BMJ  2004;328:3-4 (3 January), doi:10.1136/bmj.328.7430.3

Editorial

Treatment of major depressive disorder in children and adolescents

Most selective serotonin reuptake inhibitors are no longer recommended

On 10 December 2003 Professor Gordon Duff, chairman of the Committee on Safety of Medicines in the United Kingdom, advised that most of the antidepressant drugs in the selective serotonin reuptake inhibitor group should not be used to treat major depressive disorder in children and adolescents under the age of 18 years.¹ This is the main category of medication used in the treatment of depression in children and adolescents, and the announcement will have taken many young people who take these drugs, their parents, and doctors by surprise. Although the advice only applies to the United Kingdom, it mirrors concerns that are also being considered by the US Food and Drug Administration.²

The new advice follows the review of data from clinical trials by an expert working group, convened initially because of concerns that selective serotonin reuptake inhibitors may increase the risk of suicidal thoughts and self harm in young people. The group concluded that the balance of risks and benefits was unfavourable for three of the selective serotonin reuptake inhibitors (sertraline, citalopram, and escitalopram) and that there was insufficient evidence to support the use of a fourth, fluvoxamine. The committee had earlier advised that two other antidepressants (paroxetine and venlafaxine) should not be used to treat depression in this age group. Some of the data on which this decision was based had not previously been released to the committee.

Fluoxetine is now the only selective serotonin reuptake inhibitor for which the committee considers the balance of risks and benefits to be favourable, although it cautions that the drug is likely to be beneficial in only a minority of patients—the figure quoted is 1 in 10. It is also the only drug labelled for use in major depressive disorder in children in the United States.

The new advice raises several questions, two of which are addressed here. Firstly, how should we treat depressive disorder in children and adolescents now? Secondly, are there lessons to be learnt from the way in which these events have unfolded?

Depressive disorder is a common and debilitating condition. It costs approximately £9bn ($16bn; 13bn) in England each year,³ and worldwide is the fourth most important cause of disability.⁴ Key symptoms are low mood, loss of energy, and loss of enjoyment. Many other symptoms can occur including suicidal thoughts. It becomes increasingly common through adolescence.⁵ In recent years the number of prescriptions for antidepressant medication in this age group has grown, although the use of these drugs is beyond the scope of the product licence. About half of the estimated 40 000 young people under the age of 18 years using antidepressants in the United Kingdom are currently taking one of the newly "contraindicated" antidepressant medications.¹

For those children and adolescents currently taking one of these antidepressants for depressive disorder, the most important advice is that they should not suddenly stop taking their medication. This may result in withdrawal effects and will increase the risk of relapse of depression. Seeking medical advice is crucial—it may be that the current medication is continued or that it is gradually withdrawn or replaced.

For those children and adolescents newly presenting with depression the situation is different. Symptoms of depression are common, particularly in adolescence, and often resolve without psychological or medical intervention. The diagnosis of depressive disorder requires careful assessment. If treatment is indicated several options remain. Psychological treatments, including cognitive behaviour therapy, have been used extensively, and several randomised trials attest to its efficacy in mild or moderately severe depression.⁶ Where available, psychological treatments are often used as a first line treatment, particularly in younger adolescents and children. However, little evidence exists to support their use in young people with more severe depression, and here pharmacological treatments may be important.

Fluoxetine remains an option, and it is probably now being used as the first line pharmacological treatment in most patients. It can have problematic adverse effects, including restlessness and agitation. The other selective serotonin reuptake inhibitors may still be used in some circumstances under specialist supervision.

The other main category of antidepressant drugs is the tricyclic drugs. Their use has declined since the introduction of the selective serotonin reuptake inhibitors and particularly since a systematic review in 1995 concluded that they seem to be no more effective than placebo in the treatment of depression in children and adolescents.⁷ A more recent Cochrane systematic review showed that they may offer some benefit for adolescents with depression but not for pre-pubertal children.⁸ These drugs are associated with clinically important adverse effects, and most are toxic in overdose.

What are the lessons to be learnt from the way in which these events have unfolded? The dramatic issuing of the guidance by the Committee on Safety of Medicines is likely to lead to considerable uncertainty and some difficulty for many patients and doctors. Although the guidance is clear cut, the decisions have been based on relatively few studies. The dearth of research means that a high proportion of the 40 000 children and adolescents taking antidepressants in the United Kingdom are likely to use fluoxetine in the future on the basis of randomised trials involving a few hundred people, the largest of which was funded by the company that makes the drug. The difference in effectiveness between sertraline (subject of the new advice from the Committee on Safety of Medicines⁹) and fluoxetine^10-12 seems marginal on the basis of the available evidence. Independently funded research into the effectiveness of treatments for depression is needed.

Concerns also remain about the way in which data from trials about serious adverse effects of some antidepressant drugs, held by the pharmaceutical companies concerned, seem not to have been previously released to the Committee on Safety of Medicines. A more robust system, requiring full disclosure of information, is urgently required.

Section of Child and Adolescent Psychiatry, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX (paul.ramchandani{at}psych.ox.ac.uk)

---

PR holds a special training fellowship in health services research funded by the UK Medical Research Council and is an honorary consultant child and adolescent psychiatrist.

Competing interests: None declared.

References

1. Committee on Safety of Medicines. Use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with major depressive disorder (MDD). www.mhra.gov.uk/ (accessed 16 Dec 03).
2. Food and Drug Administration. Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Talk Paper T03-70 (27 October 2003) (www.fda.gov/bbs/topics/ANSWERS/2003/ANS01256.html) (accessed 12 Dec 03).
3. Thomas CM, Morris S. Cost of depression among adults in England in 2000. Br J Psychiatry 2003;183: 514-9.[Abstract/Free Full Text]
4. Murray CJ, Lopez AD. Regional patterns of disability-free life expectancy and disability-adjusted life expectancy: global burden of disease study. Lancet 1997;349: 1347-52.[CrossRef][ISI][Medline]
5. Meltzer H, Gatward R, Goodman R, Ford T. Mental health of children and adolescents in Great Britain. London: Stationery Office, 2000.
6. Harrington R, Whittaker J, Shoebridge P, Campbell F. Systematic review of efficacy of cognitive behaviour therapies in childhood and adolescent depressive disorder. BMJ 1998;316: 1559-63.[Abstract/Free Full Text]
7. Hazell P, O'Connell D, Heathcote D, Robertson J, Henry D. Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. BMJ 1995;310: 897-901.[Abstract/Free Full Text]
8. Hazell P, O'Connell D, Heathcote D, Henry D. Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev 2003;(4): CD002317 [GenBank] .
9. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MD, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder; two randomised controlled trials. JAMA 2003;290: 1033-41.[Abstract/Free Full Text]
10. Simeon JG, Dinicola VF, Ferguson HB, Copping W. Adolescent depression: a placebo-controlled fluoxetine study and follow-up. Prog Neuropsychopharmacol Biol Psychiatry 1990;14: 791-5.[CrossRef][Medline]
11. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, et al. A double-blind, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54: 1031-7.[Abstract]
12. Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, et al. Fluoxetine for acute treatment of depression in children and adolescents; a placebo-controlled, randomised clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41: 1205-15.[CrossRef][ISI][Medline]

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