Daniela Friedman ’18 and Hayley Walton ’18


Taylor is a sophomore at the University of Michigan. Since coming to campus, she has been struggling with severe bouts of depression and spends many days feeling lonely and sad. Her friends have noticed her skipping class more often and bailing on social gatherings. She was previously on an antidepressant medication, but it doesn’t seem to be working and all she can feel are the side effects, like feeling tired and not being able to concentrate—which as you can imagine, interferes with her role as a student. She feels like she’s tried everything to help with her depression but nothing is working. What if we told you we might have the answer for Taylor? It’s not a miracle drug, but a different way of looking at medicine.

It’s not only Taylor who is dealing with these issues. Many people struggle with their mental health and do not have the right treatment resources. For many people with psychiatric disorders, the current medications available are either nonexistent, ineffective, or have bad side effects that cause people to stop taking them. This is a major problem in our country and we are out to find a solution. Epigenetics may be that solution.

Anytime that you are exposed to something in your environment, it affects your body either positively or negatively. Like when you expose yourself to harmful sun rays, this can lead to skin damage in the form of a permanent mark or painful sore. Currently, medicine acts like a cooling aloe gel on a painful sunburn — it tries to lessen a problem that’s already there. But what if we were to go about this in a different way? What if we had given Taylor some sunscreen, or preventative measure, that would have protected her body from the dangerous environment? Or what if we had some cream that reprogrammed or erased any evidence of the burn like a spot remover? This is what we aim to do with epigenetics—prevent the negative effects from our environment from marking our bodies or, if it is too late for prevention, reprogram the damage. 

So, what is epigenetics? Every individual is born with a unique gene code—their DNA. In addition to this code based on the letters (ATGC), there are DNA tags that affect how the DNA code is read. Think of these marks like edits on a paper draft, where your environment is your proofreader. What if we could change these DNA marks, like crossing out a few words at the end of a sentence, to stop expressing the harmful genes? Would that be a possibility for treating mental illness?

Perhaps we can design drugs that, like sunscreen or spot remover, prevent people from gaining scars from their daily experiences or remove those scars. Today we will discuss HDAC inhibitors, a relatively new type of epigenetic drug, that represents a novel treatment option for a variety of mental health conditions that could potentially work for more people or decrease the side effects of the medications that are currently available.

In order to understand epigenetics as a treatment for human illnesses, we must understand the tools or mechanisms that create these DNA marks. Our DNA is wrapped around special proteins called histones and these histones can be marked in certain ways to tell the body how to read the DNA. One way the histones can be marked is through acetylation. Histone acetylation turns on the genes and tells the body to make more of that gene product.

How can we use this acetylation, or DNA activator, to change how our body functions? Firstly, acetylation is a marker that activates DNA, so when you acetylate DNA, it is like highlighting important words. A Histone Deacetylase, or HDAC, de-acetylates, which deactivates the DNA. This is as if we were to draw a line through the highlighted words with a black pen to say “don’t read this”. So something that inhibits or blocks an HDAC reverses the deactivator, (erases the striked through line) thus canceling out two negatives, ending with just highlighted words to reactivate the DNA and make more of those genes.

How this process works in real life is shown in the image below.

We want to see if neuroepigenetics realistically has a role in advancing medicine. If epigenetic treatments were used to lessen the response of DNA to the harmful elements in the environment, then this could tell us why epigenetic treatments would have a special place in the medical field—prevention and eliminating damage. So can HDAC inhibitors really be a possible treatment method or take the place of current popular but flawed drugs? Today we will dive deeper into the subject, and look into HDAC inhibitors as potential treatments for depression, schizophrenia, and Alzheimer’s Disease.

Let’s start with depression. Clinical depression is a mood disorder characterized by a persistent feeling of sadness or loss of interest. It often occurs in multiple “episodes” of varying length throughout one’s life and may require long-term treatment, often with psychotherapy, medication, or a mixture of the two. Depression, like that which Taylor is experiencing, is very common in the United States, with more than 16.2 million cases in adults in 20168 The World Health Organization has even labeled clinical depression as the most disabling medical condition in the world5.

Current medications, like Taylor’s antidepressant, can require many weeks to take effect, which can be a long time to wait for people who are dealing with depression. This can cause people to stop taking the medication because they don’t think that it is working. The currently available medications such as selective serotonin reuptake inhibitors, or SSRI’s, (like Prozac, Zoloft, or Paxil) can have side effects such as an increase in suicidal thoughts or actions in young people. Also, about one third of people do not respond to the antidepressants that are currently available3.

