Antidepressants and Pediatric Depression — The Risk of Doing Nothing
http://www.100md.com
《新英格兰医药杂志》
The editors asked two members of the Psychopharmacologic Drugs and Pediatric Advisory Committees of the Food and Drug Administration to comment on the committees' recent recommendations regarding the use of antidepressant medications in children and adolescents.
Their responses follow.
There is great concern that antidepressants used in children and adolescents may paradoxically increase their risk of suicidal thoughts and behavior. Is this concern valid, and if so, how should it modify our clinical approach to pediatric depression?
Twenty-five years ago, long before the introduction of selective serotonin-reuptake inhibitors (SSRIs), the adolescent suicide rate was increasing rapidly, having tripled over the previous two decades, but the risk factors involved were unknown. Adolescents who committed suicide were regarded as misunderstood teenagers who had been under too much stress. There was debate about whether depression could occur in children, and the prevailing view was that moodiness was normal in adolescents. Furthermore, even if we could have diagnosed depression and recognized young people who were at risk for suicide, there were no empirically validated treatments to offer.
Eventually, we learned that depression did indeed affect children and adolescents. Through retrospective interviews with family members and friends, this disorder emerged as the single most important risk factor for adolescent suicide,1 although it often acted in concert with substance abuse and impulsive aggression. Adolescents who committed suicide frequently had a history of suicidal thoughts or behavior, disclosed only to a friend who was sworn to secrecy. Most commonly, adolescents killed themselves with a gun, and guns were much more frequently available to those who had died by suicide than to those who had attempted suicide but lived.
These findings suggested some straightforward approaches to prevention. Although it had been thought that people who talk about suicide don't kill themselves, these results showed that previous suicidal behavior and current suicidal thoughts are potent risk factors for suicide and must be taken seriously. The association between the availability of guns and their use in suicides suggested that guns should be removed, or at least secured. Finally, the development and testing of treatments for pediatric depression should be given high priority.
Today, we are able to identify young people who are at high risk for suicide and to offer empirically validated treatments for depression.2 It is ironic that concern about the risks posed by antidepressants has arisen now, when the adolescent suicide rate has been decreasing for a decade (see Figure), for the first time in more than half a century. This trend is accounted for primarily by a drop in the rate of suicide by means of firearms, suggesting that more restrictive gun-control laws may be partially responsible.3 A portion of the decrease may be related to better detection of depression and suicidality (suicidal ideation, behavior, or both) and the dissemination of validated treatments. There is some ecologic evidence that increases in the number of prescriptions for SSRIs for adolescents are associated with a decrease in adolescent suicide.4
Figure. U.S. Suicide Rates among Persons 15 to 24 Years of Age, 1980–2001.
Data are from the Centers for Disease Control and Prevention.
Nevertheless, given findings showing a relationship between suicidality and completed suicide, one must take seriously the possibility that antidepressants might increase the risk of suicidality. And yet the concern about SSRIs in pediatric depression that has been aroused by the British Medicines and Healthcare Products Regulatory Agency (MHRA) (http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrioverview_101203.htm) is based, in my opinion, on an overestimation of risk and an underestimation of benefit.
Current clinical practice with regard to SSRI use for pediatric depression is based on six published studies, although five unpublished studies were much less favorable. There is the most incontrovertible evidence of efficacy for fluoxetine, which had positive results in three clinical trials. For sertraline, the results were positive but modest, with a 10 percent difference in response between drug and placebo. One study of citalopram was positive and one negative, but the latter involved both inpatients and outpatients and had a very high dropout rate. There were two negative trials of venlafaxine, but the doses used were often well below the minimal therapeutic dose for adults, and when the results were stratified according to age, venlafaxine was superior to placebo among adolescents. There have been three clinical trials of paroxetine, of which only one was positive.
In addition to questioning the benefit of these drugs, the MHRA and the Food and Drug Administration (FDA) focused attention on a possible increase in the likelihood of suicidality. In response, the MHRA declared that all antidepressants except fluoxetine were contraindicated in pediatric depression. The FDA initially advised against the use of paroxetine only, since there was some evidence of efficacy for sertraline and citalopram. More recently, the FDA labeled all antidepressants with a warning about their possible potential for inducing suicidal thoughts or behavior. The FDA also recently commissioned a blind independent review of these adverse events by a consensus panel of international experts.
