Steven P. Cuffe, M.D.
Director, Division of Child and Adolescent Psychiatry
William S. Hall Psychiatric Institute, SC Department of Mental Health
Department of Neuropsychiatry and Behavioral Science
University of South Carolina School of Medicine

The question is counter-intuitive. Could the antidepressants we use to treat depression, specifically the serotonin reuptake inhibitors (SSRI) so widely used in children and adults, actually increase the risk of suicide in children and adolescents? This question has arisen in the past year, and unless you have been in isolation in medical school or residency, you have probably seen or read something about it. This article will review the events of the past year, look at possible hypotheses to explain an increased risk, if one exists, and finally will examine what we know about the data that sparked the controversy.

In June 2003, The Medicines and Healthcare Products Regulatory Agency (MHRA), the U. S. Food and Drug Administration (FDA) counterpart in the United Kingdom, warned physicians about the possible increased risk of suicidal ideas or suicide in children and adolescents taking paroxetine (an SSRI). After further analysis of data on all the SSRI’s, the MHRA in December, 2003, found that, with the exception of fluoxetine, SSRI’s have not been proven effective for youth with depression and may increase the risk of suicidal thinking or attempts. It is important to note that “lack of proven effectiveness” is not the same as “proven ineffective”. The FDA, partly in response to the actions in the U.K., issued a warning concerning paroxetine, and held hearings on the issue of SSRI’s and suicide in February, 2004. As a result of the hearings, the FDA issued a Public Health Advisory and asked the makers of all the newer antidepressants, including fluoxetine, to add a warning statement to their labeling recommending close observation of adults and children treated with these agents for worsening depression or the emergence of suicidality. The FDA also established the Suicidality Classification Project to improve the definition of suicidal behaviors, and to re-analyze all the available data from the studies. The need for improved classification of suicidal behavior stems from the inclusion of behaviors not directly related to suicidal behavior in the MHRA analysis of suicide risk. They included non-suicidal self-harm and harm to others in the analyses. The FDA then decided to pusue further analysis of the data before taking any more action.

What could be happening to cause this effect, if it exists? There are several theories. First, a long-held belief among psychiatrists hypothesizes that as one’s depression improves, a person becomes more energetic, less apathetic, and better able to make decisions. If a patient remains suicidal when this occurs, the risk of suicide would increase. While this hypothesis has some appeal, there has never been any evidence to support or refute it. In the July 21 issue of JAMA, Jick and colleagues1 studied suicidal behavior after initiating antidepressant treatment, and found an increased risk in the first month of treatment, and particularly in the first 9 days, compared to the risk of suicidal ideas and behavior later in the course of treatment. Nothing can be inferred about whether the medications caused this increased early risk, since there is no placebo control group. In fact, the authors speculate that people starting antidepressants begin this treatment when their depression is at its worst, and therefore at highest risk for suicidal behavior. There were no significant differences in the rate of suicidal behavior among the 4 drugs studied. The study investigated two tricyclic antidepressants (amytriptyline and dothiepin) and two SSRIs (fluoxetine and paroxetine). There was also no difference in those aged 10-19 from adults. However the numbers in the study were small for this age group. This study gives some indication of increased risk of suicidal behavior early in treatment, but does not compare active drugs to placebo. The study further provides evidence against the hypothesis that withdrawal from antidepressant medication causes suicidal behavior. Also of interest is that the database they used, the UK General Practice Research Database for 1993-1999, included 15 children age 10-19 who committed suicide. None of these 15 children had received a prescription for an antidepressant medicine.

A second hypothesis concerns possible side effects of antidepressants: activation, agitation, impulsivity and disinhibition. Psychiatrists sometimes see these side effects in patients taking antidepressants, especially early in the course of treatment. Could they increase the risk of considering suicide? Again, no evidence exists to support the hypothesis, and agitation does not necessarily equate to suicidal behavior. However, clinical practice has been to consider that patients are at increased risk early in the course of treatment.

Finally, antidepressants have been found to sometimes precipitate manic episodes, especially if there is a family history of bipolar disorder. While there is also an increased risk of suicide in patients with bipolar disorder, there is no evidence that a patient switching from depression to mania due to antidepressant treatment has increased risk.

So, what are the findings that have led to these warnings about an increased risk of suicide for children and adolescents taking SSRI’s? Data available on the FDA website lists all the current randomized controlled trials (RCT) on SSRI’s (see http://www.fda.gov/ohrms/dockets/ac/04/briefing/4006B1_03_Background%20Memo%2001-05-04.pdf). For paroxetine, the drug the U.K. MHRA first warned physicians about, there are three RCT’s. Only one of the 3 studies shows a difference between drug and placebo in “possibly suicide-related” (6.5% to 1.1%) or “suicide attempts” (5.4% to 0%). For 2 other studies, there is no difference (3.9% for drug versus 4.2% for placebo, and 1.0% for drug versus 1.0% for placebo). For fluoxetine, on the other hand, 1 of three studies shows placebo having higher levels of suicidal behavior (0% to 5.3%) or attempts (0% to 5.3%), while the other 2 show no difference. It is important to note that none of the studies (analyzed individually) for any of the SSRI or SNRI antidepressants show a statistically significant difference between drug and placebo in suicidal ideation or attempts. Also, none of the over 4000 children or adolescents participating in any of the antidepressant trials actually committed suicide.

One final comment should be made concerning the U.K. MHRA decision. They based the recommendation not to use any antidepressant, with the exception of fluoxetine, in children and adolescents based on their criteria for showing a medication is effective: the MHRA requires at least 2 positive randomized trials. Only fluoxetine has 2 positive RCT’s in children and adolescents. There is also some disagreement among scientists about what constitutes a positive trial. For instance, if data from the 2 trials for sertraline are combined, the outcome is positive, while neither study in isolation reaches significance at p= 0.05. Citalopram and paroxetine (for adolescents only) also have one positive study, but not two. So there is evidence for effectiveness, but more research is needed.

