Despite the prevalence of psychiatric disorders—more than one in five U.S. adults live with a mental illness, according to the CDC (bit.ly/4b0wW3w)—treating these conditions remains a complicated and often frustrating undertaking for healthcare providers and patients alike. Although myriad drugs are available for conditions such as depression and schizophrenia, treatment failure rates remain stubbornly high, with little guidance to help clinicians choose a particular medication and dose for a given patient.
Genetic testing may offer a partial solution to these challenges.
Pharmacogenomics (PGx) tests identify genetic variants that influence how a person metabolizes drugs (bit.ly/4aUpkQj-PPN). “There is great promise in using pharmacogenomics in the field of psychiatry,” said Caroline Carney, MD, the chief medical officer of Magellan Health, who is also a practicing psychiatrist.
In her work as the psychiatric medical director of a federally qualified health center, she has witnessed several cases in which PGx testing has altered the course of a patient’s struggle with mental illness. On one “remarkable” occasion, she recollected, a patient endured severe psychosis that persisted after trying multiple antipsychotics. PGx testing revealed that the patient would likely only have a positive response to clozapine. “The patient took it, and in that Lazarus-like moment, their life completely changed,” Dr. Carney said. “They now live independently and have a life that otherwise wouldn’t have had if we had continued down the trial-and-error path that another clinic had started.”
This victory is somewhat bittersweet. “Had the patient been able to have that test earlier in their treatment, years of suffering could have been avoided,” Dr. Carney said. Nonetheless, the experience was enlightening, demonstrating the power of PGx. “Given the current cost [of testing], it may not be indicated on a population health level,” she said. However, “for many, especially those with early serious mental illness, we need to get the best treatment at the onset instead of losing precious months or years to suffering that impacts individuals, their supports and the system of care.”
PGx (also known as pharmacogenetics) is still an emerging discipline and should not be the sole driver of prescribing decisions, Dr. Carney and other experts emphasized. However, PGx has the potential to improve patients’ quality of life and lead to cost savings by helping clinicians tailor psychiatric medication prescribing—a process in which pharmacists will be vital players.
An Unmet Need
Mental health disorders are even more pervasive among U.S. adolescents than adults, occurring in nearly half of those ages 13 to 18 years, according to 2021 data. Among adolescents and adults with mental illnesses, respectively, approximately 22.2% and 24.4% faced serious impairment (bit.ly/3JzLlbe-NIH). Yet roughly half of patients do not achieve satisfactory clinical outcomes with common antidepressant and antipsychotic medications during initial treatment, and discontinuation rates range from 30% to 70% during the first year of therapy, researchers noted in an article outlining how PGx can support mental health medication therapy management (J Am Coll Clin Pharm 2024;7[2]:160-170).
The trial-and-error approach that results from these treatment failures can be protracted, said lead author Jeffrey R. Bishop, PharmD, BCPP, FCCP, a professor in the Department of Experimental and Clinical Pharmacology at the University of Minnesota College of Pharmacy, in Minneapolis. It may take four to six weeks to establish the ineffectiveness of one psychiatric medication before switching to a different one.
Dr. Carney agreed that these drawn-out periods can be a problem. “If … my patient gets frustrated and doesn’t think that anything works, or is burdened with side effects, they’re less likely to take treatment that could lead to a positive outcome as opposed to a potentially mortal outcome,” she said. Using PGx to guide earlier and more successful treatment for these disorders could change the long-term trajectory of an illness and reduce the risk for adverse outcomes such as suicide, she added.
As for which PGx genes are most frequently relevant to psychiatry, the “MVPs” are CYP2C19 and CYP2D6 because they affect the metabolism of a variety of psychotropic drugs, said Adrijana Kekic, PharmD, a pharmacogenomics clinical specialist and an associate program director of education for outpatient pharmacy at Mayo Clinic in Arizona. These drugs include antipsychotics, selective serotonin reuptake inhibitors (SSRIs), stimulants, norepinephrine dopamine reuptake inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors. The medications treat various conditions such as depression, anxiety, schizophrenia, bipolar disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder (ADHD) and post-traumatic stress disorder, Dr. Carney said.
Due to variants in these and other so-called pharmacogenes, a person might break down a medication too rapidly or too slowly. For example, SSRIs can cause gastrointestinal issues, insomnia, anxiety and headaches. If someone is a poor metabolizer of SSRIs, Dr. Kekic explained, an antidepressant that is correctly prescribed based on their age, weight and other factors may nonetheless accumulate in their bodies and lead to more pronounced side effects. Conversely, a rapid metabolizer might clear the drug from their system too quickly, resulting in a suboptimal clinical response.
