The Food and Drug Administration (FDA), on March 22, 2004, issued a public health advisory cautioning physicians, patients, families and caregivers to monitor the use of antidepressants in adults and children for warning signs of suicide. Particular vigilance for worsening depression or suicidal thoughts was recommended at the beginning of antidepressant therapy or when dosages are changed. Ten makers of antidepressant drugs were asked by the FDA to add the cautions to their labels.
It is not yet clear whether antidepressants contribute to the emergence of suicidal thinking and behavior, and the FDA has initiated a full review.
A number of recent articles in the media have raised questions about the use of a group of antidepressants, known as specific serotonin reuptake inhibitors (SSRIs) and related antidepressants, for children and adolescents, also citing the increased risk of suicide for those aged l8 and under.
Reports in the news have often been contradictory, and therefore many parents are unsure about what to believe and whether to make changes in their child’s medication. In this article we present the background and summarize the current research in this area.
What are SSRIs and how do they work?
SSRIs (Selective Serotonin Reuptake Inhibitors) belong to a class of medications used to treat children and adolescents with depression or anxiety. These medications act within the brain to improve the functioning of certain chemicals (neurotransmitters) and their receptors to regulate mood.
Following are the medications classified as SSRIs, listed by both generic and brand names:
|Generic Name||Brand Name|
|Fluoxetine||Prozac, Seromex, Seronil|
|Paroxetine||Paxil, Seroxat, Optipar, Aropax|
|Fluvoxamine maleate||Luvox, Fevarin|
|Citalopram||Celexa, Cipramil, Emocal, Sipram|
Background of the FDA review
The following is the chronology of events that led the FDA to initiate a review of this issue:
June, 2003: The British equivalent of the U.S. FDA - issued a letter regarding Seroxat (Paroxetine). Based on studies done by the pharmaceutical company GlaxoSmithKline, the letter stated “These data do not demonstrate efficacy in depressive illness in this age group and show an increase in the risk of harmful outcomes including episodes of self-harm and potentially suicidal behaviour in the Seroxat group compared to placebo. Various analyses suggest that the risk of these outcomes is between 1.5 and 3.2 times greater with Seroxat compared to placebo.”
June, 2003: The FDA issued a recommendation that paroxetine, (Paxil) not be used to treat children or adolescents with depression based on the same data.
August, 2003: Wyeth Pharmaceuticals sent a letter warning physicians that venlafaxine (Effexor and Effexor XR) was associated with an increased rate of hostility and suicidal ideation in pediatric clinical trials.
October, 2003: The FDA issued another advisory “alerting physicians to reports of suicidal thinking (and suicide attempts) in clinical studies of various antidepressant drugs in pediatric patients with major depressive disorder (MDD).”
The advisory also stated that of eight antidepressants reviewed (Celexa, Prozac, Luvox, Remeron, Serzone, Paxil, Zoloft and Effexor) only Prozac has been shown to be effective in pediatric major depressive disorder (MDD).
Finally the advisory went on to state “In the 20 placebo-controlled trials being considered for these 8 drugs, involving over 4100 pediatric patients, there have been no reports of completed suicides.”
January 21, 2004: A task force of the American College of Neuropsychopharmacology issued a report concluding that taking SSRIs or other new generation antidepressant drugs do not increase the risk of suicidal thinking or suicide attempts. Three strong lines of evidence in youth -from clinical trials, epidemiology, and autopsy studies - led to this conclusion.
Two recent journal articles published during this time period found the following:
August, 2003: A study of two randomized trials of sertraline – Zoloft – in children and adolescents with MDD which found efficacy of active medication vs. placebo was published in the Journal of the American Medical Association.
October, 2003: A study which showed an inverse relationship between regional change in the use of antidepressants in individuals ages 10-19 and the incidence of completed suicide (the greater the use of antidepressants in a geographic region the less the number of suicides) was published in the Archives of General Psychiatry.
Making sense out of conflicting advisories
Unfortunately, we must work with partial information. The initial British and FDA cautions about Paxil were based on three British, controlled studies - sponsored by GlaxoSmithKline - of depressed children and adolescents. The actual studies are not published and all the data is not available.
While the “jury” is still out, there are several possible reasons why children and adolescents may have an increase in suicidal ideation and/or behavior:
- Akathesia - which is a severe and extremely unpleasant restlessness and can be a rare side effect of these medications may trigger an increase in dysphoric mood and hopelessness.
- There is some evidence in the scientific literature that suggests that depressed youngsters may be more likely to have a bipolar disorder. A switch to mania or a mixed mood state during treatment of depression can result in suicidal behavior.
- Patients may have more energy but still be depressed and feel hopeless during the early phases of treatment, and this may result in the potential for suicidal thinking to lead to self-destructive behavior.
- Withdrawal from short acting antidepressants such as Paxil and Effexor may result in problematic physical symptoms. These effects may occur even if a child misses one or two doses.
What about the use of SSRIs for anxiety?
There is no evidence that any of the issues related to MDD is present in the treatment of childhood anxiety disorders. The efficacy of SSRIs in General Anxiety Disorder (GAD), Separation Anxiety Disorder (SAD), Social Phobia and Selective Mutism has been clearly in a number of studies. (e.g. the large multicenter RUPP trial (RUPP Anxiety Study Group (2001), Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 344:1279–1285).
Approval has been received by pharmaceutical companies for children and adolescents for the following medications for the conditions listed
Prozac - Major Depressive Disorder (MDD) & Obsessive-Compulsive Disorder (OCD)
Zoloft – OCD
Luvox - OCD
Implications for potential patients and their families
- All research studies, including those for the treatments of depression and anxiety, are rigorously reviewed for safety, by an independent panel of professionals and by the National Institute of Mental Health if they are the funding source.
- Whether treated clinically or through a research study all patients should be carefully evaluated and monitored closely for all side effects including the potential for self harm.
- If you or your child are being treated make sure that you follow up on a regular basis with your physician to monitor for side effects and suicidal thinking.
- There is no evidence that children and adolescents with anxiety disorders will have any increase in self-harm thoughts. The FDA advisory only discussed the use of these medications for depression.
- There are a number of studies that demonstrate the usefulness of this group of medicines in anxiety disorders.
- While efficacy for the treatment of depression in children and adolescents has only been demonstrated for Prozac and more recently for Zoloft, there may be a solid clinical reason to choose another antidepressant. Again, careful and frequent monitoring must be provided to all patients.