June 18, 2012 — Two comprehensive analyses of studies of fluoxetine and venlafaxine show that the drugs are effective in treating mild to moderate depression, not just severe depression, and also that they decrease suicidal thoughts and behavior in adults and geriatric patients.

"Our studies show that antidepressants fluoxetine and venlafaxine are effective in the treatment of depression relative to placebo and they do not increase the risk of suicidal thoughts and behavior. They are most effective in children and adults and less effective in the elderly, at least through 6 weeks," the principal investigator of both studies, Robert D. Gibbons, PhD, told Medscape Medical News.

Dr. Robert Gibbons

"Antidepressants decrease risk of suicidal thoughts and behavior in adults and neither increase nor decrease the rate of suicidal thoughts and behavior in children," Dr. Gibbons, professor of medicine and director of the Center for Health Statistics, University of Chicago, in Illinois, added.

The two studies are published in the June issue of Archives of General Psychiatry.

Need to Reevaluate FDA Warning?

A study published earlier this year and reported by Medscape Medical News at that time also found no evidence that fluoxetine increased the risk for suicide in youth.

The results of these studies call into question the US Food and Drug Administration's 2004 decision to issue a "black box warning" about the widely perceived link between antidepressant use and suicide.

Dr. Gibbons declined to comment on whether he thought it was time for that black box warning to be removed, but, as he told Medscape Medical News, "the relevance of the black box warning should be routinely reevaluated as new information becomes available."

In the reanalysis of all randomized controlled trials (RCTs) of fluoxetine and venlafaxine, Dr. Gibbons and his team used all intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth studies of fluoxetine and 21 adult trials of venlafaxine.

The investigators analyzed the suicide items from the Children's Depression Rating Scale–Revised (CDRS-R) and the Hamilton Depression Rating Scale (HAM-D) as well as adverse event reports of suicide attempts and suicide during active treatments in a total of 9185 patients.

The fluoxetine analysis included data from 2635 adults, 960 geriatric patients (aged 65 years and older), and 708 youths (aged 18 to 24 years). The venlafaxine analysis included data from 2421 adults treated with immediate-release venlafaxine and 2461 adults treated with extended-release venlafaxine. In all, the review comprised 53,260 person-week observations.

The researchers found that suicidal thoughts and behavior decreased over time for adult and geriatric patients randomly assigned to receive fluoxetine or venlafaxine compared with placebo, but that no differences were found for youths.

At baseline, the reported rates of suicide risk were 5% for adults, 3% for geriatric patients, and 20% for youths. Rates of suicide risk were reduced by 50% or more for both treated and control groups over time.

The study found a statistically significant difference in the reduction of suicide risk over time between patients receiving fluoxetine and venlafaxine vs those receiving placebo (P < .001).

"Suicidal thoughts and behavior decreased over time for adult and geriatric patients who were on fluoxetine or venlafaxine, but not placebo, although no difference was found for youths," Dr. Gibbons said.

The reduction in suicidal ideation and attempts was due to a reduction in depressive symptoms as a result of the medication, he said.

Furthermore, in all age groups, severity of depression significantly improved with medication, he added.

Lower Suicide Rates

Concerns about suicide due to fluoxetine have been raised since its advent, said Peter D. Kramer, MD, clinical professor of psychiatry and human behavior at Brown University, in Providence, Rhode Island.

"Since Prozac became available, almost immediately there's been this worry that these newer antidepressants sometimes cause suicide. and that culminated in the black box warning," he told Medscape Medical News.

"I think psychiatrists have been very mixed about the black box warning, because it seems in some studies to result in lower prescribing rates, and on a public health basis, it's not clear that that is a good thing, both because depression is serious in itself and also because there are very few things that seem to lower suicide rates than these drugs. In fact, the introduction of these medicines lowered suicide rates," Dr. Kramer said.

Dr. Gibbons and his team also found that antidepressants were of benefit in patients with mild to moderate depression as well as severe depression.

When they examined the 6-week patient-level outcomes from the RCTs, they found that patients in all age groups taking either fluoxetine or venlafaxine had significantly greater improvement compared with patients receiving placebo.

Adults receiving fluoxetine had the greatest improvement compared with those receiving placebo (differential rate of improvement, 34.6%). Youths had the largest response rate (24.1%) and remission rate (30.1%); adult differential rates of improvement were 15.6% for remission and 21.4% for response.

Geriatric patients had the smallest drug-placebo differences; they demonstrated an 18.5% greater rate of improvement, a 9.9% rate for response, and a 6.5% rate for remission.

The study also showed that immediate-release venlafaxine produced larger effects than extended-release venlafaxine.

"Unbiased Overview"

"This study has provided a statistically rigorous and unbiased overview of the risks and benefits of antidepressants fluoxetine and venlafaxine in all published and unpublished placebo controlled RCTs of depression," Dr. Gibbons said.

"It seems to me that there are 2 sorts of issues here," said Dr. Kramer. "One is the aggregate public health issue. Do these medicines increase or decrease suicidality, and on that basis, these metaanalyses are reassuring because it looks like the balance is in favor of the medication."

The other issue is whether or not these medicines might promote suicidality in an individual, he said.

"Are there, in those averages, some people who never would have been suicidal where the medicine had a paradoxical effect and for the first time they thought about suicide. These studies are not meant to answer that question," he said.

Dr. Kramer added that it is "reassuring" to find that fluoxetine and venlafaxine are effective in less severe depression.

"Determining efficacy in mild to moderate depression is problematic because there are fewer studies and because of the ceiling effect. When you start with fewer symptoms, and you are looking at absolute change instead of percent change, there is less improvement available, and it is easier statistically to see improvement in people who have a lot of symptoms," he said.

"I think this study has some particular virtues. It says, yes, these drugs are not acting like placebo. They are doing something."

Dr. Gibbons has served as an expert witness for the US Department of Justice, Wyeth, and Pfizer Pharmaceuticals in cases related to antidepressants and anticonvulsants and suicide. Dr. Kramer has disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2012;69:572-579. Full article

Arch Gen Psychiatry. 2012;69:580-587. Full article