Psychotropic pharmacogenetics

Genetically guided prescribing (pharmacogenetics) in psychiatry is both promising and controversial. The premise – it may reduce trial and error to find the optimal medication by matching the pharmacological profile of the medication to the associated DNA profile of the patient. But the evidence for psychotropic pharmacogenetics is not at replicated randomized control trial (RCT) level. So, the jury remains out. Yet, such reports are increasingly being advertised and sold.

Due to the pace of technological advances in DNA sequencing, regulators have been caught somewhat flat footed, genetic guidance reports not falling under the tight pre-market regulatory controls that apply to medications and medical devices. This has enabled enterprises to offer such reports with little to no direct evidence of the clinical value of their products. Increasing marketing of such reports has led to more and more patients presenting to doctors enquiring about the utility of such reports and, in some instances, presenting with such a report – their doctor not part of the test ordering decision process. This raises a number of important issues.

Is pharmacogenetics standard of care in psychiatry? Only for one narrow clinical situation. When considering prescribing carbamazepine to patients with Asian ancestry, human leukocyte antigen (HLA) genotyping (now inexpensive and accessible) should be offered to better assay the risk of Stevens–Johnson syndrome (SJS) prior to prescribing (Malhi et al., 2015). Beyond this clinical situation, pharmacogenetics is not currently standard of care in psychiatry. But there is a body of literature supportive of the limited use of such tests to guide medication dosing – particularly, antidepressants.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recently published guidelines on use of hepatic metabolizer status genotyping (cytochrome P450 CYP2D6 and 2C19) to dose various antidepressants (Hicks et al., 2015). CPIC is a non-industry-funded group of international academics co-ordinated by Stanford University. Unfortunately, CPIC guidelines are not based on prospective RCTs comparing genetically guided prescribing to unguided prescribing. As a result, they cannot shed light on the clinical utility of ordering pharmacogenetic tests prior to prescribing. Despite this, if 2D6 and 2C19 metabolizer status is known, both CPIC and US Food and Drug Administration (FDA) guidelines recommend prescribers consider such information in making medication decisions (FDA Guidelines, n.d.; Hicks et al., 2015). This has important clinical and medicolegal implications, as if such information is at hand and not considered, adverse medication outcomes could be blamed on failure to consider such information. So, as clinicians, we may find ourselves in the vexed position of a patient having such genetic data – even if we did not organize them getting it – and needing to consider such information in their care. What should a ‘reasonable’ clinician do?

First, we need to be ready for patients asking about pharmacogenetic testing and some patients even presenting with such information. Again, other than for carbamazepine in Asian patients, it is reasonable to advise patients that pharmacogenetics is not yet established standard of care in psychiatry – due to still limited evidence base. Replicated RCTs will be needed to draw firmer conclusions about the merits of such testing. To date, only two RCTs exist – both industry-sponsored, one positive and the other yielding a non-significant trend supportive of utility in prescribing antidepressants (Singh, 2015; Winner et al., 2013). More RCTs are underway and will help shed greater light on the clinical merits of such testing.

If a patient has obtained pharmacogenetic testing, clinicians should determine which lab did the DNA analysis. If it is not a government-certified lab (e.g. National Association of Testing Authorities [NATA] accredited), results should not be used in care as the analytic validity of the DNA testing cannot be relied on. If an accredited lab was used but the report does not base its guidance on peer-reviewed journal published data, it is unwise to use the information in prescribing. Such deliberations should be noted in the patient’s clinical file and explained to the patient.

The clinical science of psychotropic pharmacogenetics is still in early stages. The story will likely be much more complex than hepatic metabolizer status alone. For example, the role of blood–brain–barrier (BBB) genetics to optimal medication dosing is only just emerging (Singh, 2015). Environmental factors, drug–drug interactions, hepatic and renal impairments and compliance issues are all important for effective prescribing. Pharmacogenetics – at best – will be a helpful guide to optimal personalized prescribing, at worst, a distraction and unnecessary cost. Time will tell.

There is enormous potential in psychiatric pharmacogenetics. It is premature to ‘throw the baby out with the bathwater’. Over the next few years, RCT-level evidence will grow, shedding more clear light on the clinical value of such testing. In the meantime, it is important for clinicians to be sufficiently abreast of the area to have an informed discussion with patients seeking or presenting with such information.