Introduction

Depression is a common mental health problem all over the world, and approximately 280 million people suffer from depression.¹ Depression is often treated with antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs).¹ If a depressed person does not respond to two of these antidepressants, their depression is considered treatment resistant. ² The hallucinogen ketamine is usually more effective in treating treatment-resistant depression.² Additionally, ketamine exerts its antidepressant effects faster than SSRIs and TCAs.²

In recent years, there has been a growing interest in the interplay between antidepressants and the gut microbiome.^{4,5,6,7,8,9,10,11} The gut microbiome is the collection of trillions of micro-organisms living inside the gut. There is increasing amounts of evidence that gut dysbiosis, the disturbance of the gut microbiome, plays a role in depression.³ Understanding whether the microbiome has a role in the efficacy of antidepressants and if antidepressants can modulate the microbiome, is important because it could help in offering more personalized treatment for depression. The treatment options could include selecting an antidepressant based on the gut microbiome of the patient or treating a patient by modulating the microbiome with probiotics. This review aims to look at what the research says about how different antidepressants (SSRIs, SNRIs, TCAs, and ketamine) affect the gut microbiome, as well as whether the microbiome can affect the efficacy of those antidepressants.

Altered gut microbiome in depression

There are evidence that the gut microbiome is altered in depression.^13,14 One large cohort study looked at how the gut microbiome correlates with quality of life and depression.¹³ They found that genera Dialister and Coprococcus were depleted in depression.¹³ Another study also found lower levels of Dialister in depressed patients, along with lower levels of Prevotella.¹⁴ Several genera was also increased in depression.¹⁴ Additionally, they used fecal transplant from depressed patients to transfer the gut microbiomes from human to microbiota-deficient rats.¹⁴ This led to depressive symptoms in rats, which did not occur with fecal transplants from healthy controls.¹⁴

 Even though it is suggested that there are alterations in the gut microbiome in depressed human patients, there is not much consensus on how the microbiome is altered.¹² In a recent systematic review on the topic, the most consistent findings included decreased levels of Prevotellaceae, Faecalibacterium, Coprococcus, and Sutterella, and increased levels of Eggerthella in depressed individuals.¹² However, many of the studies included in that review failed to find any differences in these genera.¹² Also, one problem is that many of the studies included in that review did not consider the effect of the antidepressants on the microbiome¹², which can, as can be seen in the rest of this paper, affect the microbiome composition. Also, other confounding factors, such as diet, and sex of the study participants might not be considered in the studies included in that systematic review.¹²

Even among the studies that compared drug-naïve depressed patients’ microbiome to those of healthy controls’, there were differences in the microbiome compositions between the studies.^15,16,17 Dong et al. (2021) found that at phylum level, in patients with major depressive disorder (MDD), Proteobacteria and Firmicutes were increased, while Bacteroidetes were decreased.¹⁵ On the other hand, Ye et al. (2021) found that in MDD patients Proteobacteria and Bacteroidetes were increased, and Firmicutes were decreased.¹⁶ However, Ye et al. (2021) do note that their healthy controls had a slightly higher BMI, which can lower the Bacteroidetes levels.¹⁶ Furthermore, Chen et al. (2018) looked at the sex differences in first-episode drug-naïve MDD patients, and did not find any differences in the Firmicutes levels in either of the sexes, while Actinobacteria were increased in female patients, and Bacteroidetes were decreased in male patients.¹⁷ Therefore, while there is evidence that the gut microbiome is altered in depression, it is hard to pinpoint specific changes in the microbiome linked to depression.

SSRIs and TCAs can modulate the gut microbiome, and the gut and its microbes can influence the efficacy of the drugs

As mentioned above, antidepressants can affect the gut microbiome. In vitro, several antidepressants inhibited the growth of gut commensal bacteria.⁴ When it comes to in vivo studies, one study tested five different antidepressants’ (two SSRIs, two SNRIs, and one norepinephrine reuptake inhibitor) effect on the gut microbiome in mouse model of depression.⁷ It was found that the SSRIs and the SNRIs reduced the abundance of bacterial genera Ruminococcus and Adlercreutzia.⁷ When the mice were treated with one of the antidepressants, duloxetine (SNRI) and supplemented with either Ruminococcus flavefaciens or Adlercreutzia equolifaciens,⁷ R. flavefaciens, but not A. equolifaciens, was able to abolish the antidepressant effects of the drug. This result suggests that a single species of bacteria can affect the efficacy of an antidepressant.⁷

Two other studies found that antidepressants modulate the gut microbiome in a way that after the treatment it resembled the gut microbiome of the healthy controls, both in humans and in rats.^9,11 In a study using a chronic unpredictable mild stress (CUMS) paradigm in rats, research found that the CUMS rats had a gut bacteria composition that differed compared to healthy controls.¹¹ After fluoxetine (SSRI) and amitriptyline (TCA) treatments, the gut microbiome of the CUMS rats resembled the microbiome of the healthy controls.¹¹ In addition, the antidepressant treatments reduced the depressive symptoms in the CUMS rats.¹¹ Also, in humans treated with the SSRI escitalopram, the gut microbiome composition changed in a way that it was more similar to the healthy controls, than before the treatment.⁹

