Antidepressant drugs for children and teenagers: benefits are too small to justify the harms

1. Antidepressant drugs for children and teenagers: benefits are too small to justify the harms Dr Peter R Mansfield Healthy Skepticism peter@healthyskepticism.org

2. Topics • Introduction to Healthy Skepticism • Are we treating the cause? • Our BMJ paper • The Lancet paper • Criticism of us from Pfizer • Treatment of Adolescents with Depression Study (TADS) • Why do many doctors believe that antidepressant drugs work?

3. 1. Introduction to Healthy Skepticism Inc Aim: Improving health by reducing harm from misleading drug promotion www.healthyskepticism.org

4. The choice:Believe what suits you or face the evidence

5. Our main messages • Doctors are human • Drug companies are profit seeking companies • We have a system problem • People are harmed So We need to improve the system

6. Our recent publications • Rogers WA, Mansfield PR, Braunack-Mayer AJ, Jureidini JN. The ethics of pharmaceutical industry relationships with medical students. Med J Aust. 2004 Apr 19;180(8):411-4. • Mansfield P, Henry D, Tonkin A. Single-enantiomer drugs: elegant science, disappointing effects. Clin Pharmacokinet. 2004;43(5):287-90. • Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents. BMJ 2004;328:879-83 • Svensson S, Mansfield PR. Escitalopram: superior to citalopram or a chiral chimera? Psychother Psychosom. 2004 Jan-Feb;73(1):10-6. • Mansfield PR. Healthy Skepticism’s new AdWatch: understanding drug promotion. Med J Aust 2003; 179 (11/12): 644-645 • Jureidini J, Mansfield P, Menkes D. The statin wars. Lancet 2003 Nov 29; 362(9395)1854 • Katz D, Mansfield P, Goodman R, Tiefer L, Merz J. Psychological aspects of gifts from drug companies. JAMA. 2003 Nov 12;290(18):2404-5

7. 2. Are we treating the causes? • Brain chemicals (neurotransmitters) • Habits of thought • Vicious cycles of negative thoughts and feelings • Losses • Relationship problems • Competitive individualism vs groups for good causes

8. 3. Our BMJ paper • Dr Jon Jureidini, child psychiatrist, Head of Psychological Medicine, Women’s and Children’s Hospital, Adelaide • A/Prof Chris Doecke, pharmacist, Quality Use of Medicines and Pharmacy Research Centre, University of South Australia and Head of Pharmacy, Royal Adelaide Hospital • Dr Peter Mansfield, general practitioner, Dept of GP, University of Adeliade • Dr Michelle Haby, senior epidemiologist, Department of Human Services, Melbourne • Prof David Menkes, psychiatrist, University of Wales Academic Unit, UK • A/Prof Ann Tonkin, clinical pharmacologist, Dept of Pharmacology, University of Adelaide

9. Our conclusions • Benefits of antidepressants are small. We estimated a 3 to 4 point difference on a scale that ranges from 17 to 113. (95% confidence 1 to 8 points) • Adverse effects common and sometimes severe. • “The magnitude of benefit is unlikely to be sufficient to justify risking those harms” • Benefits have been overstated and adverse effects understated.

10. 4. The Lancet paper • Dr Craig J Whittington PhD a • Dr Tim Kendall MRCPsych b • Prof Peter Fonagy PhD a • Prof David Cottrell MRCPsych c • Dr Andrew Cotgrove MRCPsych d • Ellen Boddington MSc a a Centre for Outcomes Research and Effectiveness, Subdepartment of Clinical Health Psychology, University College London b Royal College of Psychiatrists’ Research Unit, London c Academic Unit of Child and Adolescent Mental Health, University of Leeds, d Pine Lodge Young People's Centre, Chester, UK

11. The Lancet paper’s conclusions • “Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people.” • “Non-publication of trials, for whatever reason, or the omission of important data from published trials, can lead to erroneous recommendations for treatment.” • Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet. 2004 Apr 24;363(9418):1341-5.

12. Our assessment of the Lancet paper • We agree except:there is no adequate justification for thinking fluoxetine (Prozac) is any better than the other SSRIs. • They did not look as closely at the flaws in the evidence for efficacy. • There is less evidence about adverse effects but that is not proof of greater safety. • The onus of proof is on Lilly.

13. 5. Criticism of us from Pfizer • Didn’t use standard quality assessment tools True, but they miss the problems we detected • Didn’t criticize CBT studies True, but our focus was on the drug studies • Our statement re failure to disclose suicidal activity is not true for one published study. But it was a general statement about drug companies not specific studies

14. More criticism of us from Pfizer • Denied over- and under-statement But the authors did claim “the results reported here support the conclusion that sertraline is an effective, safe, and well- tolerated treatment for children and adolescents with MDD ” • Claimed 10% additional benefit is worthwhile We used more data and estimated a 3 to 4 point difference on a scale that ranges from 17 to 113. (95% CI 1-8) “The magnitude of benefit is unlikely to be sufficient to justify risking those harms”

15. 6. Treatment of Adolescents with Depression Study (TADS) • Comparisons with CBT not as rigorous as the comparison of fluoxetine vs placebo. (double-blind, placebo-controlled) • Fluoxetine was no significantly more effective than placebo but there were significantly more psychiatric adverse events with fluoxetine.* • The authors did not report either finding in the abstract. • Our conclusion: “The magnitude of benefit is unlikely to be sufficient to justify risking those harms” *Fluoxetine 20/109 vs placebo 9/112 Chi2 p=0.047

16. 7. Why do many doctors believe that antidepressant drugs work well? A. Clinical experience: I prescribe the drug. The child/teenager gets better. I conclude the drug works. B. Wishful thinking: Hope for clinically worthwhile advantages. + Ambiguity about efficacy only detectable with a statistical microscope. = Illusion of potency.

17. Post hoc ergo propter hoc fallacy(After that therefore because of that) “Another line consists in representing as causes things which are not causes, on the ground that they happened along with or before the event in question.They assume that, because B happens after A, it happens because of A. Politicians are especially fond of taking this line. Thus Demades said that the policy of Demosthenes was the cause of all the mischief, ‘for after it the war occurred.’ ”- Aristotle.Rhetoric. 350 BCE

18. Other causes • Improvement that would have happened anyway. • Regression to the mean. (If something fluctuates and you catch it at an extreme it will usually be closer to the middle next time.) • Non-drug effects of the medical encounter. • A reason for believing that things will get better. • The placebo effect.