Fermented Milk Product With Probiotic and Its Impact on Mood of Patients With Treatment Resistant Depression

Theories about the association of imbalances in the gastro-intestinal (GI) microbiota and its
impact on mood states have long existed in medicine. These theories were considered "dead"
for most of the 20th century, but converging lines of evidence are now rekindling interest in
a link between the GI microbiota and the central nervous system. Newer lines of investigation
have made these dormant theories relating commensal microbiota and mood states not only
plausible, but the focus of well-designed basic research studies (Yano et al, 2015; Hsiao et
al, 2013). The microbial world influence on brain development and behavior was defined by Dr
Tom Insel, the former director of the National Institutes of Mental Health as one the "great
frontiers" of neuroscience in the next decade (Insel, 2012). Dr. Francis Collins, Director of
the National Institutes of Health, further underscored the need for research on the impact of
intestinal microbiota on brain function (Collins, 2014).

This renewed interest in understanding the role of the microbiota beyond the digestive tract
was spurred in 2007 when the Human Microbiome Project was launched. (Turnbaugh et al, 2007).
With over one million different genes and a mass equal to that of the human brain, the
genetic diversity of our bacterial commensals outnumbers the human genome by a factor of over
100 to one, and suggests the potential for the genetic variability in the GI environment to
impact other body systems, including the central nervous system (CNS). A range of
neurotransmitters relevant to mood and anxiety disorders including serotonin, GABA,
acetylcholine and endocannabinoids are produced by intestinal microbiota (Dinan et al, 2013).
This accruing data along with previous findings showing that pathological gut bacterium are
capable of inducing changes in behavior (Lyte et al, 1998) and that early life stress, an
established risk factor for major depression, induces changes in the microbiota (O'Mahony et
al, 2007) underscore the potential importance of further examining the relationship between
the microbiota and brain function with particular attention to the potential therapeutic
implications for treatment of psychiatric conditions, such as depression

Preclinical studies demonstrated that noninvasive methods that alter gut microbiota are
capable of inducing antidepressant like effects in rat models of depression (Desbonnet et al,
2010). Findings in human populations showed differences in gut flora of depressed individuals
when compared to healthy controls, including higher levels of Bacteroidetes, Proteobacteria
and Actinobacteria, and a negative correlation between Faecalibacterium and the severity of
their depression (Jiang et al, et al 2015). Other studies point to a beneficial effect of
probiotics on mood and anxiety in normal volunteers (Messaoudi et al, 2011; Benton et al,
2007), as well as in individuals with Irritable Bowel Syndrome (O' Mahoney et al, 2005) and
Chronic Fatigue Syndrome (Rao et al, 2009). However, there have been no systematic studies to
date reporting on the impact of probiotics on mood in individuals with major depression.

The majority of depressed patients remain symptomatic despite treatment with currently
available antidepressants, and a significant proportion do not respond at all. Thus, the
development of new effective antidepressant interventions remains a significant unmet public
health need. Given the accumulating evidence for a relationship between the gastrointestinal
microbiota and the central nervous system functioning and pathophysiology, including that of
affective disorders, it is cogent to measure the impact of probiotic interventions in
individuals with refractory depression. The present study proposes to examine the gut
microbiota, inflammatory milieu and impact of probiotics on mood in a population of
individuals who have been refractory to treatment with standard antidepressant agents.

This study aims to assess the impact of a chronic dietary intervention (8 weeks) with
probiotics, specifically Fermented Milk Product with Probiotic (FMPP), on the mood of
individuals with Major Depressive Disorder (MDD) refractory to standard antidepressant
therapy, and its association with changes in intestinal microbiota and markers of
inflammation.

Specific Aim 1. Examine the effect of 8 weeks of probiotic administration on depressive
symptoms in depressed patients.

Specific Aim 2. Examine the intestinal microbiota at initiation and end of probiotic
administration in order to assess the relationship of baseline and changes in gut flora with
treatment response.

Specific Aim 3. Examine baseline and endpoint inflammatory biomarkers including C-reactive
protein (CRP) and cytokines to assess the relationship of inflammation with intestinal
microbiota and treatment response.

Inclusion Criteria

1. Men and women between 21 and 65 years of age meeting DSM-V criteria for Major
Depressive Disorder and presenting a HAM-D score of 18 or higher.

2. If patients are on antidepressants (ie. fluoxetine 20 mg/d or its equivalent) the dose
needs to be stable for at least 6 weeks prior to screening.

3. Patients with Body Mass Indexes between 18 and 40.

4. No planned antibiotic treatment during study to avoid antibiotic treatments for the
duration of the study.

Exclusion Criteria

1. Patients who are vegan or observe other specific dietary patterns that are not
representative of the general population and may specifically impact their microbiomes
will be excluded from the study.

2. Lactose intolerant patients will not be able to participate due to the high likelihood
of being unable to tolerate the specific intervention being implemented.

3. Patients who have used BKP or Yogurt without probiotics daily for 12 weeks preceding
study entry and unwilling to stop.

4. Patients with a past history of Eating Disorders or Psychotic Disorders. Patients with
Bipolar Disorder, past or current, who are currently taking a mood stabilizer.

5. Patients with Substance Use Disorder. Within the past 12 months.

6. Patients with a history of 3 or more failed trials of antidepressant medications of
adequate dose or duration (i.e. fluoxetine 20 mg/d or its equivalent for 6 weeks or
more).

7. Patients with other significant clinical illnesses such as, but not limited to,
Congestive Heart Failure, Diabetes Mellitus, Chronic Obstructive Pulmonary Disease.

8. Patients who are currently using corticosteroid medications, or who have a history of
multiple treatment courses with these medications.

9. Patients on antibiotic treatment at the time of study entry or who have received such
treatment during the 30 days prior to study entry.

10. Patients using anti-inflammatory medications.

11. Patients who are actively suicidal.