MONDAY, June 4, 2012 (MedPage Today) — Short-term risks of suicidality associated with antidepressant drugs — highlighted in an FDA-mandated boxed warning — may have been exaggerated, said researchers who reviewed more than 40 controlled trials of two popular products.
http://www.everydayhealth.com/emotional-health/0605/doubt-cast-on-suicide-risk-of-antidepressants.aspx
In fact, compared with placebo, suicidal ideation was diminished with fluoxetine (Prozac) and venlafaxine (Effexor) in adults, including geriatric patients, and was not increased in children and teens in the trials, according to Robert D. Gibbons, PhD, of the University of Chicago, and colleagues.
The researchers found that suicide risk closely followed the severity of depression in adult trial participants — as depression eased, so did the likelihood of suicidal thoughts.
By the same token, Gibbons and colleagues reported in the June issue of Archives of General Psychiatry, suicide risk remained relatively high in patients who did not respond to the antidepressant treatment.
"For all adult trials, depression severity mediated the effect of antidepressant medication on suicide risk. Mediation accounted for approximately 80 percent of the overall treatment effect in adults, but less (57 percent) for geriatric patients," they wrote.
"Our findings emphasize the need to successfully treat episodes of major depressive disorder to lower the suicide risk."
Yet, in children and teens, the study also yielded a perplexing result — antidepressant treatment clearly reduced depression symptoms but with no corresponding decline in suicidality risk.
"Perhaps other psychopathology plays a more important role in suicidal behavior and ideation such as aggressive impulsive traits in youths," Gibbons and colleagues speculated.
The boxed warnings on antidepressants, indicating a heightened suicidality risk in children and teens, were first required in 2004 and were extended 2 years later to include adults 18 to 25.
They were based on adverse event data in industry-sponsored clinical trials, Gibbons and colleagues explained. An FDA meta-analysis in younger patients found an odds ratio of 1.78 for suicidality in children and adolescents receiving selective serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs/SSNRIs) relative to placebo.
A similar analysis of adult patient data found a nearly identical increase in suicidality in those ages 18 to 24 but a reduced risk in older adults including geriatric patients.
But the FDA analyses and subsequent studies did not take "the mediating role of depressive symptoms" into account, Gibbons and colleagues indicated. Moreover, the FDA examined only data connected to study endpoints, not the full longitudinal data available from the sponsors.
For the new study, Gibbons and colleagues obtained complete longitudinal data for 20 placebo-controlled trials of fluoxetine (all but one supplied by Eli Lilly) and 21 involving venlafaxine, provided by its manufacturer, Pfizer's Wyeth unit. Some of these were unpublished.
Suicide risk was evaluated in these trials with items in the Children's Depression Rating Scale-Revised and the Hamilton Depression Rating Scale, plus adverse event reports of actual suicidal behavior (attempted and successful). Such reports were rare — there were only two completed suicides and 20 attempts among participants in the 41 trials.
The data covered a total of 9,185 patients and 53,260 patient-weeks of observation, divided nearly equally between the two drugs. For venlafaxine, about half the patients had taken an immediate-release form of the drug and the others had taken an extended-release version.
Four of the fluoxetine trials were conducted in youths 17 and younger; four were in geriatric patients; and 12 were in nongeriatric adults. All the venlafaxine trials involved nongeriatric adults.
For fluoxetine, the meta-analysis indicated a lower risk of suicidality with the drug relative to placebo during the first 5 weeks of therapy, followed by an increased risk in weeks 6-8. Beyond week 8, the risk was again lower, but Gibbons and colleagues noted that the longer-term data were "sparse."
In adults and geriatric patients treated with fluoxetine, and in those receiving venlafaxine, treatment clearly reduced suicidality risk relative to placebo.
Gibbons and colleagues used a measure called "marginal maximum likelihood estimate" (MMLE) to quantify the effect of treatment on suicidality over time.
"The beneficial effect of treatment on the probability of suicide risk is apparent approximately 2 weeks following treatment initiation," the researchers wrote.
Still, the bottom line for Gibbons and colleagues was that the lack of association with fluoxetine treatment indicates that the drug did not heighten suicidality risk.
The researchers noted that their analysis in children and teens only involved fluoxetine, leaving the generalizability to other antidepressants uncertain.
Another limitation to the study included the small number of suicide attempts. "Suicidal ideation rates and the ratios to suicides and suicide attempts are higher in youths compared with adults, making ideation a potentially weaker indicator of risk of behavior in youths," Gibbons and colleagues noted.
