SSRI Study for Functional Dyspepsia (SS)
Condition: Dyspepsia; Anxiety; Depression
MeSH terms: Dyspepsia; Depression
Study type: Interventional
Phase: Phase 3

Summary: 
      Background:

      Functional dyspepsia is one of the commonest digestive disorders. The pathophysiology of
      functional dyspepsia (FD) is uncertain. Clinical experience and community studies show that
      FD is strongly associated with common mood disorders especially depression and anxiety
      disorders, which can be treated with serotonin selective uptake receptor (SSRI).

      Our previous study shows that the relief of FD symptom has an association with the change of
      plasma serotonin and ghrelin profile. However, the correlation between plasma serotonin level
      in FD patients treated with SSRI is lacking in these studies.

      Indication:

      Functional dyspepsia patients

      Study center(s):

      Prince of Wales Hospital, Hong Kong

      Aims :

        -  To evaluate the effect of SSRI treatment on change of plasma serotonin level

        -  To evaluate the relationship between dyspeptic symptom and change of plasma serotonin
           level

      Study medication:

      Escitalopram (Lexapro) 5mg daily for first 2 weeks, and then 10 mg daily for 8 weeks versus
      Placebo for 10 weeks

      Study design:

      Double-blind randomized placebo-controlled trial

      Number of subjects:72

      - 36 patients (18 male and 18 female) and 36 age-and-sex-matched healthy controls

      Patient population:

      Functional dyspepsia patients age 18-60, with element of anxiety or depression

      Duration of study: 1 June 2013 - 30 November 2015

      Primary variable(s):

      Change of serotonin and ghrelin level in blood plasma after medication treatment

      Secondary variable(s):

      Rate of adequate relief using global symptom assessment and symptom scores

      Number of visits: 2
    

Detailed description: 
      Baseline assessment:

        -  Demographic: age, gender

        -  Anthropometric measurements: body mass index, height, weight and waist circumference

        -  FGI Screening Questionnaire (v.3, 20101011) for screening of functional gastrointestinal
           disorder according to Rome III criteria.

        -  Duration of dyspeptic symptoms will be recorded

        -  A combined Functional GI symptom Questionnaire (FGISQ) (version: FGISQ 20110504) based
           on recall of the past 7 days will be used for assessment al GI symptoms including
           regurgitation, heartburn, epigastric pain, postprandial fullness, abdominal pain,
           diarrhea, constipation etc. All questions use a 4-point (0-3) Likert scale.

        -  Patient Health Questionnaire (PHQ) and Hospital Anxiety and Depression Scale (HADS) will
           be used for screening of concomitant psychological disorder such as depression and
           generalized anxiety disorder.

        -  BECK Anxiety Inventory (BAI), BECK Depression Inventory (BDI) and Anxiety Sensitivity
           Index-Revised (ASI-R) will be used for monitor the change of mood status.

        -  Trained interviewers perform semi- structured clinical interview using the
           Chinese-Bilingual version of the Structured Clinical Interview for DSM Mental
           Disorders-IV to assess for lifetime and current diagnoses of depressive and anxiety
           disorders (female patients only)

      Satiety test and ghrelin profile:

      After an overnight fast, the patients are instructed to ingest Ensure® (1.06 kcal/ml; 22%
      fat, 64% carbohydrate, and 14% protein) at constant rate of 30ml/min for a fixed calorie test
      of 28 minutes (Total calorie: 890.4 kcal). They are required to complete a Fullness Rating
      Scale (FRS) at 3-min intervals (ie. 0min, 3min, 6min…). Initial Blood sample of 16 ml will be
      taken (10ml will be taken preprandially for storage in future identification of biomarkers
      for functional GI disorders and 6 ml for assay of ghrelin and serotonin profile). Another
      blood sample (6 ml) will be taken at 120min for assay of ghrelin and serotonin profile.

