Antidepressant Medications in Children
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《新英格兰医药杂志》
In June 2003, the Medicine and Healthcare Products Regulatory Agency of the British Department of Health warned physicians to avoid the off-label use of paroxetine, a selective serotonin-reuptake inhibitor (SSRI) antidepressant, for the treatment of depression in children (18 years of age or younger). This action was taken in response to concern about a possible association between SSRIs and suicidal behavior, which includes a broad range of symptoms ranging from fleeting thoughts of self-harm to attempted suicide. Proprietary data examined by the United Kingdom regulatory agency showed a slight increase in suicidal behavior among patients who were randomly assigned to SSRI treatment, as compared with subjects who received placebo (3.7 percent vs. 2.5 percent). The U.S. Food and Drug Administration (FDA) issued a similar warning, with a note of caution that paroxetine treatment should not be discontinued suddenly, so that withdrawal reactions can be avoided.
The issue now is whether SSRIs increase the risk of suicidal behavior in depressed children. The FDA has initiated its own examination of this question. At a joint meeting on February 2, 2004, of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee, the FDA's review revealed several problems in the interpretation of the available data and outlined plans for the ongoing evaluation of the results.1 On March 22, the FDA took the additional step of requesting that labels on SSRIs and related antidepressants include a warning that all patients should be "monitored closely for worsening depression or the emergence of suicidality." (Further information is available at www.fda.gov.)
Does this mean that SSRIs are simply unsafe? As with any treatment, the safety of these drugs is a relative concept to be examined in the light of the severity of the disorder being treated and the anticipated benefits and risks of treatment.
First introduced in the late 1980s, the SSRIs are considered to represent an improvement over older antidepressants because they are better tolerated and are safer in overdose — an important feature for drugs that are prescribed to patients who are at increased risk for suicide. Over the years, the use of SSRIs in children has increased substantially. Fluvoxamine, sertraline, and fluoxetine are approved by the FDA for the treatment of obsessive–compulsive disorder in children, and fluoxetine is also approved for the treatment of major depressive disorder in patients eight years of age or older. In addition, other antidepressants, such as paroxetine, citalopram, and venlafaxine (a drug that is closely related to the SSRIs), are prescribed to children for off-label use.
Both obsessive–compulsive disorder and major depressive disorder can be severe illnesses, often having a chronic or recurrent course and causing substantial functional impairment. Although most children with depression have symptoms similar to those seen in adults, such as sad mood, apathy, lack of energy, and vegetative signs, in some children the disorder is manifested only by irritability or social isolation and may not be brought to clinical attention. Prevalence estimates suggest that up to 6 percent of adolescents currently meet the criteria for major depressive disorder, and up to 25 percent have been affected by this disorder by their late teens.2 Depression is a major risk factor for suicide, which ranks third as a cause of death among teenagers in the United States. The increased use of antidepressants among children 10 to 19 years of age has been accompanied by a significant decrease in the suicide rate in this age group.3 For each 1 percent increase in the use of SSRIs among adolescents, there was a decrease of 0.23 suicide per 100,000 adolescents per year.
However, these findings represent an epidemiologic association, rather than evidence of causality. To demonstrate a causal link, either positive or negative, between antidepressant treatment and suicide is an extremely difficult task. Suicide is a relatively rare event, and controlled clinical trials with thousands of subjects would be required in order to detect a possible treatment effect. In fact, no suicide has ever been reported among the more than 4100 subjects enrolled in pediatric clinical trials of SSRIs. Nonlethal suicidal attempts and suicidal ideation are more common, but establishing an association would still require systematic, controlled studies involving hundreds of subjects. Controlled trials typically exclude patients who are considered to be at high risk for suicide, such as those with a history of suicide attempts or current suicidal ideation. (However, suicidal ideation is not an accurate predictor of suicide, since most persons with such ideation do not attempt or die by suicide.) Data bases of spontaneously reported adverse events among community-treated patients, such as MedWatch, are also of limited usefulness in addressing this issue, because suicidal behavior can be a symptom of depression rather than a distinct toxic effect like agranulocytopenia or liver failure. Keeping these methodologic limitations in mind, what can we say about the risk–benefit balance of SSRI use in children?
