Abstract: This paper explores potential genetic testing that could help doctors prescribe antidepressants that are more effective, with fewer side effects. Various methods are explored including metabolization of psychotropic drugs and levels of DNA methylation on CpG islands and the effectiveness of the GeneSight Psychotropic Genetic Panel. The findings suggest that doctors should utilize DNA tests more, and that scientists should do more research on the tests to increase their effectiveness.

According to the National Institute for Mental Health, 16.2 million adults in the United States have had at least one depressive episode in the past year.1 This a staggering number, and those 16.2 million people need treatment. Many people opt for talk therapy and an antidepressant of some sort prescribed by a psychiatrist, but these medicines can be ineffective, and have many side effects, ranging from weight gain, to loss of sexual interest, to acne. What’s more, they take about 6-8 weeks to work at full capacity.2 This means that a person who is prescribed an antidepressant could suffer for up to two months before the medicine starts to work properly, if it starts to work at all because for most people that is not the case. It is very frustrating for patients who cannot find the correct medicine, and the frustration can be worse than the side effects themselves.

Due to the increasing difficulty in finding antidepressant, doctors should use genetic testing as a tool more than they do currently and should advocate on their patient’s behalf to get the testing done. Genetic testing could make many patients’ lives better by making it easier to find the most effective antidepressant, with the fewest side effects.

Depression is a serious mental illness that affects much of the world’s population. It causes sadness and can also cause a lack of interest in usually pleasurable things. For a clinical diagnosis, the symptoms must be present for at least two weeks.3 Various types of depression exist such as major depressive disorder, dysthymia, adjustment disorder with depression, and postpartum depression.4 The diagnoses differ in the length of time the patient is affected, the severity of the symptoms, and the cause. For example, adjustment disorder with depression is due to an event in a patient’s life, and does not last forever, and postpartum depression is caused by the birth of a child.5 Symptoms can include depressed mood, weight gain or loss not related to dieting, hypo or hypersomnia, loss of energy, difficulty thinking or concentrating, and thoughts of suicide. Each patient is different and will experience depression in a unique way. Anyone can develop depression, but risk factors include biochemistry of the brain, genetics, personality, and environmental factors such as trauma or poverty.6

Not enough is known about the cause of depression, which is why it is so difficult to treat. Two main theories exist for the cause of depression: physiological and psychological causes. Neurotransmitter levels are one biological cause.7 Research exists to support the idea that low serotonin levels can lead to depression, and that higher levels of byproducts of serotonin have been linked to increased levels of suicide. In addition, scientists believe that norepinephrine might “trigger anxiety and be involved with some types of depression,”8 and they also believe that GABA, short for gamma-aminobutyric acid, is involved with anxiety. In addition to neurotransmitters, genetics is a physiological cause of depression. Unfortunately, scientists do not know much about the genetics because the mood is affected and regulated by many genes. The best thing scientists know at this point is that many psychological disorders run in families, and depression is no exception. For example, a person with a close relative who has depression has, “an increase in risk for the condition of 1.5% to 3% over normal.”9 Although scientists still do not understand many of the biological causes of depression, the psychological causes are understood better.

The first psychological cause is temperament, meaning how easily excited one gets depending on the situation. People who get excited or withdraw more easily do so both because of their genetics, but also because of their experiences in life.10 In addition, a person’s childhood worldview, whether subconscious or not also influences how people feel.11 This makes sense: most people gain a viewpoint about themselves and the world in childhood and maintain it during adulthood. Examples of this include feeling unworthy of love and affection, or engaging in self-criticism. Another psychological cause of depression is experiencing a traumatic or stressful life event, such as the death of a loved one, loss of a pet, loss of a job or divorce. Other causes include physical, sexual or emotional abuse, or loss of a parent during childhood.12 While the traumatic event itself may not cause depression, when coupled with genetics and temperament, the results can be disastrous. Some scientists believe that trauma can cause changes in brain function that can cause symptoms of depression,13 though more research needs to be done on the linkage between trauma and depression. In addition, certain medical conditions are linked to depression, a sort of side effect of the condition itself. These conditions include degenerative nervous conditions (Huntington’s, multiple sclerosis), problems in the endocrine system (hypothyroidism), viruses or other infections (HIV, hepatitis).

