TYPE Systematic Review

PUBLISHED 09 February 2023

DOI 10.3389/fnbeh.2023.1111349

Systematic review of probiotics as

OPEN ACCESS an adjuvant treatment for
EDITED BY
Angelica Thomaz Vieira,
Federal University of Minas Gerais, Brazil
psychiatric disorders
REVIEWED BY
Alessandra Riva, Evan Forth1,2,3*, Benjamin Buehner2 , Ana Storer2 ,
University of Vienna, Austria
Fabiola M. Ribeiro, Cassandra Sgarbossa1,2,3 , Roumen Milev1,2,3,4 and
Federal University of Minas Gerais, Brazil
Arthi Chinna Meyyappan1,2,3
*CORRESPONDENCE
1
Evan Forth Department of Psychiatry, Providence Care Hospital, Kingston, ON, Canada, 2 Centre for Neuroscience
[email protected] Studies, Queen’s University, Kingston, ON, Canada, 3 Department of Psychiatry, Queen’s University, Kingston,
ON, Canada, 4 Department of Psychology, Queen’s University, Kingston, ON, Canada
SPECIALTY SECTION
This article was submitted to
Emotion Regulation and Processing,
a section of the journal
Frontiers in Behavioral Neuroscience
Introduction: Many psychiatric illnesses have been linked to the gut microbiome,
RECEIVED 29November 2022 with supplements such as probiotics showing some efficacy in alleviating the
ACCEPTED 20 January 2023
PUBLISHED 09 February 2023 symptoms of some psychiatric illnesses. The aim of this review is to evaluate
CITATION the current literature investigating the effects of adjuvant probiotic or synbiotic
Forth E, Buehner B, Storer A, Sgarbossa C, administration in combination with first-line treatments for psychiatric illnesses.
Milev R and Chinna Meyyappan A (2023)
Systematic review of probiotics as an adjuvant Method: A systematic search of four databases was conducted using key terms
treatment for psychiatric disorders.
Front. Behav. Neurosci. 17:1111349. related to treatments for psychiatric illnesses, the gut microbiome, and probiotics.
doi: 10.3389/fnbeh.2023.1111349 All results were then evaluated based on specific eligibility criteria.
COPYRIGHT
© 2023 Forth, Buehner, Storer, Sgarbossa, Milev
Results: Eight studies met eligibility criteria and were analyzed for reported changes
and Chinna Meyyappan. This is an open-access in outcome measures used to assess the symptoms of psychiatric illness and the
article distributed under the terms of the
tolerability of treatment. All Major Depressive Disorder (MDD) (n = 5) and Generalized
Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other Anxiety Disorder (GAD) (n = 1) studies found adjuvant probiotic or synbiotic treatment
forums is permitted, provided the original to be more efficacious in improving the symptoms of psychiatric illness than the
author(s) and the copyright owner(s) are
credited and that the original publication in this first-line treatment alone or with placebo. The schizophrenia studies (n = 2) found
journal is cited, in accordance with accepted adjuvant probiotic treatment to have no significant difference in clinical outcomes,
academic practice. No use, distribution or
reproduction is permitted which does not but it was found to improve the tolerability of first-line antipsychotics.
comply with these terms.
Discussion and conclusion: The findings of the studies included in this review
suggest the use of adjuvant probiotic treatment with selective serotonin reuptake
inhibitors (SSRIs) for MDD and GAD to be superior to SSRI treatment alone.
Probiotic adjuvant treatment with antipsychotics could be beneficial for improving
the tolerability of the antipsychotics, but these findings do not suggest that adjuvant
probiotic treatment would result in improved clinical outcomes for symptoms
of schizophrenia.

KEYWORDS

probiotics, psychiatric illness, psychotropics, adjuvant therapy, gut-brain-axis probiotics,

