Major depressive disorder (MDD) is a highly prevalent condition, affecting approximately 42 million people in the G7 (France, Germany, Italy, Spain, the United Kingdom, Japan, and the United States) in 2017. Notably, MDD is a highly drug-treated condition, with patients predominately receiving antidepressants, which act on select monoaminergic pathways, for their depressive symptoms. Even though the monoaminergic hypothesis (i.e., that the development of MDD symptoms results from a deficiency in the central nervous system’s concentration of monoamine transmitters) is the theory that predominately influenced the development of available antidepressants, the proposed pathogenesis of MDD extends well beyond this hypothesis. Researchers not only theorize that MDD stems from an imbalance in neurotransmitters (including monoamines, glutamate, and GABA), but also now propose that the hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis, chronic inflammation, and childhood and/or chronic stress contribute to the development of MDD.[1],[2],[3],4

Interestingly, the suggested root causes of the development of MDD overlap with the gut-brain axis’s pathways of bidirectional communication. As outlined in a prior blog post on the relationship between the microbiome and CNS disorders, the gut and brain communicate with one another through the neuronal connection (e.g., modulator of neurotransmitter concentrations via the vagus nerve), the immune connection (e.g., mediation of pro- and anti-inflammatory signals), and the neuroendocrine connection (e.g., modulation of the HPA axis). Considering that the microbiome acts through the gut-brain axis, it is not surprising that researchers have investigated the role microbiome dysbiosis (altered microbiome compositions) plays in MDD’s pathogenesis.

Outlined below are the preclinical and clinical evidence supporting the microbiome’s role in the development of MDD.

Microbiome Differences:

Extensive research has indicated that stressful life events or chronic stress exposure in childhood can result in the later-life development of MDD.[4],[5],[6] It has been suggested that stressful events will activate the HPA axis, whose dysregulation, as mentioned, has been implicated in depression.[7] The biologically altering effects of stress have also been seen in the composition of the microbiome. Preclinical studies have shown that the fecal microbiota in rats who underwent maternal separation (an animal model for depression) differed from those rats who did not experience maternal separation; these separated rats also had decreased norepinephrine levels and higher peripheral IL-6 levels (a proinflammatory marker).[8] Similar findings were observed in mice who experienced chronic stress (i.e., physical restraint) and infant rhesus monkeys who were separated from their mothers.[9],[10] Most notably, lower concentrations of Bifidobacterium and Lactobacilli were measured in infant rhesus monkeys separated from their mothers compared with their non-separated counterparts,9 indicating that these two types of bacteria may be influenced by stress exposure. A lower concentration of Lactobacillus was also measured in the microbiota of maternally separated rat pups compared with those of non-separated rat pups.[11] Notably, germ-free mice have demonstrated an exaggerated HPA reaction [as measured by adrenocorticotropic hormone (ACTH) and corticosterone levels] to restraint stress compared with specific-pathogen-free mice. However, this exaggerated HPA response was reversed when the germ-free mice received Bifidobacterium infantis,10 highlighting the influence the microbiota have on the HPA axis’s functioning and the potential opportunity for probiotics in the treatment of depression. On whole, these findings suggest that stress’s impact on the development of depression could, in part, be induced by dysbiosis of the microbiome.

Further supporting these preclinical findings, clinical research has demonstrated that MDD patients’ fecal microbiomes significantly differs from those of healthy controls.[12],[13] Compared with healthy controls’ microbiota, MDD patients’ microbiota are less heterogeneous and possesses a significantly greater abundance of Bacteroidetes and Proteobacteria and a lower concertation of Facecalibacterium (bacteria associated with anti-inflammatory activity).14 Antidepressants, including citalopram (Celexa, Allergan) and ketamine (Ketalar, Par Sterile Products), have demonstrated an effect in altering the gut microbiota in rats and mice,8,[14] suggesting that the antidepressant effects of these agents could, in part, be a result of their modification of the MDD patient’s microbiota.

