Psychiatric Symptoms in Employees Experiencing High Levels of Stress Before and After the Intake of Probiotics
Condition: Probiotics
Study type: Interventional

Summary: 
      Sub-project 1 Background:With the increasing number of shift workers required for social and
      economic activities, increasing prevalence of metabolic diseases has been found in this group
      of people. Although reasons for this include reduced physical activity owing to unfixed
      working hours, lack of sleep or disturbances in the circadian rhythm may also be related to
      the occurrences of type 2 diabetes or metabolic syndrome. The mechanism may be due to sleep
      deprivation induced activation of the hypothalamic- pituitary- adrenal axis (HPA axis) that
      affects blood glucose metabolism. The gut brain axis might adjust the HPA axis via the
      bottom-up pathway through vagus nerve, the neuroendocrine system, or the immune system. It is
      also possible that physiological or psychological stressors might influence intestinal
      function through the top-down pathways. Associations between microbiota and many chronic
      diseases, including metabolic syndrome, diabetes, obesity, neurodegenerative diseases, or
      mental diseases have been investigated in recent years. However, the application of using
      probiotics in treating sleep disorders is still lacking. The probiotics used in this proposal
      are selected to be more related to mental conditions. The PS128, which belongs to
      Lactobacillus plantarum subsp. plantarum and PS23 belongs to Lactobacillus paracasei group.
      Both PS128 and PS23 probiotic capsules contain 10 billion CFU (colony forming units) of PS128
      or PS23. The PS23 heat-treated probiotic capsule contain 10 billion PS23 cells.

      The main research hypothesis: Is it possible to develop the relevant probiotic treatment
      model?Our intended analysis was set a priori to analyze each probiotic vs. the placebo.

      Sub-project 2 Information technology (IT) is an industry related to productions of computers,
      information processing, or telecommunications. Such industry highly relies on the knowledge
      and solutions provided by professional IT specialists. Literature has described that the
      subjective stress scores were higher in IT specialists that developed diabetes, hypertension,
      and depression. Specific probiotics, also known as psychobiotics, may have the effects of
      alleviating levels of stress and mood symptoms. Therefore this open-label designed, single
      arm, baseline-controlled trial aiming to examine whether an 8-week intervention of a novel
      psychobiotic Lactobacillus plantarum PS128TM (PS128TM), may improve self-perceived stress and
      mood symptoms among high-stress IT specialists.
    

Detailed description: 
      Sub-project 1 Materials

      1. Probiotics The probiotics used in this proposal are selected to be more related to mental
      conditions. The PS128, which belongs to Lactobacillus plantarum subsp. plantarum.
      Administration of probiotics for 4 weeks in animal experiments showed significant
      improvements in depression and anxiety behaviors, and increased mobility in mice (Liu et al.,
      2016). The concentration of dopamine in the prefrontal cortex, which was reduced due to
      depression, was also restored by feeding PS128 (Liu et al., 2016). PS23 belongs to
      Lactobacillus paracasei group. In animal experiments, both live and heat-treated bacteria
      have the effect of improving depression and anxiety behaviors. The strains used in this study
      are food usable bacteria listed on the front of the Food and Drug Administration in Taiwan.
      The products have been sold in Taiwan in 2015 and there have been no serious adverse
      reactions. Relevant clinical studies have been reviewed by Institutional Review Boards in
      multiple hospitals (including the National Taiwan University Children's Hospital, Kaohsiung
      Kai-Syuan Psychiatric Hospital, Wanfang Hospital, Antai Hospital, and National Yangming
      University). These probiotics and placebo will be provided by the Yifu Biomedical Company
      Ltd. The probiotic powder contains no lactose and can be eaten by people with lactose
      intolerance. The placebo capsule contains microcrystalline cellulose. Both PS128 and PS23
      probiotic capsules contain 10 billion CFU (colony forming units) of PS128 or PS23. The PS23
      heat-treated probiotic capsule contain 10 billion PS23 cells. These products should be stored
      in the refrigerator and be protected from light. The probiotics and placebo used in the study
      are all edible fungi or food supplements approved by the Food and Drug Administration. There
      are no data on serious potential risks or side effects. Only a few gastric discomfort such as
      bloating or diarrhea have been reported.

