|The Therapeutics Initiative presents critically appraised summary evidence primarily from controlled drug trials. Such evidence applies to patients similar to those involved in the trails, and may not be generalizable to every patient. We are committed to evaluate the effectiveness of our educational activities using the Pharmacare/PharmaNet databases without identifying individual physicians, pharmacies or patients. The Therapeutics Initiative is funded by the BC Ministry of Health through a 3-year grant to the University of BC. The Therapeutics Initiative provides evidence based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.|
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No antidepressants are approved in Canada for individuals less than 19 years of age. In the United States, fluoxetine is approved for major depressive disorder (MDD) in individuals aged 8 years and older. However, the Product Monograph includes a strong warning about the potential for suicidality and various emotional and behavioral adverse effects.1 The United Kingdom (UK) regulatory agency has determined that the harm to benefit balance is unfavorable in pediatric MDD for all antidepressants but fluoxetine.2 Despite this, the UK fluoxetine monograph states that it is “not recommended” for people less than 18 years of age.
In British Columbia, as in other jurisdictions, antidepressants are commonly prescribed to individuals under 19 years of age and these prescriptions have doubled between 1998 and 2003.3 The main antidepressants being prescribed are the newer ones, selective serotonin reuptake inhibitors (SSRI), serotonin noradrenaline reuptake inhibitors (SNRI) and mirtazapine (see Table). The growth in prescribing of these drugs is particularly disconcerting in light of reports suggesting that the drugs are not proven effective and are causing serious psychiatric adverse effects in some individuals.2,4,5
|Chemical name||Brand name||Chemical name||Brand name|
A Cochrane systematic review of the tricyclic antidepressants (TCA) in
children and adolescents shows little or no benefit for TCAs as compared to
placebo.6 Controversy about the SSRIs and SNRIs
has arisen because only a selected 6 out of 15 randomized controlled trials (RCTs)
studying these agents in child and adolescent depression have been published.7-11
Only the regulatory agencies have access to the full data set from the 15 RCTs and their conclusions are as follows. Note that a positive trial is one in which the pre-defined primary outcome is statistically significantly better for the drug as compared to the placebo. Of the 15 RCTs only 3 (2 fluoxetine and 1 citalopram) were positive.2,11
Six of the 15 RCTs are published, all claiming effectiveness: 2 pooled sertraline trials12, one paroxetine trial13, two fluoxetine trials14,15, and one citalopram trial.16 However, the claims in 3 published trials (1 paroxetine and 2 sertraline) were not confirmed after independent analysis by the regulatory agencies.2,11 In the paroxetine trial Keller et al13 claimed efficacy for paroxetine and not for imipramine as compared to placebo; re-analysis by both the Medicine and Health Care Products Regulatory Agency2 and the Food and Drug Administration11 concluded this trial was negative for both antidepressants. The two sertraline trials were reported as positive when pooled together.12 Upon re-analysis, the trials were shown separately to both be negative.2,11 The following unpublished placebo controlled trials were negative: 2 paroxetine trials, 2 venlafaxine trials, 2 nefazodone trials, 2 mirtazapine trials and 1 citalopram trial.
In the 3 positive studies, the benefit was limited to a modest improvement in some symptoms, not remission of the disorder.14-16 The 2 fluoxetine trials14,15 have also been criticized on re-analysis.17
Determination of the true rates of harm is hampered by inconsistent
ascertainment, description and reporting of adverse effects. For example, in the
published adolescent paroxetine trial13, 11/93 patients discontinued paroxetine
due to “serious” psychiatric adverse effects, of which the most common was
described as “emotional lability.” This was then further defined as “suicidal
ideation/gestures, conduct problems or hostility, e.g. aggressiveness…” Such
responses led 7.5% of the initially mildly depressed outpatients placed on
paroxetine to be hospitalized. None of the placebo-treated patients required
hospitalization. This finding was dismissed in the discussion. The sertraline
trials did not include a side effect checklist in the protocol, yet the
medication was described as well-tolerated.12
Rates of suicidal ideation and attempts are low in most trials (2-3% with drug; 0-1% with placebo), and hence seldom reach statistical significance in individual trials. However, the direction of change is the opposite of that predicted if the medications are improving depression. Furthermore, observations in clinical trials and case reports from the past 12 years indicate that up to 25% of children placed on various SSRIs experience psychiatric adverse effects such as agitation, disinhibition, aggression, hyperkinesis and emotional lability.18 The recent labeling changes by Health Canada and the Food and Drug Administration emphasize these potential psychiatric and behavioral adverse effects in both children and adults.4,19
The published literature on this topic is an incomplete and inaccurate representation of the totality of evidence. The profession has had a difficult time coming to terms with this fact.7 When we are guided by meta-analyses carried out on biased datasets, we are operating under the illusion of practicing evidence-based medicine. A recent article has termed this “evidence-biased medicine”.20Clinical Implications
The prescription of an antidepressant to a child or adolescent is like an open trial with up to 80% of patients expected to improve. When improvement occurs, it is most likely due to a placebo group response, which includes spontaneous remission, response to supportive care, and other components. Because of the unfavorable harm to benefit balance for antidepressants in this age group, first-line therapy is multiple supportive interventions: sleep hygiene, exercise, regular dietary patterns, consistent parenting, and practical problem-solving regarding schooling and life stressors.21 For those who do not respond, individual or group cognitive behavioral therapy or interpersonal psychotherapy should be arranged, if possible.21,22 Medications are reserved for add-on therapy when the first two approaches are not working. When an antidepressant is prescribed, the patient must be monitored for signs of deterioration: behavioral and psychiatric changes, including increases in suicidal thinking, as emphasized by the new Health Canada labeling.4
|This Therapeutics Letter contains an assessment and synthesis of published (and whenever possible peer-reviewed) publications up to June, 2004. We attempt to maintain the accuracy of the information contained in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 50 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians.|
Food and Drug Administration public health advisory: reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD), October 27, 2003. http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01256.html Verified January 29, 2004.