Escitalopram treatment also alters the microbiome composition in CUMS mice, and mice that responded (R) to the treatment had differences in their microbiome composition compared to the non-respondent (NR) group of mice.⁶ The R group had lower levels of families Eggerthellacaea and Lactobacillacaea compared to the NR group.⁶ Interestingly, genus Lactobacillus from the Lactobacillacaea family, which are usually considered to be beneficial bacteria, was also decreased in the R group.⁶ The NR group had higher levels of the family Ruminococcaecae.⁶

To further highlight the role of the gut in the efficacy of the antidepressant treatment, vagotomy can remove the effects of an SSRI.⁸ Vagus nerve is the main pathway from the gut to the brain, and it is an important part of the gut-brain axis. Vagotomy was performed to mice, and then they were given orally either sertraline (SSRI), fluoxetine (SSRI) or bupropion (atypical antidepressant, norepinephrine dopamine reuptake inhibitor).⁸ The vagotomy inhibited the effects of the both SSRIs compared to mice that did not undergo any surgery, or that did undergo a sham surgery.⁸ The vagotomy did not prevent the bupropion for exerting its antidepressant effects.⁸ This indicates that the SSRIs work through the gut to exert their effects.⁸

Ketamine’s, and its different enantiomers’, effect on the microbiome

Like the more conventional antidepressants, ketamine can also alter the gut microbiome in animals.^5,10,18 There are two different enantiomers of ketamine, (R) and (S), but the (R)-ketamine is more potent antidepressant with longer-lasting antidepressant effects in mice.¹⁰ (R)-ketamine increased the levels of genera Lactobacillus, Sarcina, and Turicibacter, while decreasing the levels of Mucispirillium, and Ruminococcus in Wistar rats.⁵ Also, in a study using social defeat stress (CSDS) paradigm in mice it was found that R-ketamine reduced the increased levels of some bacteria.¹⁸ At the family level R-ketamine attenuated the increased levels of Rumicoccaceae and Mogibacteriaceae in susceptible mice. ¹⁸ In addition, (R)-ketamine attenuated the increased levels of genus Clostridium in susceptible mice.¹⁸

Conclusion

While there is contradicting evidence about the changes in the gut microbiome in depression, there is evidence that antidepressants can alter the microbiome composition. However, most of the studies on the antidepressants’ effects were tested on animals, therefore there is a need for similar studies in humans. The genus Ruminococcus belongs to a family Ruminococcaceae. Two of the animal studies found that antidepressants lowered the genus Ruminococcus.^5,7 None of the studies performed in humans reported changes in that genus, but there were changes at the family level in Rumibococcaceae.^16,17 Interestingly, Ruminococcaceae was either decreased¹⁶, or both increased and decreased¹⁷ in MDD patients. Given that in mice, one species of Ruminococcus was able to abolish the antidepressant effects of an SNRI, the role of Ruminococcus in depression warrants further research. It would be interesting to see whether R. flavefaciens could abolish the effects of other antidepressants besides duloxetine, and whether the genus Ruminococcus plays a role in depression in humans.

There does not seem to be a lot of research on ketamine’s effects on the gut microbiome. Those studies that could be found, were done in animals^5,10,18, and in one of those the animals were just normal Wistar rats instead of being an animal model of depression.⁵ It is still interesting to note that ketamine rapidly altered the microbiome, its effects could be seen in 3-4 days.^5,8,10 Since ketamine can be more effective in treating treatment-resistant depression, it would be important to further study its effects on the microbiome, especially since ketamine can increase the levels of Lactobacillus and decrease the levels of Ruminococcus.⁵ As mentioned, the bacteria in the genus Lactobacillus are usually considered beneficial, and species of Lactobacillus can even improve the mood in human,¹⁹ and reduce depressive-like behavior in rats.²⁰ However, escitalopram treatment decreased the Lactobacillus levels in the R group of mice,⁶ which could either indicate that too much Lactobacilli has a negative effect, or that it might not have that big of a role in depressive symptoms. Even though studies done in humans have shown that probiotics, including ones belonging to the genus Lactobacillus, can improve depressive symptoms,²¹ perhaps lowering the levels don’t have a negative effect on these symptoms.

Overall, antidepressants can alter the gut microbiome, and it seems that some genera of bacteria might affect the efficacy of antidepressants. Nonetheless, there are still a lot of unknowns, such as can R. flavefaciens lower the efficacy of other antidepressants than duloxetine, and what is the role of the genus Lactobacillus in depression. Also, all the animal studies were conducted on male animals, and only one human study looked at the sex differences in the gut microbiome in MDD patients, highlighting the need for more studies considering the sex differences.

[+] References

[+] Other Work By Meri Kokki