For the treatment of obsessive–compulsive disorder, the balance appears to be favorable: fluvoxamine, sertraline, and fluoxetine have been shown to be effective, and although they have been associated with an increased rate of adverse behavioral events such as nervousness and agitation, their benefits seem to outweigh the associated risks. For the treatment of depression, the picture is more equivocal. The efficacy of an antidepressant is considered to be proved if two separate, independently conducted, controlled clinical trials have found a statistically and clinically significant improvement with the use of the medication as compared with the use of placebo. According to this definition, efficacy has been proved only for fluoxetine.
The response rate was 56 percent with fluoxetine treatment and 33 percent with placebo in the first study, which was funded by the National Institute of Mental Health (NIMH), and 65 percent with fluoxetine treatment and 53 percent with placebo in the second study, which was funded by Eli Lilly.4,5 These data, which are not substantially different from those obtained in studies involving adults, indicate that fluoxetine is moderately effective in children, that there is a high rate of response to placebo (between one third and one half of patients), and that the medication has no benefit for about one third of patients. The rate of suicidal behavior was the same with fluoxetine treatment as with placebo in these two controlled trials. Agitation and manic symptoms were more common with fluoxetine treatment, affecting about 1 in 10 children, which is similar to the rates reported with other SSRIs. All adverse events resolved completely after the discontinuation of treatment. The other SSRIs and venlafaxine have not been proved to have a favorable risk–benefit ratio, since there have not been replicative trials confirming the superiority of these medications over placebo. The high rate of response to placebo appears to be the primary factor contributing to the lack of statistically significant differences between groups, as had been previously found in trials of antidepressant medications in adults.
It is noteworthy that adverse behavioral events such as agitation, hyperkinesia, mania, and hypomania tended to be more frequent among patients treated with SSRIs (including fluoxetine) than among those receiving placebo (1 to 6 percent vs. 0 to 4 percent).1 Although a causal link between SSRI use and suicidal behavior has not been proved by current data, it is theoretically possible that the agitation and nervousness that occur in some children treated with SSRIs might have the potential to increase the risk of self-injurious acts; clinicians must therefore monitor patients carefully for such adverse effects.
Nonpharmacologic interventions, such as cognitive–behavioral therapy and other psychotherapies, have been found to be beneficial in children with depression. One means of improving the risk–benefit balance associated with SSRIs may be to reserve medications for those children who have persistent or recurrent forms of depression that are deemed, on the basis of data from studies in adults, to be unlikely to respond to psychotherapy, behavioral or environmental change, or general emotional support. In many cases, nonpharmacologic interventions accompanied by an early follow-up appointment may be helpful in establishing the persistence of a depressive syndrome before any decision is made regarding the introduction of antidepressant medication. An NIMH-funded, multisite, controlled clinical trial, the Treatment for Adolescents with Depression Study, with more than 400 enrollees, is currently comparing the relative efficacy of fluoxetine, cognitive–behavioral therapy, and their combination; results are expected later this year.
While we search for answers to the questions raised about the safety of SSRIs, we must not ignore the documented link between depression and suicide. The sad reality is that depressed children and adolescents are at increased risk for attempting and committing suicide. The recognition and appropriate treatment of children with depressive disorders remain vitally important; unfortunately, in caring for such a patient today, when the safety of SSRIs is still under review, physicians may sometimes be forced to choose a treatment that has proven efficacy in adults with depression but has not yet been tested in children.
The views expressed in this article are those of the authors and do not necessarily reflect the views of the National Institute of Mental Health, the National Institutes of Health, or the Department of Health and Human Services.
Source Information
From the National Institute of Mental Health, Bethesda, Md.
References
Psychopharmacologic Drugs Advisory Committee and the Anti-Infective Drugs Advisory Committee. Briefing information. Rockville, Md.: Food and Drug Administration, February 2, 2004. (Accessed March 18, 2004, at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm.)
