June 2007

Using antidepressants for children

by Robert H. Blanks, PhD, President, RCS

The Association of Chiropractic Colleges (ACC) consensus statement includes three important characterizations of the profession: 1) the ACC position on chiropractic, 2) a representation of the chiropractic paradigm, and 3) clarification regarding the definition and clinical management of the subluxation.

In particular, the preamble of the ACC Position on Chiropractic clearly states the position on prescription medication: "Chiropractic is a health care discipline which emphasizes the inherent recuperative power of the body to heal itself without the use of drugs or surgery..."

However, there are instances where pharmaceutical agents and surgery may be warranted, such as in trauma or life threatening situations. How, then, are chiropractors trained to evaluate such clinical findings?

As I discussed in the April edition of The Chiropractic Journal, clinical decision‑making involves more than simply taking published results of research directly to the clinic.

There are many factors to take into account, including patient preference, study value, practitioners training and experience, etc. ‑‑ not the least of which is interpreting the results by applying reliable statistical criteria. And, even if one is not personally involved with eventually using the new technology, there are at least two criteria to evaluate as a health professional:

Clinical meaningfulness (clinical significance, clinical utility): Is the determination whether the observed changes or differences between the intervention and control groups mean something, or that they do not and should be ignored.

Numbers Needed to Treat (NNT) or to Harm (NNH): Is the number of patients needed to treat" (NNT) in order to expect a favorable outcome in just one patient. This concept can also be used to express adverse events such as side effects, etc. A "Number needed to Harm" (NNH) indicates the number of patients that must be treated on average to produce a given adverse event in one patient.

As chiropractors, the terms NNT and NNH do not translate well because the term "treat" is a medical term describing the attempt to treat a specific (diagnosed) condition. However, the concept is important and one can transpose the concept to chiropractic as meaning the number of adjustment required to correct the vertebral subluxation (NNT), or the number of adjustment before a major adverse event occurs (NNH).

The NNT for a given therapy is simply the reciprocal of the absolute risk reduction for that treatment. [1‑3] Absolute risk reduction is determined by subtracting the risk in the intervention group from the risk in controls (and conversely for NNH) as described in the previous article.

The NNT and NNH help to interpret the clinical meaningfulness of an intervention and quickly answer the critical questions:

1. Does the intervention work? Determined by applying the statistics used to evaluate clinical meaningfulness.

2. If so, how well does it work in comparison to groups receiving placebo, no treatment, or other interventions that are currently in use?

3. Is the new intervention safe?

Clinical risks and benefits for use of antidepressants in children

This is a very controversial topic. Depression is one of the most common psychological/psychiatric disorders. It affects mood, the expression of emotion and behavior. An estimated 10% of children have difficulty escaping the symptoms of depression for long periods; the rate is dramatically lower (about one percent) in children ages 1‑6 years, and is higher in older children 9‑12 years (12%).

Evidence suggests that interventions which emphasize treatment centered on the family, and not just the patient are critical for optimal outcomes.

Group and individual approaches (cognitive, behavioral, social skills, self‑control training and promotion of interpersonal skills) are usually the first treatments of choice for children and adolescents experiencing experience major depression, anxiety and related mental health (obsessive compulsive) disorders.

Medications are usually the second choice in the medical setting after a comprehensive and competent trial of psychotherapy.

In what is probably the most comprehensive review of the medical literature on antidepressant use in children, researchers found that "relative to placebo, antidepressants are efficacious for pediatric MMD (Major Depressive Disorder), OCD (Obsessive Compulsive Disorder), and non‑OCD anxiety disorders. [4]

However, consistent with earlier analyses by the FDA [5,6] this comprehensive analysis of 5,310 children and teenagers from 27 different clinical trials found evidence of an increased risk of treatment‑emergent suicidal ideation/suicide attempt.

Using a pooled random‑effects risk differences, the new study by Bridge and colleagues [4] found a risk of suicidal ideation/suicide attempt less than 1% and no completed suicides in any of the trials.

The one percent added risk of side effects in this report stands in contrast to the recent FDA review and meta‑analysis of 24 placebo‑controlled trials assessing antidepressant medications among more than 4,400 children and adolescents.

The earlier FDA report concluded that these medications pose a four percent higher incidence of suicidal thoughts and behavior among children taking antidepressants although no suicides were reported. [5,6] Moreover, based upon the latter findings, the FDA issued a warning posted on all antidepressant prescriptions for children and adolescents.

Clinical decision making

It remains to be seen whether the FDA will modify its earlier warning on antidepressant use in children based upon the new findings.

