Major Depression represents a pressing challenge for health care. The disorder is not only
highly prevalent but also shows many characteristics of a progressive disorder. If not
treated sufficiently, it tends to become more recurrent and chronic over time.
In order to address this challenge, it is imperative to provide treatments that effectively
reduce symptoms in those who are affected. In England and other parts of the United Kingdom,
Increasing Access to Psychological Therapies (IAPT) services have been introduced with the
aim of providing evidence-based psychological therapies in a timely manner. While the
introduction of these services has successfully increased access to psychological therapies,
outcome reports indicate that about 50% of the depressed patients who have completed
high-intensity evidence-based psychological therapies within IAPT do not reach recovery and
continue to show significant levels of symptoms. At the same time, progression to secondary
care remains reserved for those with complex depression and high risk for suicidality.
Mindfulness-Based Cognitive Therapy (MBCT), an eight-week, group-based intervention that
combines intensive training in mindfulness and elements from cognitive therapy for
depression, may be particularly suited for addressing this gap. While originally developed,
for the prevention of relapse in remitted patients with a history of recurrent depression,
recent research has brought promising evidence that MBCT can have significant beneficial
effects in patients with acute symptoms, and particularly in those who have not responded to
previous interventions. However, evidence is currently not sufficient to warrant endorsement
for use as a further-line treatment within the evidence-based IAPT pathway.
In order to justify and enable this use, research needs to provide evidence from a further
definitive trial. Moreover, previous research investigating MBCT as a further-line treatment
has been conducted exclusively in non-responders to antidepressant medication. In order to
provide representative estimates of benefits for inclusion in IAPT, research will have to
test clinical effectiveness following psychological therapy and demonstrate its
cost-effectiveness within this particular pathway.
This study will compare MBCT to treatment-as-usual (TAU) in IAPT high-intensity treatment
non-responders in a definitive clinical trial. We will test the immediate effects of the
intervention on depressive symptomatology as well as whether effects on symptomatology can be
sustained over a period of six months, thus taking into account the high risk of relapse in
early stages following treatment. In addition to testing clinical effectiveness, the
investigators will measure service use and collect information on quality of life in order to
provide information on the cost effectiveness of the intervention in IAPT high-intensity
treatment non-responders.
Design
The investigators will randomise 234 patients who have not responded to high-intensity IAPT
interventions for depression, but do not meet eligibility criteria for secondary care
services, in a 2-arm trial to take part in either MBCT or to continue with TAU, providing a
comparator that is reflective of the current state of care (and in most cases will entail
continued use of antidepressant medication). We will measure outcomes at baseline, 10-week
and 34-week follow-up post-randomisation. Economic analyses will investigate effects of the
interventions on subsequent service use.
Study setting
The research will be conducted at three main sites: South London and Maudsley NHS Trust,
Sussex Partnership NHS Foundation Trust, and at the AccEPT Clinic, Mood Disorders Centre,
University of Exeter, in collaboration with Devon Partnership NHS Trust.
Participants
The investigators will recruit depressed treatment non-responders to IAPT high-intensity
treatments into the study. For detailed criteria see further below.
Intervention
Participants will be allocated to receive either MBCT or TAU. MBCT combines mindfulness
training with elements from cognitive therapy. The investigators will follow the treatment
manual with minor adaptations to address the fact that patients are suffering from current
symptoms of depression following practice from our previous research. MBCT consists of eight
weekly group-based sessions and participants are asked to engage in home practice of
mindfulness meditation for about an hour per day. The intervention will be delivered by
trained MBCT therapists together with an assistant to groups with a target size of 13
patients (minimum of 8 and maximum of 16) using videoconferencing on a secure online
platform.
Participants in the TAU condition will be asked to continue with their usual care and follow
the regimes suggested by their GP or mental health professional, which in most cases will
consist of continuing use of antidepressant medication. Following previous practice in our
trials, TAU participants will be invited to an interview to prevent tendencies towards
'resentful demoralisation' and highlight the importance of their contribution.
