<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/NCT03237078</url>
  </required_header>
  <id_info>
    <org_study_id>N201702049</org_study_id>
    <nct_id>NCT03237078</nct_id>
  </id_info>
  <brief_title>Lactobacillus Plantarum PS128 in Patients With Major Depressive Disorder and High Level of Inflammation</brief_title>
  <official_title>Psychophysiological Effects of Lactobacillus Plantarum PS128 in Patients With Major Depressive Disorder and High Level of Inflammation: a Pilot Study of 8-week Open Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Taipei Medical University WanFang Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Taipei Medical University WanFang Hospital</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>
      Recent studies have suggested that gut-brain axis may be one of the mechanisms of major&#xD;
      depression disorder (MDD). In animal studies, alteration of gut microbiota can affect&#xD;
      animal's depression or anxiety-like behavior, brain neurochemistry and inflammation. In human&#xD;
      studies, the composition of gut microbiota is different between patients with MDD and healthy&#xD;
      controls. In addition, supplementation of probiotics can improve mood status in community and&#xD;
      clinical participants. Inflammation is one of possible pathway to connect gut and brain. Gut&#xD;
      permeability and inflammation level are higher in patients with MDD. Lactobacillus plantarum&#xD;
      PS128 in one of bacteria extracted from traditional fermented food, Fu-Tsai. It can alleviate&#xD;
      depressive-like behavior reduce inflammation level in maternal separation mice. This study is&#xD;
      an 8-week open trial to investigate the effects of Lactobacillus plantarum PS128 on&#xD;
      psychophysiology in patients with MDD and higher level of inflammation.&#xD;
&#xD;
      This is a two-phase study. In the first phase, we will recruited patients fulfilling the&#xD;
      following inclusion criteria: Age 20-65; fulfill Diagnostic and Statistical Manual of Mental&#xD;
      Disorders fifth version (DSM-V) criteria of major depressive episode in recent 2 years;&#xD;
      Psychotropics including antidepressants, antipsychotics and hypnotics have been kept&#xD;
      unchanged for at least 3 months. The exclusion criteria are: comorbid with schizophrenia,&#xD;
      bipolar disorder, or other substance use (except tobacco) disorder; having active suicidal or&#xD;
      homicidal ideation; known allergy to probiotics; comorbid with hypertension, diabetes&#xD;
      mellitus, irritable bowel syndrome, inflammatory bowl disease, liver cirrhosis, or autoimmune&#xD;
      diseases; known active bacterial, fungal, or viral infections in one month; use of&#xD;
      antibiotics, steroid, immunosuppressants, probiotics, or synbiotics in the month before&#xD;
      collecting blood and fecal samples; pregnant or lactating women; who state to have dietary&#xD;
      pattern changed or in diet within previous two months. Those hs-CRP &gt; 3 mg/L in the first&#xD;
      screen will be invited into the second phase intervention. In the second phase intervention,&#xD;
      we will give eligible patients Lactobacillus plantarum PS128 for 8 weeks, and compare&#xD;
      depression symptoms, gut microbiota, gut inflammation and permeability, and serum&#xD;
      inflammation level before and after intervention.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Background Major depressive disorder (MDD) is a complex and long-term illness that&#xD;
      involves marked disabilities in affected patients. It has been one of the leading causes of&#xD;
      global burden of disease, especially in the middle-age groups (GBD Lancet 2016; 388:1603-58).&#xD;
      It is also a common comorbidity in patients with irritable bowel syndrome, cardiovascular&#xD;
      disease and cancer (Musselman et al. 1998; Spiegel et al. 2003; Whitehead et al. 2002). The&#xD;
      mechanisms responsible for depression and its comorbidity are not clear, but inflammatory&#xD;
      processes may be implicated. Meta-analysis has shown that patients with depression have&#xD;
      higher levels of inflammatory markers, such as C-Reactive Protein (CRP), interleukin-1&#xD;
      (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-alpha (Dowlati et al. 2010;&#xD;
      Howren et al. 2009). Microbiota-gut-brain axis may explain higher inflammatory cytokines in&#xD;
      patients with MDD. Accumulating data now indicate that the gut microbiota can communicate&#xD;
      with the CNS--possibly through immune, neural, and endocrine pathways--and thereby influences&#xD;
      brain function and behavior (Cryan et al. 2012; Forsythe et al. 2016; Rogers et al. 2016).&#xD;
      Probiotics, which are defined as a live organism that when ingested in adequate amount exerts&#xD;
      a health benefit, can affect gut microbiota, brain neurochemistry, HPA axis, and&#xD;
      inflammation, and may be a novel class of psychotropics (Dinan et al. 2013).&#xD;
&#xD;
      1.1 Microbiota-gut-brain axis The lower gastrointestinal tract contains almost 100 trillion&#xD;
      microorganisms, most of which are bacteria. The microbiota collectively encodes more than 3.3&#xD;
      million non-redundant genes, exceeding the number encoded by the human host genome by&#xD;
      150-fold (Qin et al. 2010). Many microbial gene products have important effects on metabolism&#xD;
      and the health of the host.&#xD;
&#xD;
      There have been numerous studies supporting the communications between gut microbiota and&#xD;
      brain. Study using germ free (GF) animal is a good model to show the relationship between&#xD;
      microbiota and brain. Compared to specific pathogen free (SPF) mice with a normal gut&#xD;
      microbiota, GF mice display increased motor activity and reduced anxiety behavior. An&#xD;
      increased turnover of dopaminergic and serotonergic neurotransmitters in striatum was&#xD;
      observed in GF mice (Diaz Heijtz et al. 2011). In addition, GF mice exhibited higher&#xD;
      adrenocorticotropic hormone (ACTH) and corticosterone elevation in response to restraint&#xD;
      stimulus than SPF mice did (Sudo et al. 2004). It suggests that gut microbiota can affect&#xD;
      host's response to stress.&#xD;
&#xD;
      Several studies have shown that manipulation of gut microbiota can affect the presentation of&#xD;
      host's psychophysiology. For example, consumption of high fat diet (HFD) is associated with&#xD;
      altered microbial diversity (Daniel et al. 2014) and reduced synaptic plasticity (Liu et al.&#xD;
      2015). HFD also increased anxiety-like behavior (Sharma et al. 2013). Adult male C57BL/6 mice&#xD;
      given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and&#xD;
      stereotypical behavior compared with mice with control diet microbiota. No significant&#xD;
      differences in body weight were noted. The difference in composition of gut microbiota&#xD;
      between HFD and normal-diet groups was noted (Bruce-Keller et al. 2015).&#xD;
&#xD;
      Administration of antibiotics is another way to affect gut microbiota composition and change&#xD;
      host's psychophysiology. Oral administration of non-absorbable antimicrobials transiently&#xD;
      altered gut microbiota composition and increased exploratory behavior and hippocampal&#xD;
      expression of BDNF mRNA in mice, but intraperitoneal administration had no effect on behavior&#xD;
      (Bercik et al. 2011). Increased antibiotic exposures were associated with the risk of&#xD;
      depression and anxiety in a population study (Lurie et al. 2015). Therefore, administration&#xD;
      of probiotics may be a direct way to change the environment and composition of gut&#xD;
      microbiota, and observe its physiological effects on host.&#xD;
&#xD;
      1.2 Administration of Probiotics in animal studies Animal studies have shown that probiotics&#xD;
      affect psychophysiological markers of anxiety and depression. Desbonnet et al. did not find a&#xD;
      significant effect of Bifidobacteria infantis treatment on swim behaviors at day 3 or day 14&#xD;
      in naïve rats. However, Bifidobacteria infantis treatment attenuated pro-inflammatory immune&#xD;
      responses and elevated tryptophan, suggesting this probiotic may possess antidepressant&#xD;
      properties (Desbonnet et al. 2008). In their following study, they used maternal separation&#xD;
      (MS) rats as study animal. They found MS rats reduced swim behavior and increased immobility&#xD;
      in the forced swimming test (FST), decreased noradrenaline (NA) content in the brain, and&#xD;
      enhanced peripheral IL-6 release and amygdala corticotrophin-releasing factor (CRF) mRNA&#xD;
      levels compared to control rats (Desbonnet et al. 2010). Bifidobacteria infantis treatment&#xD;
      resulted in normalization of the immune response, reversal of behavioral deficits, and&#xD;
      restoration of basal NA concentrations in the brainstem. These changes were comparable to&#xD;