“Knowing that a patient is a CYP2D6 or CYP2C19 poor metabolizer could help clinicians either consider other antidepressants or antipsychotics not impacted by CYP2D6 or CYP2C19 genetics, respectively, or adjust their dosing and titration strategies to consider this reduced metabolic capacity,” Dr. Bishop said. “There are also hypersensitivity risk genes related to the human leukocyte antigen (HLA-A and HLA-B) that carry genetic predisposition to severe and potentially deadly hypersensitivity reactions like Stevens-Johnson syndrome in patients taking [the anticonvulsants] carbamazepine or oxcarbazepine. These genetic variations are rare, but if they are identified in a patient, they should avoid taking these medications.”
Published studies underscore the clinical efficacy and cost benefits of PGx-guided therapy (see sidebar below). Still, Dr. Carney called for more research “looking at total cost of care, but also patient satisfaction and patient-reported outcomes.” An improved outcome could mean fewer missed days of work or more stable relationships. “We have to consider the holistic picture, not just the cost of a generic [psychiatric] medication against a test,” she said.
The Clinical and Cost Benefits of Adding PGx to MDD Management
Although psychiatry is still relatively new territory for PGx, some researchers have investigated the clinical and cost benefits that accrue when using genetic testing to guide prescribing for conditions such as major depressive disorder (MDD). Consider these examples:
Machine learning. Dr. Kekic’s Mayo Clinic colleagues reported that using a machine learning algorithm that considered genomic data—along with plasma metabolomic and clinical measures such as symptom severity—predicted treatment response of patients with MDD who received citalopram or escitalopram with over 75% accuracy (Transl Psychiatry 2021;11[1]:513; bit.ly/3wPew7o-PPN).
Boosting antidepressants. In one meta-analysis, researchers calculated that patients who received PGx-guided antidepressant therapy in clinical trials were 41% (95% CI, 1.15-1.74; P=0.001) more likely to achieve MDD symptom remission than those given typical care (Clin Pharmacol Ther 2022;112[6]:1303-1317). Another meta-analysis of randomized trials of PGx testing efficacy in MDD treatment concluded that PGx-guided care significantly increased remission and response versus typical treatment, although high-quality studies that measure long-term patient outcomes are needed to “help fill the current knowledge gap” (Psychiatry Res 2023:321:115102).
Nearly $1 billion saved. Researchers in Vancouver, British Columbia, drew on these data to inform their exploration of the cost-effectiveness of PGx. They estimated that implementing PGx testing for a representative cohort of MDD patients over 20 years would result in 37% fewer patients transitioning to treatment-resistant depression, saving Canada’s healthcare system the equivalent of roughly $822 million USD (or $4,238 USD per patient) (CMAJ 2023;195[44]:E1499-E1508).
The value of CPIC-guided therapy. A systematic review of the cost-effectiveness of PGx testing for drugs with CPIC (Clinical Pharmacogenetics Implementation Consortium) guidelines evaluated 108 studies concerning 39 drugs and found that 71% (including nine of 11 antidepressant-focused studies) demonstrated that PGx testing was cost-effective or cost-saving (Clin Pharmacol Ther 2022;112[6]:1318-1328).
Mayo Clinic plans to use preemptive PGx testing for certain drug–gene pairs, Dr. Kekic said, so when a physician prescribes a particular medication, the electronic health record (EHR) will alert them if that drug has known pharmacogenomic associations or if the patient has potentially relevant genetic test results on file. During a 2022 feasibility study, she and her colleagues sequenced pharmacogenes from 10,077 Mayo Clinic Biobank volunteers, focusing on variants of 13 genes that affected 21 drug–gene pairs (Genet Med 2022; 24[5]:1062-1072). The genomes of 79% of participants carried at least three clinically actionable variants; these results were sent preemptively to the Mayo EHR.
Among the affected drugs were carbamazepine; the SNRI venlafaxine; and the SSRIs citalopram, escitalopram, fluvoxamine, fluoxetine and paroxetine.
On the whole, however, Dr. Kekic said PGx testing is not yet widespread within psychiatry. “The implementation stages and efforts vary greatly,” she noted. “It is a really eclectic arena at the moment.” (For additional testing challenges, see sidebar below.)
New Opportunities for Pharmacists
Pharmacists have a “huge opportunity” to be involved in implementing PGx testing for psychiatric drugs given their medication knowledge, said Dr. Bishop, who coauthored CPIC (Clinical Pharmacogenetics Implementation Consortium) gene/drug clinical practice guidelines for antidepressants and the ADHD medication atomoxetine, with an antipsychotic guideline under development. He said CPIC guidelines and, in some cases, FDA labeling offer a road map for incorporating PGx information into drug selection or dosing decisions.