Medicines and Health Care Products Regulatory Agency. Use of SSRIs in children and adolescents with major depressive disorder - only fluoxetine shown to have a favourable balance of risks and benefits, Dec 10, 2003. http://www.mhra.gov.uk/news/2003.htm Verified January 29, 2004.
Bramham, D. Personal communication (data from Freedom of Information Request), January 21, 2004.
Health Canada. Stronger WARNING for SSRIs and other newer antidepressants: potential for behavioural and emotional changes, including risk of self-harm. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/zoloft_hpc_e.html. Verified June 6, 2004.
Health Canada. Important Safety information Regarding Paxil in Pediatric Patients, GlaxoSmithKline, Therapeutic Products Directorate: July 10, 2003. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/paxil_e.html Verified January 29, 2004.
Hazell P, O'Connell D, Heathcote D, Henry D. Tricyclic drugs for depression in children and adolescents (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.
Koplewicz, HS. Misguided resistance to appropriate treatment for adolescent depression. J Child Adolesc Psychopharm. 2004; 14: vii.
Garland, E.J. Facing the evidence: antidepressant treatment in children and adolescents. CMAJ. 2004; 170 (4): 489-91.
Jureidini JN, Doecke CJ, Mansfield PR, et al. Efficacy and safety of antidepressants for children and adolescents. BMJ. 2004; 328: 879-883.
Whittingdon CJ, Kendall T, Fonagy P, et al. SSRIs in childhood depression: systematic review of published versus unpublished data. Lancet. 2004; 363: 1335, 1341-45.
Laughren, T. Background Comments for February 2, 2004 Meeting of Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee (PedsAC). http://www.fda.gov/ohrms/dockets/ac/04/briefing/4006B1_03_Background Memo 01-05-04.doc
Wagner KD, Ambrosini P, Rynn M, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA. 2003; 290:1033-1041.
Keller MD, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001; 40:762-772.
Emslie GJ, Rush AJ, Weinberg AW, et al. A double-blind, randomized placebo-controlled trial of fluoxetine in depressed children and adolescents. Arch Gen Psychiatry. 1997; 54:1031-7.
Emslie GJ, Heligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment in children and adolescents: a placebo-controlled randomized clinical trial. J Am Acad Child Adoles Psychiatry. 2002; 41:1205-1215.
Dineen Wagner K, Robb AS, Findling RL, et al. A randomized placebo controlled trial of citalopram for the treatment of major depression in children and adults. Am J Psychiat 2004;161:1079-83.
Center for Drug Evaluation and Research. Application 18-936-SE-064. Statistical reviews, July 2001. Fluoxetine. http://www.fda.gov/cder/foi/nda/2003/18936S064_Prozac%20Pulvules_statr.pdf Verified January 29, 2004.
Wilens T, Biederman J, Kwon A, et al. A systematic chart review of the nature of psychiatric adverse effects in children and adolescents treated with selective serotonin reuptake inhibitors. J Child Adolesc Psychopharm. 2003; 13: 143-152.
Food and Drug Adminstration. Worsening depression and suicidality in patients being treated with antidepressant medications, March 22, 2004; FDA Public Health Advisory. http://www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm
Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine- selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ. 2003; 326:1171-1175.
Garland EJ. Managing adolescent depression in the new reality. BCMAJ. 2004 (in press).
Lewinsohn PM, Clarke GN. Psychosocial treatments for adolescent depression. Clin Psychol Rev. 1999; 19: 329-42.
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