David Baxter PhD
Late Founder
No Link Between Antidepressant and Suicide in Kids
by Fran Lowry, Medscape
February 21, 2012
Study Calls FDA Black Box Warning Into Question
A close look at all randomized, placebo-controlled trials of the antidepressant fluoxetine has failed to find evidence that the drug increases the risk for suicide in youths.
And a similar look at all trials of fluoxetine and venlafaxine in adults has concluded that both antidepressants decrease depressive symptoms as well as suicidal thoughts and behavior in adult and geriatric patients.
The findings, reported online February 6 in the Archives of General Psychiatry, call into question the wisdom of the US Food and Drug Administration's 2004 decision to issue a "black box warning" about the purported link between antidepressant use and suicide, lead author Robert D. Gibbons, PhD, from the University of Chicago in Illinois, told Medscape Medical News.
Dr. Gibbons, who was on the FDA's advisory committee that voted in favor of the black box warning, said he was very concerned about the validity of the data that prompted the affirmative vote.
Not Warranted?
"The adverse event reports for suicidal thoughts and behavior showed a fairly small signal in children, but the prospective measurements showed no effect of treatment whatsoever. As a statistician, I put more weight in prospective data than these retrospective reports," he said.
"The vote was 15 to 8, so some of the members of the committee, myself included, were not persuaded by those reports and felt that the black box warning was not warranted."
In the current study, Dr. Gibbons and his team obtained all intent-to-treat person-level longitudinal data from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine (Prozac, Eli Lilly) and 21 adult trials of venlafaxine (Effexor, Wyeth). All trials were conducted by the sponsors of the 2 drugs.
"We were interested initially in looking into the efficacy of antidepressants, so we approached Eli Lilly to see if they would part with all of their longitudinal data from their randomized, placebo-controlled trials, and remarkably, they said 'yes,' " said Dr. Gibbons. "We said that we were going to analyze all the data and write a paper and were not even going to show it to them, and they said 'fine'."
Next, the researchers approached Wyeth with the same request and got the same reply.
"All of a sudden we had an awful lot of placebo-controlled, randomized clinical trial data, complete longitudinal records for every subject, and we were able to ask questions about the efficacy of antidepressants and whether or not that efficacy is moderated by the severity of illness of the patient and also whether or not there are changes over time in suicidal thoughts and behavior, whether or not those are the same in adults and the elderly and children, and whether or not any changes in suicidal thoughts and behavior are related to changes in depressive severity," Dr. Gibbons said.
The researchers analysed 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 treatment in 9185 patients.
The fluoxetine analysis included data from 2635 adults, 960 geriatric patients, and 708 youths. The venlafaxine analysis included data from 2421 adults who received immediate-release venlafaxine and 2461 adults who received extended-release venlafaxine. In all, the review comprised 53,260 person-week observations.
At baseline, the rates of suicide risk were 5% for adults, 3% for geriatric patients, and 20% for youths.
Among adult and geriatric patients, those receiving antidepressants had a greater reduction in suicide risk over time compared with patients receiving placebo. The difference was statistically significant (marginal maximum likelihood estimates [MMLE] = -.2091; standard error [SE] = .0289; P < .001).
Additionally, depressive symptoms, excluding suicidal thoughts and behavior, were reduced faster for patients receiving treatment as compared with control patients (12-week treatment difference: MMLE = -4.0337; SE = .2730; P < .001), indicating an average estimated difference in depression severity of 4.03 units on the HAM-D score between treated and control patients.
The analysis also showed that there was a statistically significant main effect of depression severity on contemporaneous suicide risk (MMLE = 0.3070; SE = .0094; P < .001).
"This indicates that depression severity is linked with suicide risk in adults," Dr. Gibbons said.
Suicidal Thoughts More Tightly Linked to Depression
In children, there were no increases or decreases in suicidal thoughts and behavior associated with antidepressant treatment with fluoxetine relative to placebo (MMLE = 0.0809; SE = 0.0595; P = .17).
However, fluoxetine did decrease the severity of depressive symptoms in children. Symptoms of depression decreased more quickly in young patients taking fluoxetine than in those taking placebo (treatment difference at 12 weeks: MMLE = -3.8976; SE = 1.5238; P = .01).
The fact that fluoxetine decreased depression severity but showed no effect on suicidal thoughts and behaviors is interesting, Dr. Gibbons said.