      those observed in the citalopram group, suggesting that some probiotic benefits are similar&#xD;
      to antidepressant effects (Desbonnet et al. 2010). Liu et al found that Lactobacillus&#xD;
      plantarum PS128 (PS128) could ameliorate anxiety-like, but not depression-like behavior in GF&#xD;
      mice, and significantly increased levels of both serotonin and dopamine in striatum, but not&#xD;
      in prefrontal cortex and hippocampus (Liu WH et al. 2016). In MS model, however, PS128&#xD;
      significantly reduced depression-like, but not anxiety-like behaviors. PS128 significantly&#xD;
      reduced anxiety-like, but not depression-like behavior in naïve mice. It also reduced&#xD;
      inflammatory cytokine, IL-6, levels and increased anti-inflammatory cytokine, IL-10, level in&#xD;
      MS mice (Liu YW et al. 2016). PS128 had more obvious effect on psychophysiology in MS mice&#xD;
      than that in naive mice suggests that probiotic administration may have more robust effect on&#xD;
      modification in behaviors, neurochemistry, and HPA in those suffering from higher stress.&#xD;
&#xD;
      1.3 Microbiota composition in patients with MDD Since compositions of gut microbiota alter&#xD;
      inflammation, neurochemistry and behavior in animal studies, several human studies compared&#xD;
      gut microbiota between patients with MDD and healthy controls. Naseribafrouei et al. compared&#xD;
      gut microbiota compositions in 37 depressed and 18 non-depressed participants. The results&#xD;
      showed Bacteroidales overpresentation, while Lachnospiraceae underrepresentation, in&#xD;
      depressed participants. At low taxonomic levels, Oscillibacter and Alistipes were associated&#xD;
      with depression (Naseribafrouei et al. 2014). Jiang et al recruited 29 active MDD (A-MDD), 17&#xD;
      responded MDD (R-MDD), and 30 healthy controls (HC) and compared their gut microbiota. They&#xD;
      found that increased fecal bacterial alpha-diversity in the A-MDD vs. the HC group but not in&#xD;
      the R-MDD vs. the HC group. Bacteroidetes, Proteobacteria, and Actinobacteria significantly&#xD;
      increased, whereas that of Firmicutes was significantly reduced in the A-MDD and R-MDD groups&#xD;
      compared with the HC group. MDD groups had increased levels of Enterobacteriaceae and&#xD;
      Alistipes, but reduced levels of Faecalibacterium (Jiang et al. 2015). Not only differences&#xD;
      in composition of gut microbiota between patients with MDD and healthy control, transplanting&#xD;
      fecal sample from MDD patients into mice can induce depressive-like behavior in recipient&#xD;
      mice. The composition of gut microbiota in recipient mice was similar to that of human host&#xD;
      (Zheng et al. 2016). This study supports that gut microbiome may have a causal role in the&#xD;
      development of depressive-like behaviors.&#xD;
&#xD;
      1.4 Effects of probiotics on mood in human studies In addition to the differences in&#xD;
      distribution of gut microbiota between depressed subjects and non-depressed subjects, several&#xD;
      human studies have shown that probiotics may have beneficial effect on mood. Benton et al.&#xD;
      demonstrated that no significant difference in change of mood, measured by Profile of Mood&#xD;
      State, between healthy participants using probiotic (containing Lactobacillus casei) milk for&#xD;
      3 weeks and those using milk without probiotic. However, they found that those who were in&#xD;
      low mood at baseline became better after using probiotic-containing milk (Benton et al.&#xD;
      2007). Mohammadi et al. also showed that participants using probiotic yogurt (containing&#xD;
      Lactobacillus acidophilus LA5 and Bifidobacterium lactis BB12) or probiotic capsule&#xD;
      (containing Actobacillus casei, L. acidophilus, L. rhamnosus, L. bulgaricus, .B. breve, B.&#xD;
      longum, S. thermophiles) for 6 weeks had significant improvement in mood, measured by GHQ and&#xD;
      Depression Anxiety and Stress Scale, but those using conventional yogurt did not have&#xD;
      significant change in these measurement. There were no differences in HPA axis indices, such&#xD;
      as cortisol and ACTH, among these three groups (Mohammadi et al. 2016). Messaoudi's study, in&#xD;
      which participants were healthy volunteer, showed that probiotics (containing L. helveticus&#xD;
      R0052 and B. longum R0175) administration could improve participants' mood symptoms, measured&#xD;
      by Hopkins Symptom Checklist-90 and Hospital Anxiety and Depression Scale, compared to those&#xD;
      used placebo (Messaoudi et al. 2011). Heightened cognitive reactivity to normal, transient&#xD;
      changes in sad mood is an established marker of vulnerability to depression and is considered&#xD;
      an important target for interventions (Kruijt et al. 2013). Steenbergen et al. found that&#xD;
      overall cognitive reactivity significantly reduced, which was largely accounted for by&#xD;
      reduced rumination and aggression subscales, in participants without current mood disorders&#xD;
      after 4 weeks multispecies probiotics administration. Because they used non-depressed&#xD;
      participants, BDI and BAI did not significantly change after intervention (Steenbergen et al.&#xD;
      2015). The efficacy of probiotics in mood symptoms is not only shown in healthy volunteers,&#xD;
      but also in clinical subjects. In patients with chronic fatigue syndrome, Rao et al. found&#xD;
      that administration of Lactobacillus casei for 2 months could improve BAI, but not BDI,&#xD;
      compared to placebo. At the same time fecal Lactobacillus and Bifidobacteria increased after&#xD;
      2-month L. casei intervention (Rao et al. 2009). Akkasheh et al. gave multi-species&#xD;
      probiotics, containing Lactobacillus acidophilum, Lactobacillus casei, and Bifidobacterium&#xD;
      bifidum, or placebo to patients with MDD for 8 weeks. They found that multi-species&#xD;
      probiotics could significantly reduce BDI scores in patients with major depressive disorder&#xD;
      (Akkasheh et al. 2016), but which strain of probiotics exerts the beneficial effect is not&#xD;
      clear.&#xD;
&#xD;
      1.5 Childhood trauma, inflammation, and gut permeability in depression In animal study, early&#xD;
      life stress, such as maternal separation, elevated IL-6 level and increased depressive-like&#xD;
      behavior (increased immobility time in FST) (Liu YW et al. 2016). One recent metaanalysis&#xD;
      showed that childhood trauma contributes to a pro-inflammatory state in adulthood (Baumeister&#xD;
      et al. 2016). In addition, childhood trauma also increased the risk of depressive disorders&#xD;
      (Norman et al. 2012). Metaanalyses have shown that patients with MDD have elevated serum&#xD;
      inflammatory cytokins (Dowlati et al. 2010; Howren et al. 2009). One possible mechanism&#xD;
      contributing to systemic inflammation in patients with MDD is bacterial translocation due to&#xD;
      increased gut permeability (leaky gut). Figure 2 shows the relationship among childhood&#xD;
      trauma, gut permeability, inflammation, and depression.&#xD;
&#xD;
      Every microbe possesses a microbe-associated molecular pattern (MAMP) or pathogen-associated&#xD;
      molecular pattern (PAMP). Microbes leaking from gut activate the MAMPs and&#xD;
      pattern-recognition receptors, such as Toll-like receptors (TLRs). Proinflammatory cytokines,&#xD;
      such as IL-6, TNF-alpha, are released from cells after a series of signal transduction.&#xD;
&#xD;
      Probiotics may affect gut permeability. HFD-derived gut microbiota increased intestinal&#xD;
      permeability, systemic inflammation, and brain inflammation (Bruce-Keller et al. 2015). One&#xD;
      in-vitro study showed that Lactobacillus rhamnosus GG ameliorates gut barrier dysfunction and&#xD;
      inflammation through inhibition of NF-kappaB (Donato et al. 2010). Administration of&#xD;
      Lactobacillus farciminis could alleviate intestinal permeability and inflammation in partial&#xD;
      restraint rats (Ait-Belgnaoui et al. 2012).&#xD;
&#xD;
      Evidence of increased gut permeability in patients with MDD was revealed by Maes' studies.&#xD;
      Maes et al found that the median values for serum IgM and IgA against LPS of gram-negative&#xD;
      enterobacteria were significantly greater in patients with MDD than in normal volunteers,&#xD;
      suggesting that increased gut permeability results in an increased translocation of&#xD;
      gram-negative microbiota (Maes et al. 2008; Maes et al. 2012). In patients with alcohol&#xD;
      dependence, those with increased gut permeability, which was measured by the radioactive&#xD;
      probe 51Cr-EDTA, had higher depression and anxiety scores than those with normal gut&#xD;
      permeability. The composition and activity of microbiota were altered in patients with&#xD;
      increased gut permeability (Leclercq et al. 2014).&#xD;
&#xD;
      1.6 Rationale of current study PS128 was found in traditional fermented food, fu-tsai, by our&#xD;
