Augmentation therapy with serotonin1A receptor partial agonists on neurocognitive function in schizophrenia: A systematic review and meta-analysis.

Background: In a previous meta-analysis, the use of serotonin1A(5-HT1A) receptor partial agonists of the azapirone class as an add-on therapy was associated with beneficial effects on positive symptoms and attention/processing speed in schizophrenia patients. This meta-analysis builds on that study by examining the effects of adjunctive treatment with 5-HT1A partial agonists in improving other domains of neurocognitive function in schizophrenia patients. Methods: A literature search was performed from 1987 to May 2023 to identify randomized controlled trials. The standardized mean difference (SMD) with 95 % confidence intervals (CI) was calculated when there were two or more studies. Four studies, involving 313 patients, met the inclusion criteria and were used in the analysis. Results: 5-HT1A partial agonists (buspirone or tandospirone) did not have a significant effect on verbal learning (SMD = 0.08, 95 % CI = -0.31 to 0.47) or working memory (SMD = 0.15, 95 % CI = -0.09 to 0.39). Regarding executive functions (Wisconsin Card Sorting Test), positive but non-significant results were seen with the category number (SMD = 0.26, 95 % CI = -0.81 to 1.32), while non-significant effects were noted for percent preservation errors (SMD = -0.10, 95 % CI = -0.53 to 0.33). Conclusions: The absence of any significant benefits in the cognitive domains studied here may have been due to the variance in the concomitant medication (typical vs atypical antipsychotic drugs), the level of cognition at baseline, or other factors. Further studies with various types of 5-HT1A agonists are warranted to examine the potential cognitive efficacy of stimulating these receptors.

Effect of 5-HT1A Receptor Partial Agonists of the Azapirone Class as an Add-On Therapy on Psychopathology and Cognition in Schizophrenia: A Systematic Review and Meta-Analysis.

BACKGROUND: There are ongoing efforts to examine the effect of 5-HT1A receptor partial agonists as an add-on therapy for several symptoms of schizophrenia. By conducting a systematic review and meta-analysis, we evaluated whether augmentation with 5-hydroxtrypatamine (5-HT)1A partial agonists of the azapirone class improves psychotic symptoms and attention/processing speed, a key domain of cognition, in patients with schizophrenia. METHODS: A literature search was performed from 1987 to February 25, 2022, to identify randomized controlled trials. The standardized mean difference (SMD) with 95% confidence intervals (CI) was calculated when there were 2 or more studies. Seven studies, involving 435 patients, met the inclusion criteria. RESULTS: Random-effects model meta-analyses revealed that add-on therapy with buspirone or tandospirone had a significant beneficial effect on overall psychotic symptoms (SMD = -1.13, 95% CI = -1.98 to -0.27) and positive symptoms (SMD = -0.72, 95% CI =-1.31 to -0.12), while the effect on negative symptoms did not reach statistical significance (SMD = -0.93, 95% CI = -1.90 to 0.04). A significant positive effect was also observed on attention/processing speed (SMD = 0.37, 95% CI = 0.12 to 0.61). CONCLUSIONS: These findings support the idea that some compounds that stimulate 5-HT1A receptors provide an effective pharmacologic enhancer in the treatment of schizophrenia. Further clinical trials are warranted to determine the benefits of the adjunctive use of 5-HT1A partial agonists in ameliorating symptoms and improving functional outcomes in patients with schizophrenia or other psychiatric disorders.

Emotional and behavioral problems in Japanese preschool children with subthreshold autistic traits: findings from a community-based sample.

BACKGROUND: Recently, there has been a growing recognition that autistic traits exist along a continuum beyond diagnostic categories and that even subclinical symptoms may be associated with an increased risk for the psychosocial well-being and mental health of children. However, as yet, there has been little research on whether preschool children with autism spectrum disorder (ASD) symptoms, who do not meet the diagnostic criteria for ASD, are more likely to experience difficulties. To address this deficit this study examined whether young children with subthreshold autistic traits have an increased risk for emotional/behavioral difficulties. METHODS: Data were analyzed from 1057 Japanese preschool children aged 5-years old collected during the first wave of the Tama Children's Survey (TCS) cohort study. Parent-reported autistic traits were assessed with the Social Responsiveness Scale (SRS), while they provided information on their child's emotional/behavioral problems using the Strengths and Difficulties Questionnaire (SDQ). Logistic regression analysis was used to examine associations. RESULTS: Preschool children with mild-to-moderate autistic traits, corresponding to subclinical autism were significantly more likely to score above the clinical thresholds for emotional/behavioral problems compared to children with fewer autistic traits. Follow-up diagnostic assessments and analyses of 72 children from the cohort confirmed these findings and showed that these children with subthreshold autistic traits also had a significantly lower intelligence quotient (IQ) as measured by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). CONCLUSIONS: Although subthreshold autistic traits are difficult to define due to the sometimes vague border between typical and atypical development, there may be a large number of preschool children with subthreshold autistic traits, who may have an increased risk for a variety of different emotional/behavioral difficulties as well as lower cognitive functioning.

