It just might be one of the most complicated issues psychiatric researchers have faced, and one that affects clinical-practice decisions almost every day. Yet despite a voluminous—and ever expanding—body of research, no consensus appears to be in sight.

A recent epidemiological/observational study has concluded that counties across the United States with higher prescribing rates of antidepressant medications have significantly lower rates of youth suicide, compared with counties with lower prescribing rates (see story at right).

Even so, in an editorial accompanying that report in the November American Journal of Psychiatry, Greg Simon, M.D., M.P.H., director of the Center for Health Studies at the Group Health cooperative in Seattle, asks, "How can we know whether antidepressants increase suicide risk?"

Simon told Psychiatric News, "I'm one of the people who does these studies for a living, so I can sit back and say that, yes, this is a really interesting and complicated problem. But that's not very helpful to my patients."

Since the mid-1980s, when the first hints of a link between antidepressant medications and self-harming or suicidal thoughts and acts appeared, researchers have been struggling to design a study that could effectively address the concern.

Now, 20 years later and with a large body of conflicting and inconclusive reports, investigators across the globe continue to pursue what some see as the Holy Grail of psychiatric research.

"I think it is very likely that we will eventually discover that there are important differences between [antidepressant] medications and vitally important differences between individual patients who take them," Simon said.

However, at the heart of the debate is the fundamental question of how to identify those differences in individual medications and how to predict higher risk in particular subsets of patients. Because suicide is such a rare event, a double-blind, placebo-controlled, randomized trial looking at one specific antidepressant and the risk of suicide, compared with placebo, "would need to include several hundred thousand patients. Such a trial will never occur," Simon said in his editorial. Observational or epidemiological studies can include very large populations, but they are subject to any number of confounding factors that could bias outcomes, he added.

Thomas Laughren, M.D., director of the Division of Psychiatry Products at the U.S. Food and Drug Administration (FDA), agreed: "I think most in the psychiatric community would now agree that there is at least some subset of people who appear to be susceptible to an increased risk of suicidality when taking these medications. Observational studies might be able to look deeper to figure out what particular factors might make an individual more susceptible," Laughren told Psychiatric News. "But we need to look much deeper at individual details and design and implement much better observational methods to identify those individual patient traits linked to higher risk."

The FDA continues to analyze patient-level data from more than 50 clinical trials of antidepressants in adults—using the same analytic methods as the agency used for its pediatric analysis of suicidality and antidepressant medications. Laughren declined to speculate as to when that analysis might be completed. However, also paralleling the pediatric analysis, the FDA" will almost certainly hold an advisory committee meeting to discuss the results."

"At this point," Simon told Psychiatric News," it is difficult to even make a solid statement that `on average, this whole group of drugs either increases or decreases risk of suicide.' But obviously, when you are sitting with an individual patient, the pertinent question isn't about averages; it's about one particular medication for one specific patient.

"My own view," he continued, "is that if there is going to be a clear explanation for this phenomenon—in terms of why some patients have wonderful results with antidepressants, while others have a terrible reaction—it's going to be in the patients' DNA. That's got to be where the explanation lies."

In Simon's editorial, he concluded with a suggested conversation clinicians should have with patients for whom they are prescribing antidepressant medications. The conversation addresses the conflicting and complex evidence base and is straightforward and critical, Simon noted, to protect the patient as well as the clinician.

"Even if antidepressants help most people who take them, some people may have very negative reactions," Simon tells his patients when he prescribes an antidepressant. "Thus, it is important that we have regular contact over the next few weeks."

"From a clinical perspective," said Darrel Regier, M.D., M.P.H., executive director of the American Psychiatric Institute for Research and Education and director of APA's Division of Research, "the summary provided by Dr. Simon at the end of the editorial provides the type of practical guidance needed for physicians managing the treatment of young patients with depression."

In the meantime, clinicians are left waiting for the FDA's adult suicidality analysis while researchers pursue new avenues in an attempt to give clinicians and their patients more precise information.

"How Can We Know Whether Antidepressants Increase Suicide Risk?" is posted at<www.ajp.psychiatryonline.org/cgi/content/full/163/11/1861>.▪