      co-PI (Tsai YC) and its genome architecture has been finished and indicated its potential&#xD;
      immunomodulatory effect. (Chao et al. 2009). Lactobacillus plantarum is generally recognized&#xD;
      as safe (GRAS). PS128 can reduce IL-6 levels and increased IL-10 level, which accompanied&#xD;
      with improved depression-like behavior, in MS mice (Liu YW et al. 2016). In the current&#xD;
      study, we would like to investigate the effect of PS128 on psychophysiology, including&#xD;
      composition of gut microbiota, gut permeability and inflammation, TLR expression, serum&#xD;
      cytokines levels, and depressive symptoms in patients with MDD.&#xD;
&#xD;
      Metaanalyses have shown that patients with MDD have higher inflammatory cytokines (Dowlati et&#xD;
      al. 2010; Howren et al. 2009), but only a subgroup of patients with MDD has a higher level of&#xD;
      inflammation. For example, according to the definition of high inflammation of hs-CRP &gt; 3&#xD;
      mg/l (Pearson et al. 2003), the proportion of patients with high inflammation was 24 % in&#xD;
      patients with MDD (Rapaport et al. 2016) and 45% in patients with treatment-resistant&#xD;
      depression (Raison et al. 2011). Baseline inflammatory level may affect treatment response.&#xD;
      For example, patients with high baseline inflammation had better treatment response to&#xD;
      infliximab (tumor necrosis factor antagonist) (Raison et al. 2013) and omega-3 fatty acids&#xD;
      (Rapaport et al. 2016) compared to those with low baseline inflammation. In Raison's study,&#xD;
      the effect of infliximab on depression symptoms was worse than placebo in those with lower&#xD;
      inflammatory level at baseline (Raison et al. 2013). Therefore, we will recruit patients with&#xD;
      MDD and high inflammatory level into our PS128 intervention study.&#xD;
&#xD;
      We hypothesize that PS128 can (1) change the composition of gut microbiota; (2) improve gut&#xD;
      permeability, which is measured by fecal zonulin level, and inflammation, which is measured&#xD;
      by fecal calprotectin level; (3) reduce the translocation of pathogen into circulation&#xD;
      system, which will be demonstrated by reduced TLR expression, (4) reduce IL-6 and TNF-alpha,&#xD;
      and hs-CRP, and increase IL-10 level. We hope the improvement in inflammation level can also&#xD;
      have a beneficial effect on depressive symptoms.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 1, 2017</start_date>
  <completion_date type="Anticipated">July 31, 2019</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes of serum hs-CRP</measure>
    <time_frame>baseline, week 4 and week 8</time_frame>
    <description>measure serum hs-CRP at baseline, week 4 and week8</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes of serum TNF-alpha</measure>
    <time_frame>baseline, week 4 and week 8</time_frame>
    <description>measure serum TNF-alpha at baseline, week 4 and week8</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes of serum IL-6</measure>
    <time_frame>baseline, week 4 and week 8</time_frame>
    <description>measure serum IL-6 at baseline, week 4 and week8</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes of serum IL-10</measure>
    <time_frame>baseline, week 4 and week 8</time_frame>
    <description>measure serum IL-10 at baseline, week 4 and week8</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes of HAMD-17</measure>
    <time_frame>baseline, week 2, week 4 and week 8</time_frame>
    <description>measure depression rating at baseline, week 2, week 4 and week 8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes of DSSS</measure>
    <time_frame>baseline, week 2, week 4 and week 8</time_frame>
    <description>measure depression rating at baseline, week 2, week 4 and week 8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Microbiota</measure>
    <time_frame>baseline and week 8</time_frame>
    <description>gut microbiota analyses at baseline and week 8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of zonulin</measure>
    <time_frame>baseline and week 8</time_frame>
    <description>measure gut permeability at baseline and week 8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of calprotectin</measure>
    <time_frame>baseline and week 8</time_frame>
    <description>measure gut inflammation at baseline and week 8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes of expression of Toll-like proteins</measure>
    <time_frame>baseline and week 8</time_frame>
    <description>measure of expression of TLPs at baseline and week 8</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Major Depressive Disorder</condition>
  <condition>Inflammation</condition>
  <condition>Probiotics</condition>
  <arm_group>
    <arm_group_label>Lactobacillus plantarum PS128</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each PS 128 capsule contains 300 mg of probiotics. PS128 will be provided 300 mg twice, in the morning and in the afternoon, daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Lactobacillus plantarum PS128</intervention_name>
    <description>Each PS 128 capsule contains 300 mg of probiotics. PS128 will be provided 300 mg twice, in the morning and in the afternoon, daily.</description>
    <arm_group_label>Lactobacillus plantarum PS128</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 20-65&#xD;
&#xD;
          2. fulfill Diagnostic and Statistical Manual of Mental Disorders fifth version (DSM-V)&#xD;
             criteria of major depressive episode in recent 2 years&#xD;
&#xD;
          3. Psychotropics including antidepressants, antipsychotics and hypnotics have been kept&#xD;
             unchanged for at least 3 months&#xD;
&#xD;
          4. hs-CRP &gt; 3 mg/L&#xD;
&#xD;
          5. HAMD-17 &lt; 14&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Comorbid with schizophrenia, bipolar disorder, or other substance use (except tobacco)&#xD;
             disorder.&#xD;
&#xD;
          2. having active suicidal or homicidal ideation&#xD;
&#xD;
          3. known allergy to probiotics&#xD;
&#xD;
          4. comorbid with hypertension, diabetes mellitus, irritable bowel syndrome, inflammatory&#xD;
             bowl disease, liver cirrhosis, or autoimmune diseases&#xD;
&#xD;
          5. known active bacterial, fungal, or viral infections in one month.&#xD;
&#xD;
          6. use of antibiotics, steroid, immunosuppressants, probiotics, or synbiotics in the&#xD;
             month before collecting blood and fecal samples&#xD;
&#xD;
          7. pregnant or lactating women&#xD;
&#xD;
          8. who obviously change dietary pattern or in diet within previous two months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chun-Hsin Chen</last_name>
    <role>Principal Investigator</role>
    <affiliation>Taipei Medical University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Chun-Hsin Chen</last_name>
    <phone>86-2-29307930</phone>
    <email>chunhsin57@yahoo.com.tw</email>
  </overall_contact>
  <location>
    <facility>
      <name>Taipei Medical University - WanFang Hospital</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chun-Hsin Chen</last_name>
      <phone>886-2-29307930</phone>
      <phone_ext>53961</phone_ext>
      <email>chunhsin57@yahoo.com.tw</email>
    </contact>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>June 28, 2018</last_update_submitted>
  <last_update_submitted_qc>June 28, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 2, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Taipei Medical University WanFang Hospital</investigator_affiliation>
    <investigator_full_name>Chun-Hsin Chen</investigator_full_name>
    <investigator_title>Attending Psychiatrist</investigator_title>
  </responsible_party>
  <keyword>probiotics</keyword>
  <keyword>major depressive disorder</keyword>
  <keyword>gut-brain axis</keyword>
  <keyword>inflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03237078
org study id: N201702049
nct id: NCT03237078
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Recent studies have suggested that gut-brain axis may be one of the mechanisms of major
      depression disorder (MDD). In animal studies, alteration of gut microbiota can affect
      animal's depression or anxiety-like behavior, brain neurochemistry and inflammation. In human
      studies, the composition of gut microbiota is different between patients with MDD and healthy
      controls. In addition, supplementation of probiotics can improve mood status in community and
      clinical participants. Inflammation is one of possible pathway to connect gut and brain. Gut
      permeability and inflammation level are higher in patients with MDD. Lactobacillus plantarum
      PS128 in one of bacteria extracted from traditional fermented food, Fu-Tsai. It can alleviate
      depressive-like behavior reduce inflammation level in maternal separation mice. This study is
      an 8-week open trial to investigate the effects of Lactobacillus plantarum PS128 on
      psychophysiology in patients with MDD and higher level of inflammation.