Another important issue to consider is whether there is evidence that antidepressants actually decrease the risk of suicide by treating the depression that brings the risk in the first place. Suicide rates have been declining since about 1987 for adults and since the mid nineties for children and adolescents.

Many factors could play a role in this decrease. Is the increased use of antidepressant medications one of the factors? For children, there are increases in the early to mid 1970s, followed by relatively stable rates of suicide in the 1980s and early 1990s. In the mid 1990s (about 1994), the rate began to decline. The use of antidepressant medicines in children has increased dramatically over the past 10-15 years2. Some epidemiological evidence suggests that antidepressant use in children and adolescents has decreased suicide rates. A study by Olfson and colleagues3 analyzed prescription data from the nation’s largest pharmacy benefit company and compared change in antidepressant medication treatment with suicide rate in youth aged 10-19. They found a significant inverse relationship between changes in antidepressant use and suicide, and concluded that there may be a role for antidepressant medications in suicide prevention efforts. While these studies are associational and do not prove causality, they do suggest that increasing use of antidepressant medication may have a role in the decrease in suicide over this time period.

Another new study, the Treatment of Adolescent Depression Study (TADS), was published August 18, 20044. This is arguably the most important study ever published on the treatment of depression in children. This study randomly assigned 439 depressed 12-17 year olds to one of 4 conditions: 1. placebo; 2. fluoxetine alone; 3. cognitive-behavioral therapy (CBT) alone; and 4. CBT combined with fluoxetine. The results are strongly supportive of the use of fluoxetine in depressed adolescents: the combination of CBT and fluoxetine was significantly more effective than placebo, CBT alone or fluoxetine alone. Neither fluoxetine alone nor CBT alone were significantly different from placebo, although the fluoxetine alone group improved significantly more than the CBT alone group. The rates of positive response to treatment among the adolescents were: CBT plus fluoxetine 71.0%, fluoxetine alone 60.6%, CBT alone 43.2%, and placebo 34.8%.

The TADS study also examined suicide-related events. All three treatment arms significantly reduced suicidal ideas compared to the placebo group. Additionally, suicide attempts were not significantly associated with SSRI use. However there was a significantly higher rate of “harm-related events” in the adolescents treated with fluoxetine. These events include both suicidal and non-suicidal (for example cutting oneself without suicidal intent) self-harm, increase in suicidal ideas, or thought or acts of harm to others or property. This much broader definition reached significance.

The results of the FDA re-analysis of the SSRI data have recently been posted on the FDA website (http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf). Although no individual drug trial shows a statistically significant increase of suicide attempt or suicidal ideas, there is a consistent increase in risk ratio of about 1.5-2 among all the antidepressants. Even when data from studies for the same drug are pooled and data on suicidal thinking is combined with suicidal behavior, only venlafaxine has a statistically significant increase from placebo (although paroxetine is very close to significant). The evidence of a signal is rather weak, but the implications are significant. These data prompted the FDA advisory panel to recommend on a split vote (15-8) a “black box” warning for all antidepressants (including tricyclic antidepressants and other new drugs). This is the most serious warning the FDA gives short of prohibiting use of the drug. Clearly, parents and teens need to be informed of this potential risk. But the risk is relatively small (a risk ratio of 1.5-2 would mean between 2 and 3 children per 100 taking these medication would have suicidal thought or behaviors as a result). The impact of a new black box warning may have unintended consequences. Parents and primary care physicians may react to this news by refusing to use antidepressant medications in children and adolescents who need them. Untreated depression in adults is associated with a 15% suicide rate. If the reduction in the rate of suicide in this country is at least partially due to the dramatic increases in the rate of SSRI use, then we may see a reversal of the trend for decreasing suicide rates in adolescents. It is critical to quickly fund further research to answer these questions.

What are we to make of all this data? Should children and adolescents be treated with antidepressants? Do they really cause an increased risk of suicidal behavior? Or do they cause a decrease in suicidal behavior? Is fluoxetine the only one that really works? Clinicians clearly believe other antidepressants are effective. The answer is we just don’t have enough research to know with any certainty. We must await further data to make a final decision. Further research on the possible long term decrease in suicide due to SSRI antidepressants is not currently available. Until we see the data and can evaluate the risks more fully, it would be wise to use SSRI’s in children and adolescents with caution, monitor for the possible problems discussed above, and pay special attention to suicide risk assessment when treating children and adolescents, especially early in their treatment, with these medications.

Finally, I would add that the strongly positive results of the TADS study indicate that medication treatment is vital for effective treatment of adolescent depression. With the confusing results of studies to date, fluoxetine is a good first choice for antidepressant treatment of adolescents. However, there may be reasons that clinicians choose to start other antidepressants instead. For instance, adolescents with a good prior response to another antidepressant, who are currently on another antidepressant with good response, or who have a history of poor response to fluoxetine, would probably be started or stay on another antidepressant.

References:

1. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004; 292:338-343

2. Zito JM, Safer DJ, DosReis S, Gardner JF, Magder, L, Soeken K, Boles M, Lynch F, Riddle MA. Psychotropic practice patterns for youth: A 10-year perspective. Arch Pediatr Adolesc Med 2003; 157(1):17-25.

3. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003; 60:978.

4. Treatment for Adolescents with Depression Study Team. Fluoxetine, Cognitive-Behavioral Therapy, and Their Combination for Adolescents With Depression: Treatment for Adolescents With Depression Study (TADS) Randomized Controlled Trial. JAMA. 2004; 292:807-820.