Dr. Bishop envisions pharmacists integrating PGx testing into comprehensive medication management assessments. Pharmacists can also identify when PGx test results ordered to probe psychiatric drug–gene interactions might be relevant to a patient’s other medications. For example, a CYP2C19 poor metabolizer would accumulate the SSRIs citalopram and sertraline rapidly at standard doses. But this gene is also necessary for converting the antiplatelet medication clopidogrel to its active metabolite. “A CYP2C19 poor metabolizer will not effectively achieve this conversion, [placing] a patient at risk for adverse cardiovascular outcomes,” Dr. Bishop said.
“There’s also an opportunity with the way that pharmacy practice is set up [for] the patient conversation, the counseling, the longitudinal contact that allows for [patient] education,” he added.
He recalled a patient with treatment-resistant depression that defied management with numerous medications, and who had experienced serious central nervous system–related side effects. PGx testing revealed that he happened to be a poor metabolizer for every medication he’d tried previously. The patient’s treatment plan was adjusted, and his depression finally began to improve. “It was like the clouds opening up,” Dr. Bishop said. “The description of how much relief was felt was very, very profound.”
However, he cautioned that PGx test results can yield mixed emotions. For patients who have tried multiple drugs to manage their mental illness, testing might bring relief. “They get sort of an aha moment when they get a test and find that there’s a genetic confounder that was in the background, maybe contributing to that journey,” Dr. Bishop said. On other occasions, patients may be disappointed when PGx test results do not reveal a simple answer to their medication difficulties. “Sometimes people have expectations, and if you don’t talk about what the test can tell you and what it doesn’t up front, it creates some challenges to explaining … the results down the road,” he noted.
‘Go Deeper’
Pharmacists can educate not only patients, but also physicians about PGx and different drug–gene associations, Dr. Kekic said. Pharmacists can also work with information technology teams to ensure that PGx data are seamlessly integrated into the EHR.
“My advice is to get engaged,” she said. “Pharmacogenomics is about genes that give instructions that make proteins that are involved in pharmacology, and pharmacists are the most trained in pharmacology of all of the healthcare professionals.” PGx offers a chance for pharmacists to “go deeper with your understanding of pharmacology,” she suggested. “You already know about pharmacokinetics, but pharmacogenomics can give you that intimate detail, intimate insight … so then you can help that person and [their] physician to really personalize and tailor their treatments.”
PGx is a continuously expanding field, but resources such as CPIC and PharmGKB can help pharmacists stay afloat amid the deluge of new evidence and updated guidelines. “You really need to be kind of keeping a pulse on what is new and coming,” Dr. Kekic said.
In their open-access paper, Dr. Bishop and his co-authors offered clinical pearls to help pharmacists apply PGx to psychiatric practice. They include:
- evaluating PGx test results with a patient’s mental health needs and goals for medication management in mind;
- setting patient expectations that PGx will not vanquish all medication problems; and
- recognizing that evidence levels supporting clinical utility of different PGx markers vary, necessitating careful review of test results.
For mental health pharmacotherapy management, Dr. Bishop said, it is particularly important to use PGx test results to enhance an evidence-based approach to dosing or drug selection decisions. PGx should “not just be used as a stand-alone tool to select medications,” Dr. Bishop said. “The patient context is super important.”
In some cases, Dr. Kekic said, she recommended medications to patients that PGx testing indicates they will metabolize normally, “and sure enough, they had excellent benefits from those medications.” But not all patients will have this result. “How you metabolize a drug is only one part of the story,” Dr. Kekic said.
A patient’s experience with a given drug will be affected by numerous other variables, Dr. Carney agreed, such as sex, height, weight, diet and other medications. It’s also important for clinicians to consider social determinants of health; if a patient does not have access to transportation or childcare, they may never return to pick up a drug that PGx testing suggested they would tolerate well.
“The medication is incredibly important, but it’s not the only factor that needs to be considered in the treatment of behavioral health conditions. Psychosocial interventions and psychotherapy should be considered for the best outcome,” Dr. Carney said. “PGx testing will never fully predict what outcome will be achieved because of the complexity of the diagnostic process, co-occurring conditions and social factors. Unfortunately, there is no magic bullet in behavioral health, but using evidence-based practices and measurement-informed care, we can successfully treat most people.”
Still, she views PGx as being on the cusp of having a major impact on psychiatric treatment. “It’s a rapidly evolving field,” Dr. Carney said. “Just because we haven’t fully figured it out, it doesn’t mean that there isn’t a there, there.”
Dr. Bishop reported a consultantship to OptumRx. Dr. Carney reported no relevant financial disclosures. Dr. Kekic is a field expert for ASHP and an associate editor of the High Yield Medication Review.
Part 3:
PGx hones chemotherapy and supportive care.
This article is from the July 2024 print issue.