One of the most debated drug-safety controversies in recent years is whether antidepressant drugs cause some people to have suicidal ideation. After analyzing DNA samples from almost 2,000 patients who received citalopram, researchers found two genetic markers with strong links to suicidal ideation in patients who developed it only after they started taking the drug. This finding may be a "smoking gun" that at least contributes to this uncommon but disturbing potential side effect of antidepressants.

Researchers at the Genetic Basis of Mood and Anxiety Disorders Unit of the Mood and Anxiety Program at the National Institute of Mental Health (NIMH) tested the blood samples of 1,915 participants of the Sequenced Treatment Alternatives to Relieve Depression (STAR^*D) clinical trial to look for any genetic difference between 1,742 participants who did not have any treatment-emergent suicidal ideation and 120 participants who did. In the study, treatment-emergent suicidal ideation was defined as any thoughts about suicide that were absent at baseline (before taking citalopram) but were reported within the 12 weeks of the treatment period. Two genetic markers were significantly more common in those who had treatment-emergent suicidal ideation. The study was funded by the National Institutes of Health and the Swedish Research Council.

The two markers were identified through a massive screening of 768 single nucleotide polymorphisms (SNPs) that were selected from a library of common variations in 68 genes. SNPs are point mutations involving just one" misspelled letter" in a strand of DNA sequence. These 68 genes were chosen because they code for proteins that are known to be involved in certain neurotransmission pathways and suspected to be affected, directly or indirectly, by antidepressants.

Both of the genetic markers identified as being linked to treatment-emergent suicidal ideation are related to the glutamate signaling system and located in genes that code for ionotropic glutamate receptors, which control the flow of ions in and out of neurons. This supports recent research implicating the glutamate pathways in certain antidepressants' mechanism of action. Those who carry both genetic markers seemed to be at even higher risk of suicidal ideation, compared with patients who carry one of the markers, and the effect appeared to be at least additive.

"We were a little surprised by the magnitude of association between the genetic markers and the suicidal ideation," Gonzalo Laje, M.D., a psychiatrist and a clinical research fellow at the Genetic Basis of Mood and Anxiety Disorders program at NIMH and the lead author of the study, told Psychiatric News. "The two markers seem highly specific, which is rare in genetic testing in psychiatry. The study shows that we are on the right path to understanding this phenomenon."

He cautioned, however, that these results need to be independently replicated by other studies involving other patient populations and other antidepressants.

The British regulatory agency and the U.S. have required strong warnings in the prescribing information of all antidepressants, which may have influenced adequate depression care for a large number of patients. The rise in suicide rates, which coincides with the warnings and the drop in antidepressant prescribing, has caused much concern among psychiatrists (Psychiatric News, October 5).

The STAR^*D clinical trial is the largest on the treatment of depression to date, according to NIMH, and lasted for seven years. The study enrolled adult outpatients from clinical sites around the country. The large number of participants who consented to genetic testing provides a rare opportunity for researchers to systematically and prospectively study treatment-emergent suicidal ideation, which occurs only in a small percentage of the population who take antidepressants. All patients received stepwise treatment for depression, starting with citalopram 20 mg/day, and adjusted according to pre-established algorithm. All participants took citalopram for at least 12 weeks.

In addition to the genetic markers, the authors also presented some curious clinical observations. Compared with those who had no treatment-emergent suicidal ideation, participants who developed suicidal ideation tended to require a higher maximum citalopram dose and were significantly less likely to go into remission. Over 90 percent of these patients reported suicidal ideation within the first month of starting the treatment. Only one participant in the DNA study population actually attempted suicide, as reported by the authors of this study (two persons did so in the entire STAR^*D study), according to the authors. The patient consistently denied suicidal ideation but did carry both of the genetic markers. "The markers.. .do not appear to be related to a general tendency toward suicide but rather to suicidal thoughts specifically emerging during antidepressant treatment," the authors wrote. "This [phenomenon] is consistent with [case] reports to regulatory agencies, in which the patients with antidepressant-emergent suicidal ideation did not actually attempt suicide," said Laje. "None of the participants who reported treatment-emergent suicidal ideation had a history of suicidal attempts."

A separate genetic study on the same group of STAR^*D participants was published in the June Archives of General Psychiatry. Roy Perlis, M.D., and colleagues identified two SNPs that were associated with treatment-emergent suicidal ideation in men. In that study, the researchers focused their search on known SNPs in one particular gene, CREB1, which codes for cyclic adenosine monophosphate response element binding (CREB) protein, and the DNA sequence near this gene (where the two identified SNPs reside). The sex-specific nature of this association is yet to be explained.

As more meaningful genetic markers are discovered, a clearer picture begins to emerge explaining why some people have unusual responses to certain drugs. Pharmacogenetics has already explained a range of adverse drug reactions that are specific to only a segment of the population. For example, genetic variations are responsible for population differences in the liver enzyme system, cytochrome P450, which metabolizes most drugs. This is why codeine is metabolized much faster in some people (known as "ultrarapid metabolizers") than others; these ultrarapid metabolizers in turn have a sharper rise in morphine blood concentration and experience exaggerated side effects. A similar mechanism may apply to the emergence of suicidal ideation with antidepressants in a minority of patients.

"The long-term goal of psychiatrists is to adequately treat patients with depression," Laje emphasized. "The best way to prevent suicide is to treat the disease."

The genetic markers discovered in this study have been licensed to Neuromark, a private company that plans to market the genetic test. AJP editors learned of the arrangement after the study was printed and will publish an addendum in an upcoming issue to disclose the additional information.

"Genetic Markers of Suicidal Ideation Emerging During Citalopram Treatment of Major Depression" is posted at<http://ajp.psychiatryonline.org/cgi/content/full/164/10/1530>.▪