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Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3769 (Published 18 June 2014) Cite this as: BMJ 2014;348:g3769

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For BMJ readers wishing to apply published results in clinical practice, the paper by Chen et al.1 investigating data from 37 936 Swedish patients with attention deficit hyperactivity disorder (ADHD) suggesting that medications prescribed for this disorder protect against suicidal behaviour raises numerous concerns, and their assertive reporting gives misleading and dangerous information.

First, seeking data to confute the known association between medications prescribed for patients with ADHD and risk of concomitant suicidal behaviour,2 3 Chen et al. designed a longitudinal study confounded with anonymous data rather than a prospective study with a long follow-up. To do so, they extracted and analysed data from the Swedish national register for patients clinically diagnosed as ADHD recorded merely for epidemiological and administrative rather than for clinical purposes. Even more important, they excluded the 120 patients who died or moved out of Sweden. A major problem is that in defining treatment times for stimulants (methylphenidate, amphetamine, dexamfetamine) and non-stimulants (atomoxetine) medications that differ in mechanisms of action and neuroreceptors, Chen et al. included only data from medical prescriptions recorded in the register, instead of investigating possible suicide ideation using standardized questionnaires or comorbid conditions.4 5 6 7 Nor did they seek patients’ data on drug abuse (blood, urine or hair tests). Convincing evidence from post-mortem examinations in persons who have died by suicide or made serious suicide attempts discloses midbrain serotonergic hypofunction suggesting a breakdown in inhibitory function predisposing to impulsive and aggressive behaviour.8 This vulnerability to deficient impulse control couples with psychiatric illnesses or other life stressors elevating the risk of acting on suicidal thoughts.8 Chen et al. also tried to confute the possible association between ADHD drugs and suicidality despite escalating drug use over the past 20 years,9 10 even though suicidality rates in the population at risk remained unchanged.11

Applying Chen et al.’s controversial findings in children and teenagers with ADHD could even have dangerous consequences.12 13 Since 2007, the Italian register14 started to record data for patients with ADHD and drugs prescribed: in the 6-18-year-old group treatment with atomoxetine decreased but suicide rates remained unchanged.15 16 In our practical paediatric clinical experience, if a child has ADHD, nothing will convince the parents that the child can be treated without medications.17 18 19 And even worse, parents of children with ADHD commonly suffer from undiagnosed or misdiagnosed depressive problems, and ignoring medical prescriptions, give their children drugs prescribed for themselves.20

Second, the study by Chen et al. has major statistical limitations. To compare the presumed protective association between drugs and suicidal behaviour they used a complex Cox regression model splitting the population into thousands of groups using each patient as their own control (within patient comparison), entailing defining additional exposures to analyse the potential influence of misclassification, thus presumably dangerously limiting their fragmented analysis to patients who will never attempt suicide, and leading to mistaken conclusions that few clinicians have time to appraise.21 In real life, because children differ in construct skills their decisions could reflect unpredictable cognitive and emotional patterns,22 determining complex interrelated variables that are difficult to analyse within each patient. Omitting and fragmenting evidence fails to give readers the simple statistical measures, such as odds ratios (proportions), number needed to treat and number needed to harm, they need to translate research and apply results in practice.23

A major flaw we wish to underline in Chen et al.’s paper is that lumping the population into two age groups (10-24 years and 25-46 years; Table 4) distorts their sensitivity analysis testing the association between drugs for ADHD and suicide-related-events, thus incurring selective and reporting bias.24 In Sweden, the highest suicide rates involve teenagers aged 15 to 19 years.25 Finally, we wonder why a research article published in the BMJ makes no mention of eventual funding from pharmaceutical industries.

In conclusion, as paediatricians working in research and clinical settings, we recommend avoiding complex statistical splitting and lumping when analysing the association between drugs and suicide.26 What we need are results from well-designed systematic reviews based on good quality clinical trials addressing the multiple social and familial factors responsible for ADHD.27 Having this information might encourage multimodal treatment and minimise inappropriate pharmacological therapy for children and teenagers with ADHD.