Sex Differences in Social Cognition and Association of Social Cognition and Neurocognition in Early Course Schizophrenia.

Background: Both impairment and sex differences in social cognition and neurocognition have been documented in schizophrenia. However, whether sex differences exist in the association between social cognition and neurocognition are not known. We aimed to investigate the contribution of areas of neurocognition to theory of mind (ToM) and hostility bias, representing social cognition, according to sex in early course schizophrenia. Methods: In this cross-sectional study, we assessed neurocognition using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS) and assessed the ToM and hostility bias subdomains of social cognition using the Social Cognition Screening Questionnaire (SCSQ) in 131 participants (65 female, 66 male) diagnosed with schizophrenia within 5 years of onset. Sex differences were analyzed using t-tests. The associations of neurocognitive subdomains with ToM and hostility bias according to sex were analyzed using multiple regression analysis. Results were adjusted by age, estimated premorbid intelligence quotient, and symptomatology. Results: No sex differences were found in ToM (p = 0.071) or hostility bias (p = 0.057). Higher verbal fluency was significantly associated with higher ToM in females (p < 0.01), whereas higher executive function was significantly associated with higher ToM in males (p < 0.05). Higher verbal fluency was significantly associated with lower hostility bias in females (p < 0.05), whereas neurocognition and hostility bias were not significantly associated in males. Conclusion: The results suggest that neurocognition associated with social cognition differ according to sex. These differences should be considered for more effective treatment of social cognition.

Efficacy and Safety of Multi-Session Transcranial Direct Current Stimulation on Social Cognition in Schizophrenia: A Study Protocol for an Open-Label, Single-Arm Trial.

BACKGROUNDS: Social cognition is defined as the mental operations underlying social behavior. Patients with schizophrenia elicit impairments of social cognition, which is linked to poor real-world functional outcomes. In a previous study, transcranial direct current stimulation (tDCS) improved emotional recognition, a domain of social cognition, in patients with schizophrenia. However, since social cognition was only minimally improved by tDCS when administered on frontal brain areas, investigations on the effect of tDCS on other cortical sites more directly related to social cognition are needed. Therefore, we present a study protocol to determine whether multi-session tDCS on superior temporal sulcus (STS) would improve social cognition deficits of schizophrenia. METHODS: This is an open-label, single-arm trial, whose objective is to investigate the efficacy and safety of multi-session tDCS over the left STS to improve social cognition in patients with schizophrenia. The primary outcome measure will be the Social Cognition Screening Questionnaire. Neurocognition, functional capacity, and psychotic symptoms will also be evaluated by the Brief Assessment of Cognition in Schizophrenia, UCSD Performance-Based Skills Assessment-Brief, and Positive and Negative Syndrome Scale, respectively. Data will be collected at baseline, and 4 weeks after the end of intervention. If social cognition is improved in patients with schizophrenia by tDCS based on this protocol, we may plan randomized controlled trial.

Characterization of aromatic acid/proton symporters in Pseudomonas putida KT2440 toward efficient microbial conversion of lignin-related aromatics.

Pseudomonas putida KT2440 (hereafter KT2440) is a well-studied platform bacterium for the production of industrially valuable chemicals from heterogeneous mixtures of aromatic compounds obtained from lignin depolymerization. KT2440 can grow on lignin-related monomers, such as ferulate (FA), 4-coumarate (4CA), vanillate (VA), 4-hydroxybenzoate (4HBA), and protocatechuate (PCA). Genes associated with their catabolism are known, but knowledge about the uptake systems remains limited. In this work, we studied the KT2440 transporters of lignin-related monomers and their substrate selectivity. Based on the inhibition by protonophores, we focused on five genes encoding aromatic acid/H+ symporter family transporters categorized into major facilitator superfamily that uses the proton motive force. The mutants of PP_1376 (pcaK) and PP_3349 (hcnK) exhibited significantly reduced growth on PCA/4HBA and FA/4CA, respectively, while no change was observed on VA for any of the five gene mutants. At pH 9.0, the conversion of these compounds by hcnK mutant (FA/4CA) and vanK mutant (VA) was dramatically reduced, revealing that these transporters are crucial for the uptake of the anionic substrates at high pH. Uptake assays using 14C-labeled substrates in Escherichia coli and biosensor-based assays confirmed that PcaK, HcnK, and VanK have ability to take up PCA, FA/4CA, and VA/PCA, respectively. Additionally, analyses of the predicted protein structures suggest that the size and hydropathic properties of the substrate-binding sites of these transporters determine their substrate preferences. Overall, this study reveals that at physiological pH, PcaK and HcnK have a major role in the uptake of PCA/4HBA and FA/4CA, respectively, and VanK is a VA/PCA transporter. This information can contribute to the engineering of strains for the efficient conversion of lignin-related monomers to value-added chemicals.