"None of these children committed suicide, and this suggests that there may be a disassociation between depression and suicidal thoughts and behavior in children that we don't see in adults. Perhaps in children, the suicidal thoughts and behavior occur for a variety of different reasons, whereas in adults and the elderly, these seem to be more tightly linked to depression," he said.
The results from this analysis are "encouraging because they show that the risk of suicidal thoughts and behavior is no greater in depressed children who are treated with an active medication versus a placebo," Dr. Gibbons continued.
"A limitation is that the only antidepressant that was examined in the child studies was fluoxetine, and in the adult studies, it was fluoxetine and venlafaxine. It's very important that these findings be replicated with other drugs," he said.
More Harm Than Good
"I think this is a very important analysis that Robert Gibbons has published," Charles F. Reynolds III, MD, professor of geriatric psychiatry from the University of Pittsburgh, told Medscape Medical News. "Robert is one of the world's most distinguished biostatisticians in mental health research and has had a long-standing interest in the questions of suicide, particularly the risk for and protective factors against suicide."
Dr. Gibbons and his group have shown that the use of antidepressant medication is protective against suicidal ideation in adults and senior adults and that the effects on suicidal ideation are mediated through the antidepressant effects on general depressive symptomatology, Dr. Reynolds pointed out.
"This makes sense if you understand that depression is a major risk factor for suicidal ideation and behavior, and so, by relieving the mental illness, in this case the depression, you remove 1 of the main drivers of suicidal ideation. This is very important to understand because there's been considerable concern about whether antidepressant medication might activate suicidal ideation in some people, particularly in young adults. But what he is finding is that the effects of the medication are neutral with respect to suicidal ideation in youth and protective in middle age and older adults."
Dr. Reynolds said he often worries that the black box warning has done more harm than good.
"The black box warning might have prevented the medically appropriate use of antidepressants in teenagers. I am very happy to see this study come out," he said.
Dr. Gibbons reports that he has been an expert witness for the US Department of Justice and Wyeth Pharmaceuticals for 2 court cases that involved antidepressants and suicide. Dr. Reynolds has disclosed no relevant financial relationships.
Arch Gen Psychiatry. Published online February 6, 2012. Full article
by Fran Lowry, Medscape
February 21, 2012
Study Calls FDA Black Box Warning Into Question
A close look at all randomized, placebo-controlled trials of the antidepressant fluoxetine has failed to find evidence that the drug increases the risk for suicide in youths.
And a similar look at all trials of fluoxetine and venlafaxine in adults has concluded that both antidepressants decrease depressive symptoms as well as suicidal thoughts and behavior in adult and geriatric patients.
The findings, reported online February 6 in the Archives of General Psychiatry, call into question the wisdom of the US Food and Drug Administration's 2004 decision to issue a "black box warning" about the purported link between antidepressant use and suicide, lead author Robert D. Gibbons, PhD, from the University of Chicago in Illinois, told Medscape Medical News.
Dr. Gibbons, who was on the FDA's advisory committee that voted in favor of the black box warning, said he was very concerned about the validity of the data that prompted the affirmative vote.
Not Warranted?
"The adverse event reports for suicidal thoughts and behavior showed a fairly small signal in children, but the prospective measurements showed no effect of treatment whatsoever. As a statistician, I put more weight in prospective data than these retrospective reports," he said.
"The vote was 15 to 8, so some of the members of the committee, myself included, were not persuaded by those reports and felt that the black box warning was not warranted."
In the current study, Dr. Gibbons and his team obtained all intent-to-treat person-level longitudinal data from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine (Prozac, Eli Lilly) and 21 adult trials of venlafaxine (Effexor, Wyeth). All trials were conducted by the sponsors of the 2 drugs.
"We were interested initially in looking into the efficacy of antidepressants, so we approached Eli Lilly to see if they would part with all of their longitudinal data from their randomized, placebo-controlled trials, and remarkably, they said 'yes,' " said Dr. Gibbons. "We said that we were going to analyze all the data and write a paper and were not even going to show it to them, and they said 'fine'."
Next, the researchers approached Wyeth with the same request and got the same reply.