gut-brain-axis, Major Depressive Disorder

Frontiers in Behavioral Neuroscience 01 frontiersin.org

Forth et al. 10.3389/fnbeh.2023.1111349

Introduction to those associated with the disorders of the donors (Bercik et al.,
2011; Neufeld et al., 2011). Certain probiotics or fecal microbiota
The human gastrointestinal (GI) tract houses trillions of transplants from healthy patients have also helped alleviate symptoms
microorganisms, which have co-evolved with their host and and induced positive outcomes in patients with psychiatric disorders
collectively contain over 100 times as many genes as the human (Meyyappan et al., 2020; Johnson et al., 2021). As such, there is
genome (Bermon et al., 2015). Colonization of the gut begins at birth, emerging evidence to suggest that the gut microbiome and the GBA
being influenced by the mode of delivery and breastfeeding (Martin play a crucial role in inducing and modulating psychiatric disorders.
et al., 2016) and through the gut’s microbial composition somewhat A significant subset of patients affected by these disorders
stabilizes throughout adulthood, factors such as the environment, are treatment-resistant or experience adverse effects when taking
diet, medication, genetics, and age continue to shape microbiota antidepressants or antipsychotics. Antipsychotic usage is commonly
composition and function throughout one’s life (Li et al., 2014; associated with adverse metabolic and endocrine effects such as
Heiman and Greenway, 2016; Odamaki et al., 2016; Cussotto et al., weight gain and insulin resistance (De Hert et al., 2011), while SSRIs
2019). There is a well-established, bidirectional connection between frequently induce unpleasant side effects such as nausea, insomnia,
the gut microbiome and the brain, known as the gut-brain-axis drowsiness and agitation (Hirsch and Birnbaum, 2017). Such adverse
(GBA). This communication includes portions of the sympathetic effects contribute to low treatment compliance and tolerability. Low
and the parasympathetic nervous system, the enteric nervous system, compliance and inconsistent efficacy indicate that there is a need
as well as both neuroimmune and neuroendocrine signaling (Cryan to explore alternative treatments, or approaches to counteract these
et al., 2019; Morais et al., 2021; Liu et al., 2022). Research suggests that unwanted side effects.
the GBA may influence a variety of neurological functions, including Interestingly, both antipsychotics and antidepressants have been
the pathology of psychiatric disorders. found to have antimicrobial properties (Munoz-Bellido et al., 2000;
Major Depressive Disorder (MDD), Generalized Anxiety Maier et al., 2018). It is thought that such psychotropic medications
Disorder (GAD) and Schizophrenia (SZ) are widely known and can modulate the gut microbiome, and consequently influence the
severe psychiatric disorders. MDD is characterized by pervasive GBA. Whether the therapeutic benefits or the adverse effects of
depressed mood and/or loss of interest or pleasure, along with an these medications are influenced, in part, by their impact on the
array of other possible psychiatric and physiological symptoms, and GBA remains to be determined, however, several recent studies
is the leading cause of disability worldwide (Evans-Lacko et al., 2018). have indicated that the gut microbiome composition could be used
GAD has a similarly significant impairment in daily functioning as a biomarker to predict pharmacological treatment outcomes
(American Psychiatric Association [APA], 2013), and is characterized (responders versus treatment resistance) in MDD and SZ (Fontana
by a persistent, exaggerated worry about everyday events. MDD and et al., 2020; Ciocan et al., 2021; Yuan et al., 2021). This suggests that
GAD are also somewhat gendered illnesses, with the prevalence in the GBA could play a significant role in the efficacy and tolerability
women being reported as 1.5 to 3 times that of men (Vesga-López of psychotropic medication. This evidence, combined with the
aforementioned therapeutic benefits of microbiome modulation
et al., 2008; Sabic et al., 2021). Antidepressant medications such
on psychiatric disorders, and the proven ability of probiotics to
as selective serotonin reuptake inhibitors (SSRIs) are considered
normalize metabolic issues (Le Barz et al., 2015), suggest that
a first-line therapy for MDD and GAD (Gelenberg et al., 2010;
combining psychotropic medication with gut microbiome targeting
Baldwin et al., 2011). SZ is a highly heterogenous psychotic disorder,
treatments could have beneficial results. The aim of this systematic
characterized by continuous or relapsing episodes of positive
review is to evaluate the current literature investigating the effect
symptoms like delusions, hallucinations and irrational thoughts or
of adjuvant probiotic or synbiotic (a combination of probiotics and
actions, and negative symptoms like lethargy, apathy, and social
prebiotics) treatment on clinical outcomes and tolerability of first-
withdrawal. Second-generation antipsychotics are considered the
line psychotropic treatments. We conducted this systematic review
first-line treatment for SZ (Patel et al., 2014). Gender differences
as a means to gather scientific evidence and provide a comprehensive
found in schizophrenia are less consistent, with some reports of equal
and current overview of this topic.
prevalence between men and women, and some reports of increased
prevalence among men (Ochoa et al., 2012).
Various studies have found the microbiota composition of
patients with these psychiatric disorders to be significantly different Methods
from those of healthy controls (Zhu et al., 2020; Nikolova et al., 2021).
Interestingly, fecal microbiota transplants from psychiatric patients Literature search strategy
to germ-free rodents have been shown to induce symptoms similar
This review was carried out according to the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA)
Abbreviations: BDI, Beck Depression Inventory; BMI, body mass index; CFU, guidelines (Figure 1; Moher et al., 2009). A systematic search
colony forming units; DSM, Diagnostic and Statistical Manual of Mental
Disorders; EC, enterochromaffin cells; GAD, Generalized Anxiety Disorder; was conducted using 4 databases (MEDLINE, EMBASE, PsycINFO,
GBA, gut brain axis; GI, gastrointestinal; GLP-1, glucagon-like Protein 1; and Web of Science) to identify relevant studies using the
HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating following search terms:(antidepressant OR selective serotonin
Scale 17-item; HPA, hypothalamic pituitary adrenal axis; ICD, International
Classification of Diseases; MDD, Major Depressive Disorder; MS, multi-strain reuptake inhibitors, SSRI OR SNRI OR TCA OR MAOI OR
probiotic; PANSS, Positive and Negative Syndrome Scale; PRISMA, Preferred anti-anxiety drugs OR anxiolytics OR benzodiazepines OR beta-
Reporting Items for Systematic Reviews and Meta-Analyses; PSS-10, Perceived blockers OR antipsychotic medication OR mood stabilizer) AND
Stress Scale 10; RCT, randomized controlled trial; RoB, risk of bias; SZA,
schizoaffective disorder; SCL-90, Symptom Checklist-90; SSRI, selective (microbiome OR microbiota OR gut bacteria OR intestinal bacteria
serotonin reuptake inhibitors; SZ, schizophrenia. OR dysbiosis OR bacteriostatic OR bactericidal OR antibiotic

Frontiers in Behavioral Neuroscience 02 frontiersin.org

Forth et al. 10.3389/fnbeh.2023.1111349

OR bacterial therapy OR bacteriotherapy OR psychobiotic OR Results

microbial therapy OR fecal microbiota transplant OR probiotic)
AND (depression OR depressive disorder OR major depression
Search results
OR bipolar OR mood disorders OR affective disorders OR stress,
psychological OR anxiety OR anxiety disorder OR generalized
Following the removal of 1072 duplicates, the search yielded
anxiety disorder OR social anxiety disorder OR PTSD OR OCD OR
3,957 results. Subsequent abstract screening and full-text screening,
mania OR panic OR phobia OR psychiatric illness). The database
according to the search criteria highlighted earlier (shown in
searches were supplemented by retrieval of any additional papers
Figure 1) resulted in 8 papers with direct relevance to the research
meeting eligibility criteria that were cited in reference lists of
question.
relevant review articles yielding 820 additional articles. Searches were
conducted in January and February 2022 and yielded 3957 studies
after duplicates were removed. Studies that were excluded during full-
Study characteristics
text screening were rejected due to wrong study design, including
the article being a review article or abstract only, and wrong study
Our findings can be grouped into studies examining three major
outcomes. Articles rejected due to “wrong study outcome” did not
categories of psychological disorders. For one, 370 patients across 5
measure changes in psychiatric symptoms in response to the use of
trials were categorized and treated as patients with MDD (Ghorbani
a microbiome-targeted therapeutic as an adjuvant to medication for
et al., 2018; Miyaoka et al., 2018; Kazemi et al., 2019; Rudzki et al.,
psychiatric illness.
2019; Arifdjanova et al., 2021). A significant majority of these patients
received traditional antidepressant medication in the form of SSRIs.
The sole trial examining 48 patients with GAD (Eskandarzadeh
Eligibility criteria et al., 2021) assessed the use of sertraline, a common SSRI, as its
psychotropic agent. The remaining two trials examined 132 patients
Eligible articles were restricted to those that were published with SZ or schizoaffective disorder (SZA) (Dickerson et al., 2014;
in peer-reviewed journals and were written in English. Studies Yang et al., 2021), one in which participants received the atypical
eligible for inclusion involved clinical samples that assessed antipsychotic Olanzapine, and the other in which participants
changes in psychiatric wellbeing after standard treatment continued taking whichever antipsychotic they were prescribed prior
indicated for psychiatric illness and an adjuvant therapeutic to enrolling in the study. As can be seen in Table 2, the studies were
targeting the microbiome. conducted across 6 different countries and on predominantly female
populations. Furthermore, while the majority of studies used an SSRI
or atypical antipsychotic, the makeup and the quantity of probiotic
administered varied greatly across trials, reducing the generalizability
Study selection of conclusions.
In all studies, a subset of patients received their psychotropic
Two authors (BB and AS) completed the initial search of the
medication in conjunction with a type of probiotic supplementation.
databases, adhering to the search strategy as described above. Two
Most of these studies were conducted in the form of a double-blinded,
authors (EF and one of BB or AS) independently assessed the titles
randomized clinical trial. Two studies, however, (Miyaoka et al., 2018;
and abstracts of records retrieved from a systematic search according Yang et al., 2021) lacked a placebo arm, following an open-label
to the identified inclusion and exclusion criteria. Two authors (BB randomized format.
and EF) completed the full-text review. Any disagreements were
resolved by a fourth author (AC). Quality assessment of eligible
articles was completed by a fifth author (CS).
Efficacy of probiotics as an adjuvant
therapy
Study quality In the eight studies examined (shown in Table 2), the medications
to treat psychiatric illness were either antidepressants (n = 6), or
Quality assessment of articles was completed using Covidence’s antipsychotics (n = 2). All studies included measures for clinical
built-in, Cochrane Handbook for Systematic Reviews of outcomes and symptom severity. In the depression studies, the
Interventions, Risk of Bias (RoB) template. The Cochrane RoB majority used the Hamilton Depression Rating Scale (Hamilton,
tool assesses the risk of bias for the following domains: sequence 1960) (HAM-D) (n = 4) or the Beck Depression Inventory (Beck
generation, allocation concealment, blinding of participants and et al., 1996) (BDI) (n = 2) to measure symptoms of mood,
personnel, blinding of outcome assessment, incomplete outcome anhedonia, sleep, anxiety, appetite, and other symptoms associated
data, and “other” sources of bias. Most studies presented with a with depression. The anxiety study used the Hamilton Anxiety Rating
low level of bias. Studies where there was no mention of blinding Scale (Hamilton, 1959) (HAM-A) (n = 1) to assess symptoms of
to participants, personnel, outcome assessors, or allocation of anxiety such as mood, tension, insomnia, physiological symptoms.
treatment, were assigned a “high” judgment in risk of bias. In studies The schizophrenia studies used the Positive and Negative Syndrome
where there was no given description or details regarding one of the Scale (Kay et al., 1987) (PANSS) (n = 2) to assess positive and
RoB domains (i.e., sequence generation), the risk of bias was assigned negative symptoms associated with schizophrenia such as delusions,
as “unsure.” A detailed summary of the quality assessment can be hallucinations, blunted affect, and social withdrawal. Higher scores
found in Table 1. on these scales correspond to an increased severity of the illness.