      This is a two-phase study. In the first phase, we will recruited patients fulfilling the
      following inclusion criteria: Age 20-65; fulfill Diagnostic and Statistical Manual of Mental
      Disorders fifth version (DSM-V) criteria of major depressive episode in recent 2 years;
      Psychotropics including antidepressants, antipsychotics and hypnotics have been kept
      unchanged for at least 3 months. The exclusion criteria are: comorbid with schizophrenia,
      bipolar disorder, or other substance use (except tobacco) disorder; having active suicidal or
      homicidal ideation; known allergy to probiotics; comorbid with hypertension, diabetes
      mellitus, irritable bowel syndrome, inflammatory bowl disease, liver cirrhosis, or autoimmune
      diseases; known active bacterial, fungal, or viral infections in one month; use of
      antibiotics, steroid, immunosuppressants, probiotics, or synbiotics in the month before
      collecting blood and fecal samples; pregnant or lactating women; who state to have dietary
      pattern changed or in diet within previous two months. Those hs-CRP > 3 mg/L in the first
      screen will be invited into the second phase intervention. In the second phase intervention,
      we will give eligible patients Lactobacillus plantarum PS128 for 8 weeks, and compare
      depression symptoms, gut microbiota, gut inflammation and permeability, and serum
      inflammation level before and after intervention.
1. Background Major depressive disorder (MDD) is a complex and long-term illness that
      involves marked disabilities in affected patients. It has been one of the leading causes of
      global burden of disease, especially in the middle-age groups (GBD Lancet 2016; 388:1603-58).
      It is also a common comorbidity in patients with irritable bowel syndrome, cardiovascular
      disease and cancer (Musselman et al. 1998; Spiegel et al. 2003; Whitehead et al. 2002). The
      mechanisms responsible for depression and its comorbidity are not clear, but inflammatory
      processes may be implicated. Meta-analysis has shown that patients with depression have
      higher levels of inflammatory markers, such as C-Reactive Protein (CRP), interleukin-1
      (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-alpha (Dowlati et al. 2010;
      Howren et al. 2009). Microbiota-gut-brain axis may explain higher inflammatory cytokines in
      patients with MDD. Accumulating data now indicate that the gut microbiota can communicate
      with the CNS--possibly through immune, neural, and endocrine pathways--and thereby influences
      brain function and behavior (Cryan et al. 2012; Forsythe et al. 2016; Rogers et al. 2016).
      Probiotics, which are defined as a live organism that when ingested in adequate amount exerts
      a health benefit, can affect gut microbiota, brain neurochemistry, HPA axis, and
      inflammation, and may be a novel class of psychotropics (Dinan et al. 2013).

