Design
This is a parallel group, double-blind, two-arm RCT. Participants will be randomly allocated to receive 5 sessions of either [ABM + real tDCS] (treatment group) or [ABM + sham tDCS] (control group) over 3-4 weeks, delivered in addition to treatment as usual. Outcomes will be measured at baseline, post-treatment and at 2-week follow-up. Participants in the control group will be offered the opportunity to receive [ABM + real tDCS] at the end of the study. The protocol is outlined in Fig.1, and Table 1 gives details of assessments and time points. Our study design will enable us to show whether ABM training alone is effective (by comparing pre- and post-treatment). Our study design will also allow us to establish whether adding tDCS to the ABM is better than ABM alone. Specifically, this will be achieved by administering the Food Approach-Avoidance Task and the Stimulus Response Compatibility Task at baseline and post-treatment to measure approach bias towards high-calorie foods in the two groups (real-tDCS and ABM vs. sham-tDCS and ABM).
Setting
The study will be conducted at the Institute of Psychiatry, Psychology and Neuroscience (IoPPN) and at inpatient and community services at the South London and Maudsley NHS Foundation Trust (SLaM).
Ethical approval and trial registration
Ethical approval for the study was obtained from the Oxford B Research Ethics Committee (REC, ref: 19/SW/0095). The study is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry (registration number: ISRCTN13280178).
Figure 1. Schematic Diagram of the study protocol
Participants and recruitment
Participants will be recruited from inpatient and community services at the South London and Maudsley NHS Foundation Trust (SLaM), through websites (such as IoPPN), through social media platforms (such as Eating Disorders Unit official Twitter account) and through the Consent 4 Contact SLaM initiative (45). Participants will be paid £90 for their time and effort.
Inclusion criteria
Male or female participants will be included if they have a current DSM-V diagnosis of schizophrenia or schizoaffective disorder, are aged 18-65 years and have been on a stable dose of antipsychotic medication for at least 6 weeks prior to study enrolment.
Exclusion criteria
Participants will be excluded if they: suffer from any significant /unstable co-morbid medical or psychiatric disorders (e.g. substance dependence); are on a dose of antidepressant medication that has not been stable for at least 6 weeks; are allergic to any of the foods used in the study; cannot understand verbal or written English. A tDCS safety questionnaire will be administered and individuals will be excluded if they: have a history of epileptic seizures, stroke or brain injury; have any implanted metal devices in the head; suffer from frequent or severe headaches or dizziness; are pregnant.
Sample size
As this is a feasibility study, no a priori sample calculation has been conducted. This study aims to provide effect sizes on which future large-scale studies can be based. Total sample sizes of n=24 to n=50 have been recommended for feasibility trials with a primary outcome measured on a continuous scale, mainly because estimates of the standard deviation for normally distributed variables tend to stabilise around this size (46, 47). We have chosen a total sample size of n=30 (which exceeds the lower end recommended for feasibility trials).
Randomisation
Generation and implementation of the randomisation sequence will be conducted independently from the trial team by a King’s College researcher using Sealed Envelope, an online randomisation tool (48). Once the baseline assessment has been conducted and the patient is recruited and has consented to the trial, she/he will be allocated to one of the two intervention arms in a ratio of 1:1. Group allocation will be communicated via phone, email or in a sealed non-transparent envelope to the appropriate member of the research team for each participant.
Intervention
Study procedures
In both groups, participants will receive 5 sessions of [ABM + real /sham tDCS] over 3-4 weeks. ABM and tDCS will be delivered at the same time, i.e. participants will engage in the ABM whilst receiving brain stimulation. Each session will last approximately 40 minutes, including preparation time, 20 minutes of [ABM + tDCS] and questionnaire administration. The ABM will start 1 minute after the start of the brain stimulation, to allow participants to get used to the brain stimulation. Thereafter, ABM will take place over 15 minutes and brain stimulation will then continue for a further 4 minutes. Throughout the study, participants will be able to access or continue treatment as usual as recommended by their treating team.
ABM training
The ABM programme is based on a modified version of the Food Approach /Avoidance Task (F-AAT). In the F-AAT task, participants are shown pictures of food and control (i.e. neutral household and office) items. They are required to pull (pictures grow bigger) or push (pictures grow smaller) a joystick in response to the outer frame of the picture (round vs. rectangular), irrespective of the picture content. The ABM task adopts an implicit learning paradigm by presenting all food pictures in the “push” (i.e. avoid) format. The study procedure for ABM administration is in accord with a protocol paper (49), with updated images of foods and non-edible objects from a food-pictures database (50).
tDCS
TDCS (both real and sham) will be delivered using a neuroConn® DC-STIMULATOR device at a constant current of 2 mA (with a 10-second fade in/out) using two 25cm² surface sponge electrodes soaked in a sterile saline solution (0.9% sodium chloride). The anode will be placed over the right dlPFC and the cathode over the left dlPFC. The stimulation site will correspond to the F3 location based on the International 10-20 system (51). In the real tDCS group, current will be delivered for the whole duration of the stimulation (20 minutes). In the sham (placebo) tDCS group, current will automatically turn off after 30 seconds.