A limited number of genetic tests are available specifically for antidepressants, yet genetic testing for other diseases has been around for a while. Many different types of testing are done depending on what disease the provider is looking for. For example, newborn testing, required in most states, tests for phenylketonuria (PKU), a deficiency of an enzyme needed to metabolize phenylalanine which can cause severe mental retardation if it is not caught early in life. Diagnostic testing is used to determine if a symptomatic person has a disease such as Huntington’s Disease. Carrier testing is preemptive testing to see if a person is a carrier for a mutation for example sickle cell anemia or Tay-Sachs and is useful if the carrier wants to have children, to determine the probability of them having an affected child.14 Prenatal testing is used to determine if an unknown child will have a genetic disorder, for example trisomy 13, which causes Down Syndrome. This is done by with a blood test of the carrying parent. These tests can sometimes help parents decide whether they should complete the pregnancy, or whether they do not want their child to needlessly suffer due to a genetic disease.15 In addition, there is a category of testing called pharmacogenetics, which studies the drug response to certain genes and genetic mutations, and this is where genetic testing for antidepressants falls.

Research is being done now about how certain mutations impact a person’s response to antidperessants. Lucas B. Walden and others from the Pharmacogenic Research Clinic in Ontario, Canada studied how the classification of patients based on the amount of a certain liver enzyme that affected the metabolism of psychotropic drugs affected patient outcomes. They used data about from other papers about single nucleotide polymorphisms (SNPs) that code for the specific enzymes, CYP2D6 and CYP2C19, with most of the focus on CYP2D6. These two enzymes help to metabolize psychological medications. Specifically, CYP2D6 metabolizes antidepressants and most antipsychotics, while CYP2C19 only helps metabolize many antidepressants.16 The researchers looked at the SNPs that affected these two enzymes and found that the SNPs affected how much of the enzyme was produced in the body, which affects how well a patient can metabolize drugs and categorized the patients based on that information.

Walden then used this information and gave it to physicians, who in turn used the information to help them prescribe medicine for their patients. The information provided in the genetic tests worked for at least some of the patients: “23% (n=14) of doctors reported that their patient had an improved outcome…41% (n=25) of physicians reported no change” and, “importantly, there was not a single physician who indicated that their patient had a worse outcome.”17 As with all technology, the genetic tests are still evolving and will get better with time. Currently only 23% of patients had an improvement, but when the tests improve theoretically more patients will benefit from the test. In addition, if no tests are done, researchers will not be able to continue to see the tests to evolve. Although 23% seems like a low number, any increased success is helpful in the treatment of depression, and in addition, given that depression can lead to suicide or debilitating impairment to a person’s life, any success in improving outcomes for patients with depression is worth pursuing. Genetic tests should continually be implemented because although not many people are benefiting now, many more people who could benefit. Anything that increases the amount of research done on this subject will benefit the patients currently suffering.

Another thing that scientists have found linked to depression has to do with DNA methylation, the process of adding methyl groups (CH3) to DNA molecules. If methylation occurs in DNA in the promoter region of a gene, then gene expression will be suppressed. T R Powell and others at the King’s College London were specifically interested in the levels of methylation at CpG islands on the Interleukin 11 (IL11) gene.18 CpG islands are regions of DNA base pairs where sequences of CG (cytosine, guanine) are more frequent than any other sequence. They used statistical analysis to determine whether their results were significant. According to their research, “CpG Unit 5 significantly predicted antidepressant response” and “lower levels of DNA methylation at CpG Unit 5 were associated with better response to antidepressants.”19 This means if a doctor had tested a patient and confirmed that a patient had an increased response to antidepressants, they could keep trying but know that it was less likely that a person would respond to the medication and attempt to find other ways to help the patient such as talk therapy.

In addition, Powell and the others looked at methylation specifically for two drugs: nortriptyline and escitalopram. They found CpG Unit 4 significantly predicted differential response to treatment” and higher levels of DNA methylation helped patients taking escitalopram but patients taking nortriptyline had a worse response.20 If more drugs were included in this study, at some point maybe scientists and doctors could know the effect of methylation on all drugs used to treat depression which could help them to prescribe the drugs as well. It makes sense that the levels of DNA methylation were different between the drugs because the two medicines are part of two different classes of antidepressants. Escitalopram belongs to a class of drugs known as selective serotonin reuptake inhibitors (SSRIs).21 These drugs block the reabsorption of serotonin in the synapse which enables the serotonin to bind to the receptors more easily. They are called selective because the drugs only affect serotonin not all neurotransmitters. Nortriptyline is part of a class of drugs known as tricyclic antidepressants, so named because of the three rings of atoms. These drugs block the reuptake of serotonin and norepinephrine along with other receptors such as histamine H1, and muscarinic M1.22 Maybe the levels of methylation for these drugs can be extrapolated for the entire classes of antidepressants, or maybe they are just outliers. If they are not outliers, other classes of drugs should be tested so doctors can have increased levels of information when prescribing antidepressants.

