Review articlePrebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials
Introduction
Depression and anxiety disorders are the two most common mental health conditions, with lifetime prevalence rates in the U.S. of 16.6% and 28.8%, respectively (Kessler et al., 2005). The societal and personal costs of these conditions are considerable. In terms of years living with disability in the U.S., these two disorders rank second and fifth, respectively, out of all mental and physical health conditions (US Burden of Disease Collaborators, 2013). Consistent with these findings, depression and anxiety are also the top two mental health conditions in terms of personal health care expenditures, with $71.1 billion spent annually in the U.S. to treat depression and $29.7 billion anxiety disorders (Dieleman et al., 2016). Furthermore, the burden of these disorders is increasing (Vos et al., 2016).
The development of novel therapeutic modalities is needed to reduce the burden of these conditions. Of several possibilities that have garnered substantial interest of late, prebiotics (i.e., chemical compounds that yield health benefits through their influence on the host gut microbiome) and probiotics (i.e., microorganisms that contribute to the host gut microbial flora when consumed, and thereby produce beneficial effects on health) hold particular appeal, in part, for being potentially free of cognitive side effects and the addictive properties of several currently available treatments for these disorders (Liu, 2017). Although the first study to evaluate the therapeutic efficacy of prebiotics or probiotics on depression or anxiety was conducted over a decade ago (Marcos et al., 2004), approximately half of all existing studies were published in the last two years alone, reflecting the rapidly growing interest in this area.
Also reflective of this burgeoning interest, there have been several recent systematic reviews of probiotics in this area (Huang et al., 2016, Liu et al., 2018, Ng et al., 2018, Pirbaglou et al., 2016, Reis et al., 2018, Wallace and Milev, 2017), including two meta-analyses of depression (Huang et al., 2016, Ng et al., 2018) and anxiety (Liu et al., 2018, Reis et al., 2018), respectively. Although these prior reviews are important for providing the first syntheses of the empirical literature in this area, they are also characterized by several notable limitations. In particular, the two aforementioned meta-analyses of probiotics and depression each included a very small number of studies (ks = 4 and 9 for studies meeting the eligibility criteria of the current review), precluding any analyses of publication bias and moderating effects to account for between-study heterogeneity in effect sizes. These meta-analyses also included a study that combined anxiety and depression as a single outcome in their analyses (Mohammadi et al., 2016) which when considered within the context of the small number of studies included in each review and important etiological distinctions between these outcomes (Clark and Watson, 1991), complicates interpretations regarding the effect of probiotics specifically in relation to depression. Additionally, and perhaps in some measure a function of the number of studies included in each, these meta-analyses yielded contradictory findings, with one finding support for an ameliorative effect of probiotics (Huang et al., 2016) and the other reporting no such effect overall (Ng et al., 2018).
Interpretation of the findings of the recent meta-analyses of probiotics and anxiety is also complicated by certain methodological concerns. In particular, over half of the effects included in one of these meta-analyses (Reis et al., 2018) were based on non-independent samples. The other meta-analysis (Liu et al., 2018) included several studies of outcomes other than anxiety as typically conceptualized (e.g., visceral sensitivity; Lorenzo-Zúñiga et al., 2014), and 42% of studies did not meet the eligibility criteria of the current review. Altogether, these meta-analyses included 7 and 11 trials eligible for inclusion in this review.
Addressing these considerations, we conducted a systematic meta-analytic review of controlled clinical trials evaluating the efficacy of prebiotics and probiotics for treating depression and anxiety. With 28 studies, including 18 with 19 unique effects for probiotics for depression and anxiety, the current review builds substantially upon the aforementioned meta-analyses. Additionally, the current review presents preliminary meta-analyses of prebiotics in relation to depression and anxiety, respectively.
Section snippets
Search strategy and eligibility criteria
A systematic search of the literature was conducted in Embase, MEDLINE, and PsycINFO to identify studies relevant to the current review. The following search string was applied: (“leaky gut” OR dysbiosis OR metagenom* OR microbiome* OR microbiota OR prebiotic* OR probiotic* OR “bacterial translocation” OR “colon flora” OR “fecal flora” OR “gut flora” OR “intestinal flora” OR “enteric bacteria” OR “fecal bacteria” OR “gut bacteria” OR “intestinal bacteria” OR “fecal microflora” OR “gut
Results
Of the 1475 unique records identified, 1230 reports were excluded based on their titles and abstracts. An additional 211 articles were excluded based on a detailed full-text review. Whenever it remained unclear after full-text inspection whether two studies reported on overlapping samples, the study authors were contacted to seek clarity on this issue. In one case where multiple studies featured overlapping samples, preference was given to the study that assessed the outcome of interest at the
Discussion
The current review provided the most comprehensive meta-analysis to date of the effects of probiotics on depression and anxiety. We also conducted the first quantitative syntheses of data on prebiotics for depression and anxiety. Although the current review did not find an ameliorative effect for prebiotics on depression or anxiety, respectively, these findings should be regarded as preliminary, given the relatively small number of eligible studies included in the analyses. We did find general
Acknowledgments
Preparation of this manuscript was supported in part by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH101138, R01MH115905, and R21MH112055, and the Brown Institute for Brain Science/Norman Prince Neurosciences Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
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