4 Research recommendations

The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.

4.1 Sequencing antidepressant treatment after inadequate initial response

What is the best medication strategy for people with depression who have not had sufficient response to a first SSRI antidepressant after 6 to 8 weeks of adequate treatment?

Why this is important

Inadequate response to a first antidepressant is a frequent problem but the best way of sequencing treatments is not clear from the available evidence. There is good evidence that the likelihood of eventual response decreases with the duration of depression and number of failed treatment attempts, so maximising the response at an early stage may be an important factor in the final outcome. The results of this study will be generalisable to a large number of people with depression and will inform choice of treatment.

This question should be addressed using a randomised controlled trial design to compare the effects of continuing on the same antidepressant (with dose increase if appropriate) and switching to another SSRI or to an antidepressant of another class. Built into the design should be an assessment of the effect of increased frequency of follow-up and monitoring alone on improvement. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators and moderators of response should be investigated.

4.2 The efficacy of short-term psychodynamic psychotherapy compared with cognitive behavioural therapy and antidepressants in the treatment of moderate to severe depression

In well-defined depression of moderate to severe severity, what is the efficacy of short-term psychodynamic psychotherapy compared with CBT and antidepressants?

Why this is important

Psychological treatments are an important therapeutic option for people with depression. CBT has the best evidence base for efficacy but it is not effective for everyone. The availability of alternatives drawing from a different theoretical model is therefore important. Psychotherapy based on psychodynamic principles has historically been provided in the NHS but provision is patchy and a good evidence base is lacking. It is therefore important to establish whether short-term psychodynamic psychotherapy is an effective alternative to CBT and one that should be provided. The results of this study will have important implications for the provision of psychological treatment in the NHS.

This question should be answered using a randomised controlled trial design that reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing interventions in order to ensure that the treatments are both robust and generalisable. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators and moderators of response should be investigated.

4.3 The cost effectiveness of combined antidepressants and CBT compared with sequenced treatment for moderate to severe depression

What is the cost effectiveness of combined antidepressants and CBT compared with sequenced medication followed by CBT and vice versa for moderate to severe depression?

Why this is important

There is a reasonable evidence base for the superior effectiveness of combined antidepressants and CBT over either treatment alone in moderate to severe depression. However the practicality, acceptability and cost effectiveness of combined treatment over a sequenced approach is less well-established. The answer has important practical implications for service delivery and resource implications for the NHS.

This question should be answered using a randomised controlled trial design in which people with moderate to severe depression receive either combined treatment from the outset, or single modality treatment with the addition of the other modality if there is inadequate response to initial treatment. The outcomes chosen should reflect both observer and patient-rated assessments for acute and medium-term outcomes to at least 6 months, and an assessment of the acceptability and burden of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design together with robust health economic measures.

4.4 The efficacy of light therapy compared with antidepressants for mild to moderate depression with a seasonal pattern

How effective is light therapy compared with antidepressants for mild to moderate depression with a seasonal pattern?

Why this is important

Although the status of seasonal depression as a separate entity is not entirely clear, surveys have consistently reported a high prevalence of seasonal (predominantly winter) depression in the UK. This reflects a considerable degree of morbidity, predominantly in the winter months, for people with this condition. Light therapy has been proposed as a specific treatment for winter depression but only small, inconclusive trials have been carried out, from which it is not possible to tell whether either light therapy or antidepressants are effective in its treatment. Clarification of whether, and to what degree, treatments are effective would help to inform the decisions that people with seasonal depression and practitioners have to make about the treatment of winter depression.

This question should be answered using a randomised controlled trial design in which people with mild to moderate depression with a seasonal pattern (seasonal affective disorder) receive light therapy or an SSRI antidepressant in a partially placebo-controlled design. The doses of both light and SSRI should be at accepted or proposed therapeutic levels and there should be an initial phase over a few weeks in which a plausible placebo treatment is administered followed by randomisation to one of the active treatments. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects, and mediators and moderators of response should be investigated.

4.5 The efficacy of CBT compared with antidepressants and placebo for persistent subthreshold depressive symptoms

What is the efficacy of CBT compared with antidepressants and placebo for persistent subthreshold depressive symptoms?

Why this is important

Persistent subthreshold depressive symptoms are increasingly recognised as affecting a considerable number of people and causing significant suffering, but the best way to treat it is not known. There are studies of the efficacy of antidepressants for dysthymia (persistent subthreshold depressive symptoms that have lasted for at least 2 years) but there is a lack of evidence for CBT. Subthreshold depressive symptoms of recent onset tend to improve but how long practitioners should wait before offering medication or psychological treatment is not known. This research recommendation is aimed at informing the treatment options available for this group of people with subthreshold depressive symptoms that persist despite low-intensity interventions.

This question should be answered using a randomised controlled trial design that reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 6 months' duration. A careful definition of persistence should be used which needs to include duration of symptoms and consideration of failure of low-intensity interventions and does not necessarily imply a full diagnosis of dysthymia. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators and moderators of response should be investigated.

