<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03801655</url>
  </required_header>
  <id_info>
    <org_study_id>R58085/RE003</org_study_id>
    <nct_id>NCT03801655</nct_id>
  </id_info>
  <brief_title>OxPALM: Oxford Study on Probiotics and Low Mood</brief_title>
  <official_title>The Effects of a Probiotic on Emotional and Cognitive Processing in Participants Experiencing Low Mood</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Oxford</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Oxford</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Probiotics are live bacteria which have been suggested to have beneficial effects not only on&#xD;
      gut function but also on psychological and cognitive functioning. This study will investigate&#xD;
      how a specific probiotic influences emotional and cognitive processing in participants with&#xD;
      low mood.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Current antidepressant treatments, which largely target monoamine pathways, are efficacious&#xD;
      in treating many aspects of major depression, however it is estimated that more than 30% of&#xD;
      depressed patients fail to respond to standard antidepressant medications. Thus, there is a&#xD;
      strong clinical need to identify and investigate novel treatment strategies that target&#xD;
      different pathways involved in the pathophysiology of mood disorders.&#xD;
&#xD;
      There is now compelling evidence for a link between the enteric microbiota and brain&#xD;
      function. The proliferation of the Bifidobacteria and Lactobacilli strains in the large&#xD;
      intestine, have anxiolytic and mnemonic effects in both rodents and humans. The intake of&#xD;
      these bacteria as live cultures (probiotics) alters the expression of genes integral to&#xD;
      neurodevelopment and complex behaviours in rodents. For instance, the oral administration of&#xD;
      Bifidobacteria to rats elevated hippocampal brain-derived neurotrophic factor (BDNF), which&#xD;
      may underlie some antidepressant actions . At present, only several probiotics have been&#xD;
      examined, but it seems likely that of the 40,000 species in the gut, there will be others&#xD;
      with psychotropic properties. A multispecies probiotic (Bio-Kult) that contains several&#xD;
      species of Bifidobacteria and Lactobacilli is now available and of the 14 types of bacteria&#xD;
      packaged into a capsule, 50% have been shown to have psychotropic effects in animals. Dietary&#xD;
      supplementation with Bio-Kult therefore, presents as an optimal strategy to test the&#xD;
      influence of beneficial gut bacteria on emotional processing and cognition because, the&#xD;
      numerous types of bacteria ingested may have a synergistic effect on the brain and so convey&#xD;
      a 'stronger' action compared to single species probiotics.&#xD;
&#xD;
      The translation from rodent to human investigations of probiotics has been surprisingly&#xD;
      robust, though many more human studies are necessary. In an important early investigation&#xD;
      male and female participants consumed either a fermented milk drink containing Lactobacillus&#xD;
      casei Shirota or a placebo. At the end of the three-week intervention, there were no overall&#xD;
      changes in self-reported affect. However, when only participants whose baseline mood scores&#xD;
      fell in the lowest third of the total range were analysed, probiotic supplementation resulted&#xD;
      in significantly more participants self-rating as happy rather than depressed, relative to&#xD;
      placebo. These results suggest that the emotional benefits of probiotics may be subject to&#xD;
      ceiling effects.&#xD;
&#xD;
      Similar effects have been observed in other investigations of mood. For instance, in a recent&#xD;
      randomised controlled trial, healthy participants consumed a placebo product or a mixture of&#xD;
      several probiotics (Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus&#xD;
      acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius&#xD;
      W24, and Lactococcus lactis W19 and W58) over a period of four weeks. Relative to placebo,&#xD;
      probiotic-treated participants exhibited substantially reduced reactivity to sad mood&#xD;
      (assessed by the Leiden Index of Depression Sensitivity Scale), an effect that was&#xD;
      specifically attributable to fewer instances of rumination and aggressive cognitions.&#xD;
&#xD;
      In a randomized and double-blind design, healthy volunteers consumed either a mixture of&#xD;
      probiotics (Lactobacillus helveticus R0052 and Bifidobacterium longum) or a placebo over 30&#xD;
      days, after which participants completed a range of self-report measures on mood and&#xD;
      distress. Participants also collected urine over 24 hours before and after the intervention,&#xD;
      enabling cortisol estimations. Relative to placebo, probiotic-treated participants showed&#xD;
      significant declines in self-reported negative mood and distress. Parallel to these changes&#xD;
      was a decrease in urinary free cortisol, which is suggestive of a potential mechanism&#xD;
      underlying the self-reported affective improvements. Interestingly, a follow-up analysis of&#xD;
      the individuals with the lowest stress (indexed by cortisol concentrations) showed similar&#xD;
      affective benefits to those with higher cortisol concentrations, to some extent contravening&#xD;
      the role of ceiling effects in determining probiotic outcomes.&#xD;
&#xD;
      The Bio-Kult probiotic supplement has been selected for use in the present study because it&#xD;
      contains the greatest number of bacterial genera and species currently on the market. In&#xD;
      preliminary studies in rats, investigators have found that once daily Bio-Kult feeding for 3&#xD;
      weeks reduces circulating corticosterone, a stress hormone that is the corollary of human&#xD;
      cortisol. This appears to be consistent with the above human investigation. Thus, taking into&#xD;
      consideration its mentioned association with stress and mood, this probiotic supplement&#xD;
      provides an interesting tool to investigate effects on cognition and emotional processing,&#xD;
      particularly negative affective biases.&#xD;
&#xD;
      Negative affective biases in emotional processing are highly relevant to clinical mood&#xD;
      disorders and they are well-recognised in the aetiology and maintenance of depression, such&#xD;
      that depressed individuals are more likely to interpret, focus on and remember negative&#xD;
      compared to positive emotional cues in self-relevant neuropsychological tasks. Recent theory&#xD;
      suggests that over time this positive change in emotional bias contributes to improved mood,&#xD;
      and therefore the investigators will study the effect of Bio-Kult on emotional processing in&#xD;
      participants experiencing low mood, compared to a placebo.&#xD;
&#xD;
      Participants will be pre-screened using a standardized self-report measure on mood (Patient&#xD;
      Health Questionnaire). After filling in the questionnaire, only those who score between 5 and&#xD;
      19 will be recruited into the study. Participants who are deemed non-eligible after filling&#xD;
      in this questionnaire will be notified via email (please see enclosed document 'email to&#xD;
