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NIMH Team IDs Markers for Suicidal Ideation, But Did NeuroMark Debut Gene Dx Prematurely?

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Following the recent publication of a National Institutes of Mental Health study identifying the first two genes associated with suicidal thinking during treatment with the antidepressant citalopram, a Colorado-based diagnostics shop announced the launch of a genetic test to identify patients who have these genetic variants and should not be taking the drug.
 
Although researchers conducting the study feel that, if replicated, their findings could be significant for the field, one investigator told Pharmacogenomics Reporter this week that marketing a diagnostic, such as the one made by NeuroMark, is premature.
 
In the October issue of the American Journal of Psychiatry, Gonzalo Laje and researchers published data showing a strong association between markers within the GRIK2 and GRIA3 genes and treatment-emergent suicidal ideation during therapy with citalopram. The drug is marketed as Celexa by Forest Laboratories.
 
According to Francis McMahon, one of the study authors and director of the Genetic Basis of Mood and Anxiety Disorders program at NIMH, replication of genetic association studies is critical since seemingly significant results often don’t hold up in other samples. Additionally, the effect size and the relationship between the marker and the treatment may be overestimated in the initial study.
 
“This is the so-called ‘winner’s curse,’” McMahon said. “The replication samples tell us whether we got a true signal or not. If we want to get an accurate estimate of the effect size, which is very important for a clinical test, it is important to have results … preferably on several different samples.” However, he noted that for these reasons “it may be too early to be offering [a diagnostic] that would be helpful in the clinic.”
 
NeuroMark did not respond to requests for comment before deadline. In a statement, NeuroMark said: “We feel a sense of responsibility, given the current climate, to provide the test to physicians immediately so that they may identify patients who would benefit from closer monitoring or even a change in therapy. It is our hope that this early test will encourage more people to consider antidepressant drug treatment who would benefit from it.”
 
Additionally, it is widely known that many antidepressants, especially selective serotonin reuptake inhibitors like Celexa, are difficult to titrate and carry unpleasant and potentially lethal side effects, including suicide. The Mark-C test “is expected to help restore public confidence” in these drugs “and help to reduce a recently announced spike in suicide rates among US youth,” NeuroMark said in a statement.
 
The company said the Mark-C test, which it launched in early October, is sold as a homebrew assay under the Clinical Laboratory Improvement Amendments of 1988. Additionally, NeuroMark expects the US Food and Drug Administration to clear the test as an in vitro diagnostic within a year.
 
According to the Centers for Disease Control, in 2004, the same year the FDA required that “black box” warnings about the risk of suicidal ideation be added to the label of all antidepressants, there was an 8-percent increase in the suicide rate among 10-19 year olds. NeuroMark also cited a recent study of 200,000 depressed veterans that found that those taking an antidepressant had one-third the risk of suicide of those who were not.
 
The Study
 
“This study has the methodologic virtues of prospectively collected clinical data and independence of the clinical data from the experimental variables (genotypes),” Elliot Gershon, professor of psychiatry and human genetics at the University of Chicago, wrote in an editorial accompanying the American Journal of Psychiatry article. “It is very strongly suggestive, and as the authors state, if replicated, it would be a major clinical and biological advance if a dangerous clinical event were associated with specific genetic variations.”
 
The genetic associations were made in a substudy of the four-year, 4,000-patient Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D), sponsored by the NIMH, the National Institute for Alcohol Abuse and Alcoholism, the National Human Genome Research Institute, the NIH, and the Swedish Research Council.
 
The research studied DNA samples submitted by 1,900 patients aged 18 to 75 with major depressive disorder. The study followed 1,742 patients, of whom 120 reported having suicidal ideation during treatment. Of these, 69 percent suffered from suicidal thoughts within the 21st day of treatment, and 92 percent had suicidal thoughts by the 28th day of therapy.
 
Patients also experienced suicidal ideation when the citalopram dose was changed. After the end of the treatment at 14 weeks suicidal ideation continued in 37 percent of patients and fluctuated in 15 percent. Depression in one-quarter of patients carrying the genetic markers went into remission compared to approximately 43 percent of patients without the genetic markers.
 
