Over the past decade there has been huge interest in the role of the microbiome-gut-brain axis in brain function and mental health (as covered in these previous Mental Elf blogs: Murray, 2024; Clarke, 2023). In particular, there is hope that microbiome-based treatments may offer a new approach to mental illness.
Bipolar disorder (BD) and schizophrenia spectrum disorder (SSD) are complex conditions. Many patients do not respond, or only partially respond, to first line pharmacological treatments that include antipsychotics and mood stabilisers (Köhler-Forsberg et al., 2021; Potkin et al., 2020). Additionally, these medications are often associated with significant side effects that can limit their usefulness for some patients.
Microbiome-based interventions such as probiotics may offer a new therapeutic paradigm for managing BD and SSD. Whilst underlying mechanisms are still being uncovered, probiotics can impact a variety of gut-brain pathways including gut permeability, inflammation, stress responsivity, short-chain fatty acid production, neurotransmitter and tryptophan metabolism (Butler et al., 2019). This study by Borkent et al. (2024) investigates the impact of a 12-week intervention with a multispecies probiotic on psychiatric symptoms and cognition in bipolar disorder (BD) and schizophrenia spectrum disorder (SSD).
Microbiome-based interventions such as probiotics may offer a new therapeutic approach for mental illnesses such as bipolar disorder and schizophrenia spectrum disorder.
Methods
This study was a double-blind, randomised, placebo-controlled, mono-centre trial in which 131 patients with BD or SSD (including diagnoses of schizophrenia, schizoaffective, schizophreniform disorder or psychotic disorder-NOS) were randomised 1:1 to receive either a multispecies probiotic (Ecologic BARRIER) (n=67) or a placebo (n=64) for 12 weeks in addition to treatment-as-usual.
The probiotic contained 9 bacterial strains (Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19, and Lactococcus lactis W58) which were selected based on their in vitro capacities to positively influence one or more parameters of intestinal barrier function (Hemert & Ormel, 2014). This multispecies probiotic had also demonstrated the ability to reduce cognitive reactivity to sad mood in healthy volunteers (Steenbergen et al., 2015). The placebo contained all components of the probiotic formulation except the bacteria, including maize starch and maltodextrin.
The primary outcomes were symptom severity assessed by the Brief Psychiatric Rating Scale (BPRS) and cognitive functioning measured by the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcomes included intestinal permeability (as measured by serum zonulin, serum lipopolysaccharide binding protein (LBP), serum sCD14, faecal zonulin, faecal alpha-1 antitrypsin and faecal calprotectin), blood inflammatory markers (CRP, S100B, interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα)), gastro-intestinal complaints and fatigue. Authors also conducted a sex-specific analysis of all outcomes as a tertiary objective.
Results
Primary outcomes
- There was no significant effect of probiotics on psychiatric symptoms (as measured by the BPRS).
- Regarding cognition (as measured by the BACS), a borderline improvement in verbal memory was noted in the probiotic group (linear mixed models (LMM) = 0.33; adjusted P= .059).
- An exploratory investigation of the impact of the probiotic on psychiatric symptoms in those with more severe psychiatric symptoms (≥median) revealed no significant changes in this subgroup either.
- No significant sex-specific effects were seen for psychiatric or cognitive changes.
Intestinal permeability
- Serum markers: A significant decrease in serum zonulin was evident in the probiotic group (LMM = −18.40; adjusted P = .002). No impact was seen on serum LBP and sCD14.
- Faecal markers: The probiotic intervention led to a decrease in faecal zonulin (LMM = −10.47; adjusted P = .014) and decrease in faecal alpha-1 antitrypsin (LMM = 9.26; adjusted P = .025). No effect was seen on faecal calprotectin.
- These findings of altered serum and faecal markers of intestinal permeability suggest that the probiotic positively impacted gut barrier function.
- Sex-specific effects were seen for serum LBP and faecal calprotectin but not for other intestinal permeability biomarkers. LBP levels decreased in women treated with the probiotic compared to placebo (LMM −1.65; adjusted P = .048). Conversely, LBP levels significantly increased in men in the probiotic group (LMM 2.34; adjusted P = .015). The mean change in calprotectin levels was more pronounced in men treated with probiotics than those administered placebo (LMM −49.08; adjusted P = .048) No significant effects were found in women.
Gastrointestinal symptoms
- Indigestion complaints significantly decreased in male participants in the probiotics group (LMM = −0.70; adjusted P = .010).
Blood metabolic biomarkers
- No impact of the probiotic intervention was seen on high-density lipoprotein (HDL), cholesterol, triglycerides, glucose or albumin.
Blood inflammatory biomarkers
- No significant treatment effect was evident on including CRP, S100B, interferon gamma (IFNγ) or tumor necrosis factor alpha (TNFα).
- Thus, the probiotic did not impact blood markers of inflammation or metabolic health.
Safety assessments
- Adverse events were similar between groups.
While probiotics decreased indigestion complaints in men, there was no evidence of a treatment effect on psychiatric symptoms in any participants.
Conclusions
Adding probiotics to treatment-as-usual in patients with BD and SSD does not appear to be beneficial for psychiatric symptoms. A borderline improvement in verbal memory was noted in the probiotic group, but other cognitive parameters were not impacted by the probiotic.
Additionally, the adjunctive probiotic appeared to have beneficial effects on some gut permeability markers in these patients, as well as improving symptoms of indigestion in male patients only.
