Pharmacogenomics Can Better Inform Treatment

“Pharmacogenomics can help create a new model of psychiatric practice that is genetically informed, neurobiologically empowered, and data oriented,” Stephen Stahl, M.D., Ph.D., told a packed room at APA’s Annual Meeting in Atlanta. Stahl, who is a professor of psychiatry at the University of California, San Diego, was the recipient of the 2016 David A. Mrazek Memorial Award, which honors the contributions of clinicians in the field of pharmacogenomics.

David Hathcox

Genomics is not a panacea but can guide new ways of thinking about diagnosis and treatment, said Stahl.

“Genes don’t code for psychiatric disorders or symptoms, just for proteins and epigenetic regulators,” he said, noting that about 20 single-nucleotide polymorphisms have been studied in depression, but each has only a small effect. “We will have to look at a portfolio of genes, not just one, to better diagnose and treat patients.”

Still, by studying genetic pathways, researchers can begin to uncover links between genes, circuits, and behavior, which may underlie variations in treatment responses.

For instance, increasing evidence suggests genetic tests that screen for pharmacokinetic metabolizing genes in the Cytochrome P450 system may help to better tailor antidepressant therapy to individual patients.

Medication doses used in clinical trials are normalized to white, male, extensive metabolizers, so a person who appears not to respond simply may be a different kind of patient, he said.

On one hand, patients with unexpectedly high serum drug levels or adverse effects may have poor P450 metabolism, while ultra-rapid metabolizers may have lower serum levels and worse efficacy and be labeled “treatment resistant” as a result.

“Patients with treatment-resistant depression who are fast metabolizers have low drug levels and exhibit poor therapeutic effects are probably not noncompliant but may require very high oral dosing or alternate routes of administration, such as intravenous or transdermal administration, to bypass metabolism in the liver,” Stahl explained.

Conversely, slow metabolizers may need lower dosage levels to tolerate medication and reduce side effects, he said. “It’s not what you take in your mouth, it’s what gets into your brain.”

Pharmacogenomic tests don’t tell which drugs will work or which will be toxic, but testing adds to the evidence the psychiatrist must weigh in deciding a course of treatment, he said.

“I look for equipoise, the balance of the evidence,” he said. Tests add more or less evidence to a decision on whether a drug should or shouldn’t be used.

When faced with a patient who is not responding to treatment and for whom there is no guidance from randomized, controlled clinical trials, Stahl suggested clinicians consider using a step-by-step approach, beginning with exhausting all existing evidence-based solutions.

“Then take a new history, including treatment responses, and find a new informant, if possible,” he said. “Reconsider the original diagnosis. Perhaps treatment-resistant depression could be bipolar disorder with mixed features, for example.”

After collecting new data, rebalance the evidence by combining the insights of neurobiology with genomics to come up with alternative treatment combinations, he suggested.

“Genetic testing is a clinical tool that is still in its infancy but has the potential right now to inform clinical decisions in some cases, especially for patients who don’t respond to or tolerate drugs as expected,” he concluded. “Psychiatry is the area of medicine that is the most exciting combination of art and science.” ■