      The test will be performed at baseline (V1) and after medication treatment (V2).

      Baseline neuroimaging studies (female subjects only):

        1. Structural MRI MRI will be performed using a 3 Tesla MRI scanner (Achieva TX series,
           Philips Healthcare, Best, Netherlands). Patients will be lying supine on the MRI
           scanning table. In each study, high resolution structural images will be acquired using
           an 8-channel receive-only head coil in the transverse orientation from the same section
           of the brain using a sagittal 3D T1-weighted sequence (TR/TE: 7.4/3.4 ms, field of view:
           250x250 mm, 285 contiguous slices, 0.6 mm (RL) thickness, reconstruction matrix:
           240x240, flip angle 8o).

           Analysis- Voxel-based morphometry and ROI approaches - We will adopt voxel-based
           morphometry to locate the differences in white matter and grey matter globally. The
           volume of the structures of interest will be quantified after segmenting by
           automatically registering with the brain template (with atlas labeling) we constructed
           based on Chinese structural brain MRI. The volume of regions of interest will be
           compared between FD and normal control groups, including the left ventrolateral
           prefrontal cortex, dorsolateral prefrontal cortex, bilateral insular cortices, bilateral
           anterior and midcingulate cortices, as well as corona radiata.

        2. Diffusion Tensor Imaging DTI will be obtained using single-shot echo planar imaging
           sequence. Diffusion sensitizing gradients will be applied along 32 non-linear directions
           (b = 1000 s/mm2), together with an acquisition without diffusion weighting (b = 0
           s/mm2). The imaging parameters will be 70 continuous axial slices with a slice thickness
           of 2 mm and no gap, field of view = 224x224 mm2, repetition time/echo time = 8924/60 ms,
           acquisition matrix = 112x109. A parallel imaging acceleration factor of 2.5 will be used
           to reduce scan time.

      Analysis- We will compare the whole brain FA/ADC map and fiber tracts between different ROIs
      as stated above. The statistical group comparison of whole brain FA/ADC values will be
      performed following the voxel-based tract based spatial-statistics (TBSS), which is an
      automated method of comparing the FA values after aligning images from multiple subjects. The
      advantage of applying TBSS lies in the robust "voxel-wise" cross-subject statistics, better
      image alignment, and projecting data onto group-mean tract skeleton. Aside from the whole
      brain FA/ADC analysis, we also intend to compare the fiber density and FA/ADC values in each
      specific ROIs. The ROI in the DTI data will be identified by registering with the structural
      data and mapping the ROI segmentation results from the structural data. The whole brain
      tractography will be performed and the density of the fibers in each ROI will be calculated
      and compared between two groups. The mean FA/ADC values in each ROI will also be compared
      between two groups.

      The tests will be performed at baseline (V1) for female patients and controls only.Functional
      neuroimaging assessment (female patients only) Functional MRI -resting state functional
      connectivity For resting-state fMRI scanning, subjects will be instructed to have their eyes
      closed for 6 minutes and hold still without falling asleep. Subjects considered not compliant
      with these instructions will be excluded from the study. Resting fMRI data will be collected
      by using a single-shot echo-planar sequence sensitive to BOLD contrast (TR: 2050ms, TE: 25ms,
      flip angle 90o, slab thickness: 150 mm, field of view: 205x205 mm, image matrix: 64x64,
      parallel imaging acceleration factor of 2) to acquire 150 dynamic scans under each condition.
      BOLD images acquired will have a nominal in-plane resolution of 3.2x3.2 mm and a temporal
      resolution of 2 s per dynamic scan.

      Analysis- The functional brain connectivity will be derived from the resting state functional
      MRI (rs-fMRI) data and compared between two groups. In particular, the rs-fMRI data will be
      co-registered with the structural MRI data. Ninety-nine brain regions will be automatically
      partitioned by mapping with the Chinese brain atlas with 90 labeled regions. The correlation
      of the low frequency time series data will be calculated between every two regions among the
      90 regions, based on which a connectivity matrix will be generated and thresholded to
      construct the functional brain connectivity network. The global, regional, and local network
      characteristics will then be derived and compared between two groups.

