Studies Bring Physicians Closer to Precision Prescribing of Antidepressants

Researchers are one step closer to the “Holy Grail” – helping clinicians determine which antidepressant medication is the best option for an individual patient, avoiding the common trial-and-error approach to prescribing. Using a novel translational medicine strategy, investigators at the University of Miami Miller School of Medicine searched for genetic variants to predict treatment response to certain antidepressant medications.

“Psychiatry has been plagued by not being able to predict treatment response for our disorders and, in particular, the biggest problem has been in depression,” said Charles B. Nemeroff, M.D., Ph.D., Leonard M. Miller Professor and Chair of the Department of Psychiatry and Behavioral Sciences at the Miller School of Medicine.

In a study published online December 28 in PLOS Biology, Nemeroff and colleagues at the Miller School, Stanford University and Emory University first compared mice that were either very good or very bad responders to specific antidepressants. They identified 259 genes expressed by these mice shared by humans. Next they analyzed genetics of human participants in previous trials, iSPOT-D and PReDICT, and were able to predict their known antidepressant responses with 76 percent accuracy.

A second study, published December 15 online in The American Journal of Psychiatry, adds a promising discovery to the quest for treatment response prediction. The variant rs28365143 of the corticotropin-releasing hormone binding protein (CRHBP) gene can predict escitalopram remission, response, and changes in depression symptom severity, particularly in people with two copies (homozygous). Importantly, the study assessed the same PReDICT patient population.

And that could be just the beginning.

“We have many FDA-approved treatments for depression, the SSRIs and the SNRTs, the tricyclic antidepressants, the MAO inhibitors. We also have psychotherapies — including cognitive behavioral therapy and electroconvulsive therapy, and other FDA approved treatments as well,” Nemeroff said.

The genetic marker treatment response idea is not unique to psychiatry either. “This has been very successful in oncology – breast cancer being a great example. We develop molecular markers of various cancers, and then based on those findings, we match the patient with the best treatment,” Nemeroff said.

Early studies demonstrated that the way a first-degree relative responded to a particular antidepressant was associated with response in a family member. This led researchers to pursue genetic drivers of treatment response. The next logical step, whole genome studies, was not as fruitful as researchers had hoped in identifying candidate gene markers for treatment response.

The fact that stress often precedes depression was a tip-off that genetics behind the “stress axis” of the brain could play a role. In the American Journal of Psychiatry paper, Nemeroff and colleagues evaluated the corticotropin-releasing hormone (CRH) neurotransmitter system in the brain. “CRH is the brain’s orchestra leader of the stress response,” he said.

CRH mediates cortisol release and endocrine changes associated with stress, as well as triggering autonomic, immune and behavioral responses. People in a depressed state tend to hyper-secrete CRH.

This research has important implications for other investigators joining the search for genetic markers for antidepressant therapy response. Using animal research to identify extreme responders and non-responders to specific therapies, then cross-analyzing candidate genes to humans could be a model for others and accelerate similar advances in this area.

“In my view, this [finding on escitalopram] coupled with a few more genetic variants or polymorphisms, will probably help us come up with a polygenic prediction score for treatment response in depression,” Nemeroff said. He added that he plans to continue the quest for additional markers.

The Miller School is well suited for this kind of research. “No department can be an expert in everything, but we have a large number of researchers and clinicians who specialize in mood disorders,” Nemeroff said. “We’re one of the largest inpatient psychiatry services in the United States. We are also a referral site for patients who have failed depression treatment nationwide and from outside the United States.”

Tags: depression, genetics, Nemeroff, treatment response