"All of a sudden we had an awful lot of placebo-controlled, randomized clinical trial data, complete longitudinal records for every subject, and we were able to ask questions about the efficacy of antidepressants and whether or not that efficacy is moderated by the severity of illness of the patient and also whether or not there are changes over time in suicidal thoughts and behavior, whether or not those are the same in adults and the elderly and children, and whether or not any changes in suicidal thoughts and behavior are related to changes in depressive severity," Dr. Gibbons said.
The researchers analysed 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 treatment in 9185 patients.
The fluoxetine analysis included data from 2635 adults, 960 geriatric patients, and 708 youths. The venlafaxine analysis included data from 2421 adults who received immediate-release venlafaxine and 2461 adults who received extended-release venlafaxine. In all, the review comprised 53,260 person-week observations.
At baseline, the rates of suicide risk were 5% for adults, 3% for geriatric patients, and 20% for youths.
Among adult and geriatric patients, those receiving antidepressants had a greater reduction in suicide risk over time compared with patients receiving placebo. The difference was statistically significant (marginal maximum likelihood estimates [MMLE] = -.2091; standard error [SE] = .0289; P < .001).
Additionally, depressive symptoms, excluding suicidal thoughts and behavior, were reduced faster for patients receiving treatment as compared with control patients (12-week treatment difference: MMLE = -4.0337; SE = .2730; P < .001), indicating an average estimated difference in depression severity of 4.03 units on the HAM-D score between treated and control patients.
The analysis also showed that there was a statistically significant main effect of depression severity on contemporaneous suicide risk (MMLE = 0.3070; SE = .0094; P < .001).
"This indicates that depression severity is linked with suicide risk in adults," Dr. Gibbons said.
Suicidal Thoughts More Tightly Linked to Depression
In children, there were no increases or decreases in suicidal thoughts and behavior associated with antidepressant treatment with fluoxetine relative to placebo (MMLE = 0.0809; SE = 0.0595; P = .17).
However, fluoxetine did decrease the severity of depressive symptoms in children. Symptoms of depression decreased more quickly in young patients taking fluoxetine than in those taking placebo (treatment difference at 12 weeks: MMLE = -3.8976; SE = 1.5238; P = .01).
The fact that fluoxetine decreased depression severity but showed no effect on suicidal thoughts and behaviors is interesting, Dr. Gibbons said.
"None of these children committed suicide, and this suggests that there may be a disassociation between depression and suicidal thoughts and behavior in children that we don't see in adults. Perhaps in children, the suicidal thoughts and behavior occur for a variety of different reasons, whereas in adults and the elderly, these seem to be more tightly linked to depression," he said.
The results from this analysis are "encouraging because they show that the risk of suicidal thoughts and behavior is no greater in depressed children who are treated with an active medication versus a placebo," Dr. Gibbons continued.
"A limitation is that the only antidepressant that was examined in the child studies was fluoxetine, and in the adult studies, it was fluoxetine and venlafaxine. It's very important that these findings be replicated with other drugs," he said.
More Harm Than Good
"I think this is a very important analysis that Robert Gibbons has published," Charles F. Reynolds III, MD, professor of geriatric psychiatry from the University of Pittsburgh, told Medscape Medical News. "Robert is one of the world's most distinguished biostatisticians in mental health research and has had a long-standing interest in the questions of suicide, particularly the risk for and protective factors against suicide."
Dr. Gibbons and his group have shown that the use of antidepressant medication is protective against suicidal ideation in adults and senior adults and that the effects on suicidal ideation are mediated through the antidepressant effects on general depressive symptomatology, Dr. Reynolds pointed out.
"This makes sense if you understand that depression is a major risk factor for suicidal ideation and behavior, and so, by relieving the mental illness, in this case the depression, you remove 1 of the main drivers of suicidal ideation. This is very important to understand because there's been considerable concern about whether antidepressant medication might activate suicidal ideation in some people, particularly in young adults. But what he is finding is that the effects of the medication are neutral with respect to suicidal ideation in youth and protective in middle age and older adults."
Dr. Reynolds said he often worries that the black box warning has done more harm than good.
"The black box warning might have prevented the medically appropriate use of antidepressants in teenagers. I am very happy to see this study come out," he said.
Dr. Gibbons reports that he has been an expert witness for the US Department of Justice and Wyeth Pharmaceuticals for 2 court cases that involved antidepressants and suicide. Dr. Reynolds has disclosed no relevant financial relationships.
Arch Gen Psychiatry. Published online February 6, 2012. Full article
