Probiotic formulation for patients with schizophrenia or bipolar disorder who have screened positive for increased intestinal permeability
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Schizophrenia and bipolar disorder are severe mental disorders, both placing
significant burden on global health (WHO 2006). Although the introduction of
antipsychotic medications in the 1950s has substantially improved clinical
symptoms of schizophrenia (Tandon et al., 2010), the disease is still causing
considerable morbidity and mortality (Saha et al., 2007). In bipolar disorder,
lithium is since many years the first-choice maintenance-treatment, with
anticonvulsants and antipsychotics as major alternatives. However, up to 50% of
patients with bipolar disorder do not respond adequately to these treatments
and still suffer from manic and/or depressive episodes, often severely
affecting functioning (Perlis et al., 2006). The pathogenesis of these
disorders is still far from elucidated, but quite certainly multifactorial,
with immune dysregulation being one of many contributing factors.
Abnormal immune responses have been reported in patients with schizophrenia and
bipolar disorder, of varying disease stages and medication status (Muller &
Schwarz, 2010; Horvath & Mirnics, 2014; Munkholm et al., 2013; Beumer et al.,
2012). For example, adult schizophrenia patients as a group have elevated serum
levels of pro-inflammatory cytokines compared to controls (Francesconi et al.,
2011; Kunz, et al., 2011; Pedrini, et al., 2012; Song et al., 2013). Both
disorders are associated with an increased pro-inflammatory gene expression in
circulating monocytes (Drexhage et al., 2010). Symptom severity is found to
correlate with levels of inflammatory markers (Fan et al., 2007; Fan et al.,
2010; Hope et al., 2013). It has therefore been hypothesized that schizophrenia
and bipolar disorder can originate from early exposure to microbial infections,
contributing to the aetiology, through chronic neuro-inflammatory and
autoimmune processes (Yolken & Torrey, 2008).
Autoimmunity, atopic disorders, early infection and, more recently, *leaky gut*
resulting from microbiome imbalance, have all been associated with
schizophrenia and bipolar disorder (Severance et al., 2014). It is interesting
to see that also intestinal microbiota imbalance is associated with
schizophrenia and bipolar disorder (Fond et al., 2014; Nemani et al., 2015;
Dickerson et al., 2017), as this may offer a non-invasive and relatively simple
strategy to improve symptoms and condition of the brain. An increased incidence
of gastrointestinal barrier dysfunction, food antigen sensitivity, inflammation
and the metabolic syndrome are observed in patients with schizophrenia and
bipolar disorder, suggesting a potential deficit in gut microbiota.

Another reason to consider probiotic supplementation in patients with
schizophrenia and bipolar disorder, is the high prevalence of gastro-intestinal
symptoms. In schizophrenia, constipation is a prevalent symptom (De Hert, Dockx
et al., 2011; De Hert, Hudyana et al., 2011; Koizumi et al., 2013). Probiotic
supplementation has been shown to improve constipation in different populations
but has not yet been studied in schizophrenia (Chmielewska & Szajewska, 2010;
Miller & Ouwehand, 2013; Dimidi et al., 2014). Bipolar disorder, in contrast,
is associated with diarrhoea and satiety, a gastro-intestinal symptom for which
probiotics are recognized to be efficacious (Sherwin et al., 2016). Several
studies have been published describing gastro-intestinal inflammation in
schizophrenia and bipolar disorder. Already back in 1953, gastro-intestinal
inflammation was associated with schizophrenia in a post-mortem study of 82
individuals with schizophrenia, where researchers found that 50% had gastritis,
88% enteritis and 92% colitis (Buscaino, 1953). Conversely, prevalence
estimates for any psychiatric comorbidity in patients diagnosed with irritable
bowel syndrome (IBS), range from 54 to 94% (Whitehead et al., 2002), and
estimates for a schizophrenia-spectrum or bipolar comorbidity approaching 20%
(Gupta et al., 1997).
There have been several studies of the fecal microbiome in healthy children and
adults (Collado et al., 2015; Lozupone et al., 2012; Zhernakova et al, 2016).
However, collection and processing of fecal samples from individuals with
severe psychiatric disorders is difficult. Up till now, studies analyzing the
fecal microbiome of individuals with schizophrenia are largely lacking. In
bipolar disorder, one study analyzing the fecal microbiome has been published
recently, providing the first detailed analysis of the gut microbiome
relationships with multiple psychiatric domains in this disorder (Evans et al.
2017). In this study, the stool microbiome from 115 individuals with bipolar
disorder and 64 control subjects were compared, using 16S ribosomal RNA (rRNA)
gene sequence analysis, revealing global community case-control differences.
Operational Taxonomical Unit (OTU) level analysis demonstrated significantly
decreased fractional representation of Faecalibacterium. In individuals with
bipolar disorder, the fractional representation of this bacterium was
associated with better self-reported health outcomes based on the Short Form
Health Survey (SF12); the Patient Health Questionnaire (PHQ9); the Pittsburg
Sleep Quality Index (PSQI); the Generalized Anxiety Disorder scale (GAD7); and
the Altman Mania Rating Scale (ASRM). This data thereby provides support for
the hypothesis that targeting the microbiome may be an effective treatment
paradigm for bipolar disorder.

