Right drug, right dose, right patient

Only 40 percent of patients treated with antidepressants experience complete remission of symptoms. Of the remaining 60 percent, many are unlikely to experience substantial improvement with the use of a different medication. There is a need to better understand "treatment resistance" and develop tools to reduce this rate of nonresponse, and by doing so, improve patients' lives.

At the Mayo Clinic Depression Center in Rochester, Minnesota, pharmacogenomic testing is often utilized to guide or better individualize treatment recommendations. The Depression Center sees about 600 patients each year who are resistant to treatment for depression or bipolar disorder. "The increasing recognition of genetic variation in the pharmacokinetics of how a drug is metabolized is starting to change our practice," says Mark A. Frye, M.D., a consultant and chair of the Department of Psychiatry and Psychology at Mayo Clinic's Minnesota campus. "We have a lot of exciting opportunities for better understanding the pharmacokinetics of the psychotropic drugs we prescribe, and to start to better understand the pharmacodynamics of therapeutic response."

Dr. Frye's remarks in the presentation "The Physician's Odyssey Applying Genomics to Practice: Right Drug, Right Dose, Right Patient" was part of a course at the 2014 Individualizing Medicine Conference, hosted by the Mayo Clinic Center for Individualized Medicine. The conference was aimed at explaining practical applications for integrating genomics and pharmacogenomics to individualized patient care.

Safety and efficacy

Pharmacogenomic testing can analyze a panel of genes in the cytochrome P450 family, whose enzymes metabolize more than 90 percent of medications prescribed to patients. The testing can pinpoint variant alleles, leading to poor metabolizing of a drug; or extra alleles, leading to ultrarapid metabolizing of a drug. Depending on whether the drug inhibits or induces cytochrome pathways, the result for patients can be toxicity or lack of efficacy.

Black box warnings from the Food and Drug Administration (FDA) about adverse drug effects highlight the value of pharmacogenomic testing. For example, a serious, potentially life-threatening rash, Stevens-Johnson syndrome, that can be caused by carbamazepine therapy is significantly more common in patients who have the human leukocyte antigen allele HLA-B*1502. This genetic variation is very common in patients of Asian and South Asian ancestry. Patients with this genetic variation who are treated with carbamazepine — which may be prescribed for bipolar disorder or epilepsy — should be tested before considering this treatment.

Another good example is the recent FDA recommendation to not prescribe citalopram beyond 20 mg daily for patients who are poor metabolizers at cytochrome P450 2C19 for concerns regarding cardiac QTc prolongation. "These types of regulatory changes are a good example of how our practice is evolving," Dr. Frye says.

This picture can get complicated for fluoxetine and paroxetine, as they are primarily metabolized through 2D6 and they themselves can inhibit this same pathway. These two pharmacokinetic parameters — genetic variation and drug-related inhibition of metabolism — are potentially clinically relevant. This relevance is particularly noteworthy when paroxetine and fluoxetine are used for obsessive-compulsive disorder (OCD) or related conditions that require higher selective serotonin reuptake inhibitor dosing. Dr. Frye notes: "In my practice, when I'm considering fluoxetine or paroxetine at high dosage for OCD or treatment-resistant depression, I am increasingly considering genotyping. Again, my practice is evolving."

Study of genomics and drug effectiveness and safety

Less understood is the impact of pharmacokinetic variations on response rates to medications or pharmacodynamic variation and adverse events. For example, the Mayo Clinic Bipolar Disorder Biobank, in collaboration with the Lindner Center of Hope (Cincinnati, Ohio) and the University of Minnesota, has identified, in a preliminary study, a genetic variation that may protect against antidepressant-induced mania and hypomania, which is always a clinical risk for patients who struggle with bipolar disorder.

To learn more, Mayo Clinic will conduct a clinical study for patients with bipolar disorder or major depression and evaluate the beneficial impact of genotyping. Study participants will have pharmacogenomic testing. Results for half of the patients will be presented to them and to their physicians before treatment is prescribed. Results for the other half won't be reported before treatment decisions are made, but will be given after the eight-week trial.

Dr. Frye hopes that comparing "guided" and "unguided" treatment decisions will answer such questions as:

  • Do mood outcomes improve if patients and physicians know about genomic variations?
  • Do patients have higher response rates to medication?
  • Do patients have higher levels of treatment adherence because of side effect burden that is less problematic?

"We're tracking very carefully what physicians do at every patient visit in this trial," Dr. Frye says. "We want to know whether treatment decisions are based on genotyping, clinical expertise, insurance concerns or some other sort of reason. We're asking patients the same questions. I think we're going to be able to understand how genotyping can impact clinical practice from the standpoint of both the clinician and the patient."

Dr. Frye expects that results of this study will shed light on whether pharmacogenomic testing should be part of regular clinical practice — before antidepressant therapy starts — to minimize the number of unsuccessful medication trials for an individual patient. "We want clinically relevant research to help transform the clinical practice for patients who struggle with treatment-resistant depression and bipolar disorder," says Dr. Frye.

For more information

Frye MA, et al. Clinical risk factors and serotonin transporter gene variants associated with antidepressant-induced mania. The Journal of Clinical Psychiatry. In press.