Caution Urged in Interpreting Antidepressant Efficacy Data

Is antidepressant drug treatment for mild and moderate depression no better than placebo?

That's what a meta-analysis of six drug trials seemed to imply at first glance, but a closer examination of the research offers a more nuanced picture of the drugs, their use, and how they are tested, said the authors.

“True drug effects (an advantage of [antidepressant medication] over placebo) were nonexistent to negligible among depressed patients with mild, moderate, and even severe baseline symptoms, whereas they were large for patients with very severe symptoms,” wrote Jay Fournier, M.A., and colleagues in the January 6 Journal of the American Medical Association. Fournier is a doctoral candidate in the Department of Psychology at the University of Pennsylvania.

The researchers concluded that medication proved “markedly superior to placebo” only in patients with a Hamilton Rating Scale for Depression score of at least 25 at baseline, considered “very severe.”

However, the study's inclusion criteria filtered out all but six randomized, controlled trials totaling 718 patients, lasting at least six weeks, and covering just two antidepressants: paroxetine and imipramine.

Because the study rests on such a narrow base, it should not be presented as applying to all antidepressants, Mark Olfson, M.D., M.P.H., a professor of clinical psychiatry at Columbia University and the New York State Psychiatric Institute, told Psychiatric News. “This is a reasonable hypothesis, but more work is needed before any sweeping generalizations are established.”

The study looked at patient-level data to get a more precise estimate of the effects of drugs. Group mean data used in previous analyses covered patients with both mild and severe symptoms, which can obscure real differences, said coauthor Robert DeRubeis, Ph.D., a professor of psychology at the University of Pennsylvania, in an interview.

Clinical trials presented to the FDA to gain approval of these drugs often screen out less severely ill patients, which results in findings of greater improvement than if they had been included, wrote the authors. Future trials should include more patients with rating scores indicating mild or moderate illness so that the effects of antidepressants can be judged more accurately, even if that requires recruiting larger numbers.

More research will be needed in a much larger database to examine not just severity but other factors like gender and chronicity before any changes in clinical practice can be recommended, said DeRubeis.

“We're not saying not to use medications [in less severely depressed patients]; we're just saying the actual treatment effects of the drugs are hard to distinguish in that group,” he said.

“The findings do not imply that the role of antidepressants should be limited to very severe depression,” said Olfson.

The new study confirms with patient-level data what others have previously reported with study-level information, namely, that baseline depressive severity robustly predicts antidepressant response, said Olfson, who was not involved in the study.

While the study's conclusions may not surprise most psychiatrists, they may bring physicians to reconsider whether antidepressant medications should be the first-line treatment across the full spectrum of depression severity in outpatient medical care, said Olfson.

The study was also a reminder of the difference between “placebo” and “no treatment,” said DeRubeis. The placebo arm of clinical trials in depression usually includes elements that may function as patient care, such as recurrent office visits, clinician's attention, expectation of improvement, and education about the disorder.

Depression is a placebo-sensitive illness, said researcher Arif Khan, M.D., of the Northwest Clinical Research Center in Bellevue, Wash. In a study published in 2007, Khan observed that higher Hamilton scores used as entry criteria masked actual patient levels of severity, possibly distorting results.

“I hope this doesn't trivialize depression and persuade people to not go for treatment,” he said in an interview.

Olfson also noted another limitation of the meta-analysis' coverage of only acute treatments: chronicity often plays a role in treating patients with depression.

“Epidemiological studies make clear that for most patients a long gap—typically years—separates the onset of major depression from their first treatment contact,” he said. “So it is not clear to what extent the new results apply to typical depressed patients presenting for psychiatric care.”

The authors concluded their report by noting that drug companies gain approval for antidepressants with trials using severely ill patients. Those trial results are then applied to “the majority of patients receiving [antidepressant medications] in clinical practice [who] present with scores below these levels.”

Patients and clinicians should know that patients with less severe depression might not benefit from the drugs and consider alternatives, they suggested.

Only trials with comparative arms designed to minimize those nondrug effects can really tease out the effects of medications, said Khan.

“A lot of chronic diseases are hard to monitor when comparing treatment to placebos,” he said

“In terms of practice,” said Olfson, “I hope the new findings will prompt more psychiatrists and other clinicians to integrate the Hamilton scale or other standardized measures into their routine care.”

An abstract of “Antidepressant Drug Effects and Depression Severity” is posted at <http://jama.ama-assn.org/cgi/content/short/303/1/47>.