary changes in young mice have been shown to decrease the likelihood of anxious behavior later in life by acting on DNA methylation of key genes. Our own thought patterns can cause epigenetic changes, too. Successful Cognitive-Behavioral Therapy (CBT) was recently linked to an increase in methylation of a gene associated with serotonin production, while mind-body therapy was also shown to cause changes in overall epigenetic status in several well-known markers. We have known for decades that certain interventions are effective for treatment, but we are now getting a glimpse into the WHY. As with previously unexplained diseases like polio or the black plague, the more we learn, the more we can understand, and the better we can fight it.
And so, our view of anxiety and depression becomes larger and more intricate. These epigenetic mechanisms provide a deeper understanding of how useful interventions may work, and research has been ramping up this past decade. Epigenetics will undoubtedly continue to unravel more of the mystery behind the human tendency towards anxiety and depression. We look forward to a bright future in above-the-genome exploration.