None of these clinical trials have included or focused on children and adolescents being treated for cancer. Risk/benefit concerns have reached the level of international regulatory concern. The Medicines and Healthcare Products Regulatory Agency of Great Britain has recommended that most of the drugs in the SSRI category not be used with children and adolescents, and the FDA raised similar concerns in a Talk Paper and subsequently issued a "black box" warning. A major meta-analysis published in the Journal of the American Medical Association reanalyzed the data from the child and adolescent studies [Level of evidence: I] (including seven studies not included in the initial meta-analysis [Level of evidence: I]) using a random-effects model. While this reanalysis found an overall increased risk of suicidal ideation/suicide attempt consistent with the initial meta-analysis, the pooled risk differences were found to be smaller and statistically insignificant. Furthermore, another study examining the U.S. and Dutch data suggests a drop in SSRI prescriptions for children and adolescents and a simultaneous increase in suicide rates in this patient population since the FDA Health Advisory was issued.
In summary, the risk/benefit equation favors appropriate use of antidepressants with careful monitoring for suicidality. The British Committee on Safety of Medicines considered only one of the SSRIs (fluoxetine) to have a favorable balance of risks and benefits, but it is only considered beneficial in approximately one in ten patients. Consistent with this finding, age-stratified analyses of the child and adolescent studies found that for children younger than 12 years who have major depression, only fluoxetine showed benefit over placebo.
As noted, none of the children or adolescents in these studies had cancer, so there are no reports available that address whether there are additional increased risks of adverse events associated with the use of SSRIs following exposure to different chemotherapeutic agents and/or CNS radiation treatment. Frontline, alternative, effective, behavioral, and pharmacologic treatments for depression should be used for children and adolescents being treated for cancer. However, if the risks of depression are significant and SSRIs are considered, consultation with a child psychiatrist or neurologist is essential, and close monitoring of potential adverse events is crucial.
Post-traumatic Stress Disorder and Post-traumatic Stress Symptoms
The cancer treatment experience may be considered a significant traumatic event, given the nature of diagnosis, the number of invasive and painful procedures, and the often long hospitalizations that children and their families must experience. On the basis of this exposure model, a number of studies have examined whether children treated for cancer are at a significantly higher risk for the development of symptoms of post-traumatic stress disorder (PTSD). The results of these studies have been mixed. One study reported that children and adolescents who were undergoing treatment reported some symptoms of post-traumatic stress; however, for most children these symptoms did not meet the criteria for a diagnosis of PTSD, and the symptoms diminished over time.[Level of evidence: II]