Pharmacogenetics in Psychiatry: Misconceptions, Challenges, and Successes

Melissa P. DelBello, MD, MS, and Olivia Bentley, PharmD, AAHIVP, CFts

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Pharmacogenetics has the potential to radically change the practice of psychiatry. Since the advent of psychopharmacology, psychiatrists and pharmacists have struggled with a set of baffling treatment outcomes: so-called idiosyncratic drug reactions, drug sensitivities, or, conversely, patients who require high doses of medication for a modest clinical benefit. As the science of pharmacogenetics has emerged over the past several years, professionals are now beginning to understand why some people in the real world react to medications far differently than clinical trial data would suggest.Those who work in this field can see a future in which psychotropics are tailored to the patient; indeed, many findings can be applied in clinical practice right now. Other pharmacogenetics applications are not quite ready for standard care, and patients with mental health disorders may be filling in our knowledge gaps with misinformation. Pharmacists can play a key role in helping patients navigate this new world of psychopharmacogenetic testing.It is encouraging that patients are increasingly aware of pharmacogenetics. They proudly proffer their red light/yellow light/green light reports to their psychiatrists and pharmacists. Unfortunately, some patients who make use of these reports are being provided too little education along with the results, leading to unrealistic expectations or misperceptions. This result is troublesome.It is common for these patients to believe that pharmacogenetics testing can identify the perfect drug for them—a truly tailored treatment. The future may indeed hold that promise, but that is not the current reality. Psychiatrists, pharmacists, and patients can learn a great deal from pharmacogenetics testing; however, that report will not magically reveal the ideal medicine for a specific patient. It is important that psychiatrists and pharmacists help patients understand their results, especially when the results come from direct-to-consumer pharmacogenetic testing. Professionals can use test results as an opening to educate patients, and to clarify misconceptions.The red, yellow, and green light reports may seem like a simple way to describe pharmacogenetics results, but many patients seem to apply their own interpretation, especially in the absence of professional counseling and education. This can interfere with quality mental health care.Without proper counseling, many patients believe that “green” medications are perfectly safe, "yellow" medications should be used only under dire circumstances, and "red" medications should be avoided at all costs. In some circumstances, a green medication may be a terrible choice for a specific patient, a yellow medication may be completely innocuous, and a red medication may be helpful, as long as the patient is given a very low dose or is willing to undergo periodic blood monitoring. Quite frequently, patients will fail to achieve a satisfactory clinical response from their first, second, or third medication trial. However, patients often are reluctant or even refuse to consider a “red” medicine because of misconceptions about what it means. This can shut the door to a potentially beneficial medication, perhaps the only one that will help the patient.The stoplight reporting is not inherently flawed. In fact, it can be a useful starting point to discuss these issues with patients. However, the red/yellow/green reporting schema is not as straightforward as it may seem to patients (or some professionals). As with other laboratory results, imaging studies, or professional consultations, the information provided should be considered in context, and by a professional. Because pharmacists have deep training and expertise in pharmacokinetics, pharmacodynamics, and pharmacogenetics, they are in the ideal position to help patients look past the simple stoplight color coding and truly customize the details provided in the reports. Moreover, educating patients may improve patient adherence, which is key to success in psychiatric treatment.While fully personalized psychiatry is still in the future, many current applications exist for pharmacogenetics in psychiatry practice. One example that arises quite commonly is in the management of patients who require antipsychotic medications, particularly aripiprazole and risperidone. People who are poor cytochrome P450 2D6 (CYP2D6) metabolizers will typically have substantial increases in circulating drug concentrations and area under the curve (AUC) on these medications. Pharmacogenetic testing of CYP2D6 can help determine if the initial and target dosage of certain antipsychotics should be lowered (eg, halved).(Aripiprazole and risperidone are also excellent examples of potentially “red” medications that can be safely and effectively dose adjusted.)Consider the common situation of a 13-year-old boy diagnosed with ADHD and bipolar disorder. The treatment plan included psychostimulants and a second-generation antipsychotic, in this case, aripiprazole. The standard starting dose is 5 mg orally daily. After a week on aripiprazole, the boy experienced terrible nausea, akathisia, and sedation. On the other hand, his manic symptoms improved. Of course, when he refuses to take the medication because of the adverse effects (AEs), the manic symptoms return. Pharmacogenetics testing later revealed that the boy was a slow CYP2D6 metabolizer. The patient eventually agreed to take the medication at a dose of 2.5 mg. At the lower dose, the boy’s symptoms were well managed by the medication and it was well tolerated.Pharmacogenetics testing may also assist in an opposite circumstance, such as when a patient is an ultra-rapid metabolizer, breaking down the active molecule at a higher-than-normal rate, making for lower-than-expected blood levels of the drug. Standard prescribed dosages, even at the high end of the recommended dosage range, may yield sub-therapeutic drug levels in ultra-rapid metabolizers.Pharmacogenetics testing also informs antidepressant use. Tricyclic antidepressants (TCAs), for example, fell out of favor as selective serotonin reuptake inhibitors (SSRIs) gained prominence. The latter drug class generally has fewer serious AEs than the former. However, TCAs still play an important role in certain conditions, for certain patients. Pharmacogenetics testing can provide an explanation for why some people experience certain AEs while taking TCAs (eg, anticholinergic effects), and this information can be used to guide management decisions.Incidentally, we are tantalizingly close to being able to use polymorphisms in serotonin transporters and receptors to determine whether patients are more or less likely to respond to a specific antidepressants class.These are just 2 examples of pharmacogenetic testing in modern clinical psychiatry. These results can also help guide the use of stimulants, mood stabilizers, and anxiolytics.When pharmacogenetics testing is performed judiciously and interpreted thoughtfully, it can be a powerful tool to maximize treatment response and tolerability of medications commonly used to treat mental health disorders. Some pharmacogenetic results can be applied in psychiatric practice today, and many more will become the standard of care by the end of this decade. The pharmacist is ideally suited to help patients and clinicians navigate this emerging and important field so that findings are correctly interpreted and put into a clinical context. As pharmacists perform medication therapy management or other clinical consultations with a patient, they may be instrumental in identifying and educating patients who can benefit from pharmacogenetic testing. The overall outcome is greater treatment efficacy, fewer AEs and drug interactions, and improved medication adherence.Dr. DelBello received funding for research from NIMH, NIDDK, PCORI, Eli Lilly, Assurex Health, Pfizer, Johnson and Johnson, Otsuka, Sunovion, Lundbeck, and Shire, and has served as a consultant for Sunovion, Neuronetics, Pfizer, Lundbeck, Takeda, and Supernus.Dr. Olivia Santoso Bentley is a leader of the Pharmacogenetic Center of Excellence and clinical pharmacist consultant to the Rxight Pharmacogenetic Program.Melissa P. DelBello, MD, MS, is a professor of psychiatry and pediatrics, and the Dr. Stanley and Mickey Kaplan Professor and Chair of the Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine. Olivia Bentley, PharmD, AAHIVP, CFts, has advanced training and certification in pharmacogenetics and precision medicine.