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Cited by 213Cancer Immunotherapy and BiomarkersPharmacovigilance and Adverse Drug ReactionsImmunotherapy and Immune Responses

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Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

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Zhou, Chaozheng, Peng, Shengkun, Lin, Anqi, Jiang, Aimin, Peng, Yuanxi, Gu, Tianqi, Liu, Zaoqu, Cheng, Quan, Zhang, Jian, Luo, Peng·2023·eClinicalMedicine
DOI 10.1016/j.eclinm.2023.101967PMC PMC10149185
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Abstract

Background With the increasing use of immune checkpoint inhibitors (ICIs) for tumour immunotherapy, the immune-related adverse events (irAEs) caused by their collateral effect on the immune system pose a key challenge for the clinical application of ICIs. Psychiatric adverse events are a class of adverse events associated with ICIs that are realistically observed in the real world. We aim to provide a comprehensive study and summary of psychiatric adverse events associated with ICIs. Methods We obtained ICI adverse reaction reports during January 2012–December 2021 from the FDA Adverse Event Reporting System (FAERS) database. ICI reports underwent screening to minimize the influence of other adverse reactions, concomitant medications, and indications for medication use that may also contribute to psychiatric disorders. Disproportionality analysis was performed to find psychiatric adverse events associated with ICIs by comparing ICIs with the full FAERS database using the reporting odds ratio (ROR). Influencing factors were explored based on univariate logistic regression analysis. Finally, the Cancer Genome Atlas (TCGA) pan-cancer transcriptome data were combined to explore the potential biological mechanisms associated with ICI-related pAEs. Findings Reports of psychiatric adverse events accounted for 2.71% of the overall ICI adverse event reports in the FAERS database. Five categories of psychiatric adverse events were defined as ICI-related psychiatric adverse events (pAEs). The median age of reports with ICI-related pAEs was 70 (interquartile range [IQR] 24–95), with 21.54% of reports having a fatal outcome. Cases with indications for lung cancer, skin cancer and kidney site cancer accounted for the majority. The odds of ICI-related pAEs increased in older patients (65–74: OR = 1.44 [1.22–1.70], P < 0.0001: ≥75: OR = 1.84 [1.54–2.20], P < 0.0001). The occurrence of ICI-related pAEs may be related to NOTCH signalling and dysregulation of synapse-associated pathways. Interpretation This study investigated psychiatric adverse events highly associated with ICI treatment, their influencing factors and potential biological mechanisms, which provides a reliable basis for further in-depth study of ICI-related pAEs. However, as an exploratory study, our findings need to be further confirmed in a large-scale prospective study. Funding This work was supported by the Natural Science Foundation of Guangdong Province (2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (2019A030317020) and the National Natural Science Foundation of China (81802257, 81871859, 81772457, 82172750 and 82172811). Guangdong Basic and Applied Basic Research Foundation (Guangdong - Guangzhou Joint Fouds) (2022A1515111212). This work was supported by Key Research and Development Projects of Sichuan Science and Technology (2022YFS0221, 2022YFS0074, 2022YFS0156 and 2022YFS0378). Sichuan Provincial People's Hospital Hospital Young Talent Fund (2021QN08).

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Fig. 1 Flow chart showing the analysis process of the study. A detailed description of the selection process of psychiatric adverse events for immune checkpoint inhibitors (ICIs) in the Food and Drug Administration Adverse Event Reporting System (FAERS).
Fig. 1 Flow chart showing the analysis process of the study. A detailed description of the selection process of psychiatric adverse events for immune checkpoint inhibitors (ICIs) in the Food and Drug Administration Adverse Event Reporting System (FAERS).CC BY-NC-ND · PubMed Central
Fig. 2 Statistics on the occurrence of psychiatric adverse events in ICIs reports from the FAERS database during 2012–2021. A) The upper bar plot shows the number of ICI reports with psychiatric adverse reactions versus ICI reports without psychiatric adverse events in the FAERS database during 2012 and 2021, as well as the overall situation. The proportional bar plot below shows the amount of ICI reports with psychiatric adverse events versus ICI reports without psychiatric adverse events in the FAERS database during 2012 and 2021, as well as the overall situation. B) The upper bar plot shows the number of ICI reports with psychiatric adverse events versus ICI reports without psychiatric adverse events for different ICI treatment strategies in the FAERS database from 2012 to 2021 and the overall situation. The proportional bar plot below shows the amount of ICI reports with psychiatric adverse events versus ICI reports without psychiatric adverse events for different ICI treatment strategies in the FAERS database from 2012 to 2021 and overall situation. The ICI treatment strategies included ICI combination therapy, ICI monotherapy, and anti-CTLA-4, anti-PD-1, and anti-PD-L1. Red indicates reports with psychiatric adverse events, and blue indicates reports without psychiatric adverse events.
