Genetic Marker Identifies Responders to New Antidepressant

This post was co-written by Eugene Rubin, MD, PhD, and Charles Zorumski, MD.

Liafensine, a new antidepressant, failed to help individuals with treatment-resistant depression (TRD) in initial clinical trials. However, investigators conducted additional analyses to determine whether there was a subgroup of individuals who did respond to the drug. Their results may lead to new approaches for identifying subgroups of patients who respond to psychotropic medications. This is an interesting and potentially important story.

Background

A substantial percentage of individuals with major depression do not respond adequately to standard treatments. An estimated 30 percent or more meet criteria for TRD, which is typically defined as having failed adequate trials of at least two antidepressant medications with different mechanisms of action. TRD is associated with substantial morbidity and mortality, and more effective treatment options for these patients are needed.

Liafensine was developed to treat TRD. It blocks reuptake of three neurotransmitters: serotonin, norepinephrine, and dopamine. However, in two large, carefully designed clinical trials, liafensine was found to be no more effective than placebo in treating patients with TRD.

Given the drug's three-pronged mechanism of action, the pharmaceutical company believed that liafensine should help at least some individuals with TRD. Researchers searched for a genetic marker in the trial participants that was associated with a better response to the antidepressant.

What is a genetic marker? The sequence of nucleic acids in our genes (DNA) provides instructions for the sequence of amino acids that make up the proteins in our bodies. A gene can have minor differences in nucleic acid sequence among different individuals that can ultimately translate into minor or major differences in protein composition—perhaps as minor as the substitution of one amino acid for another. These differences can affect protein structure and function. Additionally, many common differences occur in non-protein-coding regions of genes and alter how the genes are expressed and translated into proteins in the body and brain. This means that with certain genetic changes, more or less of a protein is made, but the protein itself is normal in structure. “Genetic markers” are typically changes in genes that are associated with certain traits, such as illnesses or responses to treatment.

The scientists studying liafensine discovered that a particular variation in a region of a gene called ANK3 correlated with better response to the medication. This variation is present in about 20 percent of individuals with TRD. As noted in the study, the product of this gene “is a scaffolding protein primarily expressed in the nervous system, plays an important role in neuronal signaling through modulation of cell membrane proteins, and is linked to psychiatric diseases, including depression” (Wang et al., 2025). The response to liafensine experienced by those with this genetic marker was not evident with several other antidepressants and, therefore, may correlate with specific actions of liafensine.

A Prospective Treatment Trial

Based on the possible importance of ANK3 as a treatment response predictor, the pharmaceutical company designed a randomized, double-blind, placebo-controlled study involving 189 individuals who fulfilled criteria for TRD and who had this genetic marker. The study was conducted at 58 sites in the U.S., Canada, and China. All participants had significant depressive symptoms as measured by standardized assessments and had failed to respond to at least two antidepressants. On average, they had not responded to three antidepressants and had been ill for 7.8 years.

Study participants were randomized into three groups in a 1:1:1 ratio: a group that received 1 mg liafensine, one that received 2 mg liafensine, and another that received placebo. The study drug and placebo were taken orally, once daily, for six weeks.

The primary outcome measure was the change in a well-known depression rating scale, the Montgomery-Åsberg Depression Rating Scale (MADRS); secondary outcome measures included the Clinical Global Impression-Severity (CGI-S) scale, the Clinical Global Impression-Improvement (CGI-I) scale, and the Sheehan Disability Scale (SDS). Safety was also carefully evaluated.

The two groups receiving liafensine demonstrated statistically significant improvement in both primary and secondary outcome measures when compared with those receiving placebo. This improvement was clinically meaningful. Improvement was evident by the one-week assessment and continued to increase over the six weeks of the trial. Thus, the possibility exists that benefits would continue to increase over time. Similar efficacy was observed for the 1 mg and 2 mg doses.

The medication was well-tolerated in terms of the safety profile.

The Importance of This Study

There are likely multiple mechanisms that contribute to TRD. Regardless of the specific underlying mechanism, the clinical manifestation results in potentially disabling symptoms that don’t respond to current treatments.

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This study demonstrates the existence of a subgroup of patients with TRD who respond to a specific pharmacologic treatment. This subgroup is defined by a specific genetic marker that appears to be present in a significant percentage of patients with TRD. This genetic marker can be detected with a blood test.

The authors note that there are cancer therapies that are only effective in individuals with certain genetic markers. The current study may be the first to demonstrate the possibility of utilizing a genetic test to identify individuals with TRD who will respond to a specific treatment. While the present results are intriguing, they will need to be replicated in larger well-designed clinical trials to determine their relevance to clinical practice and patient outcomes.

If replicated, these results have important implications for psychiatric therapeutics. In addition, such findings potentially provide lines of inquiry for investigating specific causes of treatment-resistant depression and an avenue to personalized medicine in psychiatry.