IM Goodyer,^1* B Dubicka,² P Wilkinson,¹ R Kelvin,¹ C Roberts,³ S Byford,⁴ S Breen,² C Ford,¹ B Barrett,⁴ A Leech,² J Rothwell,² L White² and R Harrington^2†

¹ Developmental Psychiatry Section, Department of Psychiatry, University of Cambridge, UK
² Department of Child and Adolescent Psychiatry, University of Manchester, UK
³ Trials Methodology Group, Medical Statistics, University of Manchester, UK
⁴ Centre for Economics of Mental Health, Institute of Psychiatry, London, UK

* Corresponding author

Background

Unipolar depression in adolescents is a serious mental disorder with a high rate of recurrence and relapse into adult life. Interventions to treat the disorder, improve adult outcomes and diminish subsequent healthcare costs are much needed. To date there have been no randomised control trials (RCTs) of selective serotonin reuptake inhibitors (SSRIs) carried out on moderate to severely depressed adolescents attending NHS facilities.

Objectives

The aim of this study was to determine if, in the short term, depressed adolescents attending routine NHS Child and Adolescent Mental Health Services (CAMHS), and receiving ongoing active clinical care, treatment with SSRIs plus cognitive behaviour therapy (CBT) compared with SSRI alone, results in better healthcare outcomes. The specific research hypotheses addressed were that compared with SSRIs alone, combined treatment would over the length of the trial:

• result in greater psychosocial improvement
• diminish the overall level of depressive symptoms
• result in fewer patients meeting diagnostic criteria at final evaluation
• decrease other public service use and be more cost-effective.

In order to achieve these objectives, an RCT of adolescent patients fulfilling criteria for DSM-IV major depression or with threshold major depression (four symptoms) and marked impairment was undertaken.

Design

A pragmatic RCT was conducted on depressed adolescents attending CAMHS who had not responded to a psychosocial brief initial intervention (BII) prior to randomisation.

Setting

Participants were recruited from two centres, Manchester in the north-west and Cambridge in the east of England. Six CAMHS participated: four in Manchester (total population 831,000) and two in Cambridge (total population 517,000).

Participants

A total of 208 patients aged between 11 and 17 years were recruited and randomised.

Interventions

All participants received active routine clinical care in a CAMHS outpatient setting and an SSRI and half were offered CBT.

Outcome measures

The duration of the trial was a 12-week treatment phase, followed by a 16-week maintenance phase. Follow-up assessments were at 6, 12 and 28 weeks. The primary outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). Secondary outcome measures were self-report depressive symptoms, interviewer-rated depressive signs and symptoms, interviewer-rated psychosocial impairment and clinical global impression of response to treatment. Information on resource use was collected in interview at baseline and at the 12- and 28-week follow-up assessments using the Child and Adolescent Service Use Schedule (CA-SUS).

Results

Of the 208 patients randomised, 200 (96%) completed the trial to the primary end-point at 12 weeks. By the 28-week follow-up, 174 (84%) participants were re-evaluated. Overall, 193 (93%) participants had been assessed at one or more time points. Clinical characteristics indicated that the trial was conducted on moderate to severely depressed group. There was significant recovery at all time points in both arms. The findings demonstrated no difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or secondary outcome measures at any time point. This lack of difference held when baseline and treatment characteristics where taken into account (age, sex, severity, co-morbid characteristics, quality and quantity of CBT treatment, number of clinic attendances). The SSRI + CBT group was somewhat more expensive over the 28 weeks than the SSRI-only group (p = 0.057) and no more cost-effective. Over the trial period there was on average a decrease in suicidal thoughts and self-harm compared with levels recorded at baseline. There was no significant increase in disinhibition, irritability and violence compared with levels at baseline. Around 20% (n = 40) of patients in the trial were non-responders. Of these, 17 (43%) showed no improvement by 28 weeks and 23 (57%) were considered minimally (n = 10) or moderately to severely worse (n = 13).

Conclusions

For moderately to severely depressed adolescents who are non-responsive to a BII, the addition of CBT to fluoxetine plus routine clinical care in moderate to severe depressions does not improve outcome or confer protective effects against adverse events and is not cost-effective. SSRIs (mostly fluoxetine) are not likely to result in harmful adverse effects.

The findings are broadly consistent with the National Institute for Health and Clinical Excellence guidelines on the treatment of moderate to severe depression. Modification is advised for those presenting with moderate (6–8 symptoms) to severe (>8 symptoms) depressions and in those with either overt suicidal risk and/or high levels of personal impairment. In such cases, the time allowed for response to psychosocial interventions should be no more than 2–4 weeks, after which fluoxetine should be prescribed.

Recommendations for future research

Further research is recommended in the following areas:

• Evaluate the efficacy of specific psychological treatments against brief psychological intervention. The current findings provide anecdotal information for the putative effectiveness of BII for some cases of depression. BII can most likely be delivered by all routine CAMHS services. It is not clear if BII would be as safe and effective as CBT, family or interpersonal psychotherapy (IPT), for adolescents with moderate depressions.
• Determine the characteristics of patients with severe depression who are non-responsive to fluoxetine. It is likely that non-responders will be heavy healthcare users into adult life. Delineating their characteristics and their pattern of healthcare use, including compliance with treatment offered as adolescents, would be a key study.
• A study into relapse prevention in severe depressions. Preventing relapse will reduce the risks associated with multiple depressive episodes. Candidate models include assertive outreach, dealing with non-health barriers to rehabilitation (education, skills development and work entry); CBT or IPT in healthcare settings; family therapies to reduce negative environments in the home; and befriending techniques to re-engage adolescent peer group often lost during a depressive episode. Relapse prevention may improve outcome into adult life and diminish healthcare cost in the medium term. A longer term study with follow up for 2 years post-remission is required to address these questions.
• Improve the tools for determining treatment responders and non-responders. A weakness in all trials to date, including this study, is the precision of measurement to assess both the nature of the disorder and treatment response. New tools are urgently required. These should go beyond surface aspects of the clinical phenotype. Such research must also determine the most efficient delivery mode to the clinic of any new and valid test procedure and its cost benefits to the service.

Publication

Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial. Health Technol Assess 2008;12(14).

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