Frontiers in Behavioral Neuroscience 03 frontiersin.org

Forth et al. 10.3389/fnbeh.2023.1111349

FIGURE 1
Flow chart showing literature search and screening process using PRISMA guidelines.

When examining the effects on symptom severity in patients with and monotherapy groups by weeks 8 and 12, adjuvant probiotic
MDD or GAD, five of the six studies found that patients who received therapy was found to eliminate the observed sex-based differences
adjuvant probiotic treatment had significant reductions in symptom in weight gain seen in the olanzapine monotherapy group. There
severity on the majority of the scales used. One study (Rudzki was no significant difference in body weight change between men
et al., 2019) did not find any significant effects on symptom severity and women in the adjuvant probiotic group, whereas there were
in patients with MDD receiving adjuvant probiotic therapy using significantly higher increases in the body weight of women compared
the HAM-D, Symptom Checklist-90 (Derogatis and Savitz, 1999) to men in the olanzapine monotherapy group.
(SCL-90), and Perceived Stress Scale-10 (Cohen et al., 1983) (PSS-
10), but did find that adjuvant probiotic treatment was correlated
with increased cognitive performance. Neither of the two studies Discussion
using patients with schizophrenia or schizoaffective disorder taking
antipsychotics found adjuvant probiotic treatment to have any effect The clinical outcome findings from the studies included in this
on the psychiatric symptoms. That being said, both studies found review suggest probiotic and synbiotic adjuvant treatment with SSRIs
adjuvant probiotic treatment to reduce the adverse events and side for MDD and GAD to be more effective in decreasing depressive and
effects associated with antipsychotic treatment, with Dickerson et al. anxious symptomology, respectively, than SSRI treatment alone. In
finding fewer reports of bowel difficulties, and Yang et al. finding a the one study included in this review that used included a prebiotic
reduced weight gain in the first 4 weeks in the adjuvant probiotic group, prebiotics alone were not found to have a significant effect
groups. Though the reduced weight gain in the study conducted by on clinical symptoms. The improved clinical outcomes of probiotic
Yang et al. was transient, with no differences between the adjuvant adjuvant treatment for MDD and GAD were found to be persistent

