Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness
Introduction
Major depressive disorder (MDD) is a common and recurrent psychiatric illness associated with significant morbidity and social burden (Nemeroff, 2007). In 2010, the Global Burden Study (GBD) considered MDD the 19th most prevalent disease in the world and the second leading cause of disability (Ferrari et al., 2013, Vos et al., 2012). The major consequence of MDD is suicide, a public-health problem (Jenkins, 2002). Also, depression has been associated with increased risk of severe chronic diseases, such as atherosclerotic heart disease and stroke (Clarke and Currie, 2009). Therefore, these findings emphasize the relevance of depression as a public-health problem and the implementation of effective interventions to reduce its burden.
The first drug used for depression treatment was iproniazid in the 1950s. The choice of this drug was based on its euphoric effects in tuberculosis patients (López-Muñoz and Alamo, 2009). At that moment, the discovery of iproniazid antidepressant effects was especially important because it could relegate Ugo Cerletti's electroconvulsive therapy, the only antidepressant treatment available with significant rates of effectiveness, but used only in highly specific cases (López-Muñoz and Alamo, 2009). Subsequently, it was demonstrated that iproniazid was a monoamine-oxidase (MAO) inhibitor, particularly MAO-A. The role of MAO-A is to convert biogenic (e.g. serotonin and catecholamines) and sympathomimetic (e.g. tyramine and benzylamine) amines into deaminated products (Johnston, 1968). This discovery led to the development of the first class of antidepressants, the MAO inhibitors (MAOIs). Examples of this class include tranylcypromine and phenelzine. Subsequently, the prototype antidepressant molecule, desmethylimipramine, was developed (Ban and Lehmann, 1962). The development of imipramine gave rise to the tricyclic antidepressants (TCAs), a class of drugs whose mechanism of action involves the inhibition of noradrenaline and serotonin reuptake by neurons (Raisman et al., 1979). Later on, the monoamine serotonin was related to the pathophysiology of depression (Lapin and Oxenkrug, 1969). Based on this discovery, the first family of psychoactive drugs with a rational design, the serotonin-specific re-uptake inhibitors (SSRIs) was developed (Altamura et al., 1988). Fluoxetine was thus the first SSRI synthesized, quickly becoming one of the most prescribed antidepressants in the world (Altamura et al., 1988, López-Muñoz and Alamo, 2009). Therefore, thanks to the discovery and subsequent therapeutic use of TCAs and MAOIs, in the 1960s, the monoaminergic theories of depression were developed (López-Muñoz and Alamo, 2009).
Despite the development of different classes of antidepressant drugs, still today delayed onset of action and high rates of drug resistance are the major limitations of antidepressant therapy. These limitations may possibly be related to other mechanisms, than monoamines deficiency, involved in the pathophysiology of depression. Vis-a-vis, oxidative/nitrosative stress, neuroinflammation, hypothalamic-pituitary-adrenal (HPA) axis, neurogenesis/neurotrophins and ion channels have been important approaches for research in this field (Bakunina et al., 2015, Castrén and Rantamäki, 2010, Iijima et al., 2010, Maes, 2011, Moylan et al., 2014). More recently, on the basis of the important evidences about the role of gut microbiota in the regulation of behavior and in the pathophysiology of several mental disorders, among them depression, the gut-brain axis and its regulation has been subject of many studies (Foster and McVey Neufeld, 2013).
Dysbiosis refers to an altered balance of the gut microbiota. Indeed, dysbiosis is characterized by decreases in commensal bacteria, most notably the phyla Bacteroidetes and Firmicutes, including the clinically relevant Faecalibacterium prausnitzii and increases in adherent/invasive Escherichia coli (Jones et al., 2014). This gut microbiota imbalance is also observed in patients suffering from intestinal and extra-intestinal disorders, i.e. allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity (Carding et al., 2015). Interestingly, both intestinal and extra-intestinal disorders are comorbidities of MDD (Filipovic and Filipovic, 2014, Mayer et al., 2001).