Fig. 2 Statistics on the occurrence of psychiatric adverse events in ICIs reports from the FAERS database during 2012–2021. A) The upper bar plot shows the number of ICI reports with psychiatric adverse reactions versus ICI reports without psychiatric adverse events in the FAERS database during 2012 and 2021, as well as the overall situation. The proportional bar plot below shows the amount of ICI reports with psychiatric adverse events versus ICI reports without psychiatric adverse events in the FAERS database during 2012 and 2021, as well as the overall situation. B) The upper bar plot shows the number of ICI reports with psychiatric adverse events versus ICI reports without psychiatric adverse events for different ICI treatment strategies in the FAERS database from 2012 to 2021 and the overall situation. The proportional bar plot below shows the amount of ICI reports with psychiatric adverse events versus ICI reports without psychiatric adverse events for different ICI treatment strategies in the FAERS database from 2012 to 2021 and overall situation. The ICI treatment strategies included ICI combination therapy, ICI monotherapy, and anti-CTLA-4, anti-PD-1, and anti-PD-L1. Red indicates reports with psychiatric adverse events, and blue indicates reports without psychiatric adverse events.CC BY-NC-ND · PubMed Central
Fig. 3 Scanning for ICI-related psychiatric adverse events based on the FAERS database. A) The heatmap shows the ROR for 76 psychiatric adverse events (with cases no less than 3) in the FAERS database under different ICI treatment strategies (including overall situation, ICI combination therapy, ICI monotherapy, anti-CTLA-4, anti-PD-1, and anti-PD-L1). Red indicates ROR values greater than 1, dark blue indicates ROR values less than 1, and light blue indicates ROR values that could not be calculated. Psychiatric adverse events labelled with dark red colour meet the criteria that in the overall situation, the lower limit of the 95% confidence interval for the ROR greater than 1 and the number of cases occurring no less than 3. B) The bar plot shows the number of reported cases for five categories of ICI-related pAEs under different ICI treatment strategies. C) Sankey diagram depicting the hierarchical relationship of PTs for five categories of ICI-related pAEs in MedDRA. NES indicates not classified elsewhere. PT indicates the preferred term, HLT indicates the high level term, HLGT indicates the high level group term, and SOC indicates the system organ class. D) Forest plot shows the ROR of ICI-related pAEs (considering the five categories of ICI-related pAEs as one category of adverse events) under different ICI treatment strategies (including overall situation, ICI combination therapy, ICI monotherapy, and anti-CTLA-4, anti-PD-1, and anti-PD-L1). NS indicates Not Significant, ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; ∗∗∗∗P < 0.0001.
Fig. 3 Scanning for ICI-related psychiatric adverse events based on the FAERS database. A) The heatmap shows the ROR for 76 psychiatric adverse events (with cases no less than 3) in the FAERS database under different ICI treatment strategies (including overall situation, ICI combination therapy, ICI monotherapy, anti-CTLA-4, anti-PD-1, and anti-PD-L1). Red indicates ROR values greater than 1, dark blue indicates ROR values less than 1, and light blue indicates ROR values that could not be calculated. Psychiatric adverse events labelled with dark red colour meet the criteria that in the overall situation, the lower limit of the 95% confidence interval for the ROR greater than 1 and the number of cases occurring no less than 3. B) The bar plot shows the number of reported cases for five categories of ICI-related pAEs under different ICI treatment strategies. C) Sankey diagram depicting the hierarchical relationship of PTs for five categories of ICI-related pAEs in MedDRA. NES indicates not classified elsewhere. PT indicates the preferred term, HLT indicates the high level term, HLGT indicates the high level group term, and SOC indicates the system organ class. D) Forest plot shows the ROR of ICI-related pAEs (considering the five categories of ICI-related pAEs as one category of adverse events) under different ICI treatment strategies (including overall situation, ICI combination therapy, ICI monotherapy, and anti-CTLA-4, anti-PD-1, and anti-PD-L1). NS indicates Not Significant, ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; ∗∗∗∗P < 0.0001.CC BY-NC-ND · PubMed Central
Fig. 4 Descriptive analysis of reports with ICI-related psychiatric adverse events. A) The bar plot shows the number of reports with ICI-related pAEs for different ICI treatment strategies. B) The site statistics for cancer occurrence in reports with ICI-related pAEs. On the left is the anatomical diagram of the patient's original cancer site and the number of cases. The darker the colour, the more cases with cancer originated form this site. The pie chart on the right shows the proportional composition of the patient's cancer original sites. The pie chart on the top shows the proportional distribution of the case numbers for organs which were greater than 15. Among them, cancer sites with a case number less than 15 are classified as other (marked in red). The pie chart at the bottom shows the proportional distribution of the case numbers for cancer originated from other. C, D and E) From the left to right, the cumulative distribution curves demonstrate the onset time of ICI-related pAEs after treatment with ICIs in different subgroups (fatal status, whether plus targeted therapy and different ICI treatment strategies). Statistical tests were conducted using the nonparametric Wilcoxon rank sum test.