      1.1 Microbiota-gut-brain axis The lower gastrointestinal tract contains almost 100 trillion
      microorganisms, most of which are bacteria. The microbiota collectively encodes more than 3.3
      million non-redundant genes, exceeding the number encoded by the human host genome by
      150-fold (Qin et al. 2010). Many microbial gene products have important effects on metabolism
      and the health of the host.

      There have been numerous studies supporting the communications between gut microbiota and
      brain. Study using germ free (GF) animal is a good model to show the relationship between
      microbiota and brain. Compared to specific pathogen free (SPF) mice with a normal gut
      microbiota, GF mice display increased motor activity and reduced anxiety behavior. An
      increased turnover of dopaminergic and serotonergic neurotransmitters in striatum was
      observed in GF mice (Diaz Heijtz et al. 2011). In addition, GF mice exhibited higher
      adrenocorticotropic hormone (ACTH) and corticosterone elevation in response to restraint
      stimulus than SPF mice did (Sudo et al. 2004). It suggests that gut microbiota can affect
      host's response to stress.

      Several studies have shown that manipulation of gut microbiota can affect the presentation of
      host's psychophysiology. For example, consumption of high fat diet (HFD) is associated with
      altered microbial diversity (Daniel et al. 2014) and reduced synaptic plasticity (Liu et al.
      2015). HFD also increased anxiety-like behavior (Sharma et al. 2013). Adult male C57BL/6 mice
      given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and
      stereotypical behavior compared with mice with control diet microbiota. No significant
      differences in body weight were noted. The difference in composition of gut microbiota
      between HFD and normal-diet groups was noted (Bruce-Keller et al. 2015).