      non-eligible participants'). The investigators expect to recruit sixty participants aged&#xD;
      between 18-55 years, who will be randomised to receive 4 weeks of Bio-Kult or a matched&#xD;
      placebo. This design will be made clear to participants.&#xD;
&#xD;
      Emotional and non-emotional cognition tests include computer-based tasks and questionnaires.&#xD;
      Sleep function will be measured by actigraphy. The investigators will also be collecting&#xD;
      biological data (blood and saliva) to assess cortisol and immune markers. In addition,&#xD;
      participants will be asked to complete questionnaires that are relevant to mood, and anxiety,&#xD;
      and to fill in a food diary to test for dietary effects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 15, 2018</start_date>
  <completion_date type="Anticipated">August 15, 2020</completion_date>
  <primary_completion_date type="Anticipated">August 15, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Facial Expression Recognition Task</measure>
    <time_frame>2 hours</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Emotional Categorization Task</measure>
    <time_frame>2 hours</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Emotional Recall Task</measure>
    <time_frame>2 hours</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Emotional Recognition Memory Task</measure>
    <time_frame>2 hours</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Attentional Dot-Probe</measure>
    <time_frame>2 hours</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Reward Learning Task</measure>
    <time_frame>2 hours</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Priming Task</measure>
    <time_frame>2 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective sleep</measure>
    <time_frame>2 weeks</time_frame>
    <description>Participants will be asked to wear a watch (actigraphy device) for one week at baseline and again during the last week of treatment to measure objective sleep.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biological measures: cortisol</measure>
    <time_frame>4 weeks</time_frame>
    <description>Assays will be conducted to determine levels of cortisol in plasma and saliva. Blood and saliva samples will be collected at pre- and post-intervention sessions. Saliva will also be collected at home by the participants before pre- and post-intervention sessions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biological measures: immune markers</measure>
    <time_frame>4 weeks</time_frame>
    <description>Assays will be conducted to determine levels of immune markers in plasma. Blood samples will be collected at pre and post-intervention sessions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Auditory Verbal Learning Task</measure>
    <time_frame>2 hours</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Mood</condition>
  <condition>Cognitive Change</condition>
  <arm_group>
    <arm_group_label>Bio-Kult</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 capsules/day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>4 capsules/day</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Bio-Kult</intervention_name>
    <description>4 capsules/day</description>
    <arm_group_label>Bio-Kult</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>4 capsules/day</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Cellulose and vegetable capsules</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants are willing and able to give informed consent for participation in the&#xD;
             study.&#xD;
&#xD;
          -  Male or female, aged between 18 and 55 years.&#xD;
&#xD;
          -  Body mass index (BMI) within the range of 18.5 - 30 kg/m2.&#xD;
&#xD;
          -  Sufficiently fluent in English to understand the tasks and instructions.&#xD;
&#xD;
          -  Score between 5 and 19 on the Patient Health Questionnaire (PHQ-9).&#xD;
&#xD;
          -  Participants not judged to be at risk of suicide or self-harm (as measured using the&#xD;
             SCID) and/or in need of immediate treatment to the discretion of the Investigators.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current history of Axis I psychiatric disorder except for depression or anxiety;&#xD;
&#xD;
          -  Current intake (or intention to take) any medication that may affect the outcomes,&#xD;
             including medications affecting brain processing, sedation, and motility (examples&#xD;
             include antidepressants, anxiolytics, among others);&#xD;
&#xD;
          -  Current psychological therapy;&#xD;
&#xD;
          -  Major medical disorders (including diseases affecting the human gastrointestinal&#xD;
             tract);&#xD;
&#xD;
          -  Intake of any other food supplements which, in the opinion of the Investigators, may&#xD;
             affect the results;&#xD;
&#xD;
          -  Any significant change in diet which, to the discretion of the Investigators, may&#xD;
             affect the results;&#xD;
&#xD;
          -  Recent participation in another research trial which, to the discretion of the&#xD;
             Investigators, may affect the results (for example, using the same / a similar battery&#xD;
             of cognitive / emotional tasks in the last 3 months);&#xD;
&#xD;
          -  Dyslexia (given the nature of the computer tasks);&#xD;
&#xD;
          -  Any other significant finding arising during the screening/selection process which, in&#xD;
             the opinion of the Investigators, may influence the participant's ability to take part&#xD;
             in the study or the study results.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Phil Burnet, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Oxford</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Rita Baiao, PhD</last_name>
    <phone>01865613128</phone>
    <email>rita.baiao@psych.ox.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>Warneford Hospital</name>
      <address>
        <city>Oxford</city>
        <state>Oxfordshire</state>
        <zip>OX3 7JX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Philip WJ Burnet, PhD</last_name>
      <phone>01865 618327</phone>
      <email>phil.burnet@psych.ox.ac.uk</email>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 4, 2018</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>January 10, 2019</last_update_submitted>
  <last_update_submitted_qc>January 10, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03801655
org study id: R58085/RE003
nct id: NCT03801655
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Probiotics are live bacteria which have been suggested to have beneficial effects not only on
      gut function but also on psychological and cognitive functioning. This study will investigate
      how a specific probiotic influences emotional and cognitive processing in participants with
      low mood.
Current antidepressant treatments, which largely target monoamine pathways, are efficacious
      in treating many aspects of major depression, however it is estimated that more than 30% of
      depressed patients fail to respond to standard antidepressant medications. Thus, there is a
      strong clinical need to identify and investigate novel treatment strategies that target
      different pathways involved in the pathophysiology of mood disorders.

