Depression and Personalized Medicine: Is Genetic Testing the Future?
By Valerie Piet

Earlier this year the Food and Drug Administration approved a version of the “party drug” ketamine for use in treating depression. This announcement, rightly so, received a lot of excitement and press coverage. Depression is very common with around 16% of Americans experiencing major depression in their lifetimes. Despite how common depression is, it has been thirty years since a novel psychiatric drug came on the market. Major depression is notoriously difficult to treat with medications. Side effects, non adherence, lack of relief of symptoms, and (temporary) remission are common.

Studies have shown that all antidepressants are considered equally effective across all populations when given comparable doses. Providers cannot predict which medications will be the most effective in a given patient and therefore use a trial-and-error approach to find the right medication. This approach can be a lengthy process as common antidepressant classes like Selective Serotonin Reuptake Inhibitors (SSRIs) and Monoamine Oxidase Inhibitors (MAOIs) can take weeks to start relieving symptoms. Unfortunately, side effects can start instantly. In the case of no symptomatic improvement, providers will need to adjust dosing regimens with the same medication and try again. As a result, patients often go months without relief from symptoms before moving on to try the next medication. In contrast, Ketamine resolves symptoms instantly—a huge advantage to suffering patients. The drug is not without its drawbacks as patients may still be susceptible to eventual relapse and the administration of ketamine must be controlled and monitored to prevent abuse and recreational use. It is currently administered as a nasal spray.

Genetic Testing and Pharmacogenetics

Did you know ketamine is not the only emerging treatment innovation for depression? Since the early 2000s, efforts have been underway to incorporate genetic testing and pharmacogenetics into improving treatment of depression through personalized medicine. There are two components of psychiatric drug therapy that may have genetic components: pharmacokinetics and pharmacodynamics. Pharmacokinetics is the study of the way drugs move through the body including absorption, distribution, metabolism, and excretion. Pharmacodynamics refers to the effects drugs have on the body. Together they influence dosing, efficacy, and side effects. For example, if a patient’s enzymes metabolize a drug too quickly, the medication may not be in the body long enough to be effective. Alternately, a patient may metabolize a drug too slowly, leading to buildup and damage in cells and tissues. A family of proteins called Cytochromes P450 are the major enzymes involved in drug metabolism. Around 75% of drugs are metabolized by these enzymes. Specifically, CYP2D6 and CYP2C19 are Cytochromes P450 (CYP) involved in the metabolism of some antidepressants. Genetic tests can look for variations in those genes as well as in CYP1A2 and NAT2 which are involved in SSRI metabolism. The latter are also involved in caffeine metabolism.

Psychiatric genetic testing is commercially available through a handful of companies. Genesight, Genelex, and Genomind are some of the companies offering this type of testing. Their tests use proprietary algorithms to analyze results from multiple genetic tests to produce recommendations as to which medications are most likely to be the most effective and which to avoid to reduce the risk of side effects. Panels include analyses with potential therapeutic implications for dozens of neuropsychotropic medications, not just for depression but also anxiety, bipolar disorder, post traumatic stress syndrome, obsessive compulsive disorder, and schizophrenia. The test offered by Gensight advertises that it analyzes genes related to over 50 medications.

Efficacy Studies & The Results

How well do these bold claims hold up? Is genetic testing to improve psychiatric treatment effective?

The short answer is no. Well, not yet anyway.

Efficacy or lack thereof for a particular medication is usually caused by a patient developing resistance or not adhering to their regiment rather than by their genetically-influenced metabolic factors. 

The heritability of depression itself is considered a complex from a genetics perspective, with many different contributing genetic and environmental factors. Major depression is influenced by a myriad of genes. Rarely is one single gene or set of genes a significant risk factor for more than a small percent of people. When it comes to personalized medicine approaches for treatment of depression, the genetics may be just as complex. 

Studies that show improved therapeutic outcomes for patients are often done on small sample sizes over a short time period and are therefore ineffective at showing statistically significant improvement. A recent 2018 Task Force by the American Psychiatric Association confirms there is not currently enough sound data to recommend genetic testing in the clinical management of depression. The task force analysis criticizes the weak data from studies that are often funded or executed by genetic testing companies. It adds that the proprietary nature of the tests’ algorithms make outside analysis and validation of their methods challenging. While there is still a long way to go, personalized medicine employing genetic testing and pharmacogenomics is surely one part of the future of medical management for major depression. Ongoing, large scale studies like EMBARC and iSPOT-D are attempting to understand genetic components behind patients’ responses to depression therapies. For those interested in genetics, genetic counseling, personalized medicine, and management of psychiatric disorders, this will be an area of research and development to keep an eye on.

• Scientific American: Behind the Buzz How Ketamine Changes the Depressed Patients Brain (2019)
• Psychology Today: When a Gene Test Could Help You Pick an Antidepressant (2017)
• American Psychiatric Association – Task Force on Gene Testing for Antidepressant Efficacy Concludes Tests Not Yet Ready for Widespread Use (2018)
• Does Pharmacogenomic Testing Improve Clinical Outcomes for Major Depressive Disorder? A Systematic Review of Clinical Trials and Cost-Effectiveness Studies. The Journal of Clinical Psychiatry (2017).