Brain derived neurotrophic factor and cognitive dysfunction in the schizophrenia-bipolar spectrum: a systematic review and meta-analysis

Background: Cognitive impairment is a core feature of disorders on the schizophrenia-bipolar spectrum, i.e., schizophrenia, bipolar disorder, and schizoaffective disorder. Brain-derived neurotrophic factor (BDNF) has been proposed to be a biomarker of cognitive impairment in these disorders as it plays a critical role in neuroplasticity and proposed to mediate some of the psychotropic effects of medication. However, despite numerous studies investigating the association between circulating BDNF and these disorders, no solid conclusions have been drawn regarding its involvement in cognitive impairment. Objectives: The current systematic review and meta-analysis aims to examine blood BDNF levels and cognitive dysfunction in patients on the schizophrenia-bipolar spectrum as well as to evaluate whether circulating BDNF measurements can act as a biomarker for cognitive dysfunction. Methods: Studies were identified by searching Embase and Medline databases for English language articles published in peer-reviewed journals between 2000 January and 2021 June according to the PRISMA guidelines. A total of 815 articles were identified of which 32 met the inclusion criteria for the systematic review – reporting on comparisons between blood BDNF levels and cognitive functions of schizophrenia or bipolar disorder patients versus healthy controls (no studies involving schizoaffective patients were specifically obtained for the time being). Twenty-four of these studies (19 with schizophrenia and 5 with bipolar disorder patients) were eligible to be included in the meta-analysis. Results: Our findings indicated that circulating BDNF levels were significantly reduced in patients experiencing an acute episode of schizophrenia or bipolar disorder compared to healthy controls. Cognitive function was also found to be significantly worse in patients, however, correlations between BDNF levels and cognitive impairment were not always detected. Interventions, especially pharmacotherapy seemed to improve certain aspects of cognition and increase circulating BDNF levels. Conclusion: Circulating BDNF alone does not seem to be a valid biomarker of cognitive dysfunction in patients with disorders on the schizophrenia-bipolar spectrum, owing to several confounding factors. Changes of the circulating levels of BDNF should be evaluated in a wider context of other stress-, immune-, and inflammatory-related factors

Sociability in a non-captive macaque population is associated with beneficial gut bacteria

The relationship between social behaviour and the microbiome is known to be reciprocal. Research in wild animal populations, particularly in primate social groups, has revealed the role that social interactions play in microbial transmission, whilst studies in laboratory animals have demonstrated that the gut microbiome can affect multiple aspects of behaviour, including social behaviour. Here we explore behavioural variation in a non-captive animal population with respect to the abundance of specific bacterial genera. Social behaviour based on grooming interactions is assessed in a population of rhesus macaques (Macaca mulatta), and combined with gut microbiome data. We focus our analyses on microbiome genera previously linked to sociability and autistic behaviours in rodents and humans. We show in this macaque population that some of these genera are also related to an individual’s propensity to engage in social interactions. Interestingly, we find that several of the genera positively related to sociability, such as Faecalibacterium, are well known for their beneficial effects on health and their anti-inflammatory properties. In contrast, the genus Streptococcus, which includes pathogenic species, is more abundant in less sociable macaques. Our results indicate that microorganisms whose abundance varies with individual social behaviour also have functional links to host immune status. Overall, these findings highlight the connections between social behaviour, microbiome composition, and health in an animal population

Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis

Reduced gut-microbial diversity (“gut dysbiosis”) has been associated with an anhedonic/amotivational syndrome (“sickness behavior”) that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients showed increased levels of zonulin (four studies reporting data on bipolar disorder and depression, SMD = 0.97; 95% Cl = 0.10–1.85; P = 0.03, I2 = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42–1.12; P I2 = 0%), antibodies against endotoxin (seven studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.99; 95% CI = 0.27–1.70; P I2 = 97.14%), sCD14 (six studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.54; 95% Cl 0.16–0.81; P I2 = 90.68%), LBP (LBP, two studies reporting data on chronic fatigue and depression, SMD = 0.87; 95% Cl = 0.25–1.48; P I2 = 56.80%), alpha-1-antitripsin (six studies reporting data on bipolar disorder, depression, and schizophrenia, SMD = 1.23; 95% Cl = 0.57–1.88; P I2: 89.25%). Elevated levels of gut dysbiosis markers positively correlated with severity of sickness behavior in patients with severe mental illness and chronic fatigue. Our findings suggest that gut dysbiosis may underlie symptoms of sickness behavior across traditional diagnostic boundaries. Future investigations should validate these findings comparing the performances of the trans-diagnostic vs. categorical approach. This will facilitate treatment breakthrough in an area of unmet clinical need

Psycho-pharmacomicrobiomics: a systematic review and meta-analysis

Background: Understanding the interactions between the gut-microbiome and psychotropic medications interact ("psycho-pharmacomicrobiomics") could improve treatment stratification strategies in psychiatry. In this systematic review and meta-analysis, we explored first, whether psychotropics modify the gut-microbiome, and second, if the gut-microbiome affects the efficacy and tolerability of psychotropics. Methods: Following PRISMA guidelines, we searched (November 2022) for longitudinal and cross-sectional studies investigating the effect of psychotropics on the gut-microbiome. The primary outcome was the difference in diversity metrics (alpha and beta) before and after treatment with psychotropics (longitudinal studies), and in medicated compared to unmedicated individuals (cross-sectional studies). Secondary outcomes included the association between gut microbiome and efficacy and tolerability outcomes. Random effect meta-analyses were conducted on alpha diversity metrics, while beta diversity metrics were pooled using distance data extracted from graphs. Summary statistics: SMD and Higgins I2 for alpha diversity metrics, F and R values for beta diversity metrics. Results: Nineteen studies were included in our synthesis; twelve investigated antipsychotics and seven antidepressants. Results showed significant changes in alpha (4 studies; SMD: 0.12; 95% CI: 0.01 to 0.23; P=0.04; I2: 14%) and beta (F=15.59; R2:0.05; P<0.001) diversity metrics following treatment with antipsychotics and antidepressants, respectively. Altered gut microbiome composition at baseline was associated with tolerability and efficacy outcomes across studies, including response to antidepressants (2 studies; alpha diversity; SMD: 2.45; 95%CI: 0.50 - 4.40; P<0.001, I2: 0%). Conclusions: Treatment with psychotropic medications is associated with altered gut microbiome composition, in turn the gut microbiome may influence the efficacy and tolerability of these medications