Frontiers in Behavioral Neuroscience 04 frontiersin.org

Forth et al. 10.3389/fnbeh.2023.1111349

throughout the course of the treatment, but further long-term follow- primarily atypical antipsychotics, but the exact degree in which each
up assessments would be needed to investigate the persistence of individual antipsychotic effects the gut microbiome is not certain. As
this effect when treatment is discontinued. For individuals with such, it is possible that the use of differing antipsychotics could have
schizophrenia, adjuvant probiotic treatment was not found to be contributed to the difference in longevity of the observed beneficial
more effective in reducing clinical symptom severity than standard effects.
antipsychotic treatment alone. Some potential limitations that could The exact mechanisms of action for these beneficial effects of
explain this lack of effect on clinical symptoms and outcomes are probiotic adjuvant treatment are not fully understood. Though the
discussed in the conclusion. Though there was no significance in exact pathway and importance of the various pathways by which
clinical findings for the schizophrenia groups, adjuvant probiotic probiotic adjuvant treatment may exert its effect is not known,
treatment was associated with a decrease in treatment associated multiple pathways have been described for ways in which the
adverse events and side effects. The findings of these studies suggest microbiome affects the brain and central nervous system. Biomarker
adjuvant probiotic treatment to have an alleviative effect on some data collected in the MDD studies suggests that the probiotic
of the gastrointestinal adverse events associated with antipsychotic adjuvant treatment exerts its therapeutic effect through effects on the
treatment, such as weight gain and bowel problems. Some of these immune system, the hypothalamic pituitary adrenal axis (HPA-axis),
beneficial effects were found to be fairly long lasting, as is the case in and the tryptophan system. Decreased concentrations of immune
the trial by Dickerson et al. (2014), but some effects were found to be markers such as interleukin-6, tumor necrosis factor-a, and nitric
transient, with Yang et al. finding a reduced weight gain for only the oxide suggests a decrease in the activity of the immune system in
first 4 weeks of adjuvant probiotic treatment (Yang et al., 2021). response to probiotic adjuvant treatment. The immune system has
As mentioned in the introduction, some antipsychotics and long been known to be intimately linked to MDD and depressive
antidepressants have been found to have antibacterial properties, symptomology, with an over-active immune system often being
as such, it is important to consider the specific medications used observed in individuals with MDD (Leonard, 2010). One proposed
in each study. All MDD and GAD studies used participants taking mechanism of action for microbiome targeting treatment for MDD
SSRIs, with Miyoaka et al. including participants taking the SNRIs is a reduction in immune system activity through a decrease in gut
duloxetine (n = 9) and milnacipran (n = 3) and Kazemi et al. including permeability. It is thought that individuals with MDD and/or other
participants taking the tricyclic antidepressant amitriptyline (n not illnesses have increased gastrointestinal permeability, allowing for
reported). The SSRIs involved in the studies included escitalopram, microorganisms and other potentially harmful toxins from the gut
citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. It to pass into the body, resulting in an increase in inflammation and
has been found SSRIs vary in the degree to which the inhibit immune system activity. Repopulation of the gut microbiome and/or
bacterial growth, with sertraline and fluoxetine having the strongest the introduction of beneficial bacteria through probiotic treatment is
antimicrobial activity, followed by paroxetine and fluvoxamine, thought to alleviate this increased gut permeability, and thus reduce
and then escitalopram and citalopram (McGovern et al., 2019). inflammation and immune system activity, leading to a decrease in
Amitriptyline has also been found to have antimicrobial effects depressive symptomology. Biomarker data from the study conducted
to around the same degree as paroxetine (Mandal et al., 2010). by Arifdjanova et al. (2021) also found cortisol levels to be decreased
The antimicrobial effect of SNRIs is less clear, with studies in the probiotic adjuvant treatment group. Cortisol is often associated
finding venlafaxine to have no effect (Ait Chait et al., 2020), with stress and is a major indicator HPA-axis activity. Individuals
and others finding the clinical effects of duloxetine to be reduced with MDD and/or GAD often are found to have an overactive
by the bacteria Ruminococcus flavefaciens (Lukić et al., 2019), HPA-axis and increased levels of cortisol. Probiotic and other gut
suggesting an interaction between duloxetine and the bacteria. microbiome targeting treatments have been frequently found to have
Despite the differences in medications used and their degree of an inhibitory effect on HPA-axis activity and has been associated
antimicrobial activity, all the MDD and GAD studies found results with decreased cortisol levels. Influencing the HPA-axis and cortisol
suggesting probiotics combined with antidepressants improved production and availability seems to be another pathway by which
clinical outcomes when compared to antidepressants alone. probiotic adjuvant treatment results in improved clinical outcomes.
For the schizophrenia studies, all participants in the study Another potential mechanism for the improved clinical outcome
conducted by Yang et al. took olanzapine, whereas participants in observed in the probiotic adjuvant treatment groups is through
the Dickerson et al. study took a variety of antipsychotics. The effects on the tryptophan system. Kazemi et al. (2019) and Rudzki
antipsychotics used in the Dickerson et al. study were clozapine et al. (2019) found an increased tryptophan/isoleucine ratio and
(n = 17), olanzapine (n = 15), risperidone (n = 15), aripiprazole decreased kynurenine (a tryptophan metabolite) concentration in the
(n = 11), quetiapine (n = 9), haloperidol (n = 7), ziprasidone (n = 5), probiotic treatment groups of their respective studies. Tryptophan
and asenapine (n = 1), including some participants that took more is a precursor to serotonin, a neurotransmitter that has long been
than one antipsychotic. Though a variety of antipsychotics were used associated with MDD and GAD. SSRIs exert their therapeutic action
in the Dickerson et al. study, all fall under the category of atypical by inhibiting serotonin reuptake transporter proteins, leading to an
antipsychotics except for haloperidol which is a butyrophenone increase in the relative abundance and concentration of serotonin
derivative. Olanzapine has been found to shift the fecal microbiota in the brain. Though serotonin is often associated with the brain
in mice toward an “obesogenic” profile (Morgan et al., 2014), and and psychiatric illnesses, up to 90% of the body’s serotonin is
all of the atypical antipsychotics used in the Dickerson et al. study produced in the gut. The mechanism by which the gut microbiome
have been found to be associated with significant changes in the gut affects serotonin production and availability is thought to be through
microbiome and a decrease in species diversity in females (Flowers interactions with microbiome metabolites and enterochromaffin cells
et al., 2017). Haloperidol has also been found to have some bacteria (EC cells) in the gut. The microbiome produces long and short
inhibiting effects (Korbee et al., 2018). Taking that into consideration, chain fatty acids (SCFA) through the fermentation of non-digestible
though the two studies used different antipsychotics, they both used carbohydrates. Long chain fatty acids influence serotonin production

Frontiers in Behavioral Neuroscience 05 frontiersin.org

Frontiers in Behavioral Neuroscience

Forth et al.
TABLE 1 Summary of quality assessment details and judgment for risk of bias of each study.

Study Sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data
Judgment Comments Judgment Comments Judgment Comments Judgment Comments Judgment Comments
Dickerson Unsure No mention of Unsure No mention of allocation Low Study was double-blind, but there was Low Study was double-blind, but Low Subjects that were
et al., 2014 sequence concealment for placebo no mention of how this was there was no mention of how excluded were
generation. vs. treatment groups. maintained. this was maintained. documented with
reasoning.
Kazemi et al., Low Patients were Low Participants, clinicians, Low Participants, clinicians, and raters Low Participants, clinicians, and Low Subjects that were
2019 randomly and raters remained blind remained blind to the allocated group raters remained blind to the excluded were
assigned to to the allocated group of of each participant. allocated group of each documented with
experimental each participant. participant. reasoning.
groups (1:1:1) in
blocks of 6.
Ghorbani Unsure No mention of Low Double-blind study with Low Double-blind study. Throughout the Low The raters (study researchers) Low Subjects that were
et al., 2018 treatment group 1:1 ratio for treatment vs. study, the psychiatrist, the rater were blind to allocation. excluded were
sequencing. placebo randomization. (study researchers), and the patients documented with
were all blind to allocation. reasoning.
Eskandarzadeh Low Patients were Low Patients were randomly Low The study is double-blind, but there Low The study is double-blind, but Low Subjects who were
et al., 2021 randomly assigned using a random was no mention as to how that was there was no mention as to if excluded were
assigned using a numbers table to either maintained. raters were blinded. documented with
random numbers treatment or placebo reasoning.
table to either groups.
treatment or
placebo groups.
06

Arifdjanova Low Participants were High No concealment of High No mention of blinding of staff. High No mention of blinding of Low Some subjects were not
et al., 2021 randomized to treatment group. raters. included at the
either beginning, but criteria
experimental or for which they were not
control group, included was not
but no mention disclosed.
as to how.
Miyaoka Unsure No mention of Unsure No mention of allocation High No mention of blinding. High No mention of blinding. Low All data was reported
et al., 2018 allocation concealment. and subjects that were
sequence. excluded were
documented with
reasoning.
Rudzki et al., Low Patients were Low The study was blinded at Low The study was blinded at group Low The study was blinded at Low Subjects that were
2019 randomly group allocator, allocator, participant, and assessor group allocator, participants, excluded were
assigned to participant, and assessor levels. and assessor levels. documented with
placebo or levels. reasoning.
probiotic group

10.3389/fnbeh.2023.1111349
using computer
generated
randomization
list.
Yang et al., Unsure No mention of High The blind method was not High Researchers were fully unblinded and High The blind method was not Low Subjects that were
frontiersin.org

2021 how the used in this study, and the aware of the medication. No mention used in this study, and the excluded were
participants were researchers were fully of unblinding to participants. researchers were fully aware of documented with
randomized. aware of the medication. the medication. reasoning.
Frontiers in Behavioral Neuroscience

Forth et al.
TABLE 2 Summary of key study characteristics and outcomes.

