Probiotics for mania

​A recent article found that taking probiotics led to a significant decrease in rehospitalization in patients who had severe manic disorder (see mania probiotics nutrition2018​ in dropbox, or DOI: 10.1111/bdi.12652).

Details:

-- 66 patients hospitalized for mania were randomized after discharge to a 24-week course of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) vs placebo.

-- Mean age 35, 65% female, 75% white/15% African-American, 40% current cigarette smokers, BMI 30, DSM-IV diagnosis: bipolar 1 manic (63%)/bipolar 1 mixed (15%)/schizoaffective disorder bipolar type 2 (2%), medications: typical antipsychotic 20%/atypical antipsychotic 80%/mood stabilizer 65%/lithium 35%/antidepressant 30%

-- BPRS (Brief Psychiatric Rating Scale): 45; YMRS (Young Mania Rating Scale): 13; MADRS (Montgomery-Asberg Depression Rating Scale): 13; RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) cognitive score: 71

-- Inflammation Score 1.2 (seems that 1.0 is the normal control. from the article noted below: the 75th percentile of their composite inflammation score in those with bipolar depression was 1.0, those admitted with mania was about 2.8, those 6-months post-admission with mania was about 2.0)

Results:

-- re-hospitalizations during the 24 week observation:

    -- Probiotic group had 8 rehospitalizations in the 33 individuals (24%) vs 24 on placebo (73%), p=0.009, adjusted for age, gender, race, and multiple hospitalizations for an individual.

        -- probiotics were associated with a significantly prolonged time to psychiatric rehospitalizations, HR 0.26, p=0.007.

    -- Probiotics led to fewer days rehospitalized (8.3 vs 2.8 days, p=0.017). Total days in the hospital were 275 vs 93 days

-- there was a significant trend, almost statistically significant, between a composite of the inflammation score at baseline and the risk of hospitalization (p=0.0596).

-- however, those individuals with higher levels of inflammation had pretty striking decreased likelihood of rehospitalization when on probiotics: those with scores greater than 50th percentile of the control group had hazard ratio of repeat psychiatric hospitalization of 0.09 (0.01-0.66), p= 0.017, adjusted for age, gender, race, and multiple episodes per individual.

-- Analysis of the curves of the cumulative hazard of rehospitalization show increasingly diverging curves over time, reflecting increasing benefit with probiotics

-- There was no significant difference comparing the probiotic and placebo groups in 2 of the psychiatric measures (BPRS, YMRS), which improve significantly over the course of the trial for all patients.

-- No significant adverse effects

Commentary:

-- patients with mania are at high risk of rehospitalization after hospital discharge, despite evidence-based treatment

-- mania as well as bipolar disorders may be associated with immunologic changes, including increased levels of inflammation. Some specific antigens include the NR2 peptide of the NMDA receptor, wheat gliadin, the Mason-Pfizer monkey virus protein p24, and the protozoan Toxoplasma gondii (These researchers created a combined marker of inflammation for people with mania based on these items, and was the inflammation score used above. Not sure why they focused on these. for their prior data see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760815/). Other studies have found higher concentrations of IL-6, interferon gamma, TNF-a, IL-2, soluble IL-6 receptor, and soluble TNF receptor 1. 

-- Several studies have shown that probiotic microorganisms, especially Lactobacillus and Bifidobacterium, modulate the inflammatory and immune responses. (see http://gmodestmedblogs.blogspot.com/search?q=bifidobacteria  for an array of articles showing the immunologic and anti-inflammatory clinical effects of these probiotics. There also seems to be a gut-brain axis, where intestinal bacteria secrete neuro-active chemicals (eg: neurotransmitters) that can affect brain function and that can modulate CNS inflammation (see Dickerson F. Brain Behav Immun 2016; 176: 566).

-- unfortunately, few adults living in the US have microbiomes where Lactobacillus or Bifidobacterium predominate

-- of note, in the above study, though there was a pretty striking decrease in rehospitalizations for mania in those on probiotics, there was not much difference in the psychiatric measurements performed (though these tended to improve equally in all patients). not sure what that means

-- also, the preparation of probiotics used in the study are not available in the US, though other products containing these specific microorganisms are. And there are concerns about actual quantity and viability of the microorganisms in different preparations.

-- Another interesting article found that probiotics helped patients with major depressive disorder (see depression probiotics nutrition2106​ in dropbox, or Akkasheh G. Nutrition 2016; 32: 315). This was a short-term study with only 40 patients who had MDD based on DSM-IV criteria, but still found that probiotics supplementation with Lactobacillus and Bifidobacterium vs placebo resulted in significantly decreased Beck Depression Inventory scores (-5.7 vs -1.5), decreased serum insulin levels (-2.3 vs 2.6 mIU), improved homeostatic model assessment of insulin resistance (-0.6 vs 0.6) and decreased hs-CRP concentrations (-1138.7 vs 188.4 ng/mL). All results statistically significant. No difference in diets.The results of the depression study is not so surprising, given that depression historically has been related to systemic inflammation (as are the markers for diabetes/metabolic syndrome as found here). And it is clear from many studies of the microbiome, that Lactobacillus and  Bifidobacterium tend to decrease inflammation and the innate immune response​. It seems that the composite inflammatory index used in the above study was not increased in those with depression or bipolar depression. my guess is that their composite does not necessarily correlate with the effect of inflammation on the usual inflammatory markers (CRP, etc, as noted)

--and, another article noted an array of inflammatory/immunological markers that were increased in those with chronic schizophrenia, though (for unclear reasons) those with new onset psychosis seem to have a reduction in the inflammatory score (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681560/ , for example. they looked at a different set of inflammatory markers, which included CRP levels but also IgG antibodies to gliadin as above and some others)

so, no doubt there are multiple reasons that people have these psychiatric conditions, but these articles above suggest that inflammation may play a significant role in at least some people.  it is notable that those with mania and more inflammation had a more dramatic response to probiotics (and the probable attendant anti-inflammatory changes in their microbiomes. they actually did not assess the microbiome changes directly, but other studies do show probiotics effectively change the microbiome).

--especially in patients with severe mania on psych meds, it seems reasonable to focus on improving the health of the microbiome, which may well include using probiotics as above, but also the usual suspects: encouraging a largely vegetarian diet (and avoiding red meat in particular), exercise, adequate sleep, minimizing stress, and avoiding unnecessary antibiotics/decreasing the use of broader-spectrum ones (eg, see http://gmodestmedblogs.blogspot.com/search?q=antibiotics​ ).