      Monitoring of adverse events and adverse reactions includes soft stools, flatulence, or
      diarrhea will be used for safety and tolerability assessment.

      A total of 2 assessments and blood draws (week 0 and 8+1 weeks) will be required during the
      study period. Subjects will be invited to participate in the study (V0) and a questionnaire
      will be assessed. Those who meet the inclusion criteria will be assessed for baseline (V1),
      and the app for working hours recording and Rhythm (mobile phone schedule) must be installed
      to participants' mobile phones to record the working hours in the hospital. The once daily
      test capsules will be consumed the next day after the evaluation for 8 weeks until week 8 +1
      (V2). At V2, a second assessment will be performed. The time of the second assessment needs
      to be the same as the first assessment. For example, the first assessment is for the day
      shift, and the second assessment must be for the day shift. The number of days consumed by
      each subject may be inconsistent, at least 28 days, and up to 35 days. Subjects are required
      to provide a working schedule for the study period for the second assessment to allow the
      investigator to match the assessment results for the analysis.

      Research methods:

        1. Investigators will enroll 240 nursing, psychologists and social workers who are working
           in the chronic and acute wards to participate. Participants will be evaluated in overall
           physical and mental health, sleep disturbances. 60 electronic employees will also be
           enrolled, participants will be evaluated in overall physical and mental health, sleep
           disturbances.

        2. Blood TAC, Cortisol and DHEAS will be examined before and after administration of
           probiotics and placebo.

        3. Subjects will need to complete several self-test scales, including the Questionnaire
           (PHQ-9), State-trait Active Inventory (form YA), Insomnia Severity Index (ISI), Buss
           Perry Offensive Scale, Quality of Life and Satisfaction Survey, 10 cm Visual Analogue
           Scale for Gastrointestinal Symptom and stress, Profile of Mood States (POMS) and
           Computerized Selective Attention Test.

        4. In this study, double blind design will be adopted for subproject one and open label
           design will be adopted for subproject two. After consenting, participants will complete
           the above baseline assessment. All participants will then be randomly assigned to
           probiotic or placebo groups according to a computer-generated random number table. These
           two groups will be administered with probiotics or placebo for 8 weeks.

      For the sub-project 2, all the participants will complete the baseline assessment and
      administered with probiotics for 8 weeks.

      Statistics

        1. General Considerations Data will be entered and error-checked by the Project Coordinator
           on IBM-compatible/Macintosh computers present both in the Psychological & Behavioral
           Science Research Laboratory in Mackay Memorial Hospital. The process of data entry,
           including preparation of data harvesting forms, database fields, data entry, and
           checking by editors will be supervised by the staff of the Psychological & Behavioral
           Science Research Laboratory, with extensive experience in both clinical trials and
           longitudinal studies with large data sets. Once the data set is entered and checked,
           analyses will be conducted using SPSS software. An "intent to treat" analysis examining
           all patients randomized to the trial will be performed to preserve the effect of
           randomization.