      Administration of antibiotics is another way to affect gut microbiota composition and change
      host's psychophysiology. Oral administration of non-absorbable antimicrobials transiently
      altered gut microbiota composition and increased exploratory behavior and hippocampal
      expression of BDNF mRNA in mice, but intraperitoneal administration had no effect on behavior
      (Bercik et al. 2011). Increased antibiotic exposures were associated with the risk of
      depression and anxiety in a population study (Lurie et al. 2015). Therefore, administration
      of probiotics may be a direct way to change the environment and composition of gut
      microbiota, and observe its physiological effects on host.

      1.2 Administration of Probiotics in animal studies Animal studies have shown that probiotics
      affect psychophysiological markers of anxiety and depression. Desbonnet et al. did not find a
      significant effect of Bifidobacteria infantis treatment on swim behaviors at day 3 or day 14
      in naïve rats. However, Bifidobacteria infantis treatment attenuated pro-inflammatory immune
      responses and elevated tryptophan, suggesting this probiotic may possess antidepressant
      properties (Desbonnet et al. 2008). In their following study, they used maternal separation
      (MS) rats as study animal. They found MS rats reduced swim behavior and increased immobility
      in the forced swimming test (FST), decreased noradrenaline (NA) content in the brain, and
      enhanced peripheral IL-6 release and amygdala corticotrophin-releasing factor (CRF) mRNA
      levels compared to control rats (Desbonnet et al. 2010). Bifidobacteria infantis treatment
      resulted in normalization of the immune response, reversal of behavioral deficits, and
      restoration of basal NA concentrations in the brainstem. These changes were comparable to
      those observed in the citalopram group, suggesting that some probiotic benefits are similar
      to antidepressant effects (Desbonnet et al. 2010). Liu et al found that Lactobacillus
      plantarum PS128 (PS128) could ameliorate anxiety-like, but not depression-like behavior in GF
      mice, and significantly increased levels of both serotonin and dopamine in striatum, but not
      in prefrontal cortex and hippocampus (Liu WH et al. 2016). In MS model, however, PS128
      significantly reduced depression-like, but not anxiety-like behaviors. PS128 significantly
      reduced anxiety-like, but not depression-like behavior in naïve mice. It also reduced
      inflammatory cytokine, IL-6, levels and increased anti-inflammatory cytokine, IL-10, level in
      MS mice (Liu YW et al. 2016). PS128 had more obvious effect on psychophysiology in MS mice
      than that in naive mice suggests that probiotic administration may have more robust effect on
      modification in behaviors, neurochemistry, and HPA in those suffering from higher stress.