The re‑evaluation boils down to interpreting the overall risk: benefit ratio using among other statistical indicators the NNT and NNH. Depending on treatment indication (depression, anxiety or OCD), the average overall NNT from all studied reviewed ranged from 3 to 10, while the NNH ‑measured as suicidal ideation/suicide attempt ‑ranged from 112 to 200." [4]

In short, across all these studies physicians must treat on average 3‑10 children with antidepressants to obtain a positive outcome in one child, and in so doing should expect one major adverse event (in this case suicidal thoughts or behavior) with treating 112‑200 patients.

These newest estimates of the risk for suicidal ideation/suicide attempt are lower (one percent) than those reported by the FDA (four percent) apparently in part because of methodological differences in how risks were calculated (random‑effects vs. a fixed‑effects model used by the FDA), and the inclusion of the three newer studies not available at the time of the FDA report.

True, although there was a slight reduction in risk by including the newer studies (one percent vs. four percent), the slight improvement in risk could have been accounted for by methodological differences in the analysis by FDA vs. the current study and not actual findings in patients.

Fortunately, the FDA has no immediate plans to soften or eliminate antidepressant warning labels as a result of the new research. The Director of the FDA division of psychiatry products, Dr. Thomas Laughren, was quoted in a recent New York Times article (Wednesday April 18, 2007) as saying, "At this time nothing indicates a need for change in the 'black box' warning , which urges attention to patients starting treatment."

What also needs to be evaluated before lifting the FDA warnings is the fact that neither study considered the marginal benefits of medication relative to other adverse effects of antidepressants, such as insomnia, and gastrointestinal tract symptoms that may be more common in children than in adolescents, [7] or other adverse effects of the medication, such as mania, irritability, and agitation, any of which may precipitate suicidal ideation/suicide attempt. [8]

The choice of treatment in the medical setting should be the result of careful diagnosis and a collaborative discussion between clinician, family, and the patient. Meta‑analyses of the scope provided by the FDA and recent Bridge et al. study should provide the informed evaluation of the potential benefits and risks of medications vs. non‑drug treatments as options. [9,10]

As chiropractic continues to advance its evidence‑based culture to establish the meaningfulness of the chiropractic adjustment, we need to learn to evaluate the literature behind the medical care our patients might be undergoing in parallel with the care being offered in our offices.

Moreover, by participating in the large study on the effectiveness of subluxation chiropractic being conducted by Research and Clinical Science (RCS), we need to remember to report our chiropractic findings in the most effective and meaningful manner. The NNT statistic appears to be the most effective in conveying the results of clinical trials to the broadest group of patients, clinicians and policy makers.

References

1. Laupacis A, Sackett DL, Roberts RS. "An assessment of clinically useful measures of the consequences of treatment." N Engl J Med. 1 988;318:1728‑33.

2. Cook RJ, Sackett DL. "The number needed to treat: a clinically useful measure of treatment effect." BMJ. 1995;310:452‑4.

3. McQuay HJ and Moore RA. "Using Numerical Results from Systematic Reviews in Clinical Practice." Ann Int Med 1997. 126:712‑720.

4. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA. "Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. A Meta‑analysis of randomized controlled trials." J Am Med Assoc 2007; 297 (15), 1683‑95.

5. Hammad TA, Laughren T, Racoosin J. "Suicidality in pediatric patients treated with antidepressant drugs." Arch Gen Psychiatry. 2006;63:332‑339.

6. US Food and Drug Administration. "Relationship between psychotropic drugs and pediatric suicidality: review and evaluation of clinical data." www.fda.gov/ohrms/dockets/ac/04/briefing/2004‑4065b1‑10‑TAB08‑Hammads‑Review.pdf (alternate: http://tinyurl.com/34lpgn) Accessed April 20, 2007.

7. Safer DJ, Zito JM. "Treatment‑emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents." J Child Adolesc Psychopharmacol. 2006;16:159‑169.

8. Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D. "Age effects on antidepressant‑induced manic conversion." Arch Pediatr Adolesc Med. 2004;158:773‑780.

9. Weisz JR, McCarty CA, Valeri SM. "Effects of psychotherapy for depression in children and adolescents: a meta‑analysis." Psychol Bull. 2006;132:132‑149.

10. James A, Soler A, Weatherall R. "Cognitive behavioural therapy for anxiety disorders in children and adolescents." Cochrane Database Syst Rev. 2005;(4):CD004690 doi:10.1002/14651858.CD004690.pub2.

(RCS co‑founder and President Dr. Robert Blanks is Professor in the Department of Biomedical Sciences at Florida Atlantic University and a past Professor of Anatomy and Neurobiology at the University of California, Irvine. Prior to this he spent two years at the Max Planck Institute for Brain Research in Frankfurt, Germany and two years in the Department of Anatomy at Harvard Medical School. Dr. Blanks is on the Advisory Board of the International Spinal Health Institute, is a Board Member of the Council on Chiropractic Practice and is actively involved in chiropractic research. To learn more about health outcomes research and RCS, call 800‑909‑1354 or 480‑303‑1694.)