Kessler RC, Avenevoli S, Merikangas KR. Mood disorders in children and adolescents: an epidemiologic perspective. Biol Psychiatry 2001;49:1002-1014.
Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry 2003;60:1236-1242.
Emslie GJ, Rush AJ, Weiberg WA, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54:1031-1037.
Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41:1205-1215.(Benedetto Vitiello, M.D.,)
The issue now is whether SSRIs increase the risk of suicidal behavior in depressed children. The FDA has initiated its own examination of this question. At a joint meeting on February 2, 2004, of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee, the FDA's review revealed several problems in the interpretation of the available data and outlined plans for the ongoing evaluation of the results.1 On March 22, the FDA took the additional step of requesting that labels on SSRIs and related antidepressants include a warning that all patients should be "monitored closely for worsening depression or the emergence of suicidality." (Further information is available at www.fda.gov.)
Does this mean that SSRIs are simply unsafe? As with any treatment, the safety of these drugs is a relative concept to be examined in the light of the severity of the disorder being treated and the anticipated benefits and risks of treatment.
First introduced in the late 1980s, the SSRIs are considered to represent an improvement over older antidepressants because they are better tolerated and are safer in overdose — an important feature for drugs that are prescribed to patients who are at increased risk for suicide. Over the years, the use of SSRIs in children has increased substantially. Fluvoxamine, sertraline, and fluoxetine are approved by the FDA for the treatment of obsessive–compulsive disorder in children, and fluoxetine is also approved for the treatment of major depressive disorder in patients eight years of age or older. In addition, other antidepressants, such as paroxetine, citalopram, and venlafaxine (a drug that is closely related to the SSRIs), are prescribed to children for off-label use.
Both obsessive–compulsive disorder and major depressive disorder can be severe illnesses, often having a chronic or recurrent course and causing substantial functional impairment. Although most children with depression have symptoms similar to those seen in adults, such as sad mood, apathy, lack of energy, and vegetative signs, in some children the disorder is manifested only by irritability or social isolation and may not be brought to clinical attention. Prevalence estimates suggest that up to 6 percent of adolescents currently meet the criteria for major depressive disorder, and up to 25 percent have been affected by this disorder by their late teens.2 Depression is a major risk factor for suicide, which ranks third as a cause of death among teenagers in the United States. The increased use of antidepressants among children 10 to 19 years of age has been accompanied by a significant decrease in the suicide rate in this age group.3 For each 1 percent increase in the use of SSRIs among adolescents, there was a decrease of 0.23 suicide per 100,000 adolescents per year.
However, these findings represent an epidemiologic association, rather than evidence of causality. To demonstrate a causal link, either positive or negative, between antidepressant treatment and suicide is an extremely difficult task. Suicide is a relatively rare event, and controlled clinical trials with thousands of subjects would be required in order to detect a possible treatment effect. In fact, no suicide has ever been reported among the more than 4100 subjects enrolled in pediatric clinical trials of SSRIs. Nonlethal suicidal attempts and suicidal ideation are more common, but establishing an association would still require systematic, controlled studies involving hundreds of subjects. Controlled trials typically exclude patients who are considered to be at high risk for suicide, such as those with a history of suicide attempts or current suicidal ideation. (However, suicidal ideation is not an accurate predictor of suicide, since most persons with such ideation do not attempt or die by suicide.) Data bases of spontaneously reported adverse events among community-treated patients, such as MedWatch, are also of limited usefulness in addressing this issue, because suicidal behavior can be a symptom of depression rather than a distinct toxic effect like agranulocytopenia or liver failure. Keeping these methodologic limitations in mind, what can we say about the risk–benefit balance of SSRI use in children?