References Study Study Sample Mean Country Intervention type Duration Probiotic Outcome measures Conclusion
population design size age (%F)
Arifdjanova Mild-moderate Placebo, n = 149 32.9 (62.2%) Russia Cipralex 6 weeks Bac-Set Forte* 3 HAM-D for depression severity, Found decreased levels of cortisol,
et al., 2021 MDD (ICD-10), double-blind (SSRI) + Placebo or capsules/day (1010 CFU) ELISA for cortisol and cytokines, dopamine, IL-6, TNF-a and nitric
18–45yo RCT Probiotic HPLC for blood plasma oxide, and a bigger reduction in
depressive symptoms in the adjuvant
PB group compared to standard
therapy.
Rudzki et al., Moderate MDD Placebo, n = 60 39 (71%) Poland Antidepressant (various 8 weeks 2 capsules/day Symptom Severity: HAM-D 17, PB correlated with increased cognitive
2019 (DSM-IV-R) double-blind SSRIs) + Probiotic or (10 × 109 CFU of SCL-90, PSS-10, cognitive performance and decreased
RCT Placebo Lactobacillus Plantarum function, biochemical parameters kynurenine concentration in MDD
299v each) also assessed patients, no significant effect on
symptom severity.
Ghorbani et al., Moderate MDD Placebo, n = 40 34.8 (70%) Iran Fluoxetine (SSRI, 6 weeks 1 capsule/day (MS HAM-D primary outcome Found a greater reduction in HAM-D
2018 (DSM-V), double-blind 20 mg/day - 4W) then probiotic**, scores in synbiotic treated patients
18–55yo RCT Fluoxetine + synbiotic 500 mg + prebiotic, compared to the placebo group.
capsule or Placebo (6W) 100 mg)
Kazemi et al., Mild-moderate Three-arm n = 81 36.5 (70.9%) Iran Antidepressant 8 weeks 1 sachet/day - probiotic BDI primary outcome, HPLC for PB resulted in a decrease in BDI score
2019 MDD (ICD-10) placebo, (sertraline, fluoxetine, (≥10 × 109 CFU serum tryptophan and branched and increased tryptophan/isoleucine
on medication, double-blind citalopram, Lactobacillus helveticus chain amino acids, ELISA for ratio compared to placebo and
18–50yo RCT amitriptyline) + Probiotic and Bifidobacterium kynurenine prebiotic. No significant results for
or Prebiotic or Placebo longum), or prebiotic prebiotic and placebo groups
(galactooligosaccharide)
Miyaoka et al., Treatment Prospective n = 40 43.5, (60%) Japan Antidepressant 8 weeks 60 mg/day (Clostridium HAM-D, BDI and the Beck PB correlated to significant
07

2018 Resistant MDD open label (fluvoxamine, butyricum MIYAIRI Anxiety Inventory improvement in depression regardless
(DSM-IV) randomized paroxetine, escitalopram, (CBM588)– of antidepressant type; well tolerated.
duloxetine, and 10 CFU/gram)
sertraline) with or
without (control)
Probiotic
Eskandarzadeh Drug-free Placebo, n = 48 33.9 (81.2%) Iran Sertraline (SSRI, 8 weeks 1 capsule/day HAM-A scale for anxiety, Beck Found Sertraline + PB group to have
et al., 2021 patients with double-blind 25 mg/day) + Placebo or (18*109 CFU Anxiety Inventory, State-Trait improved clinical outcome measures
GAD (DSM-V), RCT Probiotic Bifidobacterium longum, Anxiety Inventory as opposed to Sertraline + placebo.
18–65yo Bifidobacterium bifidum, Significance varied depending on
Bifidobacterium lactis scale used.
and Lactobacillus
acidophilus)
Dickerson et al., Mild-moderate Placebo, n = 65 46.2 (35.4%) U.S. Antipsychotic 14 weeks 1 Capsule/day (109 CFU PANSS to measure psychiatric No significant difference in
2014 SZ (DSM-IV, double-blind (various) + Placebo or combined Lactobacillus symptoms + difficulty of bowel psychiatric scores, PB well tolerated,
PANSS), RCT Probiotic rhamnosus strain and movement scale PB group had less bowel problems
18–65yo Bifidobacterium animalis associated w/treatment.

10.3389/fnbeh.2023.1111349
subsp. lactis strain Bb12)
Yang et al., 2021 First-episode SZ Open-label, RCT n = 67 43.2 (67.7%) China Olanzapine with or 12 weeks 3 capsules/day (live Body weight, BMI, appetite, No significant differences in PANSS
or SZA without (control) combined latency to increased appetite, and scores. In the first 4 weeks there was
(DSM-V), Bifidobacterium group Bifidobacterium, baseline weight increase reduced weight change and BMI for
18–55yo Lactobacillus, and of more than 7%, PANSS to PB group, but this difference
frontiersin.org

Enterococcus capsules; measure psychiatric symptoms disappeared after 4 weeks. There were
1 × 109 CFU each) no overall differences in appetite.

*Contents of Bac-Set Forte: Streptococcus thermophilus; Bifidobacterium ssp; Lactobacillus ssp. among others. **Contents of MS probiotic: L. casei = 3 × 108 , L. acidophilus = 2 × 108 , L. bulgaricus = 2 × 109 , L. rhamnosus = 3 × 108 , B. breve = 2 × 108 , B. longum = 1 × 109 ,
S. thermophilus = 3 × 108 .
Forth et al. 10.3389/fnbeh.2023.1111349

