乔纳森迈耶，医学博士
Voluntary Clinical Professor of Psychiatry – University of California, San Diego and CURESZ Board Member

 

For over a decade commercial companies have offered pharmacogenetic testing to psychiatric providers with the promise that the results will assist medication choice or dosing. While the concept of personalized medicine has great appeal and represents the forefront of research in many areas, the applicability and value in psychiatric practice remains a subject of intense debate. As will be discussed below, the problems with testing lie not only in what is reported, but also the difficulties encountered by clinicians when interpreting the significance of assay findings and implementing them to benefit patient care.

Fundamental to this debate rests on the fact that there is large variation in what various guidelines and commercial reports recommend to clinicians, even for basic information such as the significance of interactions between prescribed drugs and genetic variants that influence pharmacokinetics (i.e. drug clearance). A 2022 commentary entitled Clinical Use of Pharmacogenomics in Psychiatry: The Future Has Not Yet Arrived in the prestigious journal European Neuropsychopharmacology lamented: “The challenges of the translation of candidate genes with relevance to pharmacokinetic mechanisms (e.g., CYP2C19, CYP2D6, CYP2C9) into clinical practice is also demonstrated by the fact that various guidelines on the use of pharmacogenomic information for specific drug-gene pairs (including 33 relevant for Psychiatry) show large variation, demonstrate in part contradictions in recommendations even on the same drugs and lack wide adoption by clinical services.”1 This lack of agreement among commercial tests has been noted for over half a decade,2 with reviews and expert consensus papers in 2018 concluding that the data did not establish the value of such testing.3,4

Recently published papers do recognize the possible benefits in identifying genetic variations associated with slower drug clearance (leading to higher rates of adverse effects for a given dose) or more rapid drug clearance (leading to lack of effective drug levels), but clinicians may not fully appreciate the caveats in using this information. Commercial tests report information on 6 or more cytochrome P450 enzymes (CYP 450), yet a comprehensive 2021 review focusing on commonly used antipsychotics and antidepressants noted that evidence, guidelines, and product labels supported testing for only for 2 of these genes (CYP2D6, CYP2C19).5 Moreover, a 2019 study of patients with major depression found genetic testing did not significantly improve the average extent of symptom reduction, but did increase the proportion rated as responders.6 The conclusion from this literature is that testing can alert clinicians to situations where drug levels might be lower than expected for a given dose and thereby pursue higher dosages in those patients who clear medications more quickly, assuming that the medication is metabolized by one of those two CYP genes; however, this will not influence the maximal ability of the drug to be effective once therapeutic drug levels are reached.

While one would correctly conclude that a similar principle applies to antipsychotics, namely that certain genetic variations present a risk for drug levels that are too high or too low, the situation may be a bit more complex for several reasons:

1) Clinicians may focus so heavily on the genetic testing results that they overlook potential interactions from other co-prescribed medications that can slow or accelerate antipsychotic clearance. Patients living with schizophrenia are often on complex medication regimens;

2) Individuals may have variations in more than one CYP enzyme making it difficult to determine the net effect on drug clearance;

3) Inherent to many chronic disorders, especially serious mental illnesses such as schizophrenia, is poor adherence with oral medication therapy. Genetic testing will not help a clinician decide why a patient might be an inadequate responder to seemingly effective antipsychotic dosages – only plasma drug levels will provide that answer;7

4) Certain nutritional supplements and cigarette smoking (e.g. actual burning of the leaf, not vaping) may expose a patient to chemicals that alter antipsychotic clearance; and

5) There is no genetic test or imaging study available that predicts response to antipsychotics in general, or to specific agents.

This confluence of issues may explain why no study has found that the use of commercial genetic testing significantly improves outcomes in patients living with schizophrenia, but it does explain why there has been a resurgence of interest in directly measuring antipsychotic levels to accurately quantify how the independent effects of nonadherence, genetic variants, other medications, supplements and smoking sum to influence how a given medication is cleared and whether it is being taken as prescribed.8,9

Clozapine is an important example of the limitations imposed by use of genetic testing. Clozapine is the only medication effective for individuals with treatment resistant schizophrenia, but it has complex metabolism, with one study showing the average contributions of CYPs 1A2, 2C19, 3A4, 2C9, and 2D6 were 30%, 24%, 22%, 12%, and 6%, respectively.10 CYP1A2 is very sensitive to the effects of cigarette smoking, and those who smoke typically require dosages 50% higher than nonsmokers to achieve the same clozapine level.11 The magnitude of this effect will only be seen if the clinician orders a clozapine level. Importantly, given that population variations exist for many of these CYPs, and that a significant proportion of patients living with schizophrenia do smoke, recent recommendations focus on tailoring early clozapine dosing to the patient’s ancestry and smoking behavior to avoid unnecessarily high drug levels during the early phase of treatment, and then checking levels to determine the net effects of all of these factors for that patient. To add another layer of complexity to this situation, clozapine has an active metabolite, norclozapine, and 83% of its clearance does not rely on a CYP but instead on a renal (kidney) drug transporter called P-glycoprotein (PGP).12,13 Not surprisingly, both the expression of and the function of PGP exhibit population variations in the same manner as do CYPs,14 and this variability represents an aspect of norclozapine clearance that is not captured by many commercial genetic assays.15-17

The problems with pharmacogenetic testing (PGx) in psychiatry can be summed up nicely by a 2023 review which concluded: “Clinicians varied greatly in their application of test results for clinical decision making regarding medications, many were uncertain how much to rely on the results, and differed in perceptions about which patients would benefit from PGx.”18  There is hope that, in the future, genetic testing will significantly improve the accuracy of antipsychotic treatment and patient outcomes. That future, lamentably, has not yet arrived.

Conflicts of interest: Dr. Meyer reports having received speaking or advising fees in the past 24 months from: AbbVie, Alkermes, BioXcel, ITCI, Karuna, Neurocrine, Noven, Otsuka-USA, Sumitomo Pharma (formerly Sunovion) and Teva.

参考

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  2. Bousman CA, Dunlop BW. Genotype, phenotype, and medication recommendation agreement among commercial pharmacogenetic-based decision support tools. Pharmacogenomics J 2018;18:613-22.
  3. Nurnberger JI, Jr., et al. What should a psychiatrist know about genetics? Review and recommendations from the Residency Education Committee of the International Society of Psychiatric Genetics. J Clin Psychiatry 2018;80.
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  7. Ruan CJ, et al. Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies. Schizophr Res 2023:doi: 10.1016/j.schres.2023.07.002. Online ahead of print.
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