The reliance on depression rating-scale items and adverse event reports for the evaluation of suicidality was also a potential limitation, the researchers indicated.
Last Updated: 06/05/2012
http://www.everydayhealth.com/emotional-health/0605/doubt-cast-on-suicide-risk-of-antidepressants.aspx
In fact, compared with placebo, suicidal ideation was diminished with fluoxetine (Prozac) and venlafaxine (Effexor) in adults, including geriatric patients, and was not increased in children and teens in the trials, according to Robert D. Gibbons, PhD, of the University of Chicago, and colleagues.
The researchers found that suicide risk closely followed the severity of depression in adult trial participants — as depression eased, so did the likelihood of suicidal thoughts.
By the same token, Gibbons and colleagues reported in the June issue of Archives of General Psychiatry, suicide risk remained relatively high in patients who did not respond to the antidepressant treatment.
"For all adult trials, depression severity mediated the effect of antidepressant medication on suicide risk. Mediation accounted for approximately 80 percent of the overall treatment effect in adults, but less (57 percent) for geriatric patients," they wrote.
"Our findings emphasize the need to successfully treat episodes of major depressive disorder to lower the suicide risk."
Yet, in children and teens, the study also yielded a perplexing result — antidepressant treatment clearly reduced depression symptoms but with no corresponding decline in suicidality risk.
"Perhaps other psychopathology plays a more important role in suicidal behavior and ideation such as aggressive impulsive traits in youths," Gibbons and colleagues speculated.
The boxed warnings on antidepressants, indicating a heightened suicidality risk in children and teens, were first required in 2004 and were extended 2 years later to include adults 18 to 25.
They were based on adverse event data in industry-sponsored clinical trials, Gibbons and colleagues explained. An FDA meta-analysis in younger patients found an odds ratio of 1.78 for suicidality in children and adolescents receiving selective serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs/SSNRIs) relative to placebo.
A similar analysis of adult patient data found a nearly identical increase in suicidality in those ages 18 to 24 but a reduced risk in older adults including geriatric patients.
But the FDA analyses and subsequent studies did not take "the mediating role of depressive symptoms" into account, Gibbons and colleagues indicated. Moreover, the FDA examined only data connected to study endpoints, not the full longitudinal data available from the sponsors.
For the new study, Gibbons and colleagues obtained complete longitudinal data for 20 placebo-controlled trials of fluoxetine (all but one supplied by Eli Lilly) and 21 involving venlafaxine, provided by its manufacturer, Pfizer's Wyeth unit. Some of these were unpublished.
Suicide risk was evaluated in these trials with items in the Children's Depression Rating Scale-Revised and the Hamilton Depression Rating Scale, plus adverse event reports of actual suicidal behavior (attempted and successful). Such reports were rare — there were only two completed suicides and 20 attempts among participants in the 41 trials.
The data covered a total of 9,185 patients and 53,260 patient-weeks of observation, divided nearly equally between the two drugs. For venlafaxine, about half the patients had taken an immediate-release form of the drug and the others had taken an extended-release version.
Four of the fluoxetine trials were conducted in youths 17 and younger; four were in geriatric patients; and 12 were in nongeriatric adults. All the venlafaxine trials involved nongeriatric adults.
For fluoxetine, the meta-analysis indicated a lower risk of suicidality with the drug relative to placebo during the first 5 weeks of therapy, followed by an increased risk in weeks 6-8. Beyond week 8, the risk was again lower, but Gibbons and colleagues noted that the longer-term data were "sparse."
In adults and geriatric patients treated with fluoxetine, and in those receiving venlafaxine, treatment clearly reduced suicidality risk relative to placebo.
Gibbons and colleagues used a measure called "marginal maximum likelihood estimate" (MMLE) to quantify the effect of treatment on suicidality over time.
"The beneficial effect of treatment on the probability of suicide risk is apparent approximately 2 weeks following treatment initiation," the researchers wrote.
Still, the bottom line for Gibbons and colleagues was that the lack of association with fluoxetine treatment indicates that the drug did not heighten suicidality risk.
The researchers noted that their analysis in children and teens only involved fluoxetine, leaving the generalizability to other antidepressants uncertain.
Another limitation to the study included the small number of suicide attempts. "Suicidal ideation rates and the ratios to suicides and suicide attempts are higher in youths compared with adults, making ideation a potentially weaker indicator of risk of behavior in youths," Gibbons and colleagues noted.
The reliance on depression rating-scale items and adverse event reports for the evaluation of suicidality was also a potential limitation, the researchers indicated.
Last Updated: 06/05/2012
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