indirectly through interactions with glucagon-like protein-1 (GLP- Many of the studies included in this review also did not have
1) cells leading to increased GLP-1 which interacts with EC cells comprehensive biomarker collection. To be able to elucidate the
to increase serotonin production and availability. Short chain fatty mechanisms of action of probiotic supplementation as an adjuvant
acids interact directly with EC cells to increase serotonin production treatment, as well as to evaluate the colonization of the gut by
and availability. In addition to these interactions with EC cells, short the probiotics administered and changes in key features of the gut
chain fatty acids have the ability to cross the gut-blood and blood- such as intestinal permeability, robust and consistent biomarker
brain barriers, and are thought to have an anti-inflammatory effect, collection is necessary. This collection would include biomarkers
thus further influencing the immune system. The exact bacteria for the immune system, HPA-axis, serotonin system, and the gut
involved in these processes are not fully characterized, but some microbiome. Another limitation of the studies was the fact that
species Lactobacillus and Bifidobacterium have been found to produce many used a variety of first-line antidepressant or antipsychotic
neurotransmitters such as acetylcholine and gamma-aminobutyric treatments in combination with the probiotics, which is helpful for
acid, and Streptococcus, Enterococcus, and Escherichia have been evaluating adjunctive probiotic treatment in general but does not
found to produce serotonin, dopamine, and epinephrine (Galland, give strong insight into the effectiveness of adjunctive probiotic
2014). These biomarker findings suggest that the beneficial clinical administration with specific antidepressants and antipsychotics. As
outcomes in the adjuvant probiotic groups with MDD and GAD are different psychiatric treatments can have differing effects on the gut
a result of the adjuvant probiotic treatment affecting multiple if not all microbiome, studies or analyses focusing on one specific intervention
of the pathways by which the microbiome and brain are connected. could allow for more detail in determining what combination of
As for the observed effect of a decrease in gastrointestinal treatment would be most effective for an individual. These studies
adverse events in the adjuvant probiotic group of the schizophrenia are also limited by their length, with the majority being unable to
studies, the mechanism of action is largely unclear. The alleviation have significant long-term follow-ups to investigate the longevity
of gastrointestinal issues, such as constipation, most likely acted of the observed effects. Another limitation in this field is the lack
through interactions with the serotonin pathway. As described above, of consensus on dosages for probiotics as well as the treatments
probiotic administration may have resulted in an increase in SCFAs they are given in combination with. Dose finding studies in the
produced by the microbiome, which in turn increases serotonin future are needed, in addition to studies investigating the efficacy
synthesis through EC cells. Serotonin has been found to activate of adjuvant probiotic treatment at different stages and severity of
enteric neural circuitry to initiate peristalsis and reduce constipation the illnesses. This is especially relevant for the schizophrenia studies,
(Crowell, 2004). The transient effect of decreasing weight gain for which included populations with relatively severe clinical symptoms
the first 4 weeks could be from a variety of factors. Bifidobacterium and later stages of the illness. It is possible that in a population
administration has been linked to both weight gain and weight loss with milder symptoms and a more recent onset, adjuvant probiotic
depending on the strain (Yin et al., 2010). The exact strain used by therapy could effectively impact clinical outcomes.
Yang et al. was not reported (Miyaoka et al., 2018), but increased Despite these limitations, the findings of these studies suggest the
bacteria with bile salt hydrolase has been found to prevent weight gain use of adjuvant probiotic treatment with SSRI treatment for MDD
through the deconjugation of bile acids (Joyce et al., 2014). This may and GAD to be superior to SSRI treatment alone. Probiotic adjuvant
have been the case for the Yang et al. study, but the general negative treatment with antipsychotics could be beneficial for improving the
impact on energy by olanzapine as well as its own mechanism of GI issues associated with antipsychotics, but these findings do not
action for weight gain may have outweighed the preventative action suggest that adjuvant probiotic treatment would result in improved
of the probiotic over time. Although it is thought that probiotics may clinical outcomes for symptoms of schizophrenia. Though progress
improve clinical outcomes and symptom severity in populations with in psychiatric research is challenging, these studies have shown
schizophrenia through interaction with the immune system (Fond that combining probiotic treatment with first line pharmaceutical
et al., 2020), neither of the studies included a robust collection of treatments is promising, and their findings certainly justify continued
immune system related biomarkers, and thus the effect of adjuvant research in this area. The gut microbiome and the brain are clearly
probiotic treatment on the immune system of the patients in these linked, and these studies show that combining treatments that target
studies is unknown. both areas, respectively, is a viable and efficacious way to combat the
symptoms and treat psychiatric illnesses.

Conclusion
Data availability statement
Although the studies included in this review were generally
found to be of high quality with low risk of bias, there were still The original contributions presented in this study are included in
some limitations to these studies that impact the generalizability this article/supplementary material, further inquiries can be directed
and conclusions that could be drawn from their findings. A major to the corresponding author.
limitation is the small number of studies for each psychiatric illness
and the lack of studies investigating other psychiatric illnesses. With
only eight studies in total, five of which used a population with
MDD, it is difficult to draw strong generalizable conclusions about Author contributions
the effect of adjuvant probiotic treatment on GAD and schizophrenia.
Additionally, though the studies included had relatively large sample BB and AS completed the initial search of the databases, adhering
sizes, further larger scale, double blind, randomized controlled trials to the search strategy. EF and one of BB or AS independently assessed
are required in the future to make any definitive conclusions. the titles and abstracts of records retrieved from a systematic search

Frontiers in Behavioral Neuroscience 08 frontiersin.org

Forth et al. 10.3389/fnbeh.2023.1111349

according to the identified inclusion and exclusion criteria. BB and The remaining authors declare that the research was conducted
EF completed the full-text review. AC resolved any disagreements. in the absence of any commercial or financial relationships that could
CS completed quality assessment of eligible articles. All authors be construed as a potential conflict of interest.
contributed to the article and approved the submitted version.

Publisher’s note
Conflict of interest
All claims expressed in this article are solely those of the
RM has received consulting and speaking honoraria from authors and do not necessarily represent those of their affiliated
AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, organizations, or those of the publisher, the editors and the reviewers.
Neonmind, Otsuka, and Sunovion, and research grants from Any product that may be evaluated in this article, or claim that may
CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI, be made by its manufacturer, is not guaranteed or endorsed by the
and OMHF. AC has received CIHR Doctoral Funding. publisher.

