Are SSRIs safe for childhood depression?
Depression is a serious medical problem in children and adolescents. Suicide, although rare in children ages 10-14, is the third leading cause of death in the 15- to 24-year-old age group in the United States,1 with a prevalence rate of approximately 0.01%. Unfortunately, most depressed youth are still undiagnosed and undertreated. Although the actual rate of suicide is very low, suicidal thoughts are much more common (approximately 19%), with suicide attempts at about 9%. As one would expect, patients with more severe depression are more likely to be diagnosed and in treatment. These patients are also the ones most likely to have attempted suicide in the past or to attempt suicide in the future (35%-50%), with 2%-8% actually succeeding over a 10-year period.2 Now, with this increased risk in patients being treated for depression come case reports that patients on selective serotonin reuptake inhibitors (SSRIs) have attempted suicide, maybe even more than patients not on SSRIs.
It is also important to remember that suicidality is not the only morbidity associated with depression. Stress early in life can produce long-term changes in physiologic regulation, emotional behavior, and cognitive function. Such effects can cause problems with concentration and learning, with subsequent difficulty in school performance. The consequences of poor school performance are many and often have lifelong effects, such as decreased earning capacity and decreased self-esteem. Social functioning is also affected by depression. Youth either can be withdrawn or can exhibit increased risk-taking behaviors, both of which can have negative consequences on a child's development.3
Q. What medications were used to treat depression in the past?
A. Before SSRIs, tricyclic antidepressants (TCAs) were the primary class of drugs used as treatment for depression. A recent meta-analysis of published data on the effectiveness of TCAs for depression in children concluded that these agents were not effective.4 TCAs also have many side effects, including a risk of overdose.
With the development of SSRIs in the 1990s and subsequent publication of clinical trials demonstrating possible effectiveness of these agents for treating depression in youth with fewer side effects, clinicians began using SSRIs more and more as a first-line therapy. SSRIs are also safer than TCAs because the risk of death from overdose is minimal.
Q. Is psychotherapy effective in pediatric patients?
A. Most experts recommend that some form of “talk” or psychotherapy is beneficial to recovery from depression. Unfortunately, there are minimal published data on psychotherapy. A particular form of psychotherapy, called “cognitive behavioral therapy” (CBT), has been studied in adolescents but not in children. Many adolescents (40%-60%) improve when treated with CBT.5 But according to Aaron T. Beck, MD, author of the Beck Depression Inventory, the effectiveness of any psychotherapy improves with the motivation and maturity of the patient.6
Two recent studies demonstrated that the addition of psychotherapy to SSRI treatment in depressed adolescents led to significant improvement in 71%-75% of patients.7,8 There was also a decreased risk of suicide or suicidal thinking when these therapies were combined.
Q. What is the controversy over using SSRIs in youth all about? Do SSRIs increase suicidal behavior in children and adolescents?
A. Researchers first became aware of the connection between SSRIs and suicidal tendencies shortly after they came into use in the early 1990s. Case reports described a few individuals (adults) whose thoughts of suicide got worse after starting treatment with an SSRI. This effect sometimes resolved when the SSRI was discontinued and then recurred when it was reintroduced. In 1993, the American College of Neuropsychiatrists (ACNP) published a report on its review of these case studies and all other studies published on the topic at the time. The organization concluded that there was no increased risk of suicidality in depressed patients on SSRIs or any other antidepressants. The only thing these patients had in common was a diagnosis that increased their risk for suicide.9
Then, in June 2003, the British Yellow Card Reporting system announced the results of its examination of a database of adverse drug reactions (ADRs) in the United Kingdom. The conclusion was that there was an increased risk of suicidality in youth taking paroxetine (Paxil).10 The authors recommended that this drug not be prescribed to individuals younger than 18 years of age. The UK Committee on Safety of Medicines (CSM) of the Healthcare Products and Regulatory Agency also warned against the use of Paxil in children.11 This was followed with an additional ban on all remaining SSRIs except fluoxetine (Prozac) in December 2003.12 Health Canada followed the UK's lead and issued a public warning that the use of seven antidepressants — Paxil, buproprion (Wellbutrin), citalopram (Celexa), fluvoxamine (Luvox), mirtazapine (Remeron), sertraline (Zoloft), and venlafaxine (Effexor) — “should proceed only after consultation with the treating physician to confirm that the benefits of the drug outweigh the risk.”13
Whittington et al from the Centre for Outcomes Research and Effectiveness in the UK corroborated the conclusions of the CSM with their own meta-analysis of data from randomized controlled trials evaluating SSRI vs. placebo for treatment of depression in patients ages 5-18 years.14 One additional analysis of the available data highlights the lack of published studies and strongly chastises pharmaceutical companies for not making all of their clinical trials data available for evaluation.15
In the United States, the FDA responded with its own investigation. In March 2004, the agency issued a Public Health Advisory cautioning clinicians, patients, and families about the need to closely monitor all persons being treated with antidepressants. The FDA also requested a label change for 10 SSRIs — Prozac, Zoloft, Paxil, Luvox, Celexa, escitalopram (Lexapro), Wellbutrin, Effexor, nefazodone, and Remeron — to include stronger cautions about the need to monitor patients for signs and symptoms of worsening depression and thoughts about suicide.16
In response to all these recommendations, the ACNP formed a task force, the duty of which was to evaluate the safety and efficacy of SSRIs.