The authors concluded that their results:
Underscore the need for further research into microbiome-targeted interventions for patients with complex brain disorders.
Adding probiotics to treatment-as-usual in patients with bipolar disorder and schizophrenia spectrum disorder does not appear to be beneficial for psychiatric symptoms.
Strengths and limitations
This study is a welcome addition to the sparse literature on probiotics in bipolar disorder and schizophrenia. The sample size seems reasonable, although the authors do not provide information on power calculations. The methodology appears to be sound with a randomised, double-blind, placebo-controlled design. Baseline demographic and clinical characteristics of both groups were similar at the start of the trial.
Authors collected information on dietary intake and diet quality, important confounding factors to consider in microbiome studies. Notably, both groups had relatively healthy diets at baseline. Thus, a floor effect may have limited the potential benefit of the probiotics. Unfortunately, authors did not appear to collect information on the use of probiotics or prebiotics by subjects prior to the study, and any such use was not listed as an exclusion criterion. Given the increasing use of such supplements amongst the general public, this may be important.
The participants received this intervention alongside their usual care. On review of the supplementary data, it can be seen that there were no significant differences in medication changes between baseline or study endpoints in either group.
The study protocol was clearly defined with both groups allocated to receive the same study procedures. As part of the study was performed during the COVID-19 pandemic, some home visits had to be done through phone or video call. No details were provided in relation to the number of participants affected by this change in protocol and it is not clear if there was a differential impact between the two groups with regards to procedural changes.
The trial was pre-registered (international clinical trials registry platform (NL-OMON53363). Primary and secondary outcomes were defined in advance and the report adheres to these pre-specified outcomes. Although not mentioned in the paper, the pre-registered trial data reported that patients were selected based on screening positive for increased intestinal permeability based on LBP measurements. We enquired about this and the authors informed us that, due to practical and financial implications of measuring LBP prior to recruitment, they removed this inclusion criterion.
Another limitation is the validity of the commercial zonulin ELISA assays used in the study. These are now widely accepted as being neither adequate to measure intestinal permeability nor the postulated biomarker zonulin (Massier et al., 2021). The authors acknowledge this and advise caution in interpreting zonulin results.
While this study is a welcome addition to the sparse literature on probiotics in bipolar disorder and schizophrenia, several limitations (e.g. lack of information on prior probiotic use and poor validity of the commercial zonulin ELISA assays used) may have muddied the results.
Implications for practice
As a psychiatrist, one of the most difficult aspects of treating bipolar disorder (BD) and schizophrenia spectrum disorder (SSD) is trying to balance the benefit of psychotropic medications against the many side effects. Antipsychotics, in particular, are problematic as they are frequently associated with weight gain, metabolic disturbances, gastrointestinal side effects (commonly constipation) and cognitive blunting. Many people understandably dislike taking medications due to such adverse effects. While probiotics do not appear to hold any great promise for treating core psychiatric symptoms such as hallucinations, delusions or mania, they may be useful for improving gastrointestinal symptoms and thus the tolerability of psychotropic medications used in BD and SSP. This would be most welcome in clinical practice as side effects are a common reason that individuals discontinue antipsychotics (Stürup et al., 2023) and mood stabilisers (Mago et al., 2014).
This study also opens up the possibility that adjunctive probiotics may be beneficial for improving certain cognitive parameters in patients with severe mental illness. Cognitive dysfunction is a feature of both BD and SSP (Fett et al., 2020; Robinson et al., 2006), as well as a potential side effect of the antipsychotics (Allott et al., 2023; Husa et al., 2014) and mood stabilizers (Wingo et al., 2009) used to treat these conditions. Many times, in my clinic I have heard patients report ‘brain fog’ or ‘dulling’ from psychotropic medications. If probiotics or other microbiome-based treatments improved cognitive symptoms, it could improve treatment adherence and enhance quality of life.
It is important to acknowledge that the improvements in cognition were limited to borderline improvements in verbal memory with no significant changes in other cognitive parameters. Additionally, the reduction in indigestion with probiotic use was only seen in male patients. Thus, the potential benefit of probiotics on cognition and non-psychiatric symptoms appears to be subtle. Nevertheless, there were no adverse effects associated with the intervention and probiotics may be a well-tolerated adjunctive treatment option for patients. A microbiome-based approach to mental illness offers a new treatment paradigm that can easily be employed alongside existing therapeutic approaches including pharmacotherapy and psychotherapy. Further studies, specifically designed to assess the impact of probiotics on non-psychiatric symptoms such as gastrointestinal complaints and cognition are required.
While probiotics do not appear to hold any great promise for treating core psychiatric symptoms (e.g., hallucinations, delusions), they may be useful for improving cognition and other symptoms such as gastrointestinal complaints.
Statement of interests
Dr Butler is interested in the microbiome-gut-brain axis in mental illness and in the potential for microbiome-based treatment approaches in psychiatry. She does not have any potential conflicts of interest with regards to this blog.
Links
Primary paper
Borkent J, Ioannou M, Neijzen D, Haarman BCM, Sommer IEC (2024). Probiotic Formulation for Patients With Bipolar or Schizophrenia Spectrum Disorder: A Double-Blind, Randomized Placebo-Controlled Trial. Schizophr Bull. 6:sbae188. doi: 10.1093/schbul/sbae188. Epub ahead of print. PMID: 39504580.
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