References
Ait Chait, Y., Mottawea, W., Tompkins, T., and Hammami, R. (2020). Unravelling the with anxiety, mood, and substance use disorders: Results from the WHO world mental
antimicrobial action of antidepressants on gut commensal microbes. Sci. Rep. 10:17878. health (WMH) surveys. Psychol. Med. 48, 1560–1571. doi: 10.1017/S0033291717003336
doi: 10.1038/s41598-020-74934-9
Flowers, S., Evans, S., Ward, K., McInnis, M., and Ellingrod, V. (2017). Interaction
American Psychiatric Association [APA] (2013). Diagnostic and statistical manual between atypical antipsychotics and the gut microbiome in a bipolar disease cohort.
of mental disorders: DSM-5. Washington, DC: American psychiatric association. doi: Pharmacotherapy 37, 261–267. doi: 10.1002/phar.1890
10.1176/appi.books.9780890425596
Fond, G., Lançon, C., Korchia, T., Auquier, P., and Boyer, L. (2020). The role of
Arifdjanova, S., Abrurakhmanova, Z., Bizulya, E., Gumenyuk, L., Sorokina, L., and inflammation in the treatment of schizophrenia. Front. Psychiatry 11:160. doi: 10.3389/
Gerbali, O. (2021). The role of probiotics in combination therapy of depressive disorders. fpsyt.2020.00160
Russ. Open Med. J. 10:e0109. doi: 10.15275/rusomj.2021.0109
Fontana, A., Manchia, M., Panebianco, C., Paribello, P., Arzedi, C., Cossu, E.,
Baldwin, D., Woods, R., Lawson, R., and Taylor, D. (2011). Efficacy of drug treatments et al. (2020). Exploring the role of gut microbiota in major depressive disorder
for generalised anxiety disorder: Systematic review and meta-analysis. BMJ 342:d1199. and in treatment resistance to antidepressants. Biomedicines 8:311. doi: 10.3390/
doi: 10.1136/bmj.d1199 biomedicines8090311
Beck, A. T., Steer, R. A., and Brown, G. K. (1996). Manual for the beck depression Galland, L. (2014). The gut microbiome and the brain. J. Med. Food 17, 1261–1272.
inventory-II. San Antonio, TX: Psychological Corporation. doi: 10.1037/t00742-000 doi: 10.1089/jmf.2014.7000
Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., et al. (2011). The intestinal Gelenberg, A., Freeman, M., Markowitz, J., Rosenbaum, J., Thase, M., Trivedi, M., et al.
microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. (2010). American psychiatric association practice guidelines for the treatment of patients
Gastroenterology 141, 599–609, 609e.1–609e.3. doi: 10.1053/j.gastro.2011.04.052 with major depressive disorder. Am. J. Psychiatry 167(Suppl. 10), 9–118.
Bermon, S., Petriz, B., Kajeniene, A., Prestes, J., Castell, L., and Franco, O. (2015). The Ghorbani, Z., Nazari, S., Etesam, F., Nourimajd, S., Ahmadpanah, M., and Jahromi,
microbiota: An exercise immunology perspective. Exerc. Immunol. Rev. 21, 70–79. S. (2018). The effect of synbiotic as an adjuvant therapy to fluoxetine in moderate
depression: A randomized multicenter trial. Arch. Neurosci. 5:e60507. doi: 10.5812/
Ciocan, D., Cassard, A., Becquemont, L., Verstuyft, C., Voican, C., El Asmar, K., et al.
archneurosci.60507
(2021). Blood microbiota and metabolomic signature of major depression before and
after antidepressant treatment: A prospective case–control study. J. Psychiatry Neurosci. Hamilton, M. (1959). The assessment of anxiety states by rating. Br. J. Med. Psychol. 32,
46, E358–E368. doi: 10.1503/jpn.200159 50–55. doi: 10.1111/j.2044-8341.1959.tb00467.x
Cohen, S., Kamarck, T., and Mermelstein, R. (1983). A global measure of perceived Hamilton, M. (1960). A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23,
stress. J. Health Soc. Behav. 24, 385–396. doi: 10.2307/2136404 56–62. doi: 10.1136/jnnp.23.1.56
Crowell, M. (2004). Role of serotonin in the pathophysiology of the irritable bowel Heiman, M., and Greenway, F. L. (2016). A healthy gastrointestinal microbiome is
syndrome. Br. J. Pharmacol. 141, 1285–1293. doi: 10.1038/sj.bjp.0705762 dependent on dietary diversity. Mol. Metab. 5, 317–320. doi: 10.1016/j.molmet.2016.0
2.005
Cryan, J., O’Riordan, K., Cowan, C., Sandhu, K., Bastiaanssen, T., Boehme, M., et al.
(2019). The microbiota-gut-brain axis. Physiol. Rev. 99, 1877–2013. doi: 10.1152/physrev. Hirsch, M., and Birnbaum, R. (2017). Selective serotonin reuptake inhibitors:
00018.2018 Pharmacology, administration, and side effects, eds P. Roy-Byrne and D. Solomon
(Waltham, MA: UpToDate).
Cussotto, S., Clarke, G., Dinan, T., and Cryan, J. (2019). Psychotropics and the
microbiome: A chamber of secrets. Psychopharmacology 236, 1411–1432. doi: 10.1007/ Johnson, D., Thurairajasingam, S., Letchumanan, V., Chan, K., and Lee, L. (2021).
s00213-019-5185-8 Exploring the role and potential of probiotics in the field of mental health: Major
depressive disorder. Nutrients 13:1728. doi: 10.3390/nu13051728
De Hert, M., Dobbelaere, M., Sheridan, E., Cohen, D., and Correll, C. (2011). Metabolic
and endocrine adverse effects of second-generation antipsychotics in children and Joyce, S., MacSharry, J., Casey, P., Kinsella, M., Murphy, E., Shanahan, F., et al. (2014).
adolescents: A systematic review of randomized, placebo controlled trials and guidelines Regulation of host weight gain and lipid metabolism by bacterial bile acid modification
for clinical practice. Eur. Psychiatry 26, 144–158. doi: 10.1016/j.eurpsy.2010.09.011 in the gut. Proc. Natl. Acad. Sci. U.S.A. 111, 7421–7426. doi: 10.1073/pnas.1323599111
Derogatis, L. R., and Savitz, K. L. (1999). “The SCL-90-R, brief symptom inventory, and Kay, S., Fiszbein, A., and Opler, L. (1987). The positive and negative syndrome
matching clinical rating scales,” in The use of psychological testing for treatment planning scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. doi: 10.1093/schbul/13.
and outcomes assessment, ed. M. E. Maruish (Mahwah, NJ: Lawrence Erlbaum Associates 2.261
Publishers), 679–724.
Kazemi, A., Noorbala, A., Azam, K., Eskandari, M., and Djafarian, K. (2019). Effect
Dickerson, F., Stallings, C., Origoni, A., Katsafanas, E., Savage, C., Schweinfurth, of probiotic and prebiotic vs placebo on psychological outcomes in patients with major
L., et al. (2014). Effect of probiotic supplementation on schizophrenia symptoms and depressive disorder: A randomized clinical trial. Clin. Nutr. 38, 522–528. doi: 10.1016/j.
association with gastrointestinal functioning: A randomized, placebo-controlled trial. clnu.2018.04.010
Prim. Care Companion CNS Disord. 16:26294. doi: 10.4088/PCC.13m01579
Korbee, C., Heemskerk, M., Kocev, D., van Strijen, E., Rabiee, O., Franken, K., et al.
Eskandarzadeh, S., Effatpanah, M., Khosravi-Darani, K., Askari, R., Hosseini, A., (2018). Combined chemical genetics and data-driven bioinformatics approach identifies
Reisian, M., et al. (2021). Efficacy of a multispecies probiotic as adjunctive therapy in receptor tyrosine kinase inhibitors as host-directed antimicrobials. Nat. Commun. 9:358.
generalized anxiety disorder: A double blind, randomized, placebo-controlled trial. Nutr. doi: 10.1038/s41467-017-02777-6
Neurosci. 24, 102–108. doi: 10.1080/1028415X.2019.1598669
Le Barz, M., Anhê, F., Varin, T., Desjardins, Y., Levy, E., Roy, D., et al. (2015). Probiotics
Evans-Lacko, S., Aguilar-Gaxiola, S., Al-Hamzawi, A., Alonso, J., Benjet, C., Bruffaerts, as complementary treatment for metabolic disorders. Diabetes Metab. J. 39, 291–303.
R., et al. (2018). Socio-economic variations in the mental health treatment gap for people doi: 10.4093/dmj.2015.39.4.291

