Pharmacogenomic (PGx) testing is an evidence-based strategy to optimize the selection and dosing of certain psychotropic medications. An individual’s genetics play a role in medication response through pharmacokinetic and pharmacodynamic mechanisms. The current evidence base of psychiatric PGx mainly focuses on the metabolism of psychotropics through the cytochrome P450 (CYP) system. PGx testing and decision support tools are not yet standardized, resulting in variations in interpretation and prescribing recommendations. Clinicians are encouraged to use PGx results as part of the clinical picture, in addition to the patient’s overall clinical profile, in determining a personalized treatment plan for their patients.
Key points
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Pharmacogenomic (PGx) testing has emerged as a companion strategy for informing the prescribing of psychotropic medications alongside already established strategies.
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PGx testing and – support tools are not yet standardized, resulting in variations in interpretation and prescribing recommendations among different commercially available tests.
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Clinicians should consider PGx results as part of the clinical picture, in addition to the patient’s overall clinical profile, in determining a personalized treatment plan for their patients.
| CAP | College of American Pathologists |
| CPIC | Clinical Pharmacogenetics Implementation Consortium |
| CPNDS | Canadian Pharmacogenomics Network for Drug Safety |
| CYP | Cytochrome P450 |
| DPWG | Dutch Pharmacogenetics Working Group |
| FDA | Food and Drug Administration |
| MDD | Major Depressive Disorder |
| PGx | Pharmacogenomic |
| RNPGx | French National Network of Pharmacogenetics |
Overview
Pharmacogenomic (PGx) testing is an evidence-based strategy to guide the selection and dosing of certain psychotropic medications across a person’s lifespan. An individual’s genetics play a role in medication response (eg, therapeutic effects or adverse effects) through pharmacokinetic and pharmacodynamic mechanisms. Pharmacokinetics is what the body does to the drug, that is, how medications move throughout the body, including absorption, distribution, metabolism, and excretion. The current evidence base of psychiatric PGx mainly focuses on the metabolism of psychotropics through the cytochrome P450 (CYP) system and includes enzymes such as CYP2D6, CYP2C19, CYP2C9, CYP2B6, and CYP3A4. Individuals with genotypes that confer increased metabolism of medications are referred to as rapid or ultrarapid metabolizers . In contrast, those with decreased metabolism of medications are intermediate or poor metabolizers , while individuals with unaltered metabolism of medications are referred to as normal or extensive metabolizers . Metabolizer status can then be used to guide dosing strategies for specific medications in which those enzymes are implicated. Pharmacodynamics relates to how the medication interacts with the body and can include biological structures such as transporters, receptors, and enzymes. Variations in these biological targets may determine the effect of the drug. Therefore, clinicians can use a patient’s genetic information in conjunction with other prescribing strategies, for example, patient/family history check, therapeutic drug monitoring, hepatic/renal function testing, and clinical practice guidelines to guide the safe and effective use of medications in a more personalized manner.
In this Clinics Review , we summarize what we now know about psychiatric PGx testing and how this information can be helpful for clinicians and their patients. The article also guides clinicians in understanding the clinical indications (eg, who and when to test) and implications (eg, how to interpret the results) of using PGx testing, choosing a laboratory for the testing, and key resources to understand the evidence base and guide their prescribing decisions.
Clinical implications
Current Evidence Base and State of Implementation in Psychiatry
For individuals with moderate to severe mental illness, psychotropics are commonly prescribed medications as either the sole form of treatment or in combination with psychotherapy. Unfortunately, randomized controlled trials have shown about one-third of individuals with major depressive disorder (MDD) do not achieve symptom remission when treated according to the sequenced treatment alternatives to relieve depression protocol. Finding suitable psychotropic medicines that work for an individual is clinically challenging and can take months to years, leading to nonadherence and treatment failure. This can devastate the affected person, their family, and society. As such, there is a need for additional prescribing strategies that can augment current treatment protocols and boost effective medication management of psychiatric disorders. PGx testing is one such strategy that uses genetic information as a surrogate marker of a person’s ability to process and react to drugs, which in turn helps in guiding medication selection and dosing. This can potentially reduce the number of trials needed to choose a suitable psychotropic medication. An extensive literature has been published on the association between common genetic variants and psychotropic drug response, and the most studied drugs are antidepressants and antipsychotics. , Pooled results from 13 clinical trials (10 of them are randomized controlled trials) in a recent meta-analysis showed adult patients receiving PGx-guided antidepressant treatment were 41% (95% confidence interval [CI]: 15%–74%) more likely to achieve symptom remission relative to their counterparts who received treatment as usual. A recent study that included patients with schizophrenia, MDD, and bipolar disorder, showed that PGx-guided treatment in psychiatry led to 34.1% less adverse drug reactions, 41.2% fewer hospitalizations, 40.5% fewer readmissions, and less duration of initial hospitalizations compared to patients who received treatment as usual . Likewise, another recent study suggests that implementing PGx testing to guide the treatment of depression could save $956 million over 20 years for the public health care system in British Columbia, a province in Canada. Accordingly, the PGx-guided approach has the potential to improve psychotropic drug effectiveness and tolerability, reducing the morbidity, mortality, and cost associated with current prescribing practices. This approach has gained significant momentum recently and is fueling the precision psychiatry movement. Although in light of some negative clinical trials and health economic studies of PGx-guided psychotropic treatment and an ongoing debate whether more blinded clinical trials might be needed, psychiatric PGx testing is being clinically implemented in more than 70 health care systems worldwide and more than 100 commercial laboratories worldwide (including direct-to-consumer tests) offer PGx testing. , , Despite that a widespread uptake of PGx testing has not occurred yet, clinical guidelines now often recommend to consider PGx testing in case of difficult-to-treat cases (eg, abnormal plasma levels at standard doses, high incidence of side effects, repeated nonresponse) (eg, Canadian Network for Mood and Anxiety Treatments [CANMAT] guideline; International Society of Psychiatric Genetics [ISPG] position statement). ,
