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Antidepressants for children
- Premraj Muthuvelu (15 October 2007)
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Antidepressants have a role in persistent moderate-severe major depression
- Bernadka W Dubicka, Paul Wilkinson, Raphael Kelvin, Ian Goodyer (the ADAPT team) (17 October 2007)
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Author's reply: The devil is in the detail
- Sami Timimi (23 October 2007)
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Premraj Muthuvelu, Specialist Registrar Ty Llywely Unit, Llanfairfechan
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Sir,It is clear from an evidence based stand point that the benefit from antidepressants in 'childhood depression' is modest at best. The adverse event profile is not easily dismissed.(1) This points to childhood depression being a different entity than adult depression. This point was discussed elegantly by the same author elsewhere. (2) We know that the response to antidepressants in depression among adoloscents may follow a different trend to that of childhood depression.(1) The symptom cluster in childhood depression is different to that of adult depression as well. I propose that the reason for the disparate response to depression amongst adults and children is because the underlying condition is different. Perhaps studies designed to capture adult symptoms of depression that are thought to be uncommon in children such as loss of weight, loss of appetite,feelings of guilt, psychomotor retardation and anhedonia is the answer. The prevalence rate of such a sub-group is probably lower than that of the currently accepted rates for 'childhood depression' but this sub-group might be the one that responds to antidepressants. In any case in our present state of knowledge, I think, antidepressants for childhood depression are best avoided or at least used only as a last resort on rare occassions. References 1 Hetrick, S; Merry, S; McKenzie, J; Sindahl, P; Proctor, M SSRIs for depressive disorders in children and adoloscents, Cochrane Database of Systematic Reviews 2 Sami Timimi, Rethinking Childhood Depression, BMJ 2004;329:1394-1396. Competing interests: None declared |
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Bernadka W Dubicka, honorary lecturer, University of Manchester and locum consultant The Junction adolescent unit, Lancaster, LA1 4PW, Paul Wilkinson, Raphael Kelvin, Ian Goodyer (the ADAPT team)
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Sami Timimi expressed concern that ‘spin has taken precedence over scientific accuracy’. We therefore wish to correct a number of scientific inaccuracies presented in this debate, and question the conclusions drawn. With reference to the Treatment of Adolescents with Depression Study (TADS), we would agree there are issues regarding blinding, however, it could also be argued that an exaggerated response could have been predicted in the cognitive behaviour therapy (CBT) arm, as this was unblinded. Unfortunately CBT did not outperform placebo on any of 16 outcomes, unlike fluoxetine, which was superior to placebo on 8 out of 16 outcomes (March, Silva, Vitiello, & Team, 2006). If, as the author suggests, this was due to the poor quality of CBT, this does not explain why there appeared to be an additional effect of CBT when added to fluoxetine, although this benefit was not seen in the most severe cases, and therefore could not be attributed to the unblinding of fluoxetine (Curry et al., 2006). Moreover, a recent meta-analysis of psychological treatment in depression revealed a disappointingly low effect size (0.34), when compared to earlier, more optimistic findings (Weisz, McCarty, & Valeri, 2006). Effect sizes have reduced as trial methodology has improved, thus an alternative explanation of the TADS CBT findings is that the poorer outcomes of CBT in this trial are a result of better methodology, such as using more representative samples, rather than poorer quality treatment. Thus Timimi’s assertion that psychotherapy has a ‘well- established record of effectiveness’ is far from clear, particularly in moderate to severe major depression. With regards to overall effectiveness of fluoxetine in TADS, this trial had 2 primary outcomes, and fluoxetine was found to be significantly superior to placebo on one outcome (Clinical Global Improvement Impression Scale, CGI-I), although not the other (Children's Depression Rating Scale- Revised, CDRS-R). However, the overall effect size for fluoxetine when compared to placebo on the CDRS was 0.68, versus -0.03 for CBT. The effect size for fluoxetine compares favourably to that found for psychological treatment overall (Weisz et al., 2006). In addition, a recent meta- analysis of newer generation antidepressants that was based on primary outcomes, concluded that there was a significant overall benefit when compared to placebo, although this was more modest than that for other disorders (Bridge et al., 2007). With reference to the TADS suicidality data, there were more suicide- related events in the fluoxetine alone arm, however these were mostly accounted for by ideation. Overall, there were 4 attempts in those taking fluoxetine versus 1 in the remaining groups, out of a total of 439 adolescents (Emslie et al., 2006). The authors of this study also note that spontaneous reporting of adverse events may have led to bias, particularly in the CBT arm, where there appeared to be