No clear clinical guidelines currently exist to identify good candidates for psychiatric pharmacogenomic testing. The choice for testing is entirely at the discretion of the healthcare provider. While pharmacogenomic testing has the potential to help healthcare providers identify genetically optimal medications for all patients, this white paper identifies characteristics that may make patients more or less ideal candidates for GeneSight testing.
What types of patients are appropriate for GeneSight testing?
Patients who have failed one or more medications:
The clinical trials that demonstrate the clinical validity, clinical utility, and cost-effectiveness of the GeneSight test enrolled patients who had failed at least one medication trial.1–5 In this patient population, the GeneSight test can be used as a roadmap to identify the medications or medication classes to which the patient is most likely to respond.
Elderly patients and patients with liver damage:
Elderly patients8 and patients with liver damage9 may have impaired production of CYP450 enzymes, which can affect drug metabolism rate. This physiological impairment may exacerbate the effect of pharmacogenomic variation. Therefore, the poor metabolizer phenotype may be more extreme in elderly patients compared to younger patients. For example, a study by Waade et al. demonstrated that serum levels of venlafaxine among elderly CYP2D6 poor metabolizers were eight-fold greater than younger CYP2D6 poor metabolizers.10 GeneSight testing may help healthcare providers by providing genetically-informed relative dosing in the context of the providers’ revised dosing range for elderly patients and hepatic compromised patients. Furthermore, the GeneSight test has been shown to significantly reduce polypharmacy11, which could be especially beneficial for elderly patients who are often taking multiple medications.
Patients who are very sensitive to medications:
Side effects from medications may result from pharmacokinetic, pharmacodynamic, and psychological manifestations (i.e. nocebo effect).6 Many healthcare providers have utilized the GeneSight test to shed light on this process. GeneSight testing might reveal a compromised pharmacokinetic or pharmacodynamic gene-drug interaction yielding side effects. Additionally, a ‘normal’ test might point a healthcare provider toward ruling out a pharmacokinetic or pharmacodynamic problem, suggesting a requisite look into the psychological aspects of the patient’s sensitivity.7
When should GeneSight testing be used with caution?
While additional utility may be gained for treatment-naïve patients, this population has not been studied. Thus, the GeneSight test is recommended for patients who are currently failing or have failed at least their initial prescribed behavioral health medication.
Patients who have failed numerous medications in multiple medication classes:
Difficult-to-treat patients who have failed numerous medication trials in multiple medication classes are often highly complex, with multiple medical and psychiatric comorbidities that may obscure medication response. The GeneSight test may be able to explain why the patient has failed past medication trials. This may validate patient experience for those who have struggled with medication response. If patients have already tried many medication classes, the GeneSight test is less likely to identify a genetically optimal medication they have not yet tried. However, it may identify medications that were prescribed at sub-optimal doses, which could lead a healthcare provider to re-try a medication at an adjusted dose.
Liver transplant patients:
A transplanted liver will have the DNA (and consequent enzyme expression) of the donor, while the GeneSight test looks at the DNA of the recipient. The pharmacodynamic portion of the GeneSight test, which includes 4 genes on GeneSight Psychotropic, will still provide accurate information for these patients. However, they will not gain useful information from the pharmacokinetic portion of the GeneSight test. Since the GeneSight algorithm depends on the outcome of both pharmacokinetic and pharmacodynamic genes, the interpretive pages of the GeneSight report, which separate medications into the green, yellow, and red categories, may not be used. Therefore, a liver transplant patient should only consider having the GeneSight test if benefit can be gained from the results of the pharmacodynamic genes.
What types of patients are not appropriate for GeneSight testing?
Patients who are responding to their current medication regimen:
Patients who are doing well on their current medication regimen are not ideal candidates for the GeneSight test. The clinical utility the GeneSight test provides is based on the potential to switch patients from medications they are not responding to onto more genetically optimal medications. This does not apply to patients who are doing well on their current medication regimen. Additionally, all subjects in the clinical trials that validate the GeneSight test were not responding to their medications at the beginning of the trial, so this characteristic reflects the studied population. The GeneSight test should be used at the time when a medication dose adjustment, augmentation, discontinuation, or cross-taper is being contemplated.
1. Hall-Flavin, D. K. et al. Using a pharmacogenomic algorithm to guide the treatment of depression. Transl. Psychiatry 2, e172 (2012).
2. Hall-Flavin, D. K. et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet. Genomics 23, 535–48 (2013).
3. Winner, J., Allen, J. D., Anthony Altar, C. & Spahic-Mihajlovic, a. Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Transl. Psychiatry 3, e242 (2013).
4. Winner, J. G., Carhart, J. M., Altar, C. A., Allen, J. D. & Dechairo, B. M. A prospective, randomized, double-blind study assessing the clinical impact ofintegrated pharmacogenomic testing for major depressive disorder. Discov. Med. 16, 219–27 (2013).
5. Altar, C. A. et al. Clinical validity : Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes. 1–9 (2015). doi:10.1038/tpj.2014.85
6. Mitsikostas, D. D., Mantonakis, L. & Chalarakis, N. Nocebo in clinical trials for depression: A meta-analysis. Psychiatry Res. 215, 82–86 (2014).
7. Winner, J. G., Allen, J. D., Lorenz, J. P. & Altar, C. A. Overwhelmed by side effects. Curr. Psychiatr. 11, (2012).
8. Sotaniemi, E. a., Arranto, A. J., Pelkonen, O. & Pasanen, M. Age and cytochrome P450-linked drug metabolism in humans: An analysis of 226 subjects with equal histopathologic conditions*. Clin. Pharmacol. Ther. 61, 331–339 (1997).
9. Prescott, L. F., Forrest, J. a, Adjepon-Yamoah, K. K. & Finlayson, N. D. Drug metabolism in liver disease. J. Clin. Pathol. Suppl. (R. Coll. Pathol). 9, 62–65(1975).
10. Waade, R. B., Hermann, M., Moe, H. L. & Molden, E. Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups. Eur. J. Clin. Pharmacol. 70, 933–940 (2014).
11. Winner, J. G. et al. Combinatorial pharmacogenomic guidance for psychiatric medications reduces overall pharmacy costs in a one year prospectiveevaluation. Curr. Med. Res. Opin. 1–30 (2015).