Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents (Review)

A bit of background………

The Cochrane Collaboration, founded in 1993 is a non-profit organization who coordinate the writing and dissemination of systematic reviews of healthcare interventions. Their goal is to ensure that health practitioners and members of the public have at their fingertips the best available evidence for what works in the treatment of a variety of medical and psychological conditions. The systematic reviews are an invaluable resource for people like me (who provide healthcare interventions) as they help clarify what current research suggests are the best interventions for specific disorders.

The reviews, which are prepared by volunteer health professionals (organized into specific review groups) follow strict methodological formats in collating and analyzing current evidence. These formats are updated and developed by method groups within the Cochrane Collaboration. You can learn more about the groups within the Cochrane Collaboration here.

in 2007, the Cochrane Collaboration published a review on the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depressive disorders in children and adolescents. Authored by Hetrick, Merry, McKenzie, Sindahl & Proctor, the review sought to clarify two issues that have been highly controversial in depression management, namely:

a) the efficacy of SSRIs in the treatment of depressive disorders (i.e., do SSRIs alleviate depression symptoms?)

b) the safety of SSRIs (i.e., what are the adverse outcomes of using SSRIs?)

Depression (or depressive disorders more accurately) in children and adolescents are more common than you might think. The authors cite prevalence figures of 2.8% for children and 5.7% for adolescents (taken during a 6-12 month period). The fact that 50% remain depressed at 12 months, ~30% remain depressed at 24 months and 30% have recurrences within 5 years that often progress to episodes in adulthood means that treating depression early may prevent the immense burden of depression in adulthood.

Concerns have been raised repeatedly on the efficacy and safety of SSRIs in children and adolescents. Most pertinent has been the concern that use of SSRIs is associated with a greater risk of suicide-related behaviour and/or suicide ideation. Hetrick et al. cite two meta-analyses showing consistent and modest increases on SSRIs compared to placebo. The FDA have issued a black box warning for SSRIs.

The review itself

Cochrane reviews aggregate findings from across multiple studies. Following strict criteria, the reviews identify the best quality trials of a particular treatment (in this case SSRIs). The challenge is often the heteregeneity of the studies (i.e., varition in how they they are conducted) and this review is no exception. Hetrick et al. identified 12 relevant trials with 10 providing usable data. These trials included:

• Predominantly published reports (at least at the time of the publication of the review)

• Those looking at major depressive disorder (not sub-syndromal or dysthymic disorders) as diagnosed by DSM-III or DSM-IV criteria

• Multi centre trials (data from many countries)

• Comparisons of SSRI to placebo

• Four SSRIs: paroxetine, fluoxetine, citalopram & sertraline

• Five trials for adolescents and 7 trials for children

• Treatment period of 7-12 weeks

Making the job harder, the studies differed in their measures of depression symptom severity, cut-off scores for “improvement”, exclusion of comorbidities, attrition rates (~17-46%), length of treatment (7-12 weeks) and overall methodology. I don’t envy the task of modern systematic review writers!!

What they concluded………

With respect to efficacy, the news isn’t particularly exciting. As the authors lament, given that over 2000 young people have participated in these trials, we are still no closer to being able to answer the question on SSRI efficacy. Statistically, SSRI use was associated with a greater increase in the number of patients who improved during the trials, with a consistent effect shown for fluoxetine. However, against a backdrop of a) the extent of the change noted having questionable clinical significance, b) 3 of the four SSRIs showing inconsistent effects, c) strict exclusion criteria meaning trial patients different from those presenting to clinics and d) considerable methodological heterogeneity and bias, the authors were led to state

“there are no definitive answers for those working with children and adolescents with depressive disorder”

With respect to suicide-related outcomes, there were no completed suicides in the total sample of clients (all studies). There was however evidence of an increased risk of suicidal behaviour and/or suicidal ideation (between 1-13% of those on SSRIs versus 0-7% on placebo), consistent with what has been found in other similar reviews. This places extra importance on clinicians weighing up the potential risks/benefits of using SSRIs in the treatment of child and adolescent depression and communicating these succinctly to families seeking treatment.

Comment

Hetrick et als. review, whilst rigorous in its methodology, leaves clinicians in a kinda “no-mans land”. This is no comment on the quality of their conclusions but rather the current status of SSRI treatment trials in children and adolescents. If I am reading their report accurately, the clinician in me concludes “SSRIs have limited clinical utility (restricted to fluoxetine) in reducing symtpoms of major depression and a question mark hangs over their risk profile”. The researcher in me questions “how is it that researchers can be this far down the path of evaluating SSRIs (over 2000 patients in just the trials in this review) yet still have so many methodological issues to answer?”

As a psychologist, and therefore a stronger advocate of psychological therapies, I wonder how non-drug therapies stack up in terms of efficacy and safety. Perhaps this is a good idea for a future review 🙂