Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02957591 |
| Other study ID # |
2016-01608 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 24, 2017 |
| Est. completion date |
January 3, 2020 |
Study information
| Verified date |
April 2021 |
| Source |
Psychiatric Hospital of the University of Basel |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Recent research demonstrates that the composition of the gut microbiome is a master regulator
of key neurophysiological processes that are affected in depression. Indeed, contemporary
studies showed that faecal microbiota is altered in patients with major depressive disorder
(MDD). Furthermore, it has also been shown that supplementation of probiotics ameliorated
depressive symptoms in unmedicated patients with mild to moderate depression. However, no
study has yet explored the efficacy of a probiotic-based therapy in patients with severe MDD
in addition to a standard antidepressant treatment. As dietary and lifestyle interventions
may be a desirable, effective, pragmatical and non-stigmatizing prevention and adjuvant
therapy (in addition to antidepressant treatment) in depression, this project is aimed at
investigating for the first time if probiotic supplementation compared to a placebo treatment
improves the effect of standard antidepressant medication on depressive symptoms (i.e. better
and faster remission) in patients with severe MDD. Furthermore, this study will further test
if probiotic supplementation modulates immune signalling and inflammatory processes
(macrophage migration inhibitory factor and interleukin 1 beta),
hypothalamic-pituitaryadrenal (HPA) axis responses (saliva cortisol), neurogenesis
(brain-derived neurotrophic factor (BDNF) expression), the release of appetite-regulating
hormones (leptin and ghrelin), the composition of gut microbiota (in particular levels of
Enterobacteriaceae, Alistipes and Faecalibacterium) and brain perfusion, structure and
activation and if these changes are associated with the probiotic-induced effect on
depressive symptoms.
Description:
Major depression is a recurrent and debilitating mental disorder with a lifetime prevalence
of up to 20% in the general population, among the highest for psychiatric disorders. Its
diagnosis is based upon the presence of persisting affective, cognitive and behavioural
symptoms, with a depressive episode requiring at least five of these symptoms during a period
of at least two weeks. When considering the biological mechanisms that underpin depression,
the most conclusive findings include deficits in the serotonergic (5-HT) neurotransmission,
alterations in the expression of BDNF, deficient immune activation and neuroinflammation, and
dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, understanding the
pathophysiological mechanisms of MDD has widespread implications for the development of novel
treatment and prevention strategies. However, despite advancements in the development of
novel therapeutics, current treatment options have not reached optimal efficacy. Treatment
resistant depression occurs in up to 40% of patients and standard antidepressant medication
has a variety of undesirable side effects such as sedation, decrease of blood pressure,
increase of weight, indigestion or sexual dysfunction. This often results in patients' poor
compliance resulting in a break-up of medication with recurrence of depressive symptoms and
increased suicidal risk. As there is an unmet need to develop safer and more effective
treatments in depression, a major topic of future psychiatric care is to focus on different
possible physiologically relevant mechanisms in order to establish alternative, causative and
easy available treatment strategies.
In the past few years, it has become increasingly evident that resident gut bacteria are an
important contributor to healthy metabolism and there is significant evidence linking altered
composition of the gut microbiota and metabolic disorders such as obesity and depression.
Preclinical work in animals have reported associations between alterations of the gut
microbiome (the community of microorganism that live in the human gut) and anxiety-like
behaviour, depressive-like symptoms and stress responsiveness. In line with these preclinical
findings, a recent study found an altered composition of faecal microbiota in patients with
MDD. Most notably, the MDD group had increased levels of Enterobacteriaceae and Alistipes but
reduced levels of Faecalibacterium, which was negatively correlated with the severity of
depressive symptoms.
Accumulating evidence suggest that there exits a bi-directional communication system between
the gastrointestinal tract and the brain. Changes in gut microbiota can influence cognitive
and emotional stress processes through interactions with the brain and altered emotional
states and dysfunction of the gut microbiome-brain axis has been implicated in stress-related
disorders such as depression. Brain-gut interactions could occur in various ways: 1)
microbial compounds communicate via the vagus nerve, which connects the brain and the
digestive tract, and 2) microbially derived metabolites interact with the immune system,
which maintains its own communication with the brain. Although the pathways linking gut
bacteria with the brain are incompletely understood, one of the principal mechanisms proposed
to underlie stress-induced alterations is the "leaky gut" phenomenon. Specifically, increased
translocation of bacterial products, due to a compromised gut barrier has been linked to
activation of the immune system and HPA axis. In line with these findings, human studies have
demonstrated a stress-induced increase in bacterial translocation in depression. The
stress-induced interactions between the gut microbiome and the brain are further mediated via
central processes such as neurotransmission and neurogenesis. For instance, there is
substantial evidence to demonstrate a role for the gut commensals in the regulation and
development of the 5-HT system and the expression of BDNF. Virtually all corticolimbic brain
structures that are involved in mood regulation and stress response express 5-HT receptors.