Fig. 4 Descriptive analysis of reports with ICI-related psychiatric adverse events. A) The bar plot shows the number of reports with ICI-related pAEs for different ICI treatment strategies. B) The site statistics for cancer occurrence in reports with ICI-related pAEs. On the left is the anatomical diagram of the patient's original cancer site and the number of cases. The darker the colour, the more cases with cancer originated form this site. The pie chart on the right shows the proportional composition of the patient's cancer original sites. The pie chart on the top shows the proportional distribution of the case numbers for organs which were greater than 15. Among them, cancer sites with a case number less than 15 are classified as other (marked in red). The pie chart at the bottom shows the proportional distribution of the case numbers for cancer originated from other. C, D and E) From the left to right, the cumulative distribution curves demonstrate the onset time of ICI-related pAEs after treatment with ICIs in different subgroups (fatal status, whether plus targeted therapy and different ICI treatment strategies). Statistical tests were conducted using the nonparametric Wilcoxon rank sum test.CC BY-NC-ND · PubMed Central
Fig. 5 Factors influencing ICI-related psychiatric adverse events. A) Bar plot shows the proportion of cases with and without co-reported AEs in cases with ICI-related pAEs. B) Bar plot shows the statistics of SOC regarding PTs of co-reported adverse events. The percentage values labeled in the figure represent the proportion of cases with such adverse events out of the total ICI-related pAE cases with co-reported adverse reactions. C) Bar plot shows the statistics of the top 30% PTs of co-reported adverse events. The colour indicates the SOC of the corresponding PT. The percentage values labeled in the figure represent the proportion of cases with such adverse events out of the total ICI-related pAE cases with co-reported adverse reactions. D) The forest plot shows the results of univariate logistic regression analysis regarding the factors influencing ICI-related pAEs. The exposure factors considered included sex (red), age (light blue), outcome (green), whether combined with chemotherapy (blue), whether combined with targeted therapy (orange) and ICI treatment strategy (grey). OR indicates odds ratio. NS indicates Not Significant, AE indicates adverse event, PT indicates preferred term, SOC indicates systemic organ class, ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; ∗∗∗∗P < 0.0001.
Fig. 5 Factors influencing ICI-related psychiatric adverse events. A) Bar plot shows the proportion of cases with and without co-reported AEs in cases with ICI-related pAEs. B) Bar plot shows the statistics of SOC regarding PTs of co-reported adverse events. The percentage values labeled in the figure represent the proportion of cases with such adverse events out of the total ICI-related pAE cases with co-reported adverse reactions. C) Bar plot shows the statistics of the top 30% PTs of co-reported adverse events. The colour indicates the SOC of the corresponding PT. The percentage values labeled in the figure represent the proportion of cases with such adverse events out of the total ICI-related pAE cases with co-reported adverse reactions. D) The forest plot shows the results of univariate logistic regression analysis regarding the factors influencing ICI-related pAEs. The exposure factors considered included sex (red), age (light blue), outcome (green), whether combined with chemotherapy (blue), whether combined with targeted therapy (orange) and ICI treatment strategy (grey). OR indicates odds ratio. NS indicates Not Significant, AE indicates adverse event, PT indicates preferred term, SOC indicates systemic organ class, ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; ∗∗∗∗P < 0.0001.CC BY-NC-ND · PubMed Central
Fig. 6 Assessment of the association between ICI-related psychiatric adverse events and biological pathways. A) The bar plot shows the ROR of ICI-related pAEs in 23 different cancer types. Hematologic malignancies were not included in the analysis. Tumour types with less than 5 cases were not included in the analysis. B) The correlation analysis between the ROR of ICI-related pAEs and ssGSEA enrichment scores for the neurexins and neuroligins signature, synaptic adhesion-like molecules signature, and NOTCH signalling pathway. The Spearman's rank correlation coefficient was used for correlation analysis. LUAD: lung adenocarcinoma; SKCM: skin cutaneous melanoma; LUSC: lung squamous cell carcinoma; NSCLC: non-small cell lung carcinoma: KIRC: kidney renal clear cell carcinoma; PRAD: prostate adenocarcinoma; BLCA: bladder urothelial carcinoma; MESO: mesothelioma: BRCA: breast invasive carcinoma; UCEC: uterine corpus endometrial carcinoma; SARC: sarcoma: ESCA: esophageal carcinoma; PAAD: pancreatic adenocarcinoma; OV: ovarian serous cystadenocarcinoma; HNSC: head and neck squamous cell carcinoma: STAD: stomach adenocarcinoma; THCA: thyroid carcinoma; CHOL: cholangiocarcinoma; READ: rectum adenocarcinoma; COAD: colon adenocarcinoma; LIHC: liver hepatocellular carcinoma; LGG: brain lower-grade glioma; GBM: glioblastoma multiforme.