The data from Powell shows that the information from the genetic tests performed could be helpful for physicians trying to figure out which psychological medication to prescribe for their patients. The data was statistically significant and should not be ignored. The data also suggests not only could the levels of methylation be helpful in determining which drugs would be most effective, but also which patients were more likely to respond to treatment. These tests could save many people lots of time and money if they could find a drug that worked quickly and more easily. Perhaps Powell’s findings combined with the findings of Walden could be combined in one test that accounted for both. Then prescribers would theoretically know which people would most likely respond to drugs, how fast people would respond to the medicines (if at all), and which class of medicines would work the best.

Genesight is a company that does genetic testing specifically for antidepressants and other psychotropic medications. The clinician takes a swab of the patient’s cheek cells and sends them to the GeneSight lab to be analyzed. Genesight then uses an algorithm which combines the person’s physical traits with their genetic and metabolic profile and places every psychological drug into three categories (red, yellow, and green) according to how closely the patient should be monitored when taking the drugs.23 For example, Lamictal (a mood stabilizer) might be in the green category, which means the medicine is genetically approved for the patient and shouldn’t need close monitoring, but Buspirone (an anxiolytic for anxiety) might be in the red category which means the medicine is not recommended for that patient and should be closely monitored for gene-drug interactions and side effects. According to GeneSight’s product page there have been several successful clinical trials done with the test and patients who got the test, “achieved a clinically meaningful and significantly significant improvement in both remission rates (p<0.01) and response rates (p=0.01) at eight weeks compared to the treatment-as-usual group."24 These results are great. It is important that there is data in support of these tests because if there was not good data there would be less likelihood of these tests being continued. It is also important to note that the test was a double blind, randomized control study which increases the odds that it is a legitimate study that can be taken seriously.

Outside researchers have studied GeneSight to investigate the companies results. For example, Ontario Health Technologies systematically reviewed the various GeneSight tests to see if the results were as good as the company claimed. They explained that GeneSight is a genetic test that uses polymerase chain reactions (PCR) to amplify DNA fragments in cheek cells that are gathered from patients. They used various GeneSight tests and compared the results of each. Their results were scattered and were not completely in favor of the test. Some of the tests studied had favorable outcomes and some did not, and they concluded: “there is uncertainty about the use of GeneSight Psychotropic pharmaceutical genetic panel to guide medication selection,”25 which is interesting because their data is so much different than GeneSight’s study. Potentially this study is more accurate because it is an outside source. In addition, GeneSight does not cite where they got their statistics and no link is given to the survey they referenced. Even if these results do not seem very good, one must consider that this is a new field. The field of pharmacogenetics is just emerging, so the fact that they got any positive results from the test is a cause for optimism. These tests will just get better in the future, meaning they will have more and more positive results. But the studies will not improve if they are not done. For this reason, genetic testing needs to be implemented more, so the tests will improve and can help more people over time.

In the field of psychology, psychologists disagree on whether it is “nature” or “nurture” that shapes a person during childhood and adolescence more. Examples of “nature” include genetics, hormones, and the biochemistry of development, and examples of “nurture” include love and attention or traumatic events that occur during a person’s life time. Psychologists exist at both ends of the spectrum – nativists assume that everything in a person’s life is a product of evolution, and empiricists assume the mind is a “tabula rasa” from birth and everything must be learned from the person’s environment.26 In some people’s views antidepressants are seen as unnatural and thus they refuse to use them, or in the case of a parent refuse to let their child take the medication. They believe only natural remedies such as talk therapy or hypnosis should be used. Even still, although antidepressants and genetic testing are seen as unnatural to some people, they should be explored for the sake of others.

With the implementation of genetic testing, one of the worries is that people will resort to antidepressants and genetic testing without trying every other available option first. Psychologists have argued about this for years. To combat this, there must be restrictions on who can prescribe the genetic tests, and who can get them. Psychiatrists must also offer all other available options before resorting to genetic testing, such as talk therapy, exercise and other lifestyle changes, other biological causes, and multiple different medications or natural supplements.

