The October 2017 issue of the American Journal of Psychiatry a clinical case conference was published that draws attention to the serious problem of misuse of pharmacogenomic information (Rahman et al., 2017).
Here is a summary of what happened:
The patient was a 25-year-old man with schizophrenia who had marked positive symptoms. He had been hospitalized many times and had had many episodes of agitation and aggression that had required seclusion and restraints.
His symptoms had not improved significantly despite treatment with several oral antipsychotics (haloperidol, olanzapine, paliperidone, ziprasidone), long-acting injectable antipsychotics (haloperidol decanoate, long-acting injectable paliperidone), and mood stabilizers (lithium, valproate).
His outpatient psychiatrist obtained pharmacogenomic testing with the aim of better understanding
the “treatment resistance” of the patient’s illness.
When the patient was then admitted to a University hospital, his family and his case worker provided the results of the pharmacogenomic testing to the treatment team and insisted that it be used to guide the treatment.
The treatment team recommended that, given that the patient had failed several medications, clozapine be given. But the patient’s family and outpatient psychiatrist strongly disagreed with this.
Why, you ask? Because the pharmacogenomic test report had noted that he was a heterozygous carrier of a single-nucleotide polymorphism in the gene (DRD2) that codes for the dopamine D2 receptor. The report suggested that this polymorphism predicted “a poor response” to clozapine (and also to olanzapine and risperidone).
Do you think that the recommendation of the outpatient psychiatrist was appropriate? What do you think happened next?
After much discussion, clozapine was started anyway. The patient showed a rapid improvement on clozapine. The family members also agreed that he was better. Gradually, the patient returned to his previous level of functioning.
To support the relationship between polymorphisms of the DRD2 gene and response to antipsychotic medications, the company that had provided the pharmacogenomic test referred to one published study that had a small sample (Lencz et al., 2006). That small study had looked at response to olanzapine and risperidone and found the one variation in the DRD2 gene predicted a greater chance of response to antipsychotic treatment. The key point is that the study did not find that patients with any polymorphisms of the DRD2 gene would not respond to the antipsychotic; only that the percentage of patients responding varied.
This case highlighted how pharmacogenomic test reports can be misleading and may harm patient care if their results are not interpreted appropriately.
The main point I want to strongly emphasize is that some genetic polymorphisms may be associated with increased chances of response or adverse effects to certain medications. BUT, even for associations with the best data, this does not mean that the person definitely will or definitely will not have a response or adverse effect.
It is a serious problem that promotion by some pharmacogenetic testing companies is leading to test results being misinterpreted by clinicians and patients as definitely indicating whether or not a particular person will have either a response or adverse effects to a particular medication. Probability is being misinterpreted as certainty.
We can blame either the marketing of the pharmacogenomic tests or the lack of training that many prescribing clinicians have in understanding what the test results mean and when/how they should be factored into clinical decision-making. Either way, such misapplication of the results can harm patients as in the case we are discussing here. In addition, it takes away from what real value pharmacogenomic testing can bring to clinical practice.
There is no alternative to us taking the time to learn about how to separate the wheat from the chaff and learn to be able to interpret and apply pharmacogenomic test results.
Related Pages
Pharmacogenomics and psychotropic medications
Dopamine D2 receptor polymorphisms and response to antipsychotic medications
Dopamine D2 receptor polymorphisms and adverse effects of antipsychotic medications
References
Lencz T, Robinson DG, Xu K, Ekholm J, Sevy S, Gunduz-Bruce H, Woerner MG, Kane JM, Goldman D, Malhotra AK. DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry. 2006 Mar;163(3):529-31. PubMed PMID: 16513877.
Rahman T, Ash DM, Lauriello J, Rawlani R. Misleading Guidance From Pharmacogenomic Testing. Am J Psychiatry. 2017 Oct 1;174(10):922-924. PubMed PMID: 28965468.
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Thanks for emphasizing the limitations of pharmacogenomic testing, and for stressing the importance of properly interpreting study conclusions.
I haven’t used this kind of testing very much, but in my own, DIY mini retrospective study with absolutely no statistical meaning, I found that the testing is not too bad at identifying which medications will cause adverse effects, but terrible at identifying which will produce the desired effects. I did this by comparing testing results with the actual responses patients had to medications they had taken previously, so again, absolutely no scientific meaning to my conclusion
The one real use I’ve found for this kind of testing-and im very sad that this is the case-is that if I want to try a patient on a new or just expensive medication, their insurance is more likely to approve it if testing shows that it’s likely to be effective.
I look forward to the day when pharmacogenomic testing is more accurate.
I do not use these tests any longer because the responses are usually vague and sometimes include many choices. But the worse example was one result where the patient was only responsive to brand name medications (Rexulti, Vraylar, Latuda), and poor responder to all other second generation antipsychotics. I threw that one in the recycling bin!
Just a note regarding pharmacogenetics.
It is important to be aware that results are guidelines and possibilities. The data must be adjusted to the patient. We treat patients not labs. It is important also to keep in mind that some gene variations are not tested.
Pharmacokinetic results can be corroborated most of time, not always, with blood levels (dependent on time given, absorption and elimination).
Pharmacodynamics are more difficult since many things interact with each other such as: membrane fluidity neurotransmitter tone, dynamics of receptors etc.
In summary pharmacogenetics help us to be cautious in our prescribing habits.
Example: P450 2D6 poor metabolizer + Roux and Y surgery, given duloxetine 120mg/day in Hospital. Prescribing RN did not pay attention to genetic results. End result patient falling asleep while driving. Blood levels of duloxetine very high.