under-reporting. This is an inherent problem of all the existing suicidality data from the SSRI trials, as none of these trials prospectively measured suicidal events, and thus the interpretation of the findings is subject to bias, is based on poor quality retrospective data, as well as unrepresentative samples, where the most impaired and suicidal adolescents have been excluded. Our own ADAPT study (Goodyer et al., 2007) aimed to include such adolescents and it was for this reason that neither an active nor a passive placebo arm was included, as it was not considered ethical to randomise high risk suicidal adolescents to placebo. There was no evidence in our study that suicidality increased with the use of antidepressants, and this was based on prospective, systematic data. In fact, both arms showed a sharp decline in suicidality early in treatment. Timimi states that antidepressants may have led to avoidable suicides. However, no suicide deaths have been recorded in any of the newer generation antidepressant trials, post-mortem examinations of youth suicides rarely record the presence of antidepressants (Leon et al., 2006), and the most recent data from the US and Netherlands shows a disturbing rise in suicide deaths coinciding with a reduction in antidepressant prescribing (Gibbons et al., 2007). Finally, moderate to severe major depression characterised by at least 6 symptoms and high levels of impairment in adolescence may develop into a recurrent condition with a significant risk of chronicity (Dunn et al 2006), mortality and morbidity, which requires effective early intervention. We believe that current scientific evidence strongly suggests that the risk from untreated persistent major depression significantly outweighs any known risks arising from the use of antidepressants together with active psychosocial care, in contrast to Timimi’s conclusions. Bridge, J. A., Iyengar, S., Salary, C. B., Barbe, R. P., Boris, B., Pincus, H. A., et al. (2007). Clinical Response and Risk for Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment. A meta-analysis of randomized controlled trials. Journal American Medical Association, 297(15), 1683-1696. Curry, J., Rodhe, P., Simons, A., Silva, S., Vitiello, B., Kratochvil, C., et al. (2006). Predictors and Moderators of Acute Outcome in the Treatment for Adolescents With Depression Study (TADS). Journal American Academy Child Adolescent Psychiatry, 45(12), 1427-1438. Dunn, V., & Goodyer, I. M. (2006). Longitudinal investigation into childhood- and adolescent-onset depression: psychiatric outcome in early adulthood. British Journal of Psychiatry, 188, 216-222. Emslie, G., Kratochvil, C., Vitiello, B., Silva, S., Mayes, T., McNulty, S., et al. (2006). Treatment for adolescents with depression study (TADS): safety results. J. Am. Acad. Child Adolesc. Psychiatry, 45(12), 1440-1455. Gibbons, R. D., Brown, C. H., Hur, K., Marcus, S. M., Bhaumik, D. K., Erkens, J. A., et al. (2007). Early Evidence on the Effects of Regulators' Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents.Am J Psychiatry, 164(9), 1356-1363. Goodyer, I., Dubicka, B., Wilkinson, P., Kelvin, R., Roberts, C., Byford, S., et al. (2007). Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial. British Medical Journal, 335, 142-146. Leon, A. C., Marzuk, P. M., Tardiff, K., Bucciarelli, A., Markham Piper, T., & Galea, S. (2006). Antidepressants and Youth Suicide in New York City, 1999-2002. Journal of the American Academy of Child & Adolescent Psychiatry, 45(9), 1054-1058. March, J., Silva, S., Vitiello, B., & Team, T. T. (2006). The treatment for adolescents with depression study (TADS): methods and message at 12 weeks. Journal American Academy Child Adolescent Psychiatry, 45(12), 1393-1403. Weisz, J. R., McCarty, C. A., & Valeri, S. M. (2006). Effects of Psychotherapy for Depression in Children and Adolescents: A Meta-Analysis. Psychological Bulletin, 132(1), 132-149. Competing interests: Bernadka Dubicka has attended educational meetings sponsored by Lilly |
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Sami Timimi, Consultant Child and Adolescent Psychiatrist LIncolnshire Partnership NHS Trust, Sleaford, Lincolnshire NG34 8QA
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Dubicka et al’s (1) arguments above are unconvincing but concordant with a position that has left the medical profession vulnerable to accusations of bias, where pharmacological efficacy is over-emphasised, and risks minimised. For example stating that “no suicide deaths have been recorded in any of the newer generation antidepressant trials” would appear to gloss over the now robust finding that SSRI treatment in the young significantly increases suicidal ideation compared to placebo. Although suicidality has been highlighted for obvious reasons, risks of using SSRIs in the young are not limited to this. Emerging data should give for concern about the potential long term effects on the CNS of early exposure to SSRIs, with increased risk of conversion to bi-polar disorder amongst those prescribed SSRI antidepressants (2) and adverse changes in the behaviour of adult rats exposed to SSRIs during their growing years (3,4,5,6) being amongst recent findings. With regards the question of efficacy, much of the debate revolves around the discrepant interpretations of the TADS study (7). The first argument the authors present that “exaggerated response could have been predicted in the cognitive behaviour therapy (CBT) arm, as