Widespread pharmacogenomic testing in psychiatry needs a stronger evidence base

More research into the genomic factors influencing psychiatric medicines response is needed before widespread pharmacogenomic testing can be justified.
Illustration of a brain floating in space, with ribbons of text formed into a double helix structure breaking up as it tries to flow through, with a large question mark in the foreground

Pharmacists are expected to play a central role in optimising medicines affected by pharmacogenomics (PGx), which refers to the variable effects that a patient’s genome can have on their response to a medicine​[1]​. From service development and identifying when PGx is indicated, to patient counselling and the interpretation of PGx results, pharmacists are ideally placed to be involved in each stage of a clinical PGx service delivery​[2]​.

PGx is an area of growing interest. More than 99% of people in the UK are reported to have at least one genetic variant that may influence their response to a given medicine, while results from the ‘PREPARE’ trial have revealed that PGx-informed prescribing across a range of clinical specialities reduced adverse drug reactions (ADRs) by 30%​[3,4]​. The potential benefits of PGx testing are so significant that, in October 2018, the NHS genomic medicine service was launched to support the uptake of genomics in the NHS, including the use of genomic technology to improve medicines utilisation, aimed at increasing their efficacy and reducing the risk of ADRs​[5]​.

The genomics industry is reacting rapidly to these advancements in evidence, by developing the technical ability to adapt or tailor gene panels for specific patient groups — including for those undergoing psychiatric treatment. As more pharmacists become prescribers in the NHS, there is the potential that a pharmacist could tailor psychotropic dose titration based on PGx results, following initiation by a psychiatrist.

Nevertheless, there is still a range of barriers to improving treatment outcomes using PGx, including the cost of PGx testing, a lack of clear guidance on using PGx in psychiatry, conflicting efficacy data and unpredictable patient outcomes​[6]​.

Pharmacogenomics in mental health

There is substantial scope for developing PGx testing for those with mental illness. In a list of drugs with PGx biomarkers, produced by the US Food and Drug Administration (FDA), there are 36 psychotropic drugs with a PGx biomarker for either CYP2D6 or CYP2C19, where variation in these genes may have an impact on drug response​[7]​

Several systematic reviews on depression have found that treatment response is more likely following PGx-informed antidepressant prescribing

Evidence is growing regarding the use of PGx to reduce adverse effects associated with psychotropics and several systematic reviews on depression have found that treatment response is more likely following PGx-informed antidepressant prescribing​[8–12]​.

This is particularly important for those with treatment-resistant mental health conditions. An article published in 2019 estimated that between 20–50% of patients with schizophrenia globally have a treatment-resistant illness and up to 60% of patients will not respond to their first trial of treatment for depression​[13,14]​. In these cases, PGx testing might help us to understand the cause of treatment resistance. 

For example, CYP2D6 ultra-rapid metabolisers may be clearing their prescribed psychotropic to an extent that plasma levels are too low for the drug to exert its therapeutic effect​[15–17]​. Determining metaboliser status by using PGx testing may allow us to use higher doses of psychotropics or choose an alternative drug to avoid certain metabolic pathways. 

In the UK, PGx testing could benefit many people, yet the scale of implementing testing prior to psychotropic medicine use must not be underestimated. According to NHS data on medicines used in mental health, around 120 million psychotropic medicines were prescribed in 2022/2023. Some 86.3 million of these medicines were antidepressants prescribed for 8.6 million patients — a figure that has increased significantly since 2016​[18,19]​. Antipsychotic prescribing has also risen, with 13.4 million items prescribed in 2022/2023, an increase of 2.4 million items since 2015/2016​[18–20]​. These figures demonstrate that the widespread use of PGx testing in psychiatry is an ambitious goal and the resources necessary for this are significant.

There are several examples of successful implementation of PGx prescribing practices in mental health​[9,21]​. In 2018, there were 76 laboratories in the United States offering clinical PGx testing and this is likely to be greater in 2024​[22]​. Where a patient’s genetic ability to metabolise a medicine is known, manufacturers have started advising dosage adjustments, such as for atomoxetine and aripiprazole​[23,24]​.  

Global recommendations are emerging to guide PGx use in psychiatry, suggesting testing should be considered following multiple treatment failures because of side effects or inefficacy​[25]​. Several national organisations now advocate the use of pharmacogenomics in depression and schizophrenia; however, at time of publication, no such guidance existed in the UK​[26–28]​.  

Shortcomings in evidence

While this is an exciting step towards personalised treatment, there is debate about the significance of many drug–gene interactions and confusion over whether dose adjustments should be made​[17]​. Many psychotropics have multiple metabolic pathways; therefore, knowing a patient’s metaboliser status in one pathway may be of limited benefit. 

With time and a better understanding of the complexity of PGx influences in psychiatry, we will be able to effectively use genomic knowledge in clinical practice

For example, sertraline is primarily metabolised by the enzyme CYP2C19, but it can use up to five cytochrome P450 enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) for N-demethylation​[29]​. This makes it difficult to predict clinical outcomes, even with the knowledge of an individual’s metaboliser status in certain pathways. This may also explain why some of our expectations for adverse effects, with known pharmacogenomic profiles, do not always occur​[30]​. Additionally, there is added complexity when inhibitors or inducers of a metabolic enzyme are introduced, resulting in changes to the phenotype that the genotype cannot predict. This process, known as phenoconversion, is still poorly mapped out and yet its impact on medicines outcomes is significant​[31]​.

To develop more accurate predictions of patients’ responses to medicines, we also need to consider the wider scope of genomic influence on pharmacokinetics. For example, the absorption and transport of a medicine into and through the body, including movement across the blood–brain barrier, often relies on transporter proteins, such as P-glycoprotein, which are genetically predetermined. Modulation of ABCB1 gene expression, which encodes for P-glycoprotein, has been linked with multi-drug resistance in other areas of medicine​[32]​.

There is growing evidence relating to how genetic variation impacts on pharmacodynamic sites​[33]​. A drug’s mechanism of action or side effects may be influenced by genetically predetermined receptors at the site of action or other unintended sites​[34,35]​. Some treatment outcomes are believed to be polygenic, meaning there are multiple genes that may influence a response, such as antipsychotic-induced weight gain​[36]​.

There is no doubt that with a better understanding of the complexity of PGx influences in psychiatry, we will be able to effectively use genomic knowledge in clinical practice. However, at present, our confidence in being able to predict patient outcomes and truly personalise psychotropic treatment using pharmacogenomics is limited.

More research is vital

From a cost-effectiveness perspective, it is important that we know whether PGx tests can improve care. We must be confident that PGx results will influence our treatment choices and that the intervention will improve the likelihood for treatment success. 

We are at a crossroads. Access to PGx testing is increasing and we know there are drug–gene interactions relevant to psychiatry. With appropriate guidance we can start to envisage how we might use an evidence-based approach that integrates genomic test results to personalise treatment options. However, our confidence in being able to accurately predict psychiatric drug response using PGx knowledge is still limited. We may not be able to justify widespread pharmacogenomic testing in psychiatry at this point. But as further evidence emerges and the economic argument to use PGx testing is validated, we must start to consider how best to realise its potential benefits, such as within certain psychiatry specialities, treatment pathways, or complex clinical scenarios. 

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The Pharmaceutical Journal, PJ, January 2024, Vol 312, No 7981;312(7981)::DOI:10.1211/PJ.2024.1.210011

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