These include the prefrontal cortex, amygdala, hippocampus and nucleus accumbens. A recent
meta-analyses of fMRI studies support hyperactivation of several of these regions in response
to fearful faces in MDD, which extent correlated positively with the severity of depressive
symptoms. Furthermore, during resting state fMRI, MDD patients showed lower connectivity
between the amydgala, hippocampus, parahippocampus, and brainstem, while the connectivity
strength was inversely correlated with general depression. The hippocampus, and its
connection to other limbic, striatal and PFC regions, seems to play a key role in stress
regulation, given that hippocampal neurogenesis mediates antidepressant effects via the
ventral hippocampus' influence on the HPA axis, and mechanisms by which antidepressants may
reverse chronic stress-induced 5-HT and neurogenic changes. Notably, BDNF may contribute to
the modulation of neurogenesis in response to both stress and antidepressants, as hippocampal
BDNF levels decrease in response to chronic stress and increase in response to antidepressant
treatments.
Besides being a fundamental player in eating processes and in hypothalamic regulation of
energy balance, the appetite-regulating hormones leptin and ghrelin had been implicated in
the etiology of mood disorders. Importantly, particular species of bacteria in the gut are
know to affect the levels of leptin and ghrelin. In humans, the onset of depression was
associated with a combination of high leptin levels coupled with high visceral fat, and the
link between leptin levels and severity of depressive symptoms was mediated by adiposity. It
was suggested that leptin might influence depression by acting on leptin receptors present on
5-HT neurons within the raphe nuclei and dopamine neurons in the midbrain and, thus, might
influence reward processes. Consistent with this supposition, when leptin receptors in the
rat hippocampus were genetically deleted, a stressor-induced depressive profile was apparent,
and deletion of leptin receptors on midbrain dopamine neurons in mice elicited elevated
anxiety. Thus, identifying the key brain regions that mediate leptin's antidepressant
activity and dissecting its intracellular signal transduction pathways may provide new
insights into the pathogenesis of depression and facilitate the development of novel
therapeutic strategies for the treatment of this illness.
The gut peptide ghrelin also plays a fundamental role in eating and energy regulation and
there have been indications that ghrelin functioning might contribute to depressive illness.
Like leptin, ghrelin receptors have been reported in the midbrain and the dorsal raphe
nucleus and have been associated with reward processes, as well as stressor-induced
depressive-like symptoms, such as anhedonia. In line with a role for ghrelin in
stressor-elicited depression, negative events promote an increase of circulating ghrelin
levels and in emotionally reactive individuals the normalization of ghrelin levels after
stress may be attenuated. Moreover, ghrelin was elevated among depressed patients and
declined following pharmacotherapy and among patients who did not respond to treatment,
ghrelin levels were higher than among patients who responded positively.
Compelling preclinical data demonstrated the beneficial effect of probiotics in normalizing
HPA axis functioning, BDNF levels and 5-HT neurotransmission. In particular, certain
probiotics such as lactobacilli and bifidobacteria can reverse psychological stress-induced
HPA axis activation and possess antidepressant or anxiolytic activity in rats. A seminal work
in experimental animals showed that altered stress responsiveness has been partially reversed
by colonization of the gut. Importantly, a recent and innovative study showed that short-term
consumption of mostly animal or mostly plant diet rapidly and reproducibly altered the human
gut microbiome, suggesting that the development of dietary interventions may provide a novel
promising adjuvant therapy in addition to pharmacological antidepressant treatments in MDD.
Indeed, recent reports of trials administrating a combination of probiotics to healthy
subjects demonstrated improvements in depression or anxiety outcome measures. Moreover,
urinary free cortisol levels were significantly reduced by the probiotics, providing a
potential mechanism for the improvement in psychological symptoms observed. Consistent with
this finding, other studies in healthy subjects found that the consumption of a
probiotic-containing yogurt improved mood and that a multispecies probiotic (different
strains of lactobacilli and bifidobacteria) reduced rumination and aggressive thoughts.
Moreover, a pioneer study in healthy subjects revealed by using fMRI that consumption of
probiotic bacteria (including strains of lactobacilli and bifidobacteria) in fermented milk
for 4 weeks modulated brain activation in corticolimbic regions while viewing frightened and
angry facial expressions. Most important, a very recent study demonstrated that
administration of probiotics, a mixture of lactobacilli and bifidobacteria, ameliorated
depressive symptoms in unmedicated patients with mild to moderate depression. These studies
together suggest that restoring disturbed gut microbiome-brain interactions via probiotic
bacteria might be a desirable treatment strategy for depression, especially as most of the
clinically depressed patients additionally suffer from obesity, weight loss or gain, appetite
disturbances and constipation.
This project is aimed at investigating for the first time if probiotic supplementation
improves the effect of antidepressants on depressive symptoms (i.e. better and faster
remission) in patients with severe MDD. Furthermore, this study will also test if probiotic
supplementation modulates immune signalling and inflammatory processes, HPA axis responses,
neurogenesis, the release of appetite-regulating hormones, the composition of gut microbiota
and brain perfusion, structure and activation and if these changes are associated with the
probiotic-induced effect on depressive symptoms.