Another issue when talking about genetic tests is insurance coverage. According to GeneSight’s website any person covered by Medicare of Medicaid does not have to pay. People with private insurance will not have to pay more than $330 out of pocket, and GeneSight says they will work with people who are uninsured.27 This does seem like a lot of money for those on private insurance, but it is probably a lot less than it costs GeneSight to run the tests. In addition, one hopes that as more people get the genetic tests and more companies enter the market the costs will eventually lower so they are more affordable for everyone.

The lyrics from “Fix You” by Coldplay illustrates perfectly the life of someone with depression: “When you try your best but you don’t succeed / When you get what you want but not what you need / When you feel so tired but you can’t sleep.”28 Although the disease can manifest itself in many ways, this is the most common. Feeling sad all the time, losing interest in activities the person once found fun, either having trouble sleeping, or sleeping all the time. Antidepressants, while effective for some, have detrimental side effects or do not work for others and finding the perfect medication and dosage combination can be like trying to find a needle in a haystack. Genetic testing may, in the future, allow doctors to quickly and efficiently match the right drugs to the right patient, leading to more people who are able to overcome the debilitating effect of depression. Why would we not want to explore something that could help so many people?

Bibliography

Notes

1. “Major Depression,” National Institute of Mental Health, Updated November 2017, Accessed April 11, 2018. https://www.nimh.nih.gov/health/statistics/major-depression.shtml..

2. John M. Grohol, “How Long do Antidepressants Take to Work?” Psych Central, Accessed April 11, 2018, https://psychcentral.com/lib/how-long-do-antidepressants-take-to-work/.

3. “What is Depression?” American Psychiatry Association, Accessed April 11, 2018, https://www.psychiatry.org/patients-families/depression/what-is-depression.

4. John M. Grohol, “Warning Signs and Types of Depression,” Psych Central, Accessed April 11, 2018, https://psychcentral.com/lib/types-and-symptoms-of-depression/.

5. Ibid.

6. Ibid.

7. “What Causes Depression? Onset of Depression More Complicated than Brian Chemical Imbalance,” Harvard Health Publishing, Updated April 11, 2017, Accessed April 11, 2018, https://www.health.harvard.edu/mind-and-mood/what-causes-depression.

8. Ibid.

9. Ibid.

10. Ibid.

11. Ibid.

12. Ibid.

13. Ibid.

14. “What are the Types of Genetic Tests?” NIH United States National Library of Medicine, Published April 17, 2018, https://ghr.nlm.nih.gov/primer/testing/uses.

15. Ibid.

16. Lucas M. Walden, Eva J Brandyl, Arun K Tiwari, Sheraz Cheema, Natalie Freeman, Nicole Braganza, James L Kennedy, Daniel J Muller, “Genetic Testing for CYP2D6 and CYP2C19 Suggests Improved Outcome for Antidepressant and Antipsychotic Medication,” Psychiatry Research (2018). https://doi.org/10.1016/j.psychres.2018.02.055.

17. Ibid.

18. T R Powell, R G Smith, S Hackinger, L C Schalkwyk, R Uher, P McGufin, J Mill, KE Tansey, “DNA Methylation in Interleukin-11 Predicts Clincal Response to Antidepressants in GENDEP,” Translational Psychiatry no. 3, (2013), Doi:10.1038/tp.2013.73.

19. Ibid.

20. Ibid.

21. Ibid.

22. Annette Ogbru, “The Comprehensive List of Antidepressants,” RxList, Accessed April 13, 2018, goo.gl/GB4Ruy,

23. “What is GeneSight?” GeneSight, Accessed April 16, 2018, https://genesight.com/faq-page/.

24. “For Clinicians.” GeneSight, Accessed April 16, 2018, https://genesight.com/for-clinicians/.

25. Health Quality Ontario, “Pharmacogenomic Testing for Psychotropic Medication Selection: A Systematic Review of the Assurex GeneSight Psychotropic Test,” Ontario Health Technology Assesment Series 17: no. 4 (2017), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433545/.

26. Saul McLeod, “Nature vs. Nurture in Psychology,” Simply Psychology, Acessed April 18, 2018, https://www.simplypsychology.org/naturevsnurture.html.

27. “Cost,” GeneSight, Accessed April 18, 2018, https://genesight.com/cost/.

28. “Fix You by Coldplay,” Genius Lyrics, Accessed April 21, 2018. https://genius.com/Coldplay-fix-you-lyrics.