      Magnetic Resonance Spectroscopy:

      Localized proton MRS will be performed after structural images have been obtained to guide
      the positioning of volumes of interests in the left insula and bilateral pregenual anterior
      cingulate cortex and left primary somatosensory cortex. Signal reception for 1H-MRS will be
      achieved using the same 8-channel received-only head coil. Water-suppressed spectra will be
      acquired from each region measuring 2 x 2 x 2 cm3 using the point-resolved spectroscopic
      (PRESS) sequence (TR/TE 2000/23 ms). A short TE PRESS sequence will be employed to enable an
      optimal detection of metabolites of interest such as glutamate-glutamine (Glx) peaks.
      Optimization procedures for spectroscopy will comprised of automated receiver gain frequency
      adjustment, second-order shimming and gradient tuning. Water suppression will be achieved
      using an automated selective inversion recovery technique. From each region, 128
      water-suppressed signals will be acquired at a spectral bandwidth of 1,000Hz. The averaged
      signals will be exported and processed on an off-line computer.

      MRS Data Analysis Short TE spectra acquired will be analyzed using a fully automated and
      user-independent spectral software package LCModel, a frequency-domain postprocessing tool
      that is well suited to quantify complex signals Glx (ref). The advantage of LCModel is that
      it employs information from the whole chemical shift range of a spectrum to fit the
      amplitudes of the model spectra. The metabolites of interest in our study will be NAA, Cho,
      mI, Glx, glutamine, glutamate, GABA and creatinine. Metabolite ratios mI/Cr, Glx/Cr, NAA/Cho,
      NAA/Cr and Cho/Cr will be calculated based on peak concentration values obtained from LCModel
      analysis.

      The test will be performed at baseline (V1) and after medication treatment (V2) for female
      patients only.

      Randomization and unblinding of treatment arm

      Randomization is performed for each gender independently, so that each gender group (male and
      female) consists of 9 patients in treatment arm and 9 patients in control arm.

      The random allocation sequence is obtained from a computer-generated list of random numbers
      in blocks of 18. Concealed allocation is achieved by an independent staff who labels the
      Escitalopram 5mg/10mg and placebo according to the computer-generated list. The study arm
      allocated for each study number is printed and sealed in individual envelopes of consecutive
      study number.

      After satiety test at baseline (V1), the research staff will dispense the sealed packaged
      study medication according to the patient's study number which is given in consecutive order
      according to patient's gender. Both the investigators, research staff and patients are not
      aware of the treatment assignments throughout the study.

      At final visit (V2), the study arm that the patient is assigned to will be unblinded by
      opening the prepared sealed envelope of the patient's study number. Physician consultation
      will be given to decide further management of the disease based on patient's symptom response
      and current medication treatment. Further titration (either dose escalation or tapering) will
      be determined at the discretion of physician based on individual responses if the patient has
      been allocated to the Escitalopram group. The patient would continue his disease management
      in the hospital's specialty clinic after final visit (V2). Medication adherence is measured
      by pill counts at final visit (V2).

      Follow-up questionnaire assessment:

      The patients will report their individual dyspeptic and mood symptoms on a weekly basis until
      week 8 by completing the following self-administered questionnaires: FGISQ, BAI and BDI.
      ASI-R will only repeat at week 8.
    

Intervention name(s): Escitalopram; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Escitalopram 5mg daily will be given for the first 2 weeks and then Escitalopram 10mg daily will be given for the next 8 weeks.; Placebo will be given for the next 10 weeks.
Other intervention name(s): Lexapro
Intervention MeSH terms: Escitalopram
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Functional dyspepsia; symptom response; postprandial fullness; Anxiety; Depression