1 Chen Q, Sjölander A, Runesson B, D’Onofrio BM, Lichtenstein P, Larsson H. Drug treatment for attention-deficit/hyperactivity disorder and suicidal behavior: register based study. BMJ 2014;348:g3760.
2 Food and Drug Administration, Public health advisory: suicidal thinking in children and adolescents being treated with Strattera (atomoxetine). FDA, 2005. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPa....
3 Bangs ME, Tauscher-Wisniewski S, Polzer J, Zhang S, Acharya N, Desaiah D, et al. Meta-analysis of suicide-related behavior events in patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry 2008;47(2):209-18.
4 Whooley MA, Simon G. Managing depression in medical outpatients. N Engl J Med 2000; 343:1942-50.
5 U.S. Department of Health and Human Services. National Strategy for Suicide Prevention: Goals and Objectives for Action. Rockville, MD: U.S. Department of Health and Human Services; 2001.
6 Tidemalm D, Långström N, Lichtenstein P, Runeson B. Risk of suicide after suicide attempt according to coexisting psychiatric disorder: Swedish cohort study with long term follow-up. BMJ 2008;18:337:a2205.
7 Bonati M, Reale L. Reducing overdiagnosis and disease mongering in ADHD in Lombardy. BMJ 2013;347:17474.
8 Kamali M, Oquendo MA, Mann JJ. Understanding the neurobiology of suicidal behavior. Depress Anxiety. 2001;14(3):164-76.
9 Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attention deficit disorder in the 1990s. Pediatrics 1996;98:1084-8.
10 Salmelainen P. Trends in the prescribing of stimulant medication for the treatment of attention deficit hyperactivity disorder in children and adolescents in New South Wales. NSW Public Health Bull 2002;13 (Supplement S 1):1-65.
11 Youth Suicide Fact Sheet. Available at: http://www.suicidology.org/c/document_library/get_file?folderId=232&name...
12 Gøtzsche P. Pushing children into suicide with happy pills. In: Deadly medicines and organised crime. How big pharma has corrupted healthcare. Radcliffe Publishing, 2013;Chapter 18 pp. 217- 235. London, UK.
13 Bushe CJ, Savill NC. Suicide related events and attention-deficit hyperactivity disorder treatments in children and adolescents: a meta-analysis of atomoxetine and methylphenidate comparator clinical trials. Child Adolesc Psychiatry Ment Health 2013;19:7-19.
14 Italian Register of ADHD. Available at: http://www.iss.it/adhd/.
15 Palmieri L, Barbui C. Antidepressant use and risk of suicide. 2004. Available at: http://www.informazionisuifarmaci.it/database/fcr/sids.nsf/pagine/E3E791....
16 Capuano A, Scavone C, Rafaniello C, Arcieri R, Rossi F, Panei P. Atomoxetine in the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) and suicidal ideation (a case series). Expert Opin Drug Saf 2014;(in press).
17 Waechter F. Paroxetine must not be given to patients under 18. BMJ 2003;326:1282.
18 Oransky I. FDA questions antidepressant safety for children. Lancet 2003;362:1558.
19 Scottish Intercollegiate Guidelines Network. Management of Attention deficit and hyperkinetic disorders in children and young adults. SIGN 2009. Available at: http://www.sign.ac.uk/guidelines/fulltext/112/.
20 Martin B. Causes of attention deficit disorder. 2007. Available at: http://psychcentral.com/lib/causes-of-attention-deficit-disorder-adhd/00....
21 Rose LT, Fischer KW. Garbage in, garbage out: having useful data is everything. Measurement 2011;9:222–6.
22 Ayoub CC, O’Connor E, Rappolt-Schlichtmann G, Fisher KW, Rogosh F, Toth SL et al. Cognitive and emotional differences in young maltreated children: a translational application of dynamic skill theory. Dev Psychopathol 2006;18:679-706.
23 Patel CJ, Ioannidis JPA. Placing epidemiological results in the context of multiplicity and typical correlations of exposures. JECH 2014; Jun 12. pii: jech-2014-204195. doi: 10.1136/jech-2014-204195.
24 Gambrill E. Avoidable ignorance and the role of the Cochrane and Campbell Collaborations. Available at: http://www.campbellcollaboration.org/news_/Random_Notes_Avoidable_Ignora....
25 Sweden. Child Safety Country Profile, 2012. Available at: http://www.childsafetyeurope.org/reportcards/info/sweden-country-profile....
26 Singh I. Beyond polemics: science and ethics of ADHD. Nat Rev Neurosci 2008;9(12):957-64.
27 Zwi, M., Jones, H., Thorgaard, C., York, A., Dennis, J. Parent training interventions for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 5 o 18 years. Campbell Systematic Reviews 2011;20. doi:10.4073/csr.2012.2. Available at: http://www.campbellcollaboration.org/news_/Training_programs_for_parents....

Competing interests: No competing interests

25 July 2014
Pietro Panei
Researcher and Paediatrician, Italian Register of Children with Attention Deficit Hyperactivity Disorder (ADHD)
Rosati Paola, Researcher and Paediatrician, Unit of Clinical Epidemiology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
Italian National Institute of Health
Rome, Italy