Description of the health problem
Depression is a leading cause of disability, with more than 300 million people having depressive illness worldwide.1 According to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), depression is defined as a state of mental health that can be characterised by symptoms of low mood, loss of interest or pleasure, tearfulness, feelings of guilt or low self-worth, social withdrawal, disturbed sleep or appetite, poor concentration, tiredness and diminished activity.2
Owing to difficulties in distinguishing between clinically significant and ‘normal’ mood changes, it is now generally accepted that depressive symptoms are a continuum of severity.3 The severity of depressive illness can range from mild to severe. Even mild to moderate depression can impair people’s ability to function and cope with daily life. The diagnosis of depression is based not only on severity of symptoms but also on their duration and the degree of social and functional impairment. Depression is no longer thought of as a time-limited disorder with complete recovery after 4–6 months of treatment; it is now accepted that depression is often chronic (lasting for ≥ 2 years) or recurrent. Although it has been accepted that depression exists as a continuum, researchers and clinicians still use terms such as episode, relapse and chronicity to guide the diagnosis, and to inform and monitor treatment.
Treatment options for depression
People with depressive symptoms are mainly treated in primary care, and antidepressants are usually the first-line treatment; they are used to treat acute depressive symptoms and for maintenance treatment, that is to prevent relapse once an individual has recovered. The number of prescriptions for antidepressant medication has risen dramatically in high-income countries in recent decades, largely because of an increase in the number of patients receiving long-term treatment.4,5 Psychological treatments, such as cognitive–behavioural therapy, are also effective treatments for depression, including for those who have not responded to antidepressants.6
Economic consequences of depression
Depression not only causes marked emotional distress and interferes with daily function for the individual, but also has substantial negative social and financial impact on the wider community.7 Every year, it has been estimated that depression reduces England’s national income (gross national product) by over 4% (approximately £80M). This reduction results from increased unemployment, a larger number of sick days and reduced productivity. It is also accompanied by increased welfare expenditure.8,9
Current evidence on the effectiveness of maintenance treatment
A substantial proportion of the burden of depression arises from relapses, recurrence and chronicity. However, in contrast to the large number of drug trials in acute depression,10 there are relatively few studies assessing antidepressant efficacy in preventing relapse of depression during maintenance treatment. A number of systematic reviews and meta-analyses11–14 report a reduced risk of relapse rate in patients receiving antidepressant medication by between 50% and 70% compared with patients receiving placebo. The constituent studies had several limitations. These studies recruited patients from secondary care during an acute depressive episode, treated the patients with an open-label antidepressant and reported that only those who met criteria for recovery were eligible for randomisation to either remain on double-blind antidepressant or switch to placebo. Most studies were conducted during the 1980s or early 1990s in secondary care by pharmaceutical companies for regulatory purposes, using tricyclic antidepressants that are no longer widely used for depression. Most studies had either short (≤ 2 months) or intermediate (3–5 months) pre-randomisation treatment. It is difficult to generalise these findings to people currently receiving antidepressants in primary care, many of whom have been on maintenance treatment for some years.15,16 Studies of the effectiveness of maintenance treatment for patients receiving antidepressants for longer than 8 months are rare and have several limitations.17–19 All were very small (n < 20 participants in total) and had a poor follow-up rate.
NICE guidance on the treatment and management of depression in adults20 recommends that patients who have recovered from an episode of depression should stay on their antidepressant medication for at least 6 months after remission. The guidelines also suggest that the medication should be continued for 2 years after remission in those ‘at risk of relapse’; the risk is defined as ‘two or more episodes, residual symptoms or severe or prolonged episodes’ (© NICE 2010. Depression: Management of Depression in Primary and Secondary Care. Available from www.nice.org.uk/guidance/cg23. All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication).20 However, there is no evidence that these proposed factors (number of episodes, residual symptoms and severity of previous episodes) affected the difference between antidepressant and placebo maintenance treatment.13 NICE recommends that antidepressant maintenance treatments should continue to be used for 2 years for those at risk of relapse; however, NICE also recognise the uncertainty about the benefit of long-term maintenance treatment and recommend further research into its psychological and pharmacological effects.
At present, there is little evidence to support the use of long-term maintenance antidepressant treatment, despite its widespread use. Given the costs of treatment and medical supervision, the side effects of the medication and patients’ wish to be medication free, it is important to investigate this question further.
Health economic considerations are discussed and presented in Chapter 4.
Current evidence on withdrawal symptoms
There is also uncertainty about the frequency and severity of withdrawal symptoms after antidepressants are discontinued. Randomised, double-blind, placebo-controlled trials are required to provide robust evidence on withdrawal symptoms. A recent systematic review of such trials found evidence of withdrawal symptoms after antidepressant discontinuation, but the studies were too heterogeneous to establish the frequency, severity and timing of withdrawal effects. Almost all of these trials were rated as being of low quality because of the high risk of selection bias, attrition and incomplete outcome data.21 Withdrawal symptoms are an important risk to evaluate when considering stopping maintenance treatment. They raise an important clinical question of the benefits of antidepressants compared with the possible risks.
Aim and objectives
The ANTLER trial was funded by the National Institute for Health Research (NIHR) as part of its Health Technology Assessment (HTA) programme. The overall aim of the ANTLER trial was to answer the following research question: ‘What is the clinical effectiveness and cost-effectiveness in UK primary care of continuing on long-term maintenance antidepressants compared with a placebo in preventing relapse of depression in those who have taken antidepressants for more than 9 months and who are now well enough to consider stopping maintenance treatment?’.
The trial was pragmatic, embedded in primary care and had broad inclusion criteria to increase the generalisability to the population currently receiving maintenance antidepressants.
