Because patients with major depressive disorder are at greater risk of suicide, the guideline indicates that they should be assessed for suicide risk initially and over the course of treatment. The guideline also notes that "the risk of suicide in some patients recovering from major depressive disorder increases transiently as they develop the energy and capacity to act on self-destructive plans made earlier in the course of their illness" (1). The guideline describes factors associated with an increased risk of suicide in patients with major depressive disorder but notes that "the ability to predict suicide attempts and completed suicide is poor, with both many false positives (i.e., patients who appear more likely to make attempts or complete suicide but who do not) and false negatives (i.e., patients who appear less likely to make attempts or complete suicide but who do)" (1). With respect to children and adolescents, the guideline recommends caution when basing treatment decisions on adult data. All of these general principles remain true.

Recent research has raised concern about the safety of antidepressant use for children and adolescents and has led the FDA to add additional warnings, including a black box warning, to the labeling of all antidepressant medications (9). Although the APA practice guideline focused on treatment of adults, not children and adolescents, discussion of this research is appropriate in this watch. In 23 short-term (4- to 16-week) trials involving more than 4,400 patients receiving nine antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others), suicidal thinking or behavior was observed in 78 individuals. The average risk of suicidal thinking or behaviors was 3.8% for participants receiving a drug compared with 2.1% for those given placebo, suggesting an approximately twofold increase in risk (10). Consequently, in the new labeling, the FDA notes that pooled analyses of placebo-controlled antidepressant trials (available at http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1.htm) have shown an increased risk of suicidal thinking or behavior in children and adolescents with major depressive disorder, obsessive-compulsive disorder, and other psychiatric disorders. However, it is important to note that no suicides occurred in any of these trials. Furthermore, according to the Centers for Disease Prevention and Control, suicidal thinking and suicide attempts are common among adolescents, occurring respectively in about 17% and 8.5% of adolescents each year. As a result of such attempts, only 0.002% of girls and 0.012% of boys ultimately die (11), highlighting the fact that suicidality (i.e., suicidal thoughts and behaviors) and suicide are not equivalent.

Although the studies reviewed by the FDA showed some variations among antidepressants, it was not clear whether the increase in suicidal thinking or behavior was specific to particular antidepressants, extended to adults, or occurred with longer-term antidepressant use (i.e., beyond several months). Thus, the FDA labeling change recommends that "all pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases" (9). To facilitate this, the FDA suggests an increased frequency of face-to-face contacts (i.e., weekly for the first 4 weeks, biweekly for the next 8 weeks), with prescriptions written for "the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose." The FDA also recommends that patients be screened for bipolar disorder before antidepressant therapy is initiated. Medication guides that will accompany prescriptions of antidepressant medications are intended to alert families and caregivers of pediatric and adult patients to the need to monitor patients for the emergence of agitation, irritability, hostility (aggressiveness), impulsivity, anxiety, panic attacks, insomnia, akathisia, hypomania, mania, or unusual changes in behavior so that such symptoms can be reported immediately to health care professionals.

When signs or symptoms are observed that suggest an increased suicide risk, recommendations are available for assessing and managing suicidal behaviors in children and adolescents from the American Academy of Child and Adolescent Psychiatry (12) and in adults from the APA (13).

As with all decisions about treatment for individuals with psychiatric illnesses, the choice to initiate antidepressant therapy must balance the potential risks of treatment against the potential therapeutic benefit and the risks of untreated illness (14–16). The risks of untreated depression, including suicide and other suicidal behaviors, are high and have been clearly delineated in youths and in adults (1, 12, 13, 17). In adults, the evidence for antidepressant efficacy is also clear, as reviewed in the APA guideline.

In children and adolescents, the issue has been confounded by a smaller number of clinical trials as well as by negative trials. Positive evidence includes the studies of fluoxetine that led to its receiving an FDA indication for treatment of depression in children and adolescents and the recent Treatment for Adolescents With Depression Study (TADS) sponsored by the National Institute of Mental Health. This large, yearlong community effectiveness trial (18) of youths with moderate to severe major depressive disorder found that by 12 weeks of treatment, rates of response to fluoxetine alone (60.9%) were greater than those with either placebo (35%) or cognitive behavior therapy (CBT) alone (43.2%). In combination with CBT, fluoxetine was associated with an even greater response rate (71%)—twice that seen with placebo. Furthermore, clinically significant suicidal thinking, which was observed in 29% of study subjects prior to treatment, improved in all groups.

In addition to this direct evidence of antidepressant efficacy from clinical trials, the national decreases in youth suicide and overall suicide rates, during a period when the prescribing of antidepressants has increased, might provide indirect evidence for an overall preventive effect of antidepressant treatment on suicide (14, 19, 20).

Because additional information on the issue of antidepressants and suicide risk is likely to emerge, readers are urged to seek updates on the Web sites of the FDA (http://www.fda.gov), the American Academy of Child and Adolescent Psychiatry (http://www.aacap.org), and the APA (http://www.psych.org).


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