Gut Microbiota and SSRIs in Major Depression

CASE VIGNETTE

“Mr Richards” is a 55-year-old Caucasian male witha 20-year history of major depressive disorder (MDD), recurrent and severe with psychotic features. At his outpatient visits, his mood is chronically depressed, and he also has a chronic delusion that he suffers from gastrointestinal candidiasis. He takes a probiotic formulation that he orders online from an overseas supplier to treat the candidiasis. He frequently reports various gastrointestinal symptoms.

He is only partially adherent with his psychotropic medications and will often adjust the dose of or stop medications altogether without discussing it with his psychiatrist. He has reportedly failed 2 previous trials of selective serotonin reuptake inhibitors (SSRIs). He asks his psychiatrist about other probiotics he can take for his depression.

Many patients with MDD do not respond to treatment with SSRIs.¹ There is some evidence for alterations in gut microbiota between patients with depression and controls.^2,3 Furthermore, 1 study found that transplantation of the feces of patients with MDD into the gut of mice could induce depression-like behaviors.⁴

Outside of depression, gut microbiota can influence the effectiveness of medications via pharmacokinetic changes.⁵ There is some evidence in animal models that SSRIs can influence gut microbiota.^6,7

The Current Study

Gao and colleagues⁸ explored the association between the gut microbiome and response to SSRIs in patients with depression. They recruited 62 antidepressant-naïve patients aged 18 to 55 years with first-episode DSM-IV MDD. Participants were followed for 8 weeks of treatment with SSRIs. Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale (HAMD-17).

Study authors also recruited 41 matched healthy controls who had no history of mental disorders and a HAMD-17 score <8, and who were not currently being treated with antibiotics or probiotics. Exclusion criteria for all participants were acute or chronic diseases or infections, pregnancy or lactation, antibiotic or anti-inflammatory treatment in the past month, and history of digestive diseases.

Patients were treated with SSRIs including fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram. Response to SSRIS was defined as a ≥ 50% reduction in HAMD-17 score from baseline to week 8. Fecal samples were collected before SSRI treatment. Gut microbial communities were identified using a 16S ribosomal RNA gene sequence-based approach. Correlation coefficients were calculated for gut microbiome and clinical data. Binary logistic regression and ROC curves were used to analyze the response to SSRIs and related bacteria.

There were significant differences in the gut microbiome composition between SSRI responders, non-responders, and controls in the α-diversity analysis.

The relative abundance of 12 genera (Bacteroides, Roseburia, Faecalibacterium, Dialister, Megasphaera, Ruminococcus, Phascolarctobacterium, Parabacteroides, Oscillospira, Sutterella, Lachnospira, and Haemophilus) were increased in the control group; 5 genera (Blautia, Bifidobacterium, Coprococcus, Collinsella, and Dorea) were increased in SSRI responders; and 2 genera (Megamonas and ph2) were higher in the SSRI non-responders.

Regarding β-diversity, there was a significant difference in the gut microbial community between SSRI responders—but not SSRI non-responders—and controls. Three genera (Blautia, Bifidobacterium, and Coprococcus) were significantly correlated with the reduction in HAMD-17 scores. After controlling for age, sex, and education, the area under the ROC curve for SSRI response based on these genera was 0.93, with a sensitivity of 0.88 and a specificity of 0.92.

Study Conclusions

The authors concluded gut microbiota—specifically the presence of the genera Blautia, Bifidobacterium, and Coprococcus—was associated with increased response to SSRIs in MDD. These 3 bacterial groups are related to the production of short-chain fatty acids.⁹

Study strengths include that participants were experiencing their first episode of depression and were antidepressant naïve. Study limitations include the modest sample size and absence of a placebo group. The authors also did not control for dietary habits, which could influence the gut microbiome.

The Bottom Line

The diversity of the gut microbiome and the relative abundance of Blautia, Coprococcus, and Bifidobacterium are potential biomarkers of response to SSRIs in patients with MDD.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Zhao B, Li Z, Wang Y, et al. Manual or electroacupuncture as an add-on therapy to SSRIs for depression: a randomized controlled trial. J Psychiatr Res. 2019;114:24-33.

2. Chen Z, Li J, Gui S, et al. Comparative metaproteomics analysis shows altered fecal microbiota signatures in patients with major depressive disorder. Neuroreport. 2018;29(5):417-425.

3. Jiang H, Ling Z, Zhang Y, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015;48:186-194.

4. Kelly JR, Borre Y, O' Brien C, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016;82:109-118.

5. Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut. 2020;69(8):1510-1519.

6. Ramsteijn AS, Jašarević E, Houwing DJ, et al. Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression. Gut Microbes. 2020;11(4):735-753. doi:10.1080/19490976.2019.1705728

7. Lukić I, Getselter D, Ziv O, et al. Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior. Transl Psychiatry. 2019;9(1):133.

8. Gao M, Tu H, Liu P, et al. Association analysis of gut microbiota and efficacy of SSRIs antidepressants in patients with major depressive disorder [published online ahead of print, 2023 Mar 3]. J Affect Disord. 2023;330:40-47.

9. Sorbara MT, Littmann ER, Fontana E, et al. Functional and genomic variation between human-derived isolates of Lachnospiraceae reveals inter- and intra-species diversity. Cell Host Microbe. 2020;28(1):134-146.e4.