What if we had a way to find the root of the problem and lower the amount of that stressor in your body? Perhaps this could solve deeper problems and act faster than SSRI’s. This method of prevention or reprogramming with epigenetics may be our answer. Epigenetic medications could be like the spot cream, removing a lasting skin mark.

In one study, researchers wanted to see if histone deacetylase inhibitors (something that turns on certain genes) could decrease depression-like behavior in mice. In their experiment, they exposed the mice to long-term stress from a bully every day for 10 days, which represented a stressful social situation. These mice had less depression-like behavior after they injected the mice brains with HDAC inhibitors4. In the stressed mice, they measured depression by behavioral measures like spending less social interaction time with a new mouse and not preferring sugar water over regular water. But, the mice who got the HDAC inhibitors drug showed less of these depressive behaviors. So even mice that were chronically socially stressed (a proxy for depression) did not show depressive symptoms after they were treated with a HDAC inhibitor. Now imagine if Taylor had something like this, she would be freed from the social stresses of parties and be able to enjoy time with her friends.

One mental disorder that people tend to be less familiar with is schizophrenia. This is a severe mental disorder that is characterized by difficulties like disorganized thinking and speech, hallucinations, delusions, and lack of emotional affect. It is a chronic disorder that requires lifelong treatment. Even though less than 1% of Americans have this disorder, it can be very crippling for those who do struggle with it9.

Currently, one of the main methods of treatment for schizophrenia is with a type of medication called atypical antipsychotics, which block receptors of dopamine, a chemical that is often unusually high in people with schizophrenia. While these atypical antipsychotics generally lessen schizophrenic symptoms at most genes and help patients a lot, there is one exception. They stop making as much of one gene called mGlu2, which is important for maintaining brain function. which in turn causes psychosis-like behavior in mice. The drugs do this by decreasing histone acetylation—the highlighter marker that normally increases how much a gene is made—in mGlu2. Having less of that mGlu2 gene in turn causes psychosis-like behavior in mice.

What if we could take away this downside of atypical antipsychotics? Well maybe we can, with epigenetics. In one experiment, researchers caused mice to show schizophrenic-like behavior, such as a specific head twitch movement, a slower startle reflex, and poor memory7.  All of the mice were given atypical antipsychotics, but some of the mice were also given an HDAC inhibitor to activate, or highlight, the mGlu2 gene we talked about before. In the mice who had both drugs, the researchers saw less psychotic symptoms. So, the atypical antipsychotic, the medication we already use, works better with the HDAC inhibitors than it does by itself! Think of the atypical antipsychotic like sunscreen, it does everything to protect your skin from future damage, but it has one down side—it makes your skin dry up. Adding in the HDAC inhibitor is like adding a moisturizer to the SPF cream. It makes up for the one downside of the sunscreen. Together, the combination of SPF and moisturizer, or the combination of the atypical antipsychotic and HDAC inhibitor, leads to the best outcome. Hopefully one day, these two things will come together in just one bottle or pill.

That study looked at mice, but they also tested brains of people with schizophrenia and they found the same epigenetic marks in both humans and mice who were treated with antipsychotics, so these cases might be more similar than you think.

Lastly, let’s look into a disease more prominent in the elderly population. Alzheimer’s Disease, also called senile dementia, leads to the gradual progression of the loss of memory and cognitive abilities2. It is an extremely distressing disease for the individual who loses their life’s memories as well as the individual’s family, who must watch their loved one regress. I know from personal experience watching my grandmother’s cognitive decline that she is troubled and embarrassed by her struggle. Unfortunately, there is currently no cure to Alzheimer’s. There are some drugs being used to lessen the symptoms of memory loss, sleep disruption, and behavioral changes, but no drug or treatment that stops the progression of the disease.

Perhaps epigenetics can prevent the onset or progression of Alzheimer’s, like using sunscreen can lower your risk of developing skin cancer. In one experiment, researchers caused mice to have genes associated with Alzheimer’s and tested for typical Alzheimer’s symptoms like difficulty with memory and learning6. Mice with symptoms of Alzheimer’s who were given HDAC inhibitors had less progression of the disease after 4 months than mice who were only given water. The mice given the HDAC inhibitor performed better on cognitive and learning tasks.