      1.3 Microbiota composition in patients with MDD Since compositions of gut microbiota alter
      inflammation, neurochemistry and behavior in animal studies, several human studies compared
      gut microbiota between patients with MDD and healthy controls. Naseribafrouei et al. compared
      gut microbiota compositions in 37 depressed and 18 non-depressed participants. The results
      showed Bacteroidales overpresentation, while Lachnospiraceae underrepresentation, in
      depressed participants. At low taxonomic levels, Oscillibacter and Alistipes were associated
      with depression (Naseribafrouei et al. 2014). Jiang et al recruited 29 active MDD (A-MDD), 17
      responded MDD (R-MDD), and 30 healthy controls (HC) and compared their gut microbiota. They
      found that increased fecal bacterial alpha-diversity in the A-MDD vs. the HC group but not in
      the R-MDD vs. the HC group. Bacteroidetes, Proteobacteria, and Actinobacteria significantly
      increased, whereas that of Firmicutes was significantly reduced in the A-MDD and R-MDD groups
      compared with the HC group. MDD groups had increased levels of Enterobacteriaceae and
      Alistipes, but reduced levels of Faecalibacterium (Jiang et al. 2015). Not only differences
      in composition of gut microbiota between patients with MDD and healthy control, transplanting
      fecal sample from MDD patients into mice can induce depressive-like behavior in recipient
      mice. The composition of gut microbiota in recipient mice was similar to that of human host
      (Zheng et al. 2016). This study supports that gut microbiome may have a causal role in the
      development of depressive-like behaviors.

      1.4 Effects of probiotics on mood in human studies In addition to the differences in
      distribution of gut microbiota between depressed subjects and non-depressed subjects, several
      human studies have shown that probiotics may have beneficial effect on mood. Benton et al.
      demonstrated that no significant difference in change of mood, measured by Profile of Mood
      State, between healthy participants using probiotic (containing Lactobacillus casei) milk for
      3 weeks and those using milk without probiotic. However, they found that those who were in
      low mood at baseline became better after using probiotic-containing milk (Benton et al.
      2007). Mohammadi et al. also showed that participants using probiotic yogurt (containing
      Lactobacillus acidophilus LA5 and Bifidobacterium lactis BB12) or probiotic capsule
      (containing Actobacillus casei, L. acidophilus, L. rhamnosus, L. bulgaricus, .B. breve, B.
      longum, S. thermophiles) for 6 weeks had significant improvement in mood, measured by GHQ and
      Depression Anxiety and Stress Scale, but those using conventional yogurt did not have
      significant change in these measurement. There were no differences in HPA axis indices, such
      as cortisol and ACTH, among these three groups (Mohammadi et al. 2016). Messaoudi's study, in
      which participants were healthy volunteer, showed that probiotics (containing L. helveticus
      R0052 and B. longum R0175) administration could improve participants' mood symptoms, measured
      by Hopkins Symptom Checklist-90 and Hospital Anxiety and Depression Scale, compared to those
      used placebo (Messaoudi et al. 2011). Heightened cognitive reactivity to normal, transient
      changes in sad mood is an established marker of vulnerability to depression and is considered
      an important target for interventions (Kruijt et al. 2013). Steenbergen et al. found that
      overall cognitive reactivity significantly reduced, which was largely accounted for by
      reduced rumination and aggression subscales, in participants without current mood disorders
      after 4 weeks multispecies probiotics administration. Because they used non-depressed
      participants, BDI and BAI did not significantly change after intervention (Steenbergen et al.
      2015). The efficacy of probiotics in mood symptoms is not only shown in healthy volunteers,
      but also in clinical subjects. In patients with chronic fatigue syndrome, Rao et al. found
      that administration of Lactobacillus casei for 2 months could improve BAI, but not BDI,
      compared to placebo. At the same time fecal Lactobacillus and Bifidobacteria increased after
      2-month L. casei intervention (Rao et al. 2009). Akkasheh et al. gave multi-species
      probiotics, containing Lactobacillus acidophilum, Lactobacillus casei, and Bifidobacterium
      bifidum, or placebo to patients with MDD for 8 weeks. They found that multi-species
      probiotics could significantly reduce BDI scores in patients with major depressive disorder
      (Akkasheh et al. 2016), but which strain of probiotics exerts the beneficial effect is not
      clear.

      1.5 Childhood trauma, inflammation, and gut permeability in depression In animal study, early
      life stress, such as maternal separation, elevated IL-6 level and increased depressive-like
      behavior (increased immobility time in FST) (Liu YW et al. 2016). One recent metaanalysis
      showed that childhood trauma contributes to a pro-inflammatory state in adulthood (Baumeister
      et al. 2016). In addition, childhood trauma also increased the risk of depressive disorders
      (Norman et al. 2012). Metaanalyses have shown that patients with MDD have elevated serum
      inflammatory cytokins (Dowlati et al. 2010; Howren et al. 2009). One possible mechanism
      contributing to systemic inflammation in patients with MDD is bacterial translocation due to
      increased gut permeability (leaky gut). Figure 2 shows the relationship among childhood
      trauma, gut permeability, inflammation, and depression.

      Every microbe possesses a microbe-associated molecular pattern (MAMP) or pathogen-associated
      molecular pattern (PAMP). Microbes leaking from gut activate the MAMPs and
      pattern-recognition receptors, such as Toll-like receptors (TLRs). Proinflammatory cytokines,
      such as IL-6, TNF-alpha, are released from cells after a series of signal transduction.

      Probiotics may affect gut permeability. HFD-derived gut microbiota increased intestinal
      permeability, systemic inflammation, and brain inflammation (Bruce-Keller et al. 2015). One
      in-vitro study showed that Lactobacillus rhamnosus GG ameliorates gut barrier dysfunction and
      inflammation through inhibition of NF-kappaB (Donato et al. 2010). Administration of
      Lactobacillus farciminis could alleviate intestinal permeability and inflammation in partial
      restraint rats (Ait-Belgnaoui et al. 2012).