Probiotics are live organisms, which can confer a health benefit for the host
when administered in adequate amounts (Hill et al., 2014). Probiotics are shown
to have immune modulatory effects as well as effects on the epithelial barrier
in healthy adults (Ohland & Macnaughton, 2010; Klaenhammer et al., 2012).
Probiotic bacteria can manipulate brain functioning from the intestine by
multiple mechanisms (Forsythe et al., 2012; Dinan et al., 2013; Galland, 2014),
for example by changing immune system signals to the brain. Recent research in
a mouse model shows that probiotics can improve abnormal behaviours associated
with inflammation (D'Mello et al., 2015). They also have the capacity to
increase plasma levels of neurotransmitters, such as the GABA and serotonin
precursor tryptophan (Lesniewska et al., 2006; Desbonnet et al., 2008; Barrett
et al., 2012). Probiotic bacteria can also produce bacterial metabolites, such
as short chain fatty acids (SCFA), which can be carried by monocarboxylate
transporters, expressed at the blood-brain barrier (Maurer et al., 2004). The
vagus nerve is another important mechanism for signalling between brain and gut
and has been shown to be involved in the antidepressant effects of probiotics
in mice (Bravo et al., 2011). Although the exact mechanisms are not yet known
in human, it is likely that a combination of different pathways convey the
effects of probiotics on the brain.
Given the accumulating evidence for abnormal immune responses which are seen in
schizophrenia and bipolar disorder patients, and the observation that
intestinal microbiota and the intestinal epithelial barrier can play a role in
both diseases, probiotic therapy can be viewed as a potential candidate for
treatment in these patients, especially in those known to have signs of
decreased epithelial barrier function.
Immunomodulatory effects of probiotics (combination of Lactobacillus rhamnosus
GG and bifidobacterium animalis subsp. Lactis BB12) have already been shown in
patients with schizophrenia and the authors speculated that supplementation of
probiotics for schizophrenia patients may improve control of gastrointestinal
leakage (Tomasik et al., 2015). Patients in the probiotic arm of the
intervention study were less likely to develop severe bowel difficulty, but
this trial did not show significant differences in symptom severity between
probiotic and placebo supplementation (Dickerson et al., 2014). Possible
reasons for not finding an effect on symptom severity could be the relatively
short duration of the intervention, the daily dose of the probiotic product, or
the selection of patients with long-term schizophrenia. In addition, probiotics
may be effective for a subpopulation only. When given to an unselected sample,
efficacy in this subgroup may be obscured by inefficacy in the majority. In a
recent study of Dickerson et al. (2018) in patients with bipolar disorder they
found that administration of probiotic supplementation is associated with a
lower rate of hospitalization in patients who have been recently discharged
following hospitalization for mania.

In this study we will examine the effect of the probiotic product Ecologic
Barrier on symptom improvement, cognition and peripheral immune parameters in
patients with schizophrenia and bipolar disorder. Limited effects on symptom
severity and cognition are expected, when given to an unselected sample.
Therefore, patients will be screened using serum LPS-binding protein (LBP)
levels in blood as an indication of intestinal permeability (Only patients with
LPB >= 9 ng/ml will be included in the intervention.) and C reactive protein
(CRP) as measurement for intestinal inflammation. In this selected sample,
larger effect sizes are expected.

The primary objective of this trial is to investigate the effects of
probiotics, as compared to placebo, when given in addition to
antipsychotic/mood stabilizing medication to a selected patient sample. Our aim
will be to lower symptom severity as measured with the BPRS to assess if
probiotics can form an effective treatment paradigm for both schizophrenia and
bipolar disorder.

We will also assess improvements in cognition and disability in the probiotic
and the placebo-treated group. In addition, we expect that probiotics will
improve immune parameters which are abnormal in schizophrenia and bipolar
patients.

The current monocenter study has a randomized, placebo-controlled double-blind
study.

Treatment period of 12 weeks in which they are randomized 1: 1 in either 2
grams of probiotic formulation (1x10 ^ 10 colony forming units / day) or
placebo twice daily twice a day.

There is no potential harmful dose of probiotics known. Probiotics are already
on the market as a food supplement. There are little known risks for using
probiotics. Previous studies with probiotics in patients without
life-threatening somatic illnesses have not resulted in adverse events, besides
incidental sensations of bloating and change in stool consistency.

The risk and burden from such blood samples drawings are low and risks well
known (e.g. irritation). Stool samples will be collected at start and end of
treatment. The burden and risks are acceptable while the benefits are expected
to be considerable.