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Debunking the Myths Surrounding Genetic Testing for Psychiatric Medications

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In recent years, psychiatric care has joined other medical specialties in the quest for personalized medicine. Genetic testing is being marketed as a game-changing resource for predicting how well a patient will respond to a psychiatric medication, based on certain components of that individual’s unique genetic code. This approach, a function of the medical science known as pharmacogenomics—the study of how genes influence a person’s response to drugs—holds the promise of tailoring treatment plans to the genetic profiles of individual patients, as it has already in the area of cancer treatment. Despite this promise however, experts and research organizations have consistently expressed concern about the current utility and validity of the practice in psychiatry, noting numerous limitations and advising a cautious approach, or, as the American Psychiatric Association has advised, avoiding these tests altogether as being as yet not adequately developed for use in psychiatric treatment.

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Genetic Testing for Psychiatric Medications: An Introduction

The concept is compelling in its simplicity: Genetic testing for psychiatric medications is heralded as the epitome of personalized precision medicine, whereby the use of genetic information to guide the selection of medications is believed to lead to treatment regimens that are more likely to succeed. The test results could ostensibly save the patient and clinician from the potentially long and painful process of giving a medication 4-6 weeks to work and then tapering off, only to switch to a different medication and start the process all over again if the medication fails. However, the reality is significantly more complex, and the relative effectiveness of such tests is far from a given.

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The Science Behind the Skepticism: Lack of Proof

The term “genetic testing” encompasses many different kinds of tests. Psychiatric conditions are predicated upon networks of hundreds of interacting genes with potentially thousands of variants among them. An ideal genetic test would select for the safest and most effective medication to treat a condition in each individual. But because of the complexity of these gene networks, science is very far from being able to match a specific pattern of genetic variation in the genes that cause the condition to the specific medication that best treats a given variation. 

However, commercially available tests do not look at these illness-causing genes. Instead they look at normal variations in non-psychiatric genes that influence the absorption in the gut, the metabolism (breakdown pathways) and excretion efficiency of medications. They do not test for efficacy proper–which medications will work and which ones do not–or for genetically-determined responsiveness to a given amount of medication in the system. This responsiveness is generally a function of how well there is a lock-and-key fit between the shape of the medication molecule and the shape of the protein receptor it is meant to bind to. The shape of the receptor is determined by the exact sequence of  amino acids that comprise the protein, and that sequence is determined by the sequence of DNA base-pairs (G,T,A or C) in the DNA region that codes for that protein. There exist many variations in the coding (the gene) and therefore the shape of the receptor. Of course, one is left with the impression from marketing materials (not explicitly stated) that the latter is what is being tested for. 

What they do in practice is determine whether average therapeutic doses (the amount you ingest) will generate average concentrations in the bloodstream, or unusually high concentrations or unusually low concentrations. However, this does not tell you how good a fit there is between the medication molecule and the receptor that permits the medication to alter symptoms. It does tell you that if a physician unwisely starts treatment right off the bat with the average therapeutic dose, there will be some people who won’t respond because the lock and key fir is poor, or as a separate matter because they break the medication down too rapidly; and other people who might or might not respond well but since they break the medication down too slowly they develop intolerable side effects at that typically therapeutic dose. These pitfalls are easily gotten around by simply starting at low dosages, which one must anyway, and then slowly increase while checking for both response and for side effects. 

There is more directly usable genetic information about treatment response or side effects in a family history of responsiveness or of side effects to a given medication.

Despite the growing interest in using genetic tests to guide treatment with psychiatric medications, a confluence of scientific and commercial factors has created a dearth of well-validated tests, and left many patients and professionals in an information vacuum. The example of antidepressants is illustrative. The FDA has specifically warned against using genetic tests to guide the choice of antidepressants because “the relationship between DNA variations and the effectiveness of medication has not been established.” 

The FDA went further, warning that the use of gene-drug pairs in this way might lead to “inappropriate treatment” of patients that could cause “serious adverse health effects or death.” 

