Genetics May Play Role in Response to Antidepressant Therapy

In a genome-wide association study examining the placebo and duloxetine response in major depressive disorder (MDD), researchers found an association near the gene STAC1 and placebo response but did not find a genome-wide response to duloxetine.

Malgorzata Maciukiewicz (pictured), PhD, of the Pharmacogenetic Research Clinic at the Campbell Family Mental Health Research Institute’s Center for Addiction and Mental Health in Toronto, led the study, which aimed “to apply a hypothesis-free, genome-wide approach to uncover novel genetic association with response to placebo treatment in comparison to duloxetine treatment.”

The authors noted that while antidepressants are recommended as first-line treatments, many patients do not show adequate improvement and do not achieve remission.

Although early research has produced some interesting findings, many have not been replicated. “Given the substantial genetic contribution to the vulnerability to depression (~37%) and antidepressant response (~42%), the field of pharmacogenomics has been challenged with uncovering genetic variants associated with response in an attempt to personalize and optimize treatment,” the authors wrote.

Duloxetine, often used as a first-line treatment for MDD, has been the subject of a few pharmacogenetic studies. These studies, among others, lead the researchers to think that genetic architecture dictates drug response in multiple ways. They noted that the polygenic risk score (PRS) is a promising approach to examining the role of multiple genetic variants at the same time in order to arrive at a weighted genetic risk score.

In addition to the possibility of a polygenic drug response, there was a notably high rate of placebo response in patients with MDD, which led to uncertainty about whether or not it was “disorder-specific or a common, inherent response phenotype observed across clinical diagnoses.”

Maciukiewicz and colleagues stated that evidence seems to suggest the existence of a genetic variation that contributes to the placebo response in multiple phenotypes.

Genome-wide genotyping was performed for on 391 participants, who were drawn from 3 separate, randomized controlled trials. All of the participants were of European ancestry and all had been diagnosed with MDD and treated with either duloxetine (n=186) or placebo (n=205) for more than 2 weeks.

“In the placebo-treated subsample, we detected genome-wide significant findings with the strongest association found in rs76767803,” reported the researchers. They also found that people with different genotypes responded in significantly different ways.

Those with the rs76767803 T/T responded worse to placebo than those with the C/C genotype, but not worse than those with the C/T genotype. There was also an association between ZNF385D variant rs4261893 and duloxetine response. The results of various other studies involving ZNF385D suggest that it may be involved with cognitive impairments and could be an important factor in antidepressant response.

There are some limitations to the current study that should be considered. The sample size limited the power of the study. There may also be confounders even though the researchers performed a multivariate linear regression in order to associate variables with response phenotypes.

The researchers concluded that “these findings add important information to develop predictive clinical models of placebo and duloxetine response and should serve as stimulus for further validation including replication and functional studies.”

The full study, “Genome-wide association studies of placebo and duloxetine response in major depressive disorder” was published online in The Pharmacogenomics Journal.

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