Clinical Practice Guidelines
Approximately 35 psychotropic drugs (eg, antidepressants, antipsychotics, anticonvulsants) currently have PGx-based guidelines developed by professional groups (eg, Clinical Pharmacogenetics Implementation Consortium [CPIC]; Dutch Pharmacogenetics Working Group [DPWG]; Canadian Pharmacogenomics Network for Drug Safety [CPNDS]; and French National Network of Pharmacogenetics [RNPGx]) or mentioned in drug labeling by drug regulatory authorities (eg, US Food and Drug Administration [FDA], Health Canada) (reviewed in Bousman and colleagues 2023 ). More than half (63%) of these drugs have guidelines linked to CYP2C19 and/or CYP2D6 . Depending on the ethnic distribution of the population being tested, 37%–96% of people will carry at least 1 clinically actionable CYP2C19 genetic variant (ie, a variant for which a change in standard prescribing may be indicated) and 35%–73% will carry a CYP2D6 actionable variant.
The CPIC, DPWG, CPNDS, and RNPGx currently have prescribing guidelines for 13 antidepressants (amitriptyline, citalopram, clomipramine, desipramine, doxepin, escitalopram, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine), 7 antipsychotics (aripiprazole, brexpiprazole, haloperidol, pimozide, quetiapine, risperidone, zuclopenthixol), four anticonvulsants (carbamazepine, oxcarbazepine, phenytoin, fosphenytoin), and the ADHD medication – atomoxetine. Five pharmacokinetic genes ( CYP2D6, CYP2C19, CYP2C9, CYP2B6, CYP3A4 ) and 2 human leukocyte antigen genes ( HLA-A, HLA-B ) are implicated in these guidelines affecting 25 psychotropic drugs. While none of these guidelines recommend when and how to use or where to do PGx testing, they provide guidance on what to do when a patient’s genotype information is known. Based on the current evidence base, results of implementation and case studies, and relevant position/practice statements from professional societies, , , here we summarize how a clinician can choose and best use PGx testing for their patients ( Box 1 ). We have also provided a list of helpful resources with valuable clinical information about psychiatric PGx testing.
What are the drugs and genes that have PGx-based prescribing guidelines? a
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Seven genes ( CYP2D6 , CYP2C19 , CYP2C9 , CYP2B6 , CYP3A4 , HLA-A , HLA-B ).
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Fourteen antidepressants (amitriptyline, citalopram, clomipramine, desipramine, doxepin, escitalopram, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine, vortioxetine), 7 antipsychotics (aripiprazole, brexpiprazole, haloperidol, pimozide, quetiapine, risperidone, zuclopenthixol), 4 anticonvulsants (carbamazepine, oxcarbazepine, phenytoin, fosphenytoin), and the ADHD medication —atomoxetine.
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Who can benefit from PGx testing?
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Young people – Evidence is still emerging, but arguably the ideal population for implementation due to its cost-saving potential over one’s lifetime.
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Adults – Evidence is most robust for antidepressants (10 randomized-controlled trials have been published to date). Most testing occurs in this population.
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Older people – Same as adults but with fewer conducted studies with limited evidence.
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When should we consider ordering psychiatric PGx testing?
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Starting a medication for which a PGx-based guideline exists
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Unusual plasma levels at low or normal medication dose
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No response despite adherence to treatment
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Side effects at low doses or unusually high rates of side effects at normal doses
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Reluctance or low adherence to pharmacotherapy
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Complex comorbidities and polypharmacy
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Deprescribing, that is, tapering, stopping, discontinuing, or withdrawing drugs
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Where do you order psychiatric PGx testing?
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Health systems, commercial laboratories, or research studies.
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An ideal PGx testing laboratory should:
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Test gene-drug pairs with PGx guidelines available
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Provide transparent informaation about the gene(s) and allele(s) tested, ideally using AMP Tier 1 alleles as minimum
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Provide clinical recommendations based on published PGx guidelines
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Have the CAP, CLIA, or equivalent accreditations.
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Provide posttest results interpretation support
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How do you interpret PGx testing results?
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PGx guidelines (eg, CPIC, DPWG, CPNDS, RNPGx)
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Decision support tools
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Consult pharmacists or genetic counselors
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