For Parents of Children from Six to 19 Years

Antidepressant Medications for Children and Adolescents

FROM NATIONAL INSTITUTE OF MENTAL HEALTH

Only in the past two decades has depression in children been taken very seriously. The depressed child may pretend to be sick, refuse to go to school, cling to a parent, or worry that the parent may die. Older children may sulk, get into trouble at school, be negative, grouchy, and feel misunderstood.

Because normal behaviors vary from one childhood stage to another, it can be difficult to tell whether a child is just going through a temporary "phase" or is suffering from depression. Sometimes the parents become worried about how the child's behavior has changed, or a teacher mentions that "your child doesn't seem to be himself." In such a case, if a visit to the child's pediatrician rules out physical symptoms, the doctor will probably suggest that the child be evaluated, preferably by a psychiatrist who specializes in the treatment of children. (Get more information on depression and children.)

It is estimated that major depressive disorder (MDD) affects about 5 percent of adolescents, who have more frequent suicidal thinking and behavior and greater likelihood of substance abuse than youth in general.

Research has shown that, as in adults, depression in children and adolescents can be treated. In particular, antidepressant medication—called selective serotonin reuptake inhibitors (SSRIs) because they specifically target the neurotransmitter serotonin—have been shown to be of benefit to children and adolescents with major depressive disorder. Certain types of psychological therapies have also been shown to be beneficial. In those with moderate to severe depression they are especially useful when combined with medication. Our knowledge of antidepressant treatments in youth, though growing substantially, remains limited when compared with what we know about treatment of depression in adults.

Recently, concerns have been raised that the use of antidepressant medications themselves may induce suicidal behavior in youths. In fact, following a thorough and comprehensive review of all the available published and unpublished controlled clinical trials of antidepressants in children and adolescents, the FDA has warned the public about an increased risk of suicidal thoughts or behavior ("suicidality") in children and adolescents treated with SSRI antidepressant medications.

Studies show that there are substantial benefits from medication treatment for adolescents with moderate and severe depression, including many with suicidal ideation.

FDA Review of Clinical Trials

In the FDA review, no completed suicides occurred among nearly 2,200 children treated with SSRI medications; however, the rate of suicidal thinking or behavior, including actual suicidal attempts, was 4 percent for those on SSRI medications, twice the rate of those on inert placebo pills (2 percent).

The FDA adopted a "black box" label warning (PDF file) that antidepressants were found to increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder. A black-box warning is the most serious type of warning in prescription drug labeling.

The warning also emphasizes that children and adolescents started on SSRI medications should be closely monitored for any worsening in depression, emergence of suicidal thinking or behavior, and in general for any unusual changes in behavior—such as sleeplessness, agitation, withdraw from normal social situations. This monitoring is especially important during the first four weeks of treatment. SSRI medications usually have few side effects in children and adolescents, but for unknown reasons, can trigger agitation and abnormal behavior in certain individuals.

What Do We Know About Antidepressant Medications?

SSRI medications are considered an improvement over older antidepressant medications because they have fewer side effects and are safer if taken in an overdose (which is an issue for patients at risk for suicide). They have been extensively tested in adult populations and have been proven to be safe and effective for adults.

Use of SSRI medications has risen dramatically in the past several years in children and adolescents age 10-19. Some studies show that this increase has coincided with a significant decrease in suicide rates in this age group, but it is not known if SSRI medications are directly responsible for this improvement.

Fluoxetine (also known as Prozac) is the only medication approved by the FDA for use to treat depression in children age 8 and older. The other SSRI medications, such as sertraline, citalopram, and paroxetine, and the SSRI-related antidepressant venlafaxine, have not been approved for treatment of depression in children or adolescents, though they have been prescribed to children by physicians in "off-label use"—a use other than the FDA approved use. In June 2003, the FDA recommended that paroxetine not be used in children and adolescents for the treatment of major depressive disorder.

Fluoxetine has been shown to be helpful for treating childhood depression in three different clinical trials—two supported by NIMH and the other supported by the manufacturer of the drug. The trials found that fluoxetine by itself, and even more so when combined with cognitive behavioral therapy, reduced depression for many children better than an inert placebo pill. However, fluoxetine failed to improve depression in at least one third of patients. Also, about one in 10 children experienced adverse side effects such as agitation and mania.

In the recently completed Treatment for Adolescents with Depression Study (TADS) funded by NIMH, suicidal thinking generally decreased during treatment with fluoxetine, but 15 of the 216 youths on fluoxetine (6.94 percent) had a suicide-related event, such as a suicidal attempt or threats, as compared with 9 of the 223 on the inert placebo pill (4.04 percent).

Fluoxetine leads to significant improvement of depression overall. The drug, however, may increase the risk for suicidal behaviors in a small subset of adolescents. As with all medical decisions, doctors and families have to weigh risks and benefits of treatment for each individual patient.