      Evidence of increased gut permeability in patients with MDD was revealed by Maes' studies.
      Maes et al found that the median values for serum IgM and IgA against LPS of gram-negative
      enterobacteria were significantly greater in patients with MDD than in normal volunteers,
      suggesting that increased gut permeability results in an increased translocation of
      gram-negative microbiota (Maes et al. 2008; Maes et al. 2012). In patients with alcohol
      dependence, those with increased gut permeability, which was measured by the radioactive
      probe 51Cr-EDTA, had higher depression and anxiety scores than those with normal gut
      permeability. The composition and activity of microbiota were altered in patients with
      increased gut permeability (Leclercq et al. 2014).

      1.6 Rationale of current study PS128 was found in traditional fermented food, fu-tsai, by our
      co-PI (Tsai YC) and its genome architecture has been finished and indicated its potential
      immunomodulatory effect. (Chao et al. 2009). Lactobacillus plantarum is generally recognized
      as safe (GRAS). PS128 can reduce IL-6 levels and increased IL-10 level, which accompanied
      with improved depression-like behavior, in MS mice (Liu YW et al. 2016). In the current
      study, we would like to investigate the effect of PS128 on psychophysiology, including
      composition of gut microbiota, gut permeability and inflammation, TLR expression, serum
      cytokines levels, and depressive symptoms in patients with MDD.

      Metaanalyses have shown that patients with MDD have higher inflammatory cytokines (Dowlati et
      al. 2010; Howren et al. 2009), but only a subgroup of patients with MDD has a higher level of
      inflammation. For example, according to the definition of high inflammation of hs-CRP > 3
      mg/l (Pearson et al. 2003), the proportion of patients with high inflammation was 24 % in
      patients with MDD (Rapaport et al. 2016) and 45% in patients with treatment-resistant
      depression (Raison et al. 2011). Baseline inflammatory level may affect treatment response.
      For example, patients with high baseline inflammation had better treatment response to
      infliximab (tumor necrosis factor antagonist) (Raison et al. 2013) and omega-3 fatty acids
      (Rapaport et al. 2016) compared to those with low baseline inflammation. In Raison's study,
      the effect of infliximab on depression symptoms was worse than placebo in those with lower
      inflammatory level at baseline (Raison et al. 2013). Therefore, we will recruit patients with
      MDD and high inflammatory level into our PS128 intervention study.

      We hypothesize that PS128 can (1) change the composition of gut microbiota; (2) improve gut
      permeability, which is measured by fecal zonulin level, and inflammation, which is measured
      by fecal calprotectin level; (3) reduce the translocation of pathogen into circulation
      system, which will be demonstrated by reduced TLR expression, (4) reduce IL-6 and TNF-alpha,
      and hs-CRP, and increase IL-10 level. We hope the improvement in inflammation level can also
      have a beneficial effect on depressive symptoms.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Changes of serum hs-CRP
time frame: baseline, week 4 and week 8
description: measure serum hs-CRP at baseline, week 4 and week8
measure: Changes of serum TNF-alpha
time frame: baseline, week 4 and week 8
description: measure serum TNF-alpha at baseline, week 4 and week8
measure: Changes of serum IL-6
time frame: baseline, week 4 and week 8
description: measure serum IL-6 at baseline, week 4 and week8
measure: Changes of serum IL-10
time frame: baseline, week 4 and week 8
description: measure serum IL-10 at baseline, week 4 and week8
measure: Changes of HAMD-17
time frame: baseline, week 2, week 4 and week 8
description: measure depression rating at baseline, week 2, week 4 and week 8
measure: Changes of DSSS
time frame: baseline, week 2, week 4 and week 8
description: measure depression rating at baseline, week 2, week 4 and week 8
measure: Change of Microbiota
time frame: baseline and week 8
description: gut microbiota analyses at baseline and week 8
measure: Change of zonulin
time frame: baseline and week 8
description: measure gut permeability at baseline and week 8
measure: Change of calprotectin
time frame: baseline and week 8
description: measure gut inflammation at baseline and week 8
measure: Changes of expression of Toll-like proteins
time frame: baseline and week 8
description: measure of expression of TLPs at baseline and week 8
arm group label: Lactobacillus plantarum PS128
arm group type: Experimental
description: Each PS 128 capsule contains 300 mg of probiotics. PS128 will be provided 300 mg twice, in the morning and in the afternoon, daily.
intervention type: Dietary Supplement
intervention name: Lactobacillus plantarum PS128
description: Each PS 128 capsule contains 300 mg of probiotics. PS128 will be provided 300 mg twice, in the morning and in the afternoon, daily.
arm group label: Lactobacillus plantarum PS128
criteria: 
gender: All
minimum age: 20 Years
maximum age: 65 Years
healthy volunteers: No
last name: Chun-Hsin Chen
role: Principal Investigator
affiliation: Taipei Medical University
last name: Chun-Hsin Chen
phone: 86-2-29307930
email: chunhsin57@yahoo.com.tw
facility: 
status: Recruiting
contact: 
country: Taiwan
responsible party type: Principal Investigator
investigator affiliation: Taipei Medical University WanFang Hospital
investigator full name: Chun-Hsin Chen
investigator title: Attending Psychiatrist
mesh term: Inflammation
mesh term: Depressive Disorder
mesh term: Depression
mesh term: Depressive Disorder, Major
sharing ipd: No