      There is now compelling evidence for a link between the enteric microbiota and brain
      function. The proliferation of the Bifidobacteria and Lactobacilli strains in the large
      intestine, have anxiolytic and mnemonic effects in both rodents and humans. The intake of
      these bacteria as live cultures (probiotics) alters the expression of genes integral to
      neurodevelopment and complex behaviours in rodents. For instance, the oral administration of
      Bifidobacteria to rats elevated hippocampal brain-derived neurotrophic factor (BDNF), which
      may underlie some antidepressant actions . At present, only several probiotics have been
      examined, but it seems likely that of the 40,000 species in the gut, there will be others
      with psychotropic properties. A multispecies probiotic (Bio-Kult) that contains several
      species of Bifidobacteria and Lactobacilli is now available and of the 14 types of bacteria
      packaged into a capsule, 50% have been shown to have psychotropic effects in animals. Dietary
      supplementation with Bio-Kult therefore, presents as an optimal strategy to test the
      influence of beneficial gut bacteria on emotional processing and cognition because, the
      numerous types of bacteria ingested may have a synergistic effect on the brain and so convey
      a 'stronger' action compared to single species probiotics.

      The translation from rodent to human investigations of probiotics has been surprisingly
      robust, though many more human studies are necessary. In an important early investigation
      male and female participants consumed either a fermented milk drink containing Lactobacillus
      casei Shirota or a placebo. At the end of the three-week intervention, there were no overall
      changes in self-reported affect. However, when only participants whose baseline mood scores
      fell in the lowest third of the total range were analysed, probiotic supplementation resulted
      in significantly more participants self-rating as happy rather than depressed, relative to
      placebo. These results suggest that the emotional benefits of probiotics may be subject to
      ceiling effects.

      Similar effects have been observed in other investigations of mood. For instance, in a recent
      randomised controlled trial, healthy participants consumed a placebo product or a mixture of
      several probiotics (Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus
      acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius
      W24, and Lactococcus lactis W19 and W58) over a period of four weeks. Relative to placebo,
      probiotic-treated participants exhibited substantially reduced reactivity to sad mood
      (assessed by the Leiden Index of Depression Sensitivity Scale), an effect that was
      specifically attributable to fewer instances of rumination and aggressive cognitions.