Frontiers in Behavioral Neuroscience 09 frontiersin.org

Forth et al. 10.3389/fnbeh.2023.1111349

Leonard, B. (2010). “The concept of depression as a dysfunction of the immune Munoz-Bellido, J., Munoz-Criado, S., and Garcıa-Rodrıguez, J. (2000). Antimicrobial
system,” in Depression: From psychopathology to pharmacotherapy, Vol. 27, ed. J. F. Cryan activity of psychotropic drugs: Selective serotonin reuptake inhibitors. Int. J. Antimicrob.
(Basel: Karger Publishers), 53–71. doi: 10.1159/000319504 Agents 14, 177–180. doi: 10.1016/S0924-8579(99)00154-5
Li, J., Jia, H., Cai, X., Zhong, H., Feng, Q., Sunagawa, S., et al. (2014). An integrated Neufeld, K., Kang, N., Bienenstock, J., and Foster, J. (2011). Reduced anxiety-like
catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841. behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil.
doi: 10.1038/nbt.2942 23, 255–264, e119. doi: 10.1111/j.1365-2982.2010.01620.x
Liu, L., Huh, J., and Shah, K. (2022). Microbiota and the gut-brain-axis: Implications Nikolova, V., Hall, M., Hall, L., Cleare, A., Stone, J., and Young, A. (2021).
for new therapeutic design in the CNS. EBioMedicine 77:103908. doi: 10.1016/j.ebiom. Perturbations in gut microbiota composition in psychiatric disorders: A review and
2022.103908 meta-analysis. JAMA Psychiatry 78, 1343–1354. doi: 10.1001/jamapsychiatry.2021.2573
Lukić, I., Getselter, D., Ziv, O., Oron, O., Reuveni, E., Koren, O., et al. (2019). Ochoa, S., Usall, J., Cobo, J., Labad, X., and Kulkarni, J. (2012). Gender differences in
Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish schizophrenia and first-episode psychosis: A comprehensive literature review. Schizophr.
their effects on depressive-like behavior. Transl. Psychiatry 9:133. doi: 10.1038/s41398- Res. Treatment 2012:916198. doi: 10.1155/2012/916198
019-0466-x
Odamaki, T., Kato, K., Sugahara, H., Hashikura, N., Takahashi, S., Xiao, J., et al. (2016).
Maier, L., Pruteanu, M., Kuhn, M., Zeller, G., Telzerow, A., Anderson, E., et al. (2018). Age-related changes in gut microbiota composition from newborn to centenarian: A
Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628. cross-sectional study. BMC Microbiol. 16:90. doi: 10.1186/s12866-016-0708-5
doi: 10.1038/nature25979
Patel, K., Cherian, J., Gohil, K., and Atkinson, D. (2014). Schizophrenia: Overview and
Mandal, A., Sinha, C., Kumar Jena, A., Ghosh, S., and Samanta, A. (2010). An treatment options. Pharm. Ther. 39, 638–645.
Investigation on in vitro and in vivo antimicrobial properties of the antidepressant:
Rudzki, L., Ostrowska, L., Pawlak, D., Małus, A., Pawlak, K., Waszkiewicz, N., et al.
Amitriptyline hydrochloride. Braz. J. Microbiol. 41, 635–645. doi: 10.1590/S1517-
(2019). Probiotic Lactobacillus plantarum 299v decreases kynurenine concentration
83822010000300014
and improves cognitive functions in patients with major depression: A double-blind,
Martin, R., Makino, H., Cetinyurek Yavuz, A., Ben-Amor, K., Roelofs, M., Ishikawa, E., randomized, placebo controlled study. Psychoneuroendocrinology 100, 213–222. doi:
et al. (2016). Early-life events, including mode of delivery and type of feeding, siblings 10.1016/j.psyneuen.2018.10.010
and gender, shape the developing gut microbiota. PLoS One 11:e0158498. doi: 10.1371/
Sabic, D., Sabic, A., and Bacic-Becirovic, A. (2021). Major depressive disorder and
journal.pone.0158498
difference between genders. Mater. Sociomed. 33, 105–108. doi: 10.5455/msm.2021.33.
McGovern, A., Hamlin, A., and Winter, G. (2019). A review of the antimicrobial side 105-108
of antidepressants and its putative implications on the gut microbiome. Aust. N. Z. J.
Vesga-López, O., Schneier, F., Wang, S., Heimberg, R., Liu, S., Hasin, D., et al.
Psychiatry 53, 1151–1166. doi: 10.1177/0004867419877954
(2008). Gender differences in generalized anxiety disorder: Results from the national
Meyyappan, A., Forth, E., Wallace, C., and Milev, R. (2020). Effect of fecal microbiota epidemiologic survey on alcohol and related conditions (NESARC). J. Clin. Psychiatry
transplant on symptoms of psychiatric disorders: A systematic review. BMC Psychiatry 69, 1606–1616. doi: 10.4088/JCP.v69n1011
20:299. doi: 10.1186/s12888-020-02654-5
Yang, Y., Long, Y., Kang, D., Liu, C., Xiao, J., Wu, R., et al. (2021). Effect of
Miyaoka, T., Kanayama, M., Wake, R., Hashioka, S., Hayashida, M., Nagahama, M., Bifidobacterium on olanzapine-induced body weight and appetite changes in patients
et al. (2018). Clostridium butyricum MIYAIRI 588 as adjunctive therapy for treatment- with psychosis. Psychopharmacology 238, 2449–2457. doi: 10.1007/s00213-021-05866-z
resistant major depressive disorder: A prospective open-label trial. Clin. Neuropharmacol.
Yin, Y., Yu, Q., Fu, N., Liu, X., and Lu, F. (2010). Effects of four Bifidobacteria on
41, 151–155. doi: 10.1097/WNF.0000000000000299
obesity in high-fat diet induced rats. World J. Gastroenterol. 16, 3394–3401. doi: 10.3748/
Moher, D., Liberati, A., Tetzlaff, J., Altman, D., and Prisma Group. (2009). Preferred wjg.v16.i27.3394
reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann.
Yuan, X., Wang, Y., Li, X., Jiang, J., Kang, Y., Pang, L., et al. (2021). Gut microbial
Intern. Med. 151, 264–269. doi: 10.7326/0003-4819-151-4-200908180-00135
biomarkers for the treatment response in first-episode, drug-naïve schizophrenia:
Morais, L., Schreiber, H., and Mazmanian, S. (2021). The gut microbiota–brain axis A 24-week follow-up study. Transl. Psychiatry 11:422. doi: 10.1038/s41398-021-01
in behaviour and brain disorders. Nat. Rev. Microbiol. 19, 241–255. doi: 10.1038/s41579- 531-3
020-00460-0
Zhu, F., Guo, R., Wang, W., Ju, Y., Wang, Q., Ma, Q., et al. (2020). Transplantation
Morgan, A., Crowley, J., Nonneman, R., Quackenbush, C., Miller, C., Ryan, A., et al. of microbiota from drug-free patients with schizophrenia causes schizophrenia-like
(2014). The antipsychotic olanzapine interacts with the gut microbiome to cause weight abnormal behaviors and dysregulated kynurenine metabolism in mice. Mol. Psychiatry
gain in mouse. PLoS One 9:e115225. doi: 10.1371/journal.pone.0115225 25, 2905–2918. doi: 10.1038/s41380-019-0475-4

Frontiers in Behavioral Neuroscience 10 frontiersin.org