Meta-Analysis Finds Antidepressants' Benefits Counter Risks for Kids

COLUMBUS, OH, April 17 -- The benefits of antidepressants for children and teenagers with depression or anxiety disorders may outweigh their risks, according to a large meta-analysis.

What's more, the small increased suicidal risks that have been reported were not statistically significant, found the results of analysis, which were reported in the April 18 issue of the Journal of the American Medical Association.

The analysis of pediatric antidepressant treatment of major depressive disorder, obsessive-compulsive disorder, and other anxiety disorders showed efficacy for all three conditions, wrote Jeffrey A. Bridge, Ph.D., of Ohio State University in Columbus, and David A. Brent, M.D., of the University of Pittsburgh, and colleagues.

There was an overall small (less than 1%) increased risk of suicidal ideation or attempt, they added. There were no completed suicides in these trials.

Previous research, they said, had linked the use of antidepressants among children and adolescents with an increased risk of suicidal behavior and thoughts, resulting in an FDA boxed label warning on pediatric antidepressant medications.

To address this concern, the researchers undertook a meta-analysis of published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone (Serzone), Venlafaxine (Effexor), and mirtazapine (Remeron) in participants younger than 19 with major depression or anxiety disorders.

Twenty-seven trials were selected, including pediatric major depressive disorder (n=15), obsessive compulsive disorder (n=6), and other anxiety disorders (n=6), and risk differences for response and for suicidal ideation/suicide attempt were estimated by random-effects methods. All but four of the studies used a flexible dosing schedule, and the majority were multisite.

Pooled risk differences in rates of primary study-defined measures of responder status were strongest for non-obsessive-compulsive anxiety disorders (non-OCD), intermediate for obsessive-compulsive anxiety disorders (OCD), and more modest for major depressive disorders (MDD). Findings were:

• For major depressive disorders (11.0% [95% confidence interval , 7.1% to 14.9%]),
• OCD (19.8% [CI, 13.0% to 26.6%),
• Non-OCD anxiety disorders (37.1% [22.5%to 51.7%]).
• These results corresponded to a number needed to treat of 10 (CI, 7 to 15), 6 (CI, 4 to 8), and 3 (CI, 2 to 5), respectively.

Although there was an increased risk difference of suicidal ideation/suicide attempt across all trials, the pooled risk differences within each indication were all less than 1% and were not statistically significant, (0.7%; 95% CI, 0.1% to 1.3%) (number needed to harm, 143 [CI, 77 to 1,000]).

Suicide indications for drug versus placebo were:

• Major depressive disorders, 0.9% (95% CI,?0.1% to 1.9%),
• OCD, 0.5% (?1.2% to 2.2%),
• Non-OCD anxiety disorders, 0.7% (?0.4% to 1.8%).
• There were no completed suicides.

Age-stratified analyses showed that for children younger than 12 with major depression, only fluoxetine showed a benefit over placebo. However, the reason for this finding is unclear, but could be due to study quality, location, or a property of the medication itself, such as its long half-life, the researchers said.

The researchers also reported that they found some evidence that age, duration of the disorder, and study conditions moderated the outcome for treatment of both depression and anxiety.

In reviewing the study's limitations, the researchers cited the mixed quality of data in meta-analyses, possible baseline differences in participants, dosing, or adherence to treatment, and the fact that no trial was designed to study suicide ideation or attempts as a study outcome.

There are several recommendations for future studies that emerge from this meta-analysis, the researchers wrote. These are:

• making baseline characteristics related to treatment response and suicide ideation publicly available;
• identifying the most efficient methods for monitoring both clinical response and adverse events;
• although it would increase cost, assays of drug and metabolite levels could identify those who are nonadherent or have a very slow or fast metabolism and are not responding to the treatment for reasons other than the intrinsic properties of the medication.

The researchers wrote that "some might argue that any risk of suicide ideation or attempt cannot possibly justify treatment with antidepressants for children or adolescents."

Instead, they wrote, "We believe that the strength of evidence presented here supports the cautious and well-monitored use of antidepressant medications as one of the first-line treatment options," while recognizing that efficacy appears greatest for non-obsessive-compulsive anxiety disorders, and more modest for major depression.

"Since the choice of treatment should be the result of a collaborative discussion between clinician, family, and patient," the investigators wrote, "the information presented in this report should allow for an informed evaluation of the potential benefits and risks of these medications versus no treatment and provide a framework for their comparison with nondrug treatments as well."