The test, called the Mark-C™ test, is expected to help restore public confidence in antidepressant medication and help to reduce a recently announced spike in suicide rates among U.S. youth. "This is an exciting example of the power of genetics to address a critical need and make important drugs safer for patients worldwide," stated Kim Bechthold, NeuroMark's CEO.
In September 2007, the Centers for Disease Control (CDC), announced that in 2004 there was a 8% rise in suicide rates among 10-19 year olds, the year that the FDA issued public health warnings linking antidepressant drugs with suicidal ideation and behavior. "The largest percentage increase in rates from 2003 to 2004 was among females aged 10—14 (75.9%), followed by females aged 15—19 years (32.3%) and males aged 15—19 years (9%)," according to the CDC.
In a statement, the company 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."
"Before the NeuroMark test, we couldn't differentiate between the subset of patients who were at risk of suicidal ideation and those who could more safely take an antidepressant drug," stated NeuroMark president Dr. Peter Tolias. "The Mark-C test is highly predictive and identifies citalopram-treated patients who are at high risk for suicidal ideation. The test also identifies people at low risk, giving the physician more confidence in prescribing citalopram," he added.
A Nation-Wide Confirmatory Study
In a unique move, the company is inviting physicians and patients across the country to participate in prospectively collecting data to confirm and extend the predicted risk of the Mark-C test. The data will be compiled in the Mark-C Outcomes Database and participating physicians and patients will be notified as new data they submit confirms and extends the predictive value and clinical utility of the test.
Patients can participate by filling out a short QUIDS-SR "self-described" inventory at each appointment with their doctor. The inventory is submitted by their doctor to the database where scientists will study the results and extended information. In this way each patient is contributing to further developing the test for other patients. The patient's identity is not disclosed and each patient will be advised when the database is updated and expanded. This is the first nationwide prospective gathering of data conducted in partnership with patients and families and their physicians.
The test is being made available in accordance with the requirements and standards of the Clinical Laboratory Improvement Amendments of 1988 (CLIA). An FDA-approved version of the test is expected to be available within a year.
Importance of Identifying Those at Risk by Examining Genes
It is widely known that antidepressant use decreases the risk of suicide; a recent study of 200,000 depressed veterans found that those taking an antidepressant had one-third the risk of suicide of those who were not. "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," a company official stated.
In a discovery announced today in the American Journal of Psychiatry, scientists at the National Institutes of Mental Health (NIMH) have identified the first set of genes associated with the risk for treatment emergent suicidal ideation when a patient is prescribed the widely used antidepressant drug citalopram, which is available under the brand name Celexa® and various generic versions. NeuroMark's Mark-C test, a first-in-class test, includes the genetic markers announced today by the NIMH and the American Journal of Psychiatry, and additional markers chosen to increase the predictive power of the test. Authors of the study, "Genetic Markers of Suicidal Ideation Emerging During Citalopram Treatment of Major Depression," stated that patients found at risk for suicidal ideation "may benefit from closer monitoring, alternative treatments and/or specialty care."
FDA Black Box Warning Cited as Possible Cause of Rise
The public health warning linking antidepressant medications with suicidal thinking and behavior in young adults was issued by the FDA and European regulatory agencies in 2003 and 2004. "Black box" labeling is the highest level of warning and was mandated to be placed on all classes of antidepressant drugs by the agency. A decrease in the use of antidepressant drugs began in that year. The decrease in prescribing is linked to the significant rise in U.S. suicide rates that began in the same year, according to a recently published paper by Gibbons et al. in the September issue of the American Journal of Psychiatry. The increase in suicides came after a 28% decline in suicides rates over a 15 year period. According to Nemeroff, et.al, (Archives of General Psychiatry, April 2007) antidepressant drug prescriptions declined by an average of 4% per month from April 2002 to February 2004.
According to the CDC, suicides account for more than 32,000 deaths annually in the U.S. The National Alliance for the Mentally Ill reports that suicide deaths consistently outnumber homicide deaths by a margin of three to two.
There was broad news coverage in 2004 of the risk of suicidal thinking and behavior associated with antidepress- ant drugs and the action taken by the U.S. Food and Drug Administration. The U.S. agency recently expanded the warning label to include people up to the age of 24.
Genes Identified in the NIMH STAR*D Trial
A study, called the Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D), sponsored by the National Institute of Mental Health (NIMH), the National Institute for Alcohol Abuse and Alcoholism, the National Human Genome Research Institute, the NIH and the Swedish Research Council, enrolled 4,000 patients over four years. The study was the largest trial of its kind ever undertaken. Participating patients were diagnosed with Major Depressive Disorder and ranged in age from 18 to 75. Patients submitting DNA numbered 1,915. The scientists chose 768 genetic markers to screen in the 68 genes that sampled five broad signaling pathways of potential importance in antidepressant drugs. Suicidal ideation emerged during treatment in 120 out of 1742 patients sampled in the study. Suicidal ideation occurred very early in the course of treatment, 69% by the 21st day and 92% by the 28th day. It also occurred upon change in medication dose. After the end of the 14 week treatment period the authors studied, suicidal ideation persisted in 37% of patients and fluctuated in 15%, or a total of 52% of patients. Twenty-four percent of patients carrying the genetic markers went into remission compared to 42.8% of controls.
How the Mark-C Test Works
The Mark-C test is very simple. It requires a cotton swab to be brushed inside of the patient's cheek to obtain a sample of DNA. Test results are reported to the physician Test results are reported to the physician within 2-4 days from receipt of the sample. Two of the markers probed by the Mark-C test reside in genes that encode receptors for the excitatory neurotransmitter glutamate. These are the genes GRIK2 and GRIA3, both of which encode ionotropic glutamate receptors, the most prominent neuronal membrane receptors in the mammalian brain activated by normal neurophysiologic processes.