The Uses of Pharmacogenetic Testing in Psychiatry: Medication Intolerability and Resistance

Genetic Testing in PsychiatryTCPR: Dr. Hamilton, why would a psychiatrist want or need to order genetic testing on a patient?

Dr. Hamilton: I tend to consider genetic testing for two specific types of cases. One is serial intolerability—poor tolerance of multiple medications, for instance, across SSRIS or even between classes of medications. This gets me wondering if a person has some perturbation in their metabolism; a genetic variant that might affect how they process these drugs. The other indication is when a patient shows resistance to antipsychotics or to antidepressants.

TCPR: Can you summarize briefly some of the genes that are tested in pharmacogenetic testing in psychiatry?

Dr. Hamilton: Because of their connection to a broad swath of psychotropic drugs, it really boils down to two cytochrome P450 genes: 2D6 and 2C19. This is because nearly all psychotropics are metabolized to some extent by the enzymes encoded by these genes. More importantly, there is ample genetic variation in these genes, specifically related to people being poor metabolizers, and these are fairly common in the general population. And with CYP2D6, there is an added level of complexity in that you can have individuals who are what we term ultra-metabolizers, meaning their gene products work at a much higher rate of efficiency than the normal level of functioning.

TCPR: You talk about people being normal metabolizers or poor metabolizers on these genes. What is the evidence that metabolizer status correlates with blood levels of medication and/or clinical outcome?

Dr. Hamilton: There has been a lot of effort put into looking at the correlation between drug levels and polymorphism status. The evidence is good in the case of tricyclic antidepressants. The classic study from the ‘90S showed that nortriptyline levels were highly correlated with metabolizer status for 2D6 (Dalen P et al, Clin Pharmacol Ther 1998;63(4):444-452). Those who were ultra-metabolizers had almost unmeasurable amounts of nortriptyline in their system. SO there are a few clinical observations, such as this, but these are typically clinical pharmacokinetic laboratory studies. What’s really missing are large prospective studies looking at actual clinical outcomes based on metabolizer status.

TCPR: Do you think it is possible that there is a sort of intuitive pharmacogenetics going on all the time in psychiatry? That patients who are regular or poor metabolizers end up on the appropriate dose of medication through the normal process of monitoring and titrating medication?

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Dr. Hamilton: Some research shows that, yes, clinicians frequently alter the dose of an individual’s medication in the direction that fits, using a sort of intuitive pharmacogenetics. An older study looked at the genotypes of people taking risperidone (Risperdal). Investigators looked at individuals’ doses of risperidone over time, and later looked at their genotypes. YOU would expect that individuals who were poor metabolizers probably couldn’t tolerate higher doses because it was cleared less efficiently. Sure enough, individuals who had poor-metabolizer status were placed on lower doses, even though the clinicians did not know anything about their P-450 enzymes (Mas S et al, 2012 Pharmacogenomics J;12(3):255-259).

TCPR: The massive STAR*D trial found no individual antidepressant strategy to be better than any other. Is it possible that applying pharmacogenetic strategies to patients in order to guide treatment might have led to better outcomes in a study like STAR*D?

Dr. Hamilton: My own work was involved with genetic studies of the STAR*D sample. We carried out a retrospective genome-wide association study (GWAS) of the STAR*D data. The results we found and published did not meet the standard levels of statistical significance, and were not robust enough to have warranted changing the treatment, even if we had that information before the STAR*D study began. There is an exception to that. We found that CYP2D6 or CYP2C19 metabolizer status did not predict response, and published that finding some time ago (Peters EJ et al, 2008 PLoS One, 3(4):el872). However, in work that we did not publish then, we looked at 2D6 and 2C19 metabolizer status and found that the rates of intolerability—defined by STAR*D as whether an individual could continue taking the medication based on side effects—was correlated with 2D6 and 2C19 genotypes. Knowing that ahead of time may have been useful, because one of the primary predictors of antidepressant response in STAR*D was drug intolerability.

TCPR: Are there any guidelines for the use of pharmacogenetic testing to optimize drug therapy?

Dr. Hamilton: There are about 25 psychotropic drugs for which the FDA has guidance for pharmacogenetics (these can be found at It is an interesting list that I would urge clinicians to check out. Another resource is the Clinical Pharmacogenetics Implementation Consortium (CPIC), a partly NIH-funded group of researchers, in this field, who have come together to create guidelines ( They provide recommendations for a broad array of medications, including several tricyclic antidepressants.

TCPR: Isn’t it true that behavioral factors contribute to drug response in a way that might outweigh the genetic factors?

Dr. Hamilton: Absolutely. Genetics only make up a small part of the likelihood of drug response or tolerability, and other issues are strong contributors. Other exogenous substances, such as tobacco or dietary supplements, may interfere with the metabolism of antidepressants and other metabolic issues related to age, disease (eg, hepatic disorders), and gender can influence these things. Genetics likely plays some discrete, but measurable, role, but it needs to be taken into account with all these other nongenetic factors.

The Uses of Pharmacogenetic Testing in Psychiatry: Medication Intolerability and Resistance

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This article was published in print 10/2014 in Volume:Issue 12:10.


APA Reference
Hamilton,, S. (2016). The Uses of Pharmacogenetic Testing in Psychiatry: Medication Intolerability and Resistance. Psych Central. Retrieved on July 9, 2020, from


Scientifically Reviewed
Last updated: 30 Jan 2016
Last reviewed: By John M. Grohol, Psy.D. on 30 Jan 2016
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