Economic evaluation
The economic evaluation will take a health and social care perspective, as required for
evidence presented to NICE. In addition, the cost perspective will be broadened to include
the costs of time off productivity losses, since these are known to be relevant and important
in those attending IAPT services. Costs will be calculated by collecting service use
information using the Adult Service Use Schedule (AD-SUS), as self-report measure developed
by the team at King's and used in previous trials of MBCT, modified for use online, to which
routine unit costs will be applied. The investigators will collect data on all service use
not just use related to mental health conditions, because there is evidence that successful
treatment in IAPT can reduce use of all healthcare services. Data on the use of the MBCT
intervention will be collected via therapist records and costs estimated using the standard
approach set out by Curtis et al., acknowledging the challenges of costing group-based
interventions. Outcomes for the economic evaluation will be QALYs, calculated using health
utilities derived from the EQ-5D-5L. Costs and outcomes will be combined first in a
cost-utility analysis using QUALYS and second in a cost-effectiveness analysis using the
PHQ-9, providing information on whether or not MBCT is worthwhile in terms of costs savings
elsewhere or improvements in outcomes, and information will be provided to decision makers
with statistical analysis of differences in costs, cost-effectiveness planes and
cost-effectiveness acceptability curves.
Qualitative analyses
Qualitative analyses will be used to explore patient experience of the intervention and to
understand how the treatment might best benefit patients in the IAPT pathway. The
investigators will investigate:
patients' views on acceptability of MBCT and mindfulness practice,
patients' views of the changes they experience and their utilization of mindfulness
skills, and
patients' views of the broader impact of MBCT on their lives.
A subsample of participants in the MBCT arm, estimated to be 24 (or until data saturation has
been reached), will be invited to a qualitative telephone interview conducted by trained
research assistants. Recruitment will be purposive, including patients across all sites, and
seeking to achieve maximum variation in relation to:
completion/non-completion of treatment,
response/non-response to treatment, and
recruitment site (to examine contextual factors). Written feedback provided in the
protocol sheets that MBCT participants receive on a weekly basis will be used to inform
subsampling and will also provide us with the opportunity to explore any unanticipated
experiences and effects in more depth.
Interviews will be audio-recorded, transcribed verbatim, and anonymized. Thematic analysis of
interview transcripts will be conducted using a Framework approach, involving the coding and
sorting of textual units according to both deductive and inductively-derived categories, and
the use of matrices to review the coded data, investigate commonalities and differences and
search for patterns.
Recruitment
Participating IAPT services will identify patients who are coming to the end of their
high-intensity treatment and have not responded (PHQ-9≥10) or patients who within a 6-month
window following the end of high-intensity therapy show levels of symptoms above caseness
without prior remission.
Randomisation
The investigators will allocate individual participants to either MBCT or TAU at a ratio of
1:1 through remote randomisation at the UKCRC-registered Exeter Clinical Trials Unit
(ExeCTU), following informed consent, completion of baseline assessment and enrolment in the
trial. Randomisation will use minimisation on depression severity (PHQ-9<19 versus ≥19),
antidepressant use at baseline and recruitment site.
Data collection methods
At baseline, trained research assistants will administer clinical interviews and self-report
questionnaires at each of the sites. Post-treatment and follow-up assessments will be
conducted remotely by asking participants to complete self-report questionnaires via secure
online portal.
Blinding
As baseline assessment of participants is carried out prior to randomisation, there is no
risk of disclosure of treatment allocation to the assessor at the time. Use of remote
assessments, initiated through automated email, will rule out any potential effects of
assessors on assessments of outcomes. The statistician analysing outcome data will remain
blind to treatment allocation throughout the analysis.
Data management
Randomisation, data management, and quality assurance will be undertaken by ExeCTU under the
supervision of the principal investigator, trial statistician and quality assurance manager.
Statistical methods
All analyses will be carried out using an a priori statical analysis plan as agreed with the
TMG and TSC.
Participant characteristics at baseline (including number of previous depressive episodes and
IAPT service) will be set out descriptively by treatment arm. The primary analysis approach
will use the intention-to-treat (ITT) principle (all participants will be included in the
analysis according to their randomised allocation irrespective of the treatment actually
received) including observed data only. All outcomes will be reported descriptively at
baseline, and at 10 and 34 weeks' follow-up. Continuous outcomes will be analysed using
linear regression models. The binary outcome variables will be analysed using logistic
regression. All analyses will adjust for participant covariates used in randomisation, with
adjustment for baseline scores for continuous outcomes. We will assess other participant
characteristics at baseline and will consider adjusting for any covariates that are found to
be substantively unbalanced, should such covariates be considered predictive of outcome.
Inferential between group comparisons (MBCT vs TAU) for the primary and all secondary
outcomes will be performed at 34-week follow-up. As a sensitivity analysis, the investigators
will perform a complier average causal effect (CACE) analysis for continuous outcomes only,
to estimate the treatment effect while accounting for non-adherence to treatment. Mixed
effects regression models with a random effect on individual participant will be performed
for continuous and binary outcomes, including participants with outcome data reported for at
least one follow-up time. Sensitivity analyses are described in the protocol and statistical
analysis plan.