Posted July 2022.

When deciding to prescribe a medicine to alleviate depression, doctors and patients face a fraught process of trial and error. After the initial clinical evaluation, a doctor’s first choice of antidepressant has a 50–50 chance of working, which usually takes several weeks​​.

This fuzzy standard of care comes with real risks. Patients may have to manage side effects, such as weight gain or agitation while remaining uncertain about whether the drug will quell their depression symptoms. This may result in some patients discontinuing their prescription and distrusting their doctors. Worse still, when faced with the possibility of unremitting depression, it may even lead some patients to suicide.

“We know that it is an inexact process. Physicians admit that patients experience it, so we need more personalized prescribing strategies,” says Chad Bousman, a pharmacogenomics researcher at the University of Calgary, Canada.

Trial and Error

Fortunately, a range of antidepressant medicines is available, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants.

However, this variety compounds the difficulty of finding an effective medicine for a particular person, and it can take multiple tries before getting it right.

“If a patient bounces back and forth between drugs trying to get stabilized, they do worse later on,” says John Papastergiou, a pharmacist and pharmacy owner in Toronto, Canada.

“But when patients get on the right drugs faster, they do better down the line.”

Those who do not get relief face a long and challenging road. Long durations of unremitted depression are associated with a worse prognosis, including poorer clinical outcomes, greater side effects, higher medical costs, and decreased work productivity​​.

Pharmacogenomic information could help avoid these consequences by expediting these treatment choices. Individuals differ in their genetic makeup, which could translate into differences in how the body breaks down a drug or how it acts on the body (see Box). Knowing a person’s genotype across different genes related to drug metabolism or drug targets could optimize drug efficacy and avoid adverse effects. This possibility is being studied for various drugs and conditions, including studies focusing on depression.

Interest in pharmacogenomic testing may be outpacing the evidence base. Several commercially available pharmacogenomic tests differ in the genetic variants they evaluate. Meanwhile, researchers are still uncovering gene-drug interactions and establishing standards for those worth attention.

Some randomized clinical trials of pharmacogenomic tests show some promise for prescribing in depression, and more extensive trials are on the way. At the same time, healthcare systems need to put into place infrastructure that will allow pharmacogenomic testing to become a routine part of prescribing — something pharmacists will be instrumental in.

The trick will be to ride the enthusiasm for pharmacogenomics while adhering to rigorous standards.

“This is just the beginning, and so it’s exciting,” says Bousman, who is also a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC), where he is involved in creating practice guidelines about which pharmacogenomic results should guide antidepressant prescribing.

“But we need to keep these commercial companies [that manufacture and market the tests] from imploding the whole field because they want to implement pharmacogenomics faster than it should be,” he warns.

Mixed Evidence

Current pharmacogenomic tests detect genetic variation within a limited panel of genes, including cytochrome P450 (CYP) enzymes and a handful of others. Unlike a whole-genome sequence, the restricted search gives results quickly and cheaply. Tests differ in the details of which variants are included — some tests, such as GeneSight, focus on genetic variation relevant to psychiatric drugs. In contrast, others, such as Pill check, are generalists examining genetic variation related to a broad range of medicines for various conditions.

The variability in allele frequencies across different populations, combined with the other genes included in the different panels, can make the usefulness of pharmacogenomic testing tricky to pin down.

Randomized clinical trials are making headway into this, but the current evidence for antidepressant prescribing shows mixed results. In 2019, results from a 1,167-participant trial — GUIDED (‘Genomics used to improve depression decisions’) — in the United States showed that patients who had inadequately responded to previous medicines showed a higher rate of symptom improvement and remission after pharmacogenomic-guided prescribing​. Results from a smaller trial in Canada, published in 2022, found similar benefits but fell short of statistical significance​.

To make sense of the available trials, Bousman published a meta-analysis in 2019, combining results from five randomized clinical trials, including the GUIDED trial. This found that those receiving pharmacogenomic-guided prescriptions were 71% more likely to have remission of their symptoms than those receiving standard care without pharmacogenomic testing​​.

“The trial data are leaning toward this being a useful tool,” says Bousman. He notes two potential sources of bias: companies making the panels also funded the studies, and trial participants were predominate of European genetic background, which makes the generalisability of the findings uncertain.

More extensive studies may help address these issues. In the EU, a multi-center study across seven countries — PREPARE (‘PREemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions’) — examines whether pharmacogenomic testing of 44 variants in 12 genes reduces adverse drug reactions in nearly 7,000 study participants taking a wide range of drugs, including antidepressants​​. In the United States, a prominent trial — PRIME Care — is focused on pharmacogenomic testing for antidepressant prescribing in 2,000 veterans with depression​​.