Probiotic treatment:

Like SSRIs and SNRIs, which are the most commonly prescribed therapies for depression, probiotics have demonstrated antidepressant effects in both clinical and preclinical research. For example, the administration of the probiotic Bifidobacterium infantis in rats who underwent maternal separation resulted in the attenuation of the HPA axis’s activation (e.g., a modulation of noradrenaline and IL-10 levels). These changes were also observed in those rats treated with citalopram, but these changes were greater in magnitude in citalopram-treated rats than Bifidobacterium infantis-treated rats.8 Consistent with these results, the daily administration of a probiotic formulation (Latcobacillius helevticus and Bifidobacterium longum) in stressed rats and in healthy volunteers over 14 days and 30 days, respectively, reduced both populations’ depressive and anxiety symptoms, as measured by the Coping Checklist and Hospital Anxiety and Depression Scale and Hopkins Symptom Checklist, respectively.[15] Thus, these studies’ results further confirm that the microbiome impacts the presentation of depressive symptoms and suggest that probiotics may be valuable treatment option for MDD patients.

Fecal Microbiota Transplantation:

Most recently, fecal microbiota transplantation (FMT) has been used in preclinical research to further explicate the microbiome’s influence on the development of depression. Typically, FMT is a procedure where a healthy donor’s fecal microbiota is transferred into the intestine of the ill recipient. However, in two preclinical FMT studies, the fecal microbiota of MDD patients and healthy controls were transferred into germ-free and microbiota-depleted rats. In both these studies, the rats that received the MDD patients’ fecal microbiota demonstrated significantly greater depressive symptoms compared with those rats that received the healthy FMT,13,[16] further indicating that microbiome dysbiosis contributes to MDD’s pathogenesis.

Currently, no clinical studies have provided data on the impact of transferring a healthy fecal microbiota into a MDD patient, but a few small clinical studies are ongoing.[17],[18] If these studies prove FMT to be effective in reducing depressive symptoms and relatively safe and tolerable, there will be a considerable market opportunity for a company to explore the development of a microbiome-based treatment.

Future of MDD Treatments:

Even though Metchnikoff proposed that gut dysfunction contributed to the development of mental health disorders over 100 years ago,[19] the field is still in the beginning stages of fully understanding the microbiome’s role in the pathogenesis of MDD. Given that the majority of studies investigating the role of the microbiome have been conducted in the preclinical phase, there is an obvious need for more clinical studies to better elucidate the impact of the microbiome on the development of depression and to facilitate and to initiate the translation of preclinical findings into the development of pharmacological treatments. Notably, those clinical studies that have assessed the composition of depression patients’ microbiome and the effect of probiotics on the microbiome have only been conducted in a small number of MDD patients. Thus, there is a need not only for additional clinical studies but also larger-sized clinical studies, which will more thoroughly evaluate the role the microbiome has on development of depression and the feasibility of creating effective microbiota-related treatments.

Academic research institutes have started to address these needs and are conducting multiple clinical studies, investigating on both a large and small scale the composition of depressed patients’ microbiome and the effects of probiotics and FMT on depressive symptom. The First Affiliated Hospital Xi’an Jiaotong University in China is one of the institutes running a large clinical study; the group’s study aims to recruit 240 patients (80 with MDD, 80 with bipolar disorder, 40 healthy controls) and to analyze the relationship between the gut microbiota and disease-associated symptoms over a three-month period.[20] These findings could provide confirmatory results of prior clinical studies and/or identify additional bacterial targets for probiotic treatments.

At the time of this writing, no company is developing a microbiome agent for the treatment of MDD, which is likely, in part, due to many pharmaceutical companies’ focus on developing fast-acting agents (e.g., NMDA receptor modulators) for the treatment of MDD and treatment-resistant depression. However, this focus could change if positive results are obtained from a few academic clinical studies, exploring the therapeutic potential of modifying MDD patients’ microbiome. Both the Psychiatric Hospital of the University of Basel and the Jinling Hospital in China are investigating the clinical effect of FMT in MDD patients and in constipated patients with anxiety and/or depression, respectively.18,19

Despite the current lack of industry interest in microbiome-based therapies for the treatment of MDD, there is a great opportunity for those drug developers who enter this field. Not only are one-third of MDD patients’ treatment-resistant, underscoring the need for novel agents, but all available MDD agents are prescribed chronically. Thus, a microbiome agent that effectively and acutely treats MDD symptoms with long-term effect would be highly differentiated from available antidepressants and would likely experience modest use as a first-line treatment for MDD patients and considerable uptake among TRD patients, who are desperate for an efficacious agent.

Recent Reports

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