Overcoming Treatment Resistance: Can Pharmacogenetics Help?

Pharmacogenetic testing can provide helpful guidance in the choice of treatment and should be interpreted as a decision-support tool to assist in thoughtful implementation of good clinical care.

Psychiatric disorders affect more than 1 billion people globally and are among the leading causes of disability worldwide in all age ranges from 5 to 75 years.1,2 A careful clinical evaluation is the first step in making an accurate diagnosis and treatment decision. However, the complexity of many cases or the effect of unmeasured biological markers (biomarkers) may make this approach difficult. Various psychotropic medications belonging to different classes are available, which contributes to the difficulty in making treatment decisions. Consequently, multiple drug switches or combinations/augmentations are a frequent practice and months may be required before finding an effective and well-tolerated treatment.3 Approximately 50% of patients with depression do not respond to at least one antidepressant.4 Moreover, poor treatment adherence often due to adverse effects is frequent and may be one of the causes of treatment resistance.5

In this scenario, the use of biomarkers, and specifically genetic variants, to tailor treatment to the individual is an option to improve mental health care by increasing remission rates and reducing the incidence of adverse effects. Genetic variants are involved in the inter-individual differences in psychotropic drug pharmacokinetics and pharmacodynamics. Compared with other types of biomarkers such as neuroimaging brain measures or plasma proteins, genotyping has several advantages: it is easy and quick to perform (the patient can collect the sample using a saliva kit at home), it is economically affordable, and the information generated does not change over time and can be used life-long. These facts explain why psychiatric pharmacogenetics has become a central interest for academic and non-academic institutions and of course for patients and caregivers.

The circumstances requiring the prescription and/or interpretation of a pharmacogenetic test are becoming more and more frequent in everyday psychiatric clinical practice. In some cases, a patient may come for the initial visit to a psychiatrist’s office with the results of a pharmacogenetic test. He or she asks for “the right” prescription based on the results. Some key questions arise at this point: is this test the best option to guide treatment choice in this patient? How to translate the information into a prescription?

In other cases, it might be the clinician who wonders if pharmacogenetic testing should be recommended: for example, in a patient with a history of treatment resistance or poor tolerability to several drugs. The answers are not always straightforward.

Pharmacogenetic testing: genotyping

There is sufficient evidence for the clinical application of pharmacogenetic testing guiding drug choice and dose (Table).6 Except for the HLA-A and HLA-B genes, which code for the human leukocyte antigens involved in the pathogenesis of the Steven-Johnsons Syndrome, all the other reported genetic variants affect both the risk of nonresponse and adverse effects, because they mediate drug hepatic metabolisms and drug plasma levels. Two cytochrome P450 (CYP450) enzymes, CYP2C19 and CYP2D6, metabolize the most antidepressants and antipsychotics, and the corresponding genes are highly polymorphic. Polymorphisms carried by an individual in each of these CYP450 genes define the patient’s metabolizing status, which can be normal (extensive metabolizer), increased (ultrarapid metabolizer), decreased (intermediate metabolizer), or severely decreased/completely defective (poor metabolizer).

Variants in the CYP2D6 gene are examples of pharmacogenetic biomarkers supported both by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG) for several antidepressants and antipsychotics. Recommendations include to avoid drugs mostly metabolized by CYP2D6 (eg, several tricyclic antidepressants, paroxetine, risperidone) in patients with altered function of this enzyme or alternatively they suggest dose adjustments and increased monitoring to avoid adverse effects in poor metabolizers and treatment failure in ultrarapid metabolizers (Table and Figure 1).