Pharmacodynamic Search

Much less is known about genetic variation that affects drug pharmacodynamics — how the drug exerts its effect on the body. Though current pharmacogenomic tests examine candidate genes suspected to be involved in drug action, such as SLC6A4 or HTR2A — which encode a serotonin transporter and a serotonin receptor, respectively — these and other genes’ relationships to drug response are unproven.

“I think it is 100% marketing when those genes are included [in the panels],” Bousman says. “It has nothing to do with science.”

However, the search space for these genes is vast. Instead of guessing which genes might be involved, the Psychiatric Genomics Consortium (PGC) has opted for an unbiased scan of the entire genome to look for common variants that make a difference in antidepressant response. The first crack at this did not detect any genome-wide specific associations with treatment response in more than 5,000 participants. Still, it did find that part of the treatment response was indeed heritable​.

“We need to have a much broader view that engages with the more complex and undiscovered question of how the body responds to a given drug,” says Andrew McIntosh, a psychiatrist at the University of Edinburgh, who also co-chairs the PGC’s Major Depressive Disorder Working Group.

Future studies must be much more significant to detect a meaningful signal. The PGC — already more than 200 investigators strong — will need to incorporate data from others willing to share.

In the meantime, McIntosh says that he would not advocate using current CYP gene-dominated panels to guide his drug decisions for his patients with depression. Standard practice involves starting a person at a low drug dose and carefully monitoring them for side effects and efficacy, which can indirectly reveal whether someone unusually metabolizes the drug.

“It’s kind of incorporating the patient’s genotype, but not explicitly,” he says.

“Genotyping for side effect risk or treatment response may, one day, provide meaningful information,” he adds.

“I think the evidence isn’t yet compelling, but it’s important that people conduct these studies.”

Real-World Preparation

The evidence is already sufficient for some health care insurers. In particular, results from a 2021 study led by Papastergiou prompted Green Shield Canada, which funded the study, to pay for genetic tests. Operated out of three community pharmacies in Toronto, Canada, the study recruited more than 200 outpatients with depression or anxiety, administered a Pillcheck test to a randomized subset, and then used validated questionnaires to measure symptoms of depression or anxiety at baseline and at different follow-up times. By six months, those who had received pharmacogenomic testing reported more symptom relief than those who did not​.

“This was a real-world study that showed the value of this type of testing,” says Papastergiou.

It also showed that pharmacists could be instrumental in implementing pharmacogenomics: pharmacists conducted the tests, then conveyed the results to prescribers, who made the final decisions.

“Pharmacists can play a big role here because they understand drugs, how they work, and because they see the patient regularly,” he adds.

Even as insurers come on board, experts work to establish which gene-drug interactions are actionable. The Pharmacogenomics Knowledgebase is an online database that lists gene-drug pairs with sufficient evidence, as determined by the CPIC, the Dutch Pharmacogenetics Working Group, and the Canadian Pharmacogenomics Network for Drug Safety. This kind of database helps users interpret the results returned from tests​.

“In the UK, every single hospital, GP practice, and community pharmacy has a completely separate [prescribing] system,” says Victoria Rollinson, a clinical pharmacist at Cheshire and Wirral Partnership NHS Foundation Trust. She recruited patients at the University of Liverpool for the PREPARE study.

The NHS Genomic Medicine Service is currently developing infrastructure plans for pharmacogenomic testing​​. Decisions will need to be made about who to genotype, how it will be done, where it will be done, and how to return the results. Ideally, a person’s test results could be kept in an electronic health record, with potential drug-gene interactions flagged by a computer. This would have to be updated as new evidence comes in.

Despite these challenges, interest is high among patients and clinicians in mental health settings, says Adam Jameson, a mental health pharmacist and researcher at the Bradford District Care NHS Foundation Trust.

In 2021, Jameson and colleagues published a review of studies regarding attitudes towards pharmacogenomic testing for mental health​. While the review identified barriers such as the cost of testing or lack of infrastructure as challenges to its implementation in mental healthcare settings, it also held up enabling factors, such as shared interest among patients and clinicians for pharmacogenetic testing and an expectation that it would become more routine in the future.

Some clinicians also suggested the benefits of pharmacogenomic-guided prescribing could extend beyond a drug’s action in the brain if it improved the rapport between clinicians and patients.

For depression, a solid patient-clinician relationship is not simply nice to have, but it can be fundamental to a person regaining their mental health.

“This could be very important because the relationship between the patient and the prescriber is key in psychiatry,” Jameson says.

Original Post: https://pharmaceutical-journal.com/article/feature/personalising-antidepressants-should-we-be-genetic-testing