With regard to the main outcome, suicidality (the combination of new suicide attempts, new-onset suicidal ideation, and worsening of existing suicidal ideation), the FDA analysis, presented to an advisory committee in a public hearing September 13 and 14, 2004, found an increase by a factor of 1.8 associated with drug treatment, which translates to a difference of 1.7 percentage points between drug and placebo (3.8 percent vs. 2.1 percent). Although the difference is small, it seems likely that the effect is real, because the findings were statistically significant in aggregate and are consistent across multiple studies of various agents.
Although the initial MHRA report and the FDA analysis found that fluoxetine treatment was not associated with suicidality, an FDA analysis of a new clinical trial found otherwise — but the results help to put the benefits and risks into perspective.3 In this study, cognitive–behavioral therapy and fluoxetine treatment, alone and in combination, were compared with each other and with placebo. Fluoxetine was much more likely than placebo to result in a significant clinical improvement (in 61 percent of cases vs. 35 percent) but, according to the FDA analysis, was associated with a significant increase by a factor of 4.6 in the rate of suicidal events (8.3 percent vs. 1.8 percent). Once a suicidal event was detected, the patient was withdrawn from the trial. Although depression and suicidality are both significant risk factors for suicide, depression improved in these patients four times as frequently as suicidality developed, which seems to represent an acceptable risk–benefit ratio. Fluoxetine plus cognitive therapy was not superior to fluoxetine alone according to most measures of depression, but the combination was superior to all other treatments in reducing the intensity of suicidal thoughts. This finding suggests that the optimal treatment for suicidality in a depressed patient may be multimodal — a logical approach, given the multiple risk factors for suicide.
In light of these concerns, why use SSRIs at all? Although cognitive–behavioral therapy appears to be more effective than other psychosocial treatments for depression, this comparison between it and medication found it inferior to fluoxetine therapy. And although the risk–benefit ratio is best for fluoxetine, nearly 40 percent of depressed adolescents do not have a response to this drug, and others cannot tolerate it. Other agents with some evidence of efficacy should be considered for these patients.
In addition to increasing the risk of suicidality, SSRIs are twice as likely as placebo to result in agitation and hostility. The FDA could not test whether hostility and suicidality were linked, but the drugs most closely associated with one were also most closely associated with the other. In addition, treatment with antidepressants is much more likely to unmask an underlying bipolar disorder in children or adolescents than it is in adults,5 which can result in the induction of a mixed manic and depressive state — a condition that carries a very high risk of suicidal behavior.
As SSRIs have gained in popularity, their ease of use and relatively favorable side-effect profile may have led to an overly casual approach to the treatment of depression. All depressed patients who are treated with antidepressants must be closely monitored for emergent suicidality, hostility, agitation, and mania. Families and patients must be informed about the benefits and risks of these drugs and should be educated about monitoring for emergent side effects, as recommended in recent public statements and labeling changes made by the FDA. Because children and adolescents generally metabolize antidepressants more rapidly than adults, they must receive doses adequate to achieve a clinical response. Suicidality in depressed patients may be best treated by a combination of psychotherapy and medication.
The FDA's recent analysis suggests that the risk of emergent suicidality in children and adolescents receiving SSRIs is real — but small. The FDA's advisors recommended stronger warnings in labeling and better information for patients and caregivers, but they stopped short of recommending contraindications for these drugs. However, many participants in the public hearing seemed convinced that the pharmacologic treatment of pediatric depression should be banned or severely curtailed. That would turn the clock back 25 years, to a time when the only thing we could offer the families of suicide victims was the hope that someday we would have effective treatments. Ideally, the FDA, families, and clinicians will find the right balance between the risk of suicidality and another, greater risk: the risk that lies in doing nothing.
Source Information
From the Western Psychiatric Institute and Clinic, Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh.
References
Brent DA, Perper JA, Goldstein CE, et al. Risk factors for adolescent suicide: a comparison of adolescent suicide victims with suicidal inpatients. Arch Gen Psychiatry 1988;45:581-588.
March JS, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004;292:807-820.
Webster DW, Vernick JS, Zeoli AM, Manganello JA. Association between youth-focused firearm laws and youth suicides. JAMA 2004;292:594-601.
Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60:978-982.
Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D. Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med 2004;158:773-780.(David A. Brent, M.D.)
Their responses follow.
There is great concern that antidepressants used in children and adolescents may paradoxically increase their risk of suicidal thoughts and behavior. Is this concern valid, and if so, how should it modify our clinical approach to pediatric depression?
Twenty-five years ago, long before the introduction of selective serotonin-reuptake inhibitors (SSRIs), the adolescent suicide rate was increasing rapidly, having tripled over the previous two decades, but the risk factors involved were unknown. Adolescents who committed suicide were regarded as misunderstood teenagers who had been under too much stress. There was debate about whether depression could occur in children, and the prevailing view was that moodiness was normal in adolescents. Furthermore, even if we could have diagnosed depression and recognized young people who were at risk for suicide, there were no empirically validated treatments to offer.
Eventually, we learned that depression did indeed affect children and adolescents. Through retrospective interviews with family members and friends, this disorder emerged as the single most important risk factor for adolescent suicide,1 although it often acted in concert with substance abuse and impulsive aggression. Adolescents who committed suicide frequently had a history of suicidal thoughts or behavior, disclosed only to a friend who was sworn to secrecy. Most commonly, adolescents killed themselves with a gun, and guns were much more frequently available to those who had died by suicide than to those who had attempted suicide but lived.
These findings suggested some straightforward approaches to prevention. Although it had been thought that people who talk about suicide don't kill themselves, these results showed that previous suicidal behavior and current suicidal thoughts are potent risk factors for suicide and must be taken seriously. The association between the availability of guns and their use in suicides suggested that guns should be removed, or at least secured. Finally, the development and testing of treatments for pediatric depression should be given high priority.
Today, we are able to identify young people who are at high risk for suicide and to offer empirically validated treatments for depression.2 It is ironic that concern about the risks posed by antidepressants has arisen now, when the adolescent suicide rate has been decreasing for a decade (see Figure), for the first time in more than half a century. This trend is accounted for primarily by a drop in the rate of suicide by means of firearms, suggesting that more restrictive gun-control laws may be partially responsible.3 A portion of the decrease may be related to better detection of depression and suicidality (suicidal ideation, behavior, or both) and the dissemination of validated treatments. There is some ecologic evidence that increases in the number of prescriptions for SSRIs for adolescents are associated with a decrease in adolescent suicide.4
Figure. U.S. Suicide Rates among Persons 15 to 24 Years of Age, 1980–2001.
Data are from the Centers for Disease Control and Prevention.
Nevertheless, given findings showing a relationship between suicidality and completed suicide, one must take seriously the possibility that antidepressants might increase the risk of suicidality. And yet the concern about SSRIs in pediatric depression that has been aroused by the British Medicines and Healthcare Products Regulatory Agency (MHRA) (http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrioverview_101203.htm) is based, in my opinion, on an overestimation of risk and an underestimation of benefit.
Current clinical practice with regard to SSRI use for pediatric depression is based on six published studies, although five unpublished studies were much less favorable. There is the most incontrovertible evidence of efficacy for fluoxetine, which had positive results in three clinical trials. For sertraline, the results were positive but modest, with a 10 percent difference in response between drug and placebo. One study of citalopram was positive and one negative, but the latter involved both inpatients and outpatients and had a very high dropout rate. There were two negative trials of venlafaxine, but the doses used were often well below the minimal therapeutic dose for adults, and when the results were stratified according to age, venlafaxine was superior to placebo among adolescents. There have been three clinical trials of paroxetine, of which only one was positive.
In addition to questioning the benefit of these drugs, the MHRA and the Food and Drug Administration (FDA) focused attention on a possible increase in the likelihood of suicidality. In response, the MHRA declared that all antidepressants except fluoxetine were contraindicated in pediatric depression. The FDA initially advised against the use of paroxetine only, since there was some evidence of efficacy for sertraline and citalopram. More recently, the FDA labeled all antidepressants with a warning about their possible potential for inducing suicidal thoughts or behavior. The FDA also recently commissioned a blind independent review of these adverse events by a consensus panel of international experts.
