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Background: Atypical antipsychotics (AAPs)-induced sexual dysfunction (SD) is a frequent issue in clinical practice, often underestimated by clinicians and not extensively researched. The current study aimed to quantify the strength of association between the use of different AAPs and SD using real-world data from the FDA Adverse Event Reporting System (FAERS), as well as investigate the receptor mechanisms that are involved. Methods: Data from the FAERS database from the first quarter of 2004 to the third quarter of 2023 were queried through OpenVigil 2.1. Disproportionality analysis was estimated using the reporting odds ratio (ROR) and information component (IC) methods, and linear regression was used to investigate the relationship between ROR and receptor occupancy which was estimated using in vitro receptor binding profiles. Results: Our analysis yielded 4839 reports that co-mentioned AAP and SD events, and the findings revealed statistical associations between 12 AAPs and SD. The highest signal value was identified for iloperidone reporting retrograde ejaculation with iloperidone (ROR = 832.09, ROR025 = 552.77; IC = 9.58, IC025 = 6.36), followed by compulsive sexual behavior with aripiprazole (ROR = 533.02, ROR025 = 435.90; IC = 7.30, IC025 = 5.97), and psychosexual disorder for aripiprazole (ROR = 145.80, ROR025 = 109.57; IC025 = 6.47, IC025 = 4.86). Different characteristics of the SD side effects in each AAPs were discovered after further data mining. Regression analysis revealed potential effects for receptor occupancy of D2, D3, and 5-HT1A receptors on ROR. However, no significant correlation persisted following sensitivity analyses. Conclusion: This is the first study to investigate the AAP-SD associations by using FAERS. In this study, we report for the first time a significant association between aripiprazole and SD based on real-world data. The study suggests that different AAPs have varying levels of association with SD, and the D2, D3, and 5-HT1A receptor occupancy may contribute to potential mechanisms. The findings of this study warrant further validation of more studies and clinical causality assessment.
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Background: The role of human lineage mutations (HLMs) in human evolution through post-transcriptional modification is unclear. Aims: To investigate the contribution of HLMs to human evolution through post-transcriptional modification. Methods: We applied a deep learning model Seqweaver to predict how HLMs impact RNA-binding protein affinity. Results: We found that only 0.27% of HLMs had significant impacts on RNA-binding proteins at the threshold of the top 1% of human common variations. These HLMs enriched in a set of conserved genes highly expressed in adult excitatory neurons and prenatal Purkinje neurons, and were involved in synapse organisation and the GTPase pathway. These genes also carried excess damaging coding mutations that caused neurodevelopmental disorders, ataxia and schizophrenia. Among these genes, NTRK2 and ITPR1 had the most aggregated evidence of functional importance, suggesting their essential roles in cognition and bipedalism. Conclusions: Our findings suggest that a small subset of human-specific mutations have contributed to human speciation through impacts on post-transcriptional modification of critical brain-related genes.
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Background: Pharmacogenomics (PGx) is a promising tool to realise tailored drug therapy for depression. Aims: To investigate the treatment efficacy of PGx for treatment-resistant depression (TRD) compared with treatment as usual. Methods: A systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science and PsycINFO to identify relevant studies published from inception to 15 April 2023. Two-arm randomised controlled trials (RCTs) exploring the efficacy of PGx-guided versus unguided treatment for TRD were included. The risk of bias in the included studies was evaluated using the Cochrane risk of bias assessment tool. The overall quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results: Seven RCTs (n=3003) comparing PGx-guided (n=1492) and unguided (n=1511) groups were identified and analysed. PGx-guided treatment was superior to treatment as usual in response (relative risk (RR)=1.31; 95% confidence interval (95% CI): 1.15 to 1.49; p<0.001) and remission (RR=1.40; 95% CI: 1.09 to 1.80; p=0.009) improvements. Effect sizes for acceptability (RR=0.90; 95% CI: 0.80 to 1.02; p=0.100) and side effect burden (RR=0.58; 95% CI: 0.29 to 1.15; p=0.120) between the two groups were not statistically different. The overall quality of evidence was rated from 'very low' (25%) to 'low' (75%) based on the GRADE criteria. Conclusions: PGx-guided treatment has shown a small overall effect in improving the response and remission rates for patients with TRD. However, these results should be interpreted cautiously because of the few included studies and the low quality of evidence. Further high-quality clinical trials are warranted to confirm the findings. PROSPERO registration number: CRD42022340182.