For the treatment of obsessive–compulsive disorder, the balance appears to be favorable: fluvoxamine, sertraline, and fluoxetine have been shown to be effective, and although they have been associated with an increased rate of adverse behavioral events such as nervousness and agitation, their benefits seem to outweigh the associated risks. For the treatment of depression, the picture is more equivocal. The efficacy of an antidepressant is considered to be proved if two separate, independently conducted, controlled clinical trials have found a statistically and clinically significant improvement with the use of the medication as compared with the use of placebo. According to this definition, efficacy has been proved only for fluoxetine.
The response rate was 56 percent with fluoxetine treatment and 33 percent with placebo in the first study, which was funded by the National Institute of Mental Health (NIMH), and 65 percent with fluoxetine treatment and 53 percent with placebo in the second study, which was funded by Eli Lilly.4,5 These data, which are not substantially different from those obtained in studies involving adults, indicate that fluoxetine is moderately effective in children, that there is a high rate of response to placebo (between one third and one half of patients), and that the medication has no benefit for about one third of patients. The rate of suicidal behavior was the same with fluoxetine treatment as with placebo in these two controlled trials. Agitation and manic symptoms were more common with fluoxetine treatment, affecting about 1 in 10 children, which is similar to the rates reported with other SSRIs. All adverse events resolved completely after the discontinuation of treatment. The other SSRIs and venlafaxine have not been proved to have a favorable risk–benefit ratio, since there have not been replicative trials confirming the superiority of these medications over placebo. The high rate of response to placebo appears to be the primary factor contributing to the lack of statistically significant differences between groups, as had been previously found in trials of antidepressant medications in adults.
It is noteworthy that adverse behavioral events such as agitation, hyperkinesia, mania, and hypomania tended to be more frequent among patients treated with SSRIs (including fluoxetine) than among those receiving placebo (1 to 6 percent vs. 0 to 4 percent).1 Although a causal link between SSRI use and suicidal behavior has not been proved by current data, it is theoretically possible that the agitation and nervousness that occur in some children treated with SSRIs might have the potential to increase the risk of self-injurious acts; clinicians must therefore monitor patients carefully for such adverse effects.
Nonpharmacologic interventions, such as cognitive–behavioral therapy and other psychotherapies, have been found to be beneficial in children with depression. One means of improving the risk–benefit balance associated with SSRIs may be to reserve medications for those children who have persistent or recurrent forms of depression that are deemed, on the basis of data from studies in adults, to be unlikely to respond to psychotherapy, behavioral or environmental change, or general emotional support. In many cases, nonpharmacologic interventions accompanied by an early follow-up appointment may be helpful in establishing the persistence of a depressive syndrome before any decision is made regarding the introduction of antidepressant medication. An NIMH-funded, multisite, controlled clinical trial, the Treatment for Adolescents with Depression Study, with more than 400 enrollees, is currently comparing the relative efficacy of fluoxetine, cognitive–behavioral therapy, and their combination; results are expected later this year.
While we search for answers to the questions raised about the safety of SSRIs, we must not ignore the documented link between depression and suicide. The sad reality is that depressed children and adolescents are at increased risk for attempting and committing suicide. The recognition and appropriate treatment of children with depressive disorders remain vitally important; unfortunately, in caring for such a patient today, when the safety of SSRIs is still under review, physicians may sometimes be forced to choose a treatment that has proven efficacy in adults with depression but has not yet been tested in children.
The views expressed in this article are those of the authors and do not necessarily reflect the views of the National Institute of Mental Health, the National Institutes of Health, or the Department of Health and Human Services.
Source Information
From the National Institute of Mental Health, Bethesda, Md.
References
Psychopharmacologic Drugs Advisory Committee and the Anti-Infective Drugs Advisory Committee. Briefing information. Rockville, Md.: Food and Drug Administration, February 2, 2004. (Accessed March 18, 2004, at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm.)
Kessler RC, Avenevoli S, Merikangas KR. Mood disorders in children and adolescents: an epidemiologic perspective. Biol Psychiatry 2001;49:1002-1014.
Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry 2003;60:1236-1242.
Emslie GJ, Rush AJ, Weiberg WA, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54:1031-1037.
Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41:1205-1215.(Benedetto Vitiello, M.D.,)