4.6 The efficacy of counselling compared with low-intensity cognitive behavioural interventions and treatment as usual in the treatment of persistent subthreshold depressive symptoms and mild depression

In persistent subthreshold depressive symptoms and mild depression, what is the efficacy of counselling compared with low-intensity cognitive behavioural interventions?

Why this is important

Psychological treatments are an important therapeutic option for people with subthreshold symptoms and mild depression. Low-intensity cognitive and behavioural interventions have the best evidence base for efficacy but the evidence is limited and longer-term outcomes are uncertain, as are the outcomes for counselling. It is therefore important to establish whether either of these interventions is an effective alternative to treatment as usual and should be provided in the NHS. The results of this study will have important implications for the provision of psychological treatment in the NHS.

This question should be answered using a randomised controlled trial design which reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing interventions in order to ensure that the treatments are both robust and generalisable. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators and moderators of response should be investigated.

4.7 The efficacy of behavioural activation compared with CBT and antidepressants in the treatment of moderate to severe depression

In well-defined depression of moderate to severe severity, what is the efficacy of behavioural activation compared with CBT and antidepressants?

Why this is important

Psychological treatments are an important therapeutic option for people with depression. Behavioural activation is a promising treatment but does not have the substantial evidence base that CBT has. The availability of alternatives drawing from a different theoretical model is important because outcomes are modest even with the best supported treatments. It is therefore important to establish whether behavioural activation is an effective alternative to CBT and one that should be provided. The results of this study will have important implications for the provision of psychological treatment in the NHS.

This question should be answered using a randomised controlled trial design which reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the reproducibility of the treatment model and training and supervision of those providing interventions in order to ensure that the treatments are both robust and generalisable. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators and moderators of response should be investigated.

4.8 The efficacy and cost effectiveness of different systems for the organisation of care for people with depression

In people with mild, moderate or severe depression, what system of care (stepped care versus matched care) is more clinically effective and cost effective in improving outcomes?

Why this is important

The best structures for the delivery of effective care for depression are poorly understood. Stepped-care models are widely implemented but the efficacy of this model compared with matched care is uncertain. Evidence on the relative benefits of the two approaches and the differential effects by depression severity is needed. The results of this study will have important implications for the structure of depression treatment services in the NHS.

This question should be answered using a randomised controlled trial design which reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. In stepped care the majority of patients will first be offered a low-intensity intervention by a paraprofessional unless there are significant risk factors dictating otherwise. In matched care a comprehensive mental health assessment will determine which intervention a patient should receive. The full range of effective interventions (both psychological and pharmacological) should be made available in both arms of the trial. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects, and moderators (including the severity of depression) of response should be investigated.

4.9 The efficacy and cost effectiveness of cognitive behavioural therapy, interpersonal therapy and antidepressants in prevention of relapse in people with moderate to severe recurrent depression

In people with moderate to severe recurrent depression, what is the relative efficacy of CBT, interpersonal therapy (IPT) and antidepressants in preventing relapse?

Why this is important

Psychological and pharmacological treatments are important therapeutic options for people with depression, but evidence on the prevention of relapse (especially for psychological interventions) is limited. All of these treatments have shown promise in reducing relapse but the relapse rate remains high. New developments in the style and delivery of CBT and IPT show some promise in reducing relapse but need to be tested in a large-scale trial. The results of this study will have important implications for the provision of psychological treatment in the NHS.

This question should be answered using a randomised controlled trial design which reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 24 months' duration. Particular attention should be paid to the development and evaluation of CBT, IPT and medication interventions tailored specifically to prevent relapse, including the nature and duration of the intervention. The outcomes chosen should reflect both observer and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators (including the focus of the interventions) and moderators (including the severity of the depression) of response should be investigated.

4.10 The effectiveness of maintenance ECT for relapse prevention in people with severe and recurring depression that does not respond to pharmacological or psychological interventions

Is maintenance ECT effective for relapse prevention in people with severe and recurring depression that does not respond to pharmacological or psychological interventions?

Why this is important

A small number of people do not benefit in any significant way from pharmacological or psychological interventions but do respond to ECT. However, many of these people relapse and need repeated treatment with ECT. This results in considerable suffering to them and it is also costly, because ECT often necessitates inpatient care. A small number of studies suggest possible benefits from maintenance ECT but it is used little in the NHS. The outcome of the audit and clinical trial should supply information on patient characteristics, outcomes, feasibility and acceptability in relation to the use of maintenance ECT and potentially inform its wider use in the NHS. The results therefore may have important implications for the provision of ECT in the NHS.

This question should be addressed through first establishing a national audit for the collection of data on all people receiving maintenance ECT. The characteristics of the people who are likely to be considered for maintenance ECT make a randomised controlled trial unfeasible, but a clinical trial using alternative methods (for example, mirror image or a carefully characterised non-randomised study) should be undertaken depending on the outcome of the audit.

The number of people receiving maintenance ECT is small, and considerable uncertainty surrounds its use, such as its long-term efficacy and acceptability and possible side effects, which include cognitive impairment. The outcomes chosen for the audit and clinical trial should reflect both observer and patient-rated assessments of improvement, the impact on cognitive function and an assessment of the acceptability of ECT as a maintenance treatment.

  • National Institute for Health and Care Excellence (NICE)