What Remains Unknown

Currently, there is no way of telling who may be sensitive to an SSRI's positive or adverse effects. Results thus far are based on populations—some individuals may show marked improvement, some may see no change, and some may be vulnerable to adverse effects. The response to medication of an individual patient cannot be predicted with certainty from the kind of studies that have been done so far.

It is extremely difficult to determine whether SSRI medications do or do not increase the risk of completed suicide, especially since depression itself increases the risk for suicide and because completed suicide is a rare event. Controlled trials typically include only hundreds of patients, not the thousands needed to detect effects for rare events. In addition, controlled trials typically exclude patients considered at high risk for suicide, such as those with a history of suicide attempts.

What Should You Do for a Child With Depression?

Major depression in children and adolescents is a serious condition that should be adequately treated, which includes careful follow-up and monitoring.

Each child should be carefully and thoroughly evaluated by a physician to determine if medication is appropriate. Those who are prescribed an SSRI medication should receive ongoing medical monitoring, with particular care paid in the first four weeks of taking the drug.

Psychotherapy is often used as an initial treatment for milder forms of depression. Many times, psychotherapy accompanied by an early follow-up appointment may help to establish the persistence of depression before a decision is made to try antidepressant medications. Psychotherapies include "cognitive behavioral therapy" and "interpersonal therapy." For moderate to severe forms of depression, especially if persistent, the current evidence supports the use of fluoxetine alone or in combination with cognitive-behavioral therapy (CBT). See results for the recently completed Treatment for Adolescents with Depression Study (TADS).

Should suicidal thinking or behavior, nervousness, agitation, irritability, mood instability, or sleeplessness emerge or worsen during treatment with SSRI medications, parents should obtain a prompt evaluation by a clinician with expertise in these medications.

Children already on any of the SSRI medications should remain on the drug if it has been helpful but they should also be carefully monitored by a physician for evidence of side effects. Once started, treatment with these medications should not be abruptly stopped, because of potential side effects. Families should not discontinue treatment without consulting with their physician.

All treatments can be associated with side effects. A careful weighing of risks and benefits, with appropriate follow-up to help reduce risks, is the best that can be currently recommended.

Information posted on the website of the National Institute of Mental Health 2-8-05

What NIMH Is Doing

In August of 2004, findings from the first phase of the NIMH-funded Treatment for Adolescents with Depression Study (TADS) demonstrated a combination of medication and psychotherapy to be the most effective treatment. The clinical trial of 439 adolescents with major depressive disorder (MDD) compared cognitive-behavioral therapy (CBT) with fluoxetine (Prozac), currently the only antidepressant approved by the FDA for use in children and adolescents. The results of the first 12 weeks of the trial, conducted at 13 sites nationwide, show that 71 percent responded to the combination of fluoxetine and CBT. The other three treatment groups, of participants between the ages of 12 and 17, also showed improvement, with a 60.6 percent response to fluoxetine-only treatment, and 43.2 percent response to CBT only. The response rate was 34.8 percent for the group that received an inert placebo pill with periodic clinical monitoring.

Clinically significant suicidal thinking, which was present in 29 percent of the TADS participants at the beginning of the study, improved significantly in all four treatment groups, with those receiving medication and CBT showing the greatest reduction in suicidal thinking. The rate of harm-related adverse events (aggression towards self and or others) was higher among patients who took the medication (10 percent) than among those who did not (5 percent). In particular, the rate of suicidal-related adverse events was 7 percent in the two medication groups and 4 percent in the two non-medication groups.

The combination of fluoxetine and CBT is the most effective treatment for adolescents with major depressive disorder. Fluoxetine alone is effective, but not as effective as the combination. CBT alone is less effective than fluoxetine and not significantly more effective than placebo. Taking both risk and benefit into account, the combination of fluoxetine and CBT appears superior as a short-term treatment for major depressive disorder in adolescents.

The TADS study is the first large, federally funded study using an antidepressant medication to treat adolescents suffering with moderate to severe depression. TADS was conducted between the spring of 2000 and the summer of 2003, with results published August 18, 2004, in JAMA.

NIMH is currently funding other studies involving adolescents with depression, including Treatment of Resistant Depression in Adolescents (TORDIA), which is enrolling about 400 12-18 year-olds with depression to investigate how best to treat those whose condition is "resistant" to the first SSRI medication they have tried.

NIMH is also supporting the Treatment of Adolescent Suicide Attempters (TASA) study, which is currently enrolling about 120 participants who have recently attempted suicide. Participants will receive antidepressant medications or cognitive behavioral therapy, or both.

Get a complete list of all National Institutes of Mental Health clinical trials

For more information on this topic, see Antidepressant Medications in Children, Vitiello, B, Swedo, S. National Institute of Mental Health, Bethesda, MD. New England Journal of Medicine Apr 8;350(15):1489-91.