Recommending pharmacogenetic testing

Current guidelines provide no advice on when, or to whom, genetic testing should be offered. This is due to the lack of data regarding which patients will garner the most benefit from testing and for whom it will be most cost effective. Large non-sponsored trials are expected to clarify this point in the next few years, but in the meanwhile we must rely on available evidence.7

Findings from clinical trials suggest that testing is likely most beneficial for individuals who have experienced an adverse drug reaction or inadequate response to a previous treatment (Figure 1).8 For these patients, testing may be particularly indicated before prescribing a drug with a narrow therapeutic index, such as a tricyclic antidepressant. In these cases, the cost of the test may be refunded by some health insurance companies or the test is provided by some national health care services.9 In patients who experienced poor efficacy/tolerability to a number of different treatments, genetic testing can help to identify effective medications or guide appropriate dose adjustments.10-12

Compared with therapeutic drug monitoring (TDM), which is a broadly available method to guide dose adjustments, pharmacogenetic testing has some advantages. It can save time that would be spent waiting for the drug to reach steady-state concentration, and the results of the test remain the same life-long so there is no need for retesting. The information can be used to guide future prescriptions of psychotropic drugs as well as medications of other classes metabolized through the same enzyme. This is particularly relevant since chronic medical disorders are common in patients with psychiatric disorders. (An average of 3.5 chronic medical disorders was reported in depressed patients.13)

Choice of the pharmacogenetic test and interpretation of the results

There are a number of direct-to-consumer pharmacogenetic tests for purchase on the Internet or in drug stores. These tests include variants in the genes reported in Table 1. Most tests also add other variants with a more heterogeneous level of evidence for association with psychotropic drug response/adverse effects (Figure 2).6 The results are usually provided in less than a week, and they distinguish drugs that can be prescribed as directed from those that require increased monitoring or should be avoided based on the genetic profile.

Several commercial tests were evaluated in terms of clinical benefits compared with standard care, mostly in non-randomized studies with other methodological limitations. The strongest evidence is an improvement in symptom remission rate in the tested group compared with standard care, but long-term data are not available.14 Until the additional genes included in commercial tests are endorsed by clinical guidelines such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) their clinical relevance is uncertain.

The need for a cautious interpretation is confirmed by a case report showing that pharmacogenetic testing may be misleading when the scientific evidence is not definitive, and a complete clinical evaluation is not performed. In this case, the patient had treatment-resistant schizophrenia and had been struggling with the disease for years. He had had multiple hospitalizations and lack of response to multiple medications, including haloperidol, olanzapine, ziprasidone, and paliperidone. The clinical team considered the patient’s documented history of antipsychotic resistance and concluded that a trial of clozapine would be the next appropriate step. However, the results of a pharmacogenetic test advised against the prescription of clozapine because of a variant in the dopamine receptor 2 (DRD2) gene, which was associated with poor clozapine response. Nonetheless, the clinical team reached a consensus to try clozapine; the patient subsequently had a rapid improvement on 400-mg clozapine daily and gradually returned to the previous level of autonomous functioning.15

Besides DRD2, other genes that had insufficient levels of evidence for guiding antipsychotic prescription were included in the used pharmacogenetic test, such as HTR2C and MTHFR (Figure 2). Besides considering which genes are tested, it is also important that the laboratory performing the test has a clinical certification that guarantees good analytical and clinical validity.

Conclusions

Pharmacogenetic testing can provide helpful guidance in the choice of treatment when applied in accordance to the available guidelines (Table). The current evidence suggests that testing can be helpful in patients who have experienced an adverse drug reaction or inadequate response to at least one previous treatment, including patients with treatment-resistant disorders.

Pharmacogenetic testing should be interpreted as a decision-support tool to assist in thoughtful implementation of good clinical care, and prescriptions should not be based exclusively on the pharmacogenetic results. Clinical-demographic factors (eg, personal and family history, concomitant medications) and lifestyle (eg, diet) should be always taken into account when making prescriptive decisions.

Disclosures:

Dr Fabbri is a Postdoctoral Research Fellow, Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK; Dr Serretti is Professor of Psychiatry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Dr Fabbri reports no conflicts of interest concerning the subject matter of this article. Dr Serretti reports that he is/has been a consultant/speaker for Abbot, Abbvie, Angelini, Astra Zaneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier.

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