Fig. 6 Assessment of the association between ICI-related psychiatric adverse events and biological pathways. A) The bar plot shows the ROR of ICI-related pAEs in 23 different cancer types. Hematologic malignancies were not included in the analysis. Tumour types with less than 5 cases were not included in the analysis. B) The correlation analysis between the ROR of ICI-related pAEs and ssGSEA enrichment scores for the neurexins and neuroligins signature, synaptic adhesion-like molecules signature, and NOTCH signalling pathway. The Spearman's rank correlation coefficient was used for correlation analysis. LUAD: lung adenocarcinoma; SKCM: skin cutaneous melanoma; LUSC: lung squamous cell carcinoma; NSCLC: non-small cell lung carcinoma: KIRC: kidney renal clear cell carcinoma; PRAD: prostate adenocarcinoma; BLCA: bladder urothelial carcinoma; MESO: mesothelioma: BRCA: breast invasive carcinoma; UCEC: uterine corpus endometrial carcinoma; SARC: sarcoma: ESCA: esophageal carcinoma; PAAD: pancreatic adenocarcinoma; OV: ovarian serous cystadenocarcinoma; HNSC: head and neck squamous cell carcinoma: STAD: stomach adenocarcinoma; THCA: thyroid carcinoma; CHOL: cholangiocarcinoma; READ: rectum adenocarcinoma; COAD: colon adenocarcinoma; LIHC: liver hepatocellular carcinoma; LGG: brain lower-grade glioma; GBM: glioblastoma multiforme.CC BY-NC-ND · PubMed Central

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Authors
Zhou, C., Peng, S., Lin, A., Jiang, A., Peng, Y., Gu, T., Liu, Z., Cheng, Q., Zhang, J., & Luo, P.
Affiliations
  • Zhujiang Hospital (CN)
  • University of Electronic Science and Technology of China (CN)
  • Second Military Medical University (CN)
  • First Affiliated Hospital of Zhengzhou University (CN)
  • Central South University (CN)
Corresponding author
  • Cheng, Quan
  • Zhang, Jian
  • Luo, Peng
ORCID
Venue
eClinicalMedicine
Publisher
Elsevier BV
Published
2023-05
Volume
59
Pages
101967
ISSN
2589-5370 (ISSN-L)
DOI
10.1016/j.eclinm.2023.101967
PMC
PMC10149185
OpenAlex
W4366712080
Cited by
213
References
59
Citations by year
2026: 51 · 2025: 94 · 2024: 62 · 2023: 6
FWCI
25.87
Type
journal article
Language
en
Open access
Licence
Locations
  • EClinicalMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81772457, 81802257, 81871859, 82172750, 82172811)
  • Natural Science Foundation of Guangdong Province (2018A030313846, 2021A1515012593)
  • Science and Technology Planning Project of Guangdong Province (2019A030317020)
  • Basic and Applied Basic Research Foundation of Guangdong Province
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
immune checkpoint inhibitors, immune-related adverse events, psychiatric adverse events, immune-related encephalitis, immune-related dermatitis, immune-related colitis, immune-related endocrinopathy, immune-related pneumonitis, immune-related hypophysitis, immune-related hepatitis, immune-related nephritis

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