Microbiome-Gut-Brain Axis: Mounting Evidence in Psychiatry

In the Psychiatry MasterClass training programs, we teach the importance of the Gut-Brain Axis. In the literature, the emerging term is the Microbiome-Gut-Brain axis. The microbiome is a 4.4 pound organ in the body whose known functions are growing logarithmically. While we are beginning to appreciate the clinically importance of the microbiome, we are still waiting for direction about which probiotics in what doses. Nonetheless, I do recommend probiotics for my patients. I agree with the wisdom on the street that it makes sense to rotate organisms (i.e. finish one or two bottles of this and then one or two bottles of that, etc.). In this product category, it makes good sense to use professional brands. In a healthy person without a big antibiotic history who has a good diet, consumption of organic raw vegetables (probiotics live inside!) and fermented foods (found in nearly all indigenous diets) may be sufficient. However, our patients working through psychiatric syndromes, including Major Depressive Disorder (MDD), don’t fall into that group. I recommend maintenance probiotics for patients who are working on ongoing symptoms or maintaining a remission. I dose those with symptoms of inflammation, “pre-autoimmune” symptoms, irritable bowel syndrome, and metabolic syndrome at about 50 billion cfu per day. Otherwise, maintenance dosing is about 25 cfu daily. For those with autoimmune disorders or inflammatory bowel disease, dosing should be more aggressive (100 cfu daily or more). Here are five recent studies that illustrate recent advances.

Jutkiewicz. Gut Microbial Community and Behavioral Changes in a Chronic Mild Stress Model of Depression in Rats. J Neuropsychopharmacology. 2016;41, S1-S115.

Rats exposed to 7 weeks of chronic mild stress showed a decrease in microbiome diversity (a marker of gut health) and a subsequent increase in both sucrose drinking (a marker of anhedonia) and despair-like behavior in a forced swim test (phenotypic for depression in rats). When the stressed microbiome was transplanted into control mice, behaviors shifted toward the depression-like phenotype within 5 days. Transplantation of the control microbiome into the stressed rats did not reverse the behavioral changes.

Comments: Decreased microbiome diversity predated the development of behavioral changes in these stressed rats lending support to the hypothesis that stress may cause depression via the microbiome. Interestingly, the low diversity microbiome caused behavioral changes in control rats but the control microbiome did not reverse the behavioral changes in stressed rats. This could indicate that improving microbiome diversity is not sufficient to reverse the depressogenic effects of stress.

Cepeda et al. Microbiome-Gut-Brain Axis: Probiotics and Their Association With Depression. J Neuropsychopharmacology. 2016;41, S1-S115.

In a cross-sectional study of 18,019 subjects over 7 years, the 14% who had taken a probiotic on the interview day had a 42% (OR = 0.58) lower chance of scoring 10 or more on the PHQ (marker for depression). When data was corrected for “characteristics associated with depression and probiotic use,” the odds ratio increased to 0.82 which was still improved but no longer statistically significant.

Comments: Having taken a probiotic on just the day of the study is a low bar for gut health. Even so, the risk of depression is reduced in this population by that simple action.

Huang et al. Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2016; 8(8), 483.

This meta-analysis of five trials published 2011-15 (183 subjects and 182 controls), found that probiotics significantly decreased depression scale scores in both healthy and MDD subjects under the age of 65. The one study done in healthy patients over 65 found a non-significant benefit.

Comments: The majority of the subjects in this analysis were healthy (v. MDD). It is interesting to note that depression scores improve for both healthy and MDD subjects. This supports the idea that probiotics might be useful to prevent depression or to maintain remission. The only one of these 5 studies to look at probiotics in MDD was:

Akkasheh et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition. 2016; 32(3), 315-320.

40 adult patients with DSM-IV MDD received either a probiotic or placebo for 8 weeks. There was no difference in reported dietary intake between the two groups. After 8 weeks, Beck scores were down 5.7 for probiotic v. 1.5 for placebo (p=.001). Other positive changes in the probiotic group when compared with the placebo group were: reduced insulin, reduced hsCRP (C reactive protein), increased glutathione, and reduced HOMA-IR (a homeostasis model of insulin resistance).

Comments: This study out of Iran shows broad reaching benefits for the use of probiotics in Major Depression. Psychiatric symptoms, metabolic markers and anti-oxidant status are all improved. This is compelling evidence to include a probiotic in the treatment of every depressed patient.

Flowers. Interaction Between Atypical Antipsychotics and the Microbiome in a Bipolar Disease Cohort. J Neuropsychopharmacology. 2016;41, S1-S115.

This study examined the microbiome of 117 subjects (49 with bipolar disorder), 52 of whom received atypical antipsychotic medication. Microbiome species diversity, an indicator of gut health, was significantly reduced in women but not men who received atypical antipsychotics. The reduction in diversity was greater in the women (with bipolar on atypical) who gained weight compared with the women (with bipolar on atypical) who did not gain weight.

Comments: The mechanism by which atypical antipsychotics cause metabolic syndrome is unknown. Atypical antipsychotics have been found to gradually shift the composition of the microbiome. This study suggests that reduced microbiome diversity may be related to weight gain in women taking atypical antipsychotics. Atypicals are in widespread use in the US. Given the other benefits of probiotic supplementation, it would be a winning proposition to add probiotics for those taking atypical antipsychotics.