        2. Power determination for the test of null hypothesis The power analysis will be conducted
           using the effect size from previous publications and the relevant studies of probiotics
           intervention. A minimally significant difference in PSS or ISI changes between
           treatments would be defined as a reduction of 20% or more in the score levels. Based on
           a power of 80% and assuming a 30% dropout rate and an alpha level of 0.05, a sample of
           500 participants (120 per group) will be required. All results will be analyzed using an
           intent-to-treat analysisbased on treatment assignment, whether they complete treatment
           or not. It will also conduct a per-protocol analysis based on 'treated' participants,
           defined as those who received treatment and completed assessments at 0 and 8+1 weeks
           after allocation. To test the adequacy of randomization, it will conduct between group
           comparisons of baseline characteristics on all measures, using t tests for continuous
           variables and chi-square tests for dichotomous variables. Two tailed P-values<0.05 is
           considered significant. All analyses will be performed with SPSS version 12.0. To define
           better the link between changes in questionnaires and treatment response, changes in
           assessment scores will be assessed within the following categories according to
           treatment response as stated in previous literature: for PSS, ISI, STAI: 0% improvement;
           >0 to <=10% improvement; >10 to <=20% improvement and >20% improvement. Finally, to
           ensure that the observed effect will not better explained by changes in medication
           during follow-up or by antidepressant treatment, these two variables (changes in
           medication yes/no and taking antidepressant yes/no) will also be added into the models
           as covariates. The results of regression models will be presented as standardized
           regression coefficients (b) with 95% confidence intervals that can be interpreted as
           effect size. The threshold of significance was P=0.05.

      For the sub-project 1 our intended analysis was set a priori to analyze each probiotic vs.
      the placebo.

      Potential Benefits:

      To the patients:

      It may be possible to improve the stress, sleep or gastrointestinal symptoms of high-pressure
      nurses by supplementing probiotics.

      To the participating researchers:

      All participating assessors will be able to master the interview skills after the intensive
      interviewer training, in particular, familiar with semi-structured psychiatric interview and
      a package of self-report questionnaires. The laboratory researcher will be able to master the
      laboratory skills of performing epigenetic analysis, which can also be helpful in extending
      his research experience.

      Scientific expectations:

      The study will fill the research gap of shift work, metabolism, and probiotics in generally
      healthy high stress nursing staff. The results will provide empirical evidence for Asian
      scientists where there is still a lack of studies linked to changes before and after
      protiotics intervention. The knowledge for probiotics towards health promotion is expected to
      be increase and hope to lead to more personalized stratification for disease-risk models and
      for targeting effective interventions.

      Sub-project 2 Materials: Probiotics The probiotics used in this proposal are selected to be
      more related to mental conditions. The PS128, which belongs to Lactobacillus plantarum subsp.
      plantarum.

      Method:

      IT specialists from a large IT company in Northern Taiwan were invited and first screened by
      the Perceived Stress Scale (PSS) 10 items version. Participants with a PSS-10 items score of
      27 or higher were included in our study. Those currently under antibiotic or psychotropic
      treatments, have cancer, or other chronic physical or mental diseases were excluded. Two
      capsule that contained 300 mg of PS128TM powder, equivalent to 10 billion colony forming
      units, were suggested to be taken daily by the included participants. Other self-report
      measures included the Job Stress Scale, Visual Analogue Scale of Stress, the Insomnia
      Severity Index, the State and Trait Anxiety Index, The Questionnaire for Emotional Trait and
      State, the Patient Health Questionnaire, the Quality of Life Enjoyment and Satisfaction
      Questionnaire, and the Gastrointestinal Severity Index. Objective measures included Saliva
      levels of stress biomarkers include cortisol, α-amylase, Immunoglobulin A (IgA), lactoferrin,
      and lysozymes, and Tests on Attentional Performance.
    

Intervention name(s): PS128; PS23 live; PS23 heat-treated; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement; Other
Intervention description(s): PS128 belongs to Lactobacillus plantarum subsp. plantarumand. Probiotic capsules contain 10 billion CFU (colony forming units) of PS128; PS23 belongs to Lactobacillus paracasei group.Probiotic capsules contain 10 billion CFU (colony forming units) of PS23; The PS23 heat-treated probiotic capsule contain 10 billion of PS23 cells.; The placebo capsule contains microcrystalline cellulose.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Sub-project 1 is a RCT study (Nurses) Sub-project 2 is an open label design (IT Employees)
Masking: Single (Outcomes Assessor)
Primary purpose: Supportive Care