This means that the mice with the genes for Alzheimer’s, that were supposed to show cognitive decline over time, actually did not show the symptoms of Alzheimer’s as they aged. For patients like my grandmother, a woman who has a family history of Alzheimer’s disease, this would be an excellent option to prevent the progression of her memory loss. The HDAC inhibitor that prevented the progression of the disease could be the future sunscreen of Alzheimer’s Disease.

After learning about how epigenetics could be used to treat depression, schizophrenia, and Alzheimer’s disease, we also must note that there are a few limitations before we jump right in to using HDAC inhibitors for mental health problems.

Many of these studies are being done on animal models, and while these are helpful to advance our knowledge of epigenetics, they may not directly correlate to humans. We are relying on certain behaviors in mice, like freezing when a bully is around, to serve as a proxy for complicated human conditions like depression, so the mouse model may not perfectly correlate to humans.

Another limitation of using HDAC inhibitors is the fact that it could require combining multiple drugs together. Using drugs in combination, such as the HDAC inhibitor with an atypical antipsychotic, would require ever stricter safety criteria than a treatment that only involves one drug. So, we need more research to determine whether this could be a viable treatment option for psychiatric disorders1. However, combining these treatments would give doctors the ability to craft more individualized treatment plans for their patients10.

Although we still have many years and studies to go before using epigenetics in treatments, the studies that we have discussed about depression, schizophrenia, and Alzheimer’s Disease shine a light on the exciting premise of using epigenetics to create better treatments for patients.

Epigenomes are unique, like an individual’s personal fingerprint. Every person has their own special pattern of feedback on the ‘essay’ of their DNA, which causes the paper to be read in a certain way. The highlights, underlines, and X’s, are the DNA markers that make them who they are. Ideally, one day, doctors could sequence an individual’s epigenome to pinpoint the root of their disease and then add in new marks or cross out old ones to fix their disorder. This would give physicians the opportunity to tailor their treatment to perfectly fit the patient’s medical history and lifestyle.

Maybe in the future we will be able to pair epigenetics with current drugs to get rid of difficult side effects or even use them independently to treat diseases that we don’t currently have treatments for. Although there are many obstacles to overcome before getting epigenetic treatments in the hands of physicians, the opportunities here are endless.

We hope that a few years down the line, epigenetics will fill the gap in medical care for mental health. We hope that people like Taylor will be able to get individual attention and well-crafted treatments to give them the best health outcome with the least side effects. We hope that with the quickly advancing field of epigenetics, there will be better treatments for these disorders in the decades to come.

References

  1. Akbarian, Schahram. “Epigenetic Mechanisms in Schizophrenia.” Dialogues in Clinical Neuroscience 16.3 (2014): 405–417. Print.
  2. “Alzheimer’s Disease & Dementia.” Alzheimer’s Association, www.alz.org/alzheimers_disease_what_is_alzheimers.asp.
  3. Cipriani, Andrea, et al. “Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults with Major Depressive Disorder: a Systematic Review and Network Meta-Analysis.” The Lancet, 21 Feb. 2018.
  4. Covington, Herbert E. et al. “Antidepressant Actions Of HDAC Inhibitors.” The Journal of neuroscience : the official journal of the Society for Neuroscience 29.37 (2009): 11451–11460. PMC. Web. 20 Mar. 2018.
  5. “Depression.” World Health Organization, World Health Organization, 7 Apr. 2017, www.who.int/mental_health/management/depression/en/.
  6. Green, Kim N. et al. “Nicotinamide Restores Cognition in AD Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau.” The Journal of neuroscience : the official journal of the Society for Neuroscience 28.45 (2008): 11500–11510. PMC. Web. 20 Mar. 2018.
  7. Kurita, Mitsumasa et al. “HDAC2 Regulates Atypical Antipsychotic Responses through the Modulation of mGlu2 Promoter Activity.” Nature neuroscience 15.9 (2012): 1245–1254. PMC. Web. 20 Mar. 2018.
  8. “Major Depression.” National Institute of Mental Health, U.S. Department of Health and Human Services, Nov. 2017, www.nimh.nih.gov/health/statistics/major-depression.shtml.
  9. “Schizophrenia.” National Institute of Mental Health, U.S. Department of Health and Human Services, Feb. 2018, www.nimh.nih.gov/health/statistics/schizophrenia.shtml.
  10. Tang, B, B Dean, and E A Thomas. “Disease- and Age-Related Changes in Histone Acetylation at Gene Promoters in Psychiatric Disorders.” Translational Psychiatry 1.12 (2011): e64–. PMC. Web. 20 Mar. 2018.

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