Safety
Study procedures and parameters are in accord with safety and application guidelines for tDCS (52). Treatment will be delivered by personnel trained in tDCS administration. A case record form for each trial participant will be kept to monitor session attendance and any side effects or adverse events according to prespecified criteria. Any protocol violations will also be recorded there. To ensure safety, participants’ blood pressure and pulse will be monitored before and after each stimulation. TDCS is generally well-tolerated and is associated with relatively minor side effects. According to the review of 567 tDCS sessions adverse events (and occurrence rates) included: tingling sensation (70.6%), moderate fatigue (35.3%), light itching sensation under the stimulation electrodes (30.4%), headache (11.8%), nausea (2.9%) and insomnia (0.98%) (53). Another review of 209 tDCS studies found similar rates of adverse events in both real and sham stimulation groups (54). In the event of mild side effects (e.g. a slight headache) participants will not be withdrawn, but will be able to discontinue tDCS treatment if they wish. TDCS will be immediately halted if the participant experiences a more serious adverse event or if any other indicators of serious medical risk emerge. Treatment will only be restarted if it is deemed safe to continue by a medical professional. Standard King’s College London insurance and NHS indemnity arrangements will apply to this study.
Table 1. Study schedule of enrolment, interventions and assessments
|
STUDY PERIOD
|
|
Screen Visit (all participants)
|
Baseline (all participants)
|
Training: ABM + real tDCS
|
Training: ABM + sham tDCS
|
Post-assessment (all participants)
|
Follow-up (all participants)
|
Study end (all participants)
|
Timepoint
|
-t1
|
0
|
t1
|
t1
|
t2
|
t3
|
t4
|
Participant information sheet, inclusion /exclusion criteria and tDCS safety screen
|
X
|
|
|
|
|
|
|
Informed consent
|
|
X
|
|
|
|
|
|
Demographic information
|
|
X
|
|
|
X
|
|
|
Questionnaires
|
|
X
|
|
|
X
|
|
|
Food related tasks
|
|
X
|
|
|
X
|
|
|
Approach bias assessment tasks
|
|
X
|
|
|
X
|
|
|
Pre-[ABM + tDCS] measures: multiple VASs, blood pressure and pulse
|
|
|
X
|
X
|
|
|
|
Anodal real tDCS to dlPFC
|
|
|
X
|
|
|
|
|
Anodal sham tDCS to dlPFC
|
|
|
|
X
|
|
|
|
Approach bias modification training
|
|
|
X
|
X
|
|
|
|
Post-[ABM + tDCS] measures: multiple VASs, blood pressure and pulse
|
|
|
X
|
X
|
|
|
|
Tolerance, discomfort and side effects of tDCS
|
|
|
X
|
X
|
|
|
|
Acceptability questionnaire
|
|
|
|
|
X
|
|
|
Blinding assessment questionnaire
|
|
|
|
|
X
|
|
|
Follow-up questionnaires
|
|
|
|
|
|
X
|
|
Unblinding
|
|
|
|
|
|
|
X
|
Procedure
A flowchart outlining study procedures is presented in Fig. 1. Table 1 presents the time schedule of enrolment, interventions and assessments, consistent with the figure provided in the SPIRIT Statement (2013) (55) recommendations for reporting protocols (see Additional File 1 for SPIRIT checklist).
Screening
Potential participants will be referred by their clinician or will self-refer. Researchers will screen participants for eligibility. Screening questionnaires include a tDCS safety screen, and a short inclusion /exclusion study specific screen, including an assessment of medical and psychiatric history, and medication dosage and stability. In line with the CONSORT guidelines (56, 57), we will record the number and reasons for any participants we must exclude, or any who decline consent or withdraw from the study.
Baseline assessment
Once eligibility has been confirmed, the participant’s written informed consent will be obtained by the researcher. Participants will be asked to complete a number of questionnaires and experimental procedures assessing eating behaviours and mood, as well as computer tasks that assess attention bias towards food cues. Once the baseline assessment is complete, participants will be randomly allocated to the treatment [ABM + real tDCS] or control [ABM + sham tDCS] group.