In the genetic association study, the authors tested 768 SNPs in approximately 70 candidate genes and found associations within markers in the GRIA3 and GRIK2 genes. “Both these genes encode ionotropic glutamate receptors,” Gershon wrote. “The biological meaning of these variations remains to be established; they are not part of coding exons of the genes.”
 
In the study, NIMH researchers used Illumina’s GoldenGate assay to analyze patients’ genes, running more than 10,000 duplicate genotypes, “and they were perfect,” McMahon said. “There was not one discrepancy.”
 

“If we want to get an accurate estimate of the effect size, which is very important for a clinical test, it is important to have results … preferably on several different samples … “ Therefore, “it may be too early to be offering [a diagnostic] that would be helpful in the clinic.”

According to McMahon, the researchers have started to look more broadly genome-wide in the same sample using the Illumina Infinium assay. “We’ve done that now with the Infinium 109K chip, which is now two or three generations old,” he said. “The long-term plan would be to look with a more comprehensive chip, as well.”
 
The NIMH researchers are working with the Max Planck Institute in Germany to garner some replication data from a smaller sample collected for an inpatient study of several hundred depression patients treated with antidepressants.
 
The NIMH has no plans to expand the current STAR*D substudy, however. McMahon noted that the NIH has funded several new studies to collect samples, including blood for DNA, for mental health studies. “We’re hoping that when those studies begin to bear fruit, we can start to put together a reasonably sized sample, it should be possible to go back and look at this again,” he added.
 
“The issue of replication is so important, we would ideally have another sample of 2,000 people off the shelf in whom we can look at this right away. But it just isn’t in the offing.”
 
Although the study only looked at the treatment effect with Celexa, the markers may be linked to suicidal ideation with other SSRIs.
 
“Celexa is a pretty standard serotonin selective reuptake inhibitor; it’s highly selective for the serotonin transporter,” said McMahon. “But its downstream effects would be expected to be very similar to those that would be seen with most SSRIs.
 
“Although we cannot say yet with certainty based on our data, I would expect that this kind of phenomenon should be extendable to other SSRIs,” he added.
 
Finally, McMahon hopes that the study results will capture the attention of pharmaceutical companies that make antidepressants and encourage them to study whether patients with GRIK2, GRIA3, or other markers experience suicidal thoughts in clinical trials, either during treatment with investigational compounds or with marketed SSRIs.
 
“That was one of our motivations in deciding to publish these study results,” McMahon said. “One of the things we were hoping this would stimulate is a serious look at the existing samples, to see whether these or other genetic markers might be there. It’s a way to inject some science into this controversy about suicidal thinking and antidepressants.”
 
The Test
 
The company did not answer questions about the technology behind the test. To conduct the test, physicians take a buccal swab to obtain a DNA sample from patients. The test results are reported to the physician within two to four days after receiving the sample.
 
NeuroMark is inviting patients to prospectively collect data to confirm the predicted risk and clinical utility of the Mark-C test. Patients can fill out a "self-described" inventory following their appointment with their doctor. The inventory will be submitted by their doctor to the Mark-C Outcomes Database. Then NeuroMark scientists will study and interpret the results. Patients’ data will be anonymized, the company said.
 
“In this way each patient is contributing to further developing the test for other patients,” NeuroMark said in a statement. “This is the first nationwide prospective gathering of data conducted in partnership with patients and families and their physicians.”
 
The company justified launching the test by noting that with the availability of the Mark-C assay, the subset of patients that should not receive the drug can be identified, thereby not depriving the large proportion of patients that respond well to antidepressant treatment.
 
“It is widely known that antidepressant use decreases the risk of suicide. … That is why identifying the small number of patients at risk is so beneficial for the clinician; many more patients can safely benefit from treatment,” the company said.
 

When the FDA required a “black box” to be added to the labels of antidepressants, prescriptions for these types of drugs began to drop off, the company noted. NeuroMark cited a study by Gibbons et al. in the September issue of the American Journal of Psychiatry which linked the decrease in antidepressants scripts to a significant rise in US suicide rates between 2002 and 2004.

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