this was unblinded”, is so ludicrous that I suspect most lay people can easily see why it is inappropriate to compare unblinding with active medication with unblinding with psychotherapy, as the placebo response like psychotherapy is dependent on psychological principles for its effects. The comparison effect size for psychotherapeutic approaches that Dubicka et al quote of a “disappointingly low effect size (0.34)” they attribute to better methodology (presumably of the TADS study type?). However, a reading of the meta-analysis that reported this effect size (unlike previous meta- analysis that have reported effect sizes (ES) of between 0.72 and 1.27) (8), reveals considerable differences in methodology to previous meta- analysis, for example inclusion of non published studies, active treatment control groups, non-diagnosed sample groups, as well as different analytic methods. Whether this is ‘better’ than previous methodologies is open to question. Interestingly, the authors of this meta-analysis have the same concerns about the quality of the CBT in the TADS study that I had, stating “the CBT ES generated in TADS is not characteristic of most CBT or psychotherapy effects on youth depression; 20 of the 23 other CBT programs in the table showed larger ES than the TADS version of CBT, and the mean ES value across the non-TADS CBT programs in the table was 0.48, markedly higher than the −0.07 ES associated with the TADS CBT intervention”. Questions about the efficacy of fluoxetine thus remain and cannot be simply wished away by methodology that tries to side-step the inconvenient finding that when compared to placebo, fluoxetine, like other SSRIs, struggles to establish any advantage and has never done so on any parent or young person rated outcome scales. Why the TADS did not contain a CBT plus placebo group (instead of or as well as a CBT alone group) that would have enabled more accurate conclusions about the relative efficacy of fluoxetine in this arm of the study, is baffling. Finally, Dubicka et al raise the important issue of a possible association between a fall in SSRI prescribing to the young and an increase in suicide (9). Such an association if proven would be a concern to all of us – clinicians, researchers and patients – and would need further study to elucidate the possible reasons for such an association (such as the effects of sudden treatment withdrawal, the availability of treatment options, the mediating effect of other factors such as substance misuse, use of other medications, psychosocial factors etc.). However this study’s own findings raise more questions than it appears able to answer. For example their US graphs show little decrease in antidepressant prescribing for 2004, but a 17% increase in suicides amongst the young that year (compared to 2003). The figure for decreasing rates of antidepressant prescription is based on the 2005 prescription levels; however, figures for 2005 suicides are not available until December 2007. The graphs on the Netherlands are not striaghtforward either with rather mixed findings. For example, 2002 shows a 25% increase in suicides compared with 2001, yet it was also the year with their highest rates of prescribing of antidepressants for the young. What I think we can all agree on however, is that children and adolescents are deserving of timely, efficacious, safe, and closely monitored treatments. The available evidence suggests (in line with NICE guidelines) that at least in the first instance this should be psychological approaches. Whilst I accept that – providing the young person is monitored closely – it may prove necessary (even if it was just for its placebo effect) to use an antidepressant due to a lack of availability of quickly accessible psychological therapies, we should not let understandable pragmatic solutions to sub-optimal circumstances dictate what should be the evidence based clinical norm: Good quality psychological therapies available to all young people with childhood depression type presentations and their families. (1) Bernadka W Dubicka, Paul Wilkinson, Raphael Kelvin, Ian Goodyer (the ADAPT team). Antidepressants have a role in persistent moderate- severe major depression. BMJ 2007; e-letter. (2) 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 (3)Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004; 306:879–881 (4) Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology 2006; 31:47–57 (5) Maciag D, Coppinger D, Paul IA. Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development. Brain Res 2006; 1125: 171–175 (6) LaRoche RB, Morgan RE. Adolescent fluoxetine exposure produces enduring, sex-specific alterations of visual discrimination and attention in rats. Neurotoxicol Teratol 2007; 29:96–107 (7) March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, et al. Fluoxetine, cognitive-behavioural therapy, and their combination for adolescents with depression. Treatment for adolescents with depression study (TADS) randomized controlled trial. JAMA 2004; 292:807-20. (8) Weisz JR, McCarty CA, Valeri, SM. Effects of Psychotherapy for Depression in Children and Adolescents: A Meta-Analysis. Psychol Bulletin 2006; 132: 132-149. (9) Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, et al. Early Evidence on the Effects of Regulators' Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents. Am J Psychiatry 2007; 164: 1356-1363 Competing interests: None declared |
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