Post-treatment assessment
Post-treatment assessment will take place after the last treatment session and include the same elements as the baseline assessment. Blinding success will be evaluated by asking participants and researchers to guess the treatment allocation.
Follow-up
Two weeks after post-treatment assessment, a follow-up session will be conducted. This short session will consist of questions regarding mood, food cravings and eating behaviours. Participants’ weight will be measured.
Measures
Screening measures
A tDCS safety screen will be conducted to check for contraindications to tDCS.
Outcome measures
Since this is a feasibility study, a broad range of outcome measures are included to determine which are most sensitive to detecting a treatment effect. This will enable us to determine primary outcome(s) for a future large-scale RCT.
Clinical outcomes related to eating behaviours
(1) Questionnaires including Eating Disorder Examination Questionnaire (EDE-Q) (58) and Food Cravings Questionnaire-Trait-Reduced (FCQ-T-r) (59) will be administered at baseline and post-treatment. The FCQ-T-r will also be administered at a 2-week follow-up.
(2) Food tasks including the Food Challenge Task (FCT) (40) examining cue-induced food craving and the Taste Test measuring actual food consumption will be administered at baseline and post-treatment. Within each session, Visual analogue scales (VASs) regarding current experiences (level of hunger, feeling full, urge to eat, feeling low, level of tension, level of stress, level of anxiety) will be completed before and after the food tasks.
(3)Computer tasks including the Food Approach-Avoidance Task (F-AAT) (33) and the Stimulus Response Compatibility Task (SRC) (60) measuring approach bias towards high-calorie food items will be administered at baseline and post-treatment.
(4) Participant’s body weight will be measured at baseline, post-treatment and follow-up.
Other clinical outcomes
(1) Questionnaires assessing: depression - Depression, Anxiety and Stress Scale (DASS-21) (61); cognitive deficits - Montreal Cognitive Assessment (MoCA) (62); and impulsivity - Barratt Impulsiveness Scale (BIS-11) (63); will be administered at baseline and post-treatment. The DASS-21 will also be administered at a 2-week follow-up.
(2) Symptoms of schizophrenia will be assessed by the Simplified Negative and Positive Symptoms Interview (SNAPSI) (64) and rated using the Positive and Negative Syndrome Scale (PANSS-6) (65) at baseline and post-treatment.
Intervention related outcomes
(1) Acceptability of the intervention will be measured as follows: (a) before and after each treatment session by collecting VAS scores on the levels of tension, stress and anxiety; (b) before and after each treatment session by asking about any comments about the treatment; (c) at the end of the study, by asking participants if they would like to take part in a therapeutic trial of tDCS if this was available; (d) by the number of recruited participants.
(2) Treatment tolerability will be measured after each session by a VAS assessing levels of discomfort.
Blinding
This will be a double-blind study, where participants and researchers conducting assessments and delivering tDCS are blinded to treatment allocation. Sufficient blinding will be ensured by utilising a parallel design and a built-in neuroConn® DC-STIMULATOR blinding feature. With this, real and sham stimulations are assigned different codes, which the researcher enters into the device to start the stimulation. The real stimulation continues for 20 minutes, whereas the sham stimulation stops after 30 seconds, which triggers the same sensations on the skin (to improve blinding). To assess whether allocation concealment has been successful, participants and researchers will be asked to guess the treatment allocation at the end of the tDCS treatment and to indicate how certain they are of this guess. Participants will be debriefed and unblinded to group allocation at the end of the study. At that time, participants in the sham condition will be offered [ABM + real tDCS] treatment following the protocol as described above.
Analyses
Feasibility
The decision as to whether to progress the study to a future large-scale RCT will be based on a number of criteria. These include the number of patients we are able to recruit, the proportion of patients retained, the proportion of patients completing the real and sham [ABM + tDCS] intervention, the acceptability and tolerability of the tDCS and the effect sizes of treatment outcomes. At the end of the study, these factors will be used to decide the case for progressing to a substantive RCT.
Clinical outcomes
Analyses will use the intention-to-treat principle. Descriptive statistical analyses and graphical methods will be used to determine quality, completeness and variability of the outcome measures. The size of the treatment effect on each outcome measure (questionnaires, tasks) will be the difference in outcome data between those in the two treatment conditions at post-treatment and follow-up. Group differences will be estimated using linear mixed effects regression models, controlling for the baseline level of the outcome. The aim of the analysis is to establish a suitably precise effect size for the primary outcome at the post-treatment assessment in a future large-scale RCT.