      In a randomized and double-blind design, healthy volunteers consumed either a mixture of
      probiotics (Lactobacillus helveticus R0052 and Bifidobacterium longum) or a placebo over 30
      days, after which participants completed a range of self-report measures on mood and
      distress. Participants also collected urine over 24 hours before and after the intervention,
      enabling cortisol estimations. Relative to placebo, probiotic-treated participants showed
      significant declines in self-reported negative mood and distress. Parallel to these changes
      was a decrease in urinary free cortisol, which is suggestive of a potential mechanism
      underlying the self-reported affective improvements. Interestingly, a follow-up analysis of
      the individuals with the lowest stress (indexed by cortisol concentrations) showed similar
      affective benefits to those with higher cortisol concentrations, to some extent contravening
      the role of ceiling effects in determining probiotic outcomes.

      The Bio-Kult probiotic supplement has been selected for use in the present study because it
      contains the greatest number of bacterial genera and species currently on the market. In
      preliminary studies in rats, investigators have found that once daily Bio-Kult feeding for 3
      weeks reduces circulating corticosterone, a stress hormone that is the corollary of human
      cortisol. This appears to be consistent with the above human investigation. Thus, taking into
      consideration its mentioned association with stress and mood, this probiotic supplement
      provides an interesting tool to investigate effects on cognition and emotional processing,
      particularly negative affective biases.

      Negative affective biases in emotional processing are highly relevant to clinical mood
      disorders and they are well-recognised in the aetiology and maintenance of depression, such
      that depressed individuals are more likely to interpret, focus on and remember negative
      compared to positive emotional cues in self-relevant neuropsychological tasks. Recent theory
      suggests that over time this positive change in emotional bias contributes to improved mood,
      and therefore the investigators will study the effect of Bio-Kult on emotional processing in
      participants experiencing low mood, compared to a placebo.

      Participants will be pre-screened using a standardized self-report measure on mood (Patient
      Health Questionnaire). After filling in the questionnaire, only those who score between 5 and
      19 will be recruited into the study. Participants who are deemed non-eligible after filling
      in this questionnaire will be notified via email (please see enclosed document 'email to
      non-eligible participants'). The investigators expect to recruit sixty participants aged
      between 18-55 years, who will be randomised to receive 4 weeks of Bio-Kult or a matched
      placebo. This design will be made clear to participants.

      Emotional and non-emotional cognition tests include computer-based tasks and questionnaires.
      Sleep function will be measured by actigraphy. The investigators will also be collecting
      biological data (blood and saliva) to assess cortisol and immune markers. In addition,
      participants will be asked to complete questionnaires that are relevant to mood, and anxiety,
      and to fill in a food diary to test for dietary effects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Double (Participant, Investigator)
measure: Facial Expression Recognition Task
time frame: 2 hours
measure: Emotional Categorization Task
time frame: 2 hours
measure: Emotional Recall Task
time frame: 2 hours
measure: Emotional Recognition Memory Task
time frame: 2 hours
measure: Attentional Dot-Probe
time frame: 2 hours
measure: Reward Learning Task
time frame: 2 hours
measure: Priming Task
time frame: 2 hours
measure: Objective sleep
time frame: 2 weeks
description: Participants will be asked to wear a watch (actigraphy device) for one week at baseline and again during the last week of treatment to measure objective sleep.
measure: Biological measures: cortisol
time frame: 4 weeks
description: Assays will be conducted to determine levels of cortisol in plasma and saliva. Blood and saliva samples will be collected at pre- and post-intervention sessions. Saliva will also be collected at home by the participants before pre- and post-intervention sessions.
measure: Biological measures: immune markers
time frame: 4 weeks
description: Assays will be conducted to determine levels of immune markers in plasma. Blood samples will be collected at pre and post-intervention sessions.
measure: Auditory Verbal Learning Task
time frame: 2 hours
arm group label: Bio-Kult
arm group type: Experimental
description: 4 capsules/day
arm group label: Placebo
arm group type: Placebo Comparator
description: 4 capsules/day
intervention type: Dietary Supplement
intervention name: Bio-Kult
description: 4 capsules/day
arm group label: Bio-Kult
intervention type: Other
intervention name: Placebo
description: 4 capsules/day
arm group label: Placebo
other name: Cellulose and vegetable capsules
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Phil Burnet, PhD
role: Principal Investigator
affiliation: University of Oxford
last name: Rita Baiao, PhD
phone: 01865613128
email: rita.baiao@psych.ox.ac.uk
facility: 
status: Recruiting
contact: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Depression