Research studies have produced inconsistent results regarding the ability of genetic tests to predict how individuals with psychiatric conditions will respond to a variety of psychotropic medications. The causes of these inconsistent results are multiple and complex. Mental health disorders are complex, nutritionally influenced, environmentally impacted conditions that are the result of numerous genetic, environmental and personal experiential factors. Genomic testing cannot determine if a person has a psychiatric disorder; if they do, which disorder it is; or—most importantly, as explained—which medications work most effectively for them even though marketing materials make it seem this is what they do. Furthermore, because of their spectrum nature, psychiatry patients almost always have multiple psychiatric “disorders” that blend into one another with fuzzy boundaries, meaning their genetic profile is immensely complex, making it exceedingly difficult to match specific medications with a patient.

What makes identifying the genetics of psychiatric conditions so challenging is that they are predicated upon not a single or nor handful of genes, but rather gene networks that run into the hundreds of mutually interacting genes, with different conditions sharing many of the same genes and blending clinically into each other. The prospect of actually testing for the condition and matching it to the medication is going to require very much more research then in those cases in the rest of medicine where single gene variations can be matched to a given medication protocol. Indeed, psychiatry requires an entirely different approach to diagnosis as well than the rigid categories of the DSM.

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Two observations: 

First, the network structure of the genetic background to psychiatric conditions is analogous to the network structure of symptoms. However there is not a one-one-one correspondence between a gene and a symptom–they are different networks altogether though based on a similar principle that orders many different levels of biological systems. 

Second, you can see directly whether looking at the gene network or the symptom network that a spectrum model of diagnosis emerges naturally in contrast to the black and white diagnostic “boxes” that we are familiar with. In fact, this familiar rigid categorical structure of diagnosis was known to be inaccurate in the 1950’s when it was developed for the first DSM (Diagnostic and Statistical Manual). It was deliberately imposed firstly to make psychiatric diagnosis look more like diagnosis in the rest of medicine and secondly because the makers of the DSM thought the accurate, spectrum, model would be too confusing for people. This decision has caused many more problems than it has solved–and most people in fact intuitively understand that the boxed categories are not correct. Fortunately, it is slowly being dismantled by research necessities.

There are research projects underway that do look at the gene network structure, trying to find from all its huge number of individual variations a manageably small number that are especially influential, and then trying to find the correlation of network variants to medication response. But as you might imagine looking at the complexity of the network example above, the task of translating this into medical decision-making for an individual is still a ways off.

Marketing May be Misleading

Despite these limitations, genetic tests are being aggressively marketed to prescribers of medication, to specialists, to general practitioners, and to the public, and are leaving some patients with an implicit impression that the tests definitively forecast which medications are best for them. Disillusion on the one hand, or else exaggerated belief on the other hand, ensue when the tests, simply by chance, proves either incorrect or correct—a distortion either way. Insurance companies such as Blue Cross Blue Shield and Anthem have likewise established that the tests show a “lack of compelling evidence of the medical necessity of the test” and that these tests “do not improve health outcomes.” Like other research techniques that have been brought to market prematurely, these tests are therefore also costly.

Comprehensive Evaluation is Paramount

Experts advocate a comprehensive review of symptoms, titration of medication doses, and consultation with one or more subspecialists (e.g. a clinical psychiatrist, and/or a child psychiatrist) as more fruitful alternatives to genetic testing. Such professionals should have extensive psychopharmacologic training–to know the recipes and algorithms well–and experience–to know when and how to go beyond. 

The Future of Genetic Testing in Psychiatry

Potential for Personalized Medicine

Although the current evidence doesn’t support the widespread use of today’s available genetic testing in the selection of psychiatric medications, there is a future where that won’t be the case. The technology involved is always improving. When reliable tests emerge, ones that prove to play an important role in customizing psychiatric treatment, the psychiatrists at Sterling Institute, with strong research backgrounds, will deploy them immediately

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In Summary …

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