With regard to the main outcome, suicidality (the combination of new suicide attempts, new-onset suicidal ideation, and worsening of existing suicidal ideation), the FDA analysis, presented to an advisory committee in a public hearing September 13 and 14, 2004, found an increase by a factor of 1.8 associated with drug treatment, which translates to a difference of 1.7 percentage points between drug and placebo (3.8 percent vs. 2.1 percent). Although the difference is small, it seems likely that the effect is real, because the findings were statistically significant in aggregate and are consistent across multiple studies of various agents.
Although the initial MHRA report and the FDA analysis found that fluoxetine treatment was not associated with suicidality, an FDA analysis of a new clinical trial found otherwise — but the results help to put the benefits and risks into perspective.3 In this study, cognitive–behavioral therapy and fluoxetine treatment, alone and in combination, were compared with each other and with placebo. Fluoxetine was much more likely than placebo to result in a significant clinical improvement (in 61 percent of cases vs. 35 percent) but, according to the FDA analysis, was associated with a significant increase by a factor of 4.6 in the rate of suicidal events (8.3 percent vs. 1.8 percent). Once a suicidal event was detected, the patient was withdrawn from the trial. Although depression and suicidality are both significant risk factors for suicide, depression improved in these patients four times as frequently as suicidality developed, which seems to represent an acceptable risk–benefit ratio. Fluoxetine plus cognitive therapy was not superior to fluoxetine alone according to most measures of depression, but the combination was superior to all other treatments in reducing the intensity of suicidal thoughts. This finding suggests that the optimal treatment for suicidality in a depressed patient may be multimodal — a logical approach, given the multiple risk factors for suicide.
In light of these concerns, why use SSRIs at all? Although cognitive–behavioral therapy appears to be more effective than other psychosocial treatments for depression, this comparison between it and medication found it inferior to fluoxetine therapy. And although the risk–benefit ratio is best for fluoxetine, nearly 40 percent of depressed adolescents do not have a response to this drug, and others cannot tolerate it. Other agents with some evidence of efficacy should be considered for these patients.
In addition to increasing the risk of suicidality, SSRIs are twice as likely as placebo to result in agitation and hostility. The FDA could not test whether hostility and suicidality were linked, but the drugs most closely associated with one were also most closely associated with the other. In addition, treatment with antidepressants is much more likely to unmask an underlying bipolar disorder in children or adolescents than it is in adults,5 which can result in the induction of a mixed manic and depressive state — a condition that carries a very high risk of suicidal behavior.
As SSRIs have gained in popularity, their ease of use and relatively favorable side-effect profile may have led to an overly casual approach to the treatment of depression. All depressed patients who are treated with antidepressants must be closely monitored for emergent suicidality, hostility, agitation, and mania. Families and patients must be informed about the benefits and risks of these drugs and should be educated about monitoring for emergent side effects, as recommended in recent public statements and labeling changes made by the FDA. Because children and adolescents generally metabolize antidepressants more rapidly than adults, they must receive doses adequate to achieve a clinical response. Suicidality in depressed patients may be best treated by a combination of psychotherapy and medication.
The FDA's recent analysis suggests that the risk of emergent suicidality in children and adolescents receiving SSRIs is real — but small. The FDA's advisors recommended stronger warnings in labeling and better information for patients and caregivers, but they stopped short of recommending contraindications for these drugs. However, many participants in the public hearing seemed convinced that the pharmacologic treatment of pediatric depression should be banned or severely curtailed. That would turn the clock back 25 years, to a time when the only thing we could offer the families of suicide victims was the hope that someday we would have effective treatments. Ideally, the FDA, families, and clinicians will find the right balance between the risk of suicidality and another, greater risk: the risk that lies in doing nothing.
Source Information
From the Western Psychiatric Institute and Clinic, Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh.
References
Brent DA, Perper JA, Goldstein CE, et al. Risk factors for adolescent suicide: a comparison of adolescent suicide victims with suicidal inpatients. Arch Gen Psychiatry 1988;45:581-588.
March JS, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004;292:807-820.
Webster DW, Vernick JS, Zeoli AM, Manganello JA. Association between youth-focused firearm laws and youth suicides. JAMA 2004;292:594-601.
Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60:978-982.
Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D. Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med 2004;158:773-780.(David A. Brent, M.D.)