Based on iproniazid antidepressant effects, it is not surprisingly that, at present, drugs belonging to new classes of antidepressants still have antimicrobial effects. In this regard, the antimicrobial effects of antidepressants range from weak to strong depending on the drug (Munoz-Bellido et al., 2000a). For instance, several new antidepressant drugs such as sertraline, fluoxetine, escitalopram and older drugs such as tranylcypromine and imipramine present antimicrobial effects (Lieb, 2004, Munoz-Bellido et al., 2000a). Conversely, β-lactams and tetracyclines also have potential antidepressant properties (Mello et al., 2013, Miyaoka et al., 2012). However, some antimicrobials, such as fluoroquinolones, have also been associated with neuropsychiatric adverse events and mood dysregulation, including depression (Ahmed et al., 2011, Grassi et al., 2001), manic (Bhalerao et al., 2006) and anxiety disorders (Kaur et al., 2016, Rollof and Vinge, 1993).
Thus, in the light of: i) the involvement of dysbiosis in depression and its comorbidities, ii) the antimicrobial effect of some antidepressant drugs and iii) the evidences for antidepressant effect of some antimicrobial agents; this review aims to compile the studies regarding the influences of gut microbiota in behavior and depression as well as to give evidences of antimicrobial effect of antidepressant drugs. We aim to further discuss the possible contribution of the antimicrobial effect of antidepressant drugs to its effectiveness/resistance.
Section snippets
Methods
For this narrative review, articles published in English from November 1984 to February 2016 were searched in relevant web datasets (PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge). Search terms included combinations of the following: “MDD and gut microbiota”; “MDD and dysbiosis”; “behavior and germ-free animals”; “behavior and gut microbiota”; “antimicrobials and antidepressant activity”; “antidepressants and antimicrobial activity”. Two authors (AJMCF and DM) performed independent
Gut microbiota composition
The human gut contains a complex ecosystem, called intestinal microflora, consisting of a wide range of bacteria (Gerritsen et al., 2011). Studies have estimated that the intestinal microflora has at least 1800 bacterial genera and over 40,000 species of these microorganisms, which together possess about 100 times more genes than the human genome (Forsythe et al., 2010). Recently, the structure of the microbial flora has been better elucidated. Despite the presence of many phyla of bacteria in
Antidepressant agents with antimicrobial effect
As previously mentioned, since its historical origin antidepressant drugs present antimicrobial effects (Chessin et al., 1957, Kristiansen, 1990; Munoz-Bellido et al., 2000b; Lieb, 2004). Currently, the treatment of depression by antidepressants is associated with mechanism unrelated to the antimicrobial effect of these drugs.
In this context, iproniazid shares similar properties with isoniazid. The mechanism of isoniazid bactericidal activity is through formation of isonicotinoyl radicals.
Antimicrobial agents with antidepressant effects
In recent years antimicrobial compounds were studied for their neuroprotective properties and for their potential as psychotropic medications (Obregon et al., 2012). In this regard drugs like β-lactam antibiotics, for instance, ceftriaxone, were found to promote the expression of the glutamate transporter GLT1, thus presenting neuroprotective properties in animal models of depression (Mineur et al., 2007). Indeed, glutamatergic transmission has emerged as a potential therapeutic target for the
Discussion
As previously mentioned, studies have associated dysbiosis, increased gut permeability and bacterial translocation with the pathophysiology of MDD (Dinan and Cryan, 2013, Jiang et al., 2015, Maes et al., 2012). Conversely, these alterations are also observed in extra-intestinal and intestinal comorbidities of MDD, for instance, irritable bowel syndrome (Carding et al., 2015, Fadgyas-Stanculete et al., 2014). Intestinal microbial dysbiosis observed in depressed patients is associated with
Conclusion and future directions
Both antidepressants and antimicrobials present neuroprotective/antidepressant and antimicrobial effects. One proposition of this review is that the antimicrobial effect of antidepressants could be important for the correction of intestinal dysbiosis observed in MDD patients, restoring then the balance of gut microbiota. Contrary to this idea, the chronic use of drugs presenting antimicrobial effects may be related to the development of adaptive alterations in gut microbiota, which effects
Authors contributions
AJMCF, DFL and DM performed the articles search. AJMCF wrote the first draft. DFL and DM wrote the final version of the review. CNS, JQ, HVNJ and TB designed the tables and figure and revised the final version of the manuscript.
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These authors contributed equally and should be considered co-first authors.