Effect of add-on transcranial alternating current stimulation (tACS) in major depressive disorder: A randomized controlled trial.

BACKGROUND: The effect of transcranial alternating current stimulation (tACS) on major depressive disorder (MDD) was not confirmed. OBJECTIVE: To evaluate the feasibility, safety, and efficacy of tACS as an add-on treatment for the symptoms of depression and to understand how tACS affects brain activity. METHODS: The 4-week, double-blind, randomized, sham-controlled trial was performed from January 29, 2023 to December 22, 2023. Sixty-six participants were recruited and randomly assigned to receive 20 40-min sessions of either active (77.5Hz, 15 mA) or sham stimulation, with one electrode on the forehead and two on the mastoid, each day (n = 33 for each group) for four weeks (till Week 4). The participants were followed for 4 more weeks (till Week 8) without stimulation for efficacy/safety assessment. During the 4-week trial, all participants were required to take 10-20 mg of escitalopram daily. The primary efficacy endpoint was the change in HAMD-17 scores from baseline to Week 4 (with 20 treatment sessions completed). Resting-state electroencephalography (EEG) was collected with a 64-channel EEG system (Brain Products, Germany) at baseline and the Week 4 follow-up. The chi-square test, Fisher's exact test, independent-sample t-test, or Wilcoxon rank-sum test were used, as appropriate, to compare the differences in variables between groups. The effect of the intervention on the HAMD-17 score was also evaluated with linear mixed modeling (LMM) as sensitivity analysis. The correlation between the mean reduction in EEG and the mean reduction in the HAMD-17 total score was evaluated using Spearman correlation analysis. RESULTS: A total of 66 patients (mean [SD] age, 28.4 [8.18] years; 52 [78.8 %] female) were randomized, and 57 patients completed the study. Significant differences were found in the reductions in the HAMD-17 scores at Week 4 (t = 3.44, P = 0.001). Response rates at Week 4 were significantly higher in the active tACS group than in the sham tACS group (22 out of 33 patients [66.7 %] versus 11 out of 33 [33.3 %], P = 0.007). In the active tACS group, a correlation between the mean change in alpha power and HAMD-17 scores at Week 4 was found (r = 2.38, P = 0.024), and the mean change in alpha power was significantly bigger for responders (Z = 2.46, P = 0.014). No serious adverse events were observed in this trial. CONCLUSION: The additional antidepressant effect of tACS is significant, and the combination of tACS with antidepressants is a feasible and effective approach for the treatment of MDD. The antidepressant mechanism of tACS may be the reduction in alpha power in the left frontal lobe. Future research directions may include exploring more appropriate treatment parameters of tACS.

Identifying the core residual symptom in patients with major depressive disorder using network analysis and illustrating its association with prognosis: A study based on the national cohorts in China.

OBJECTIVE: To identify the core residual symptom of MDD and assess its relationship with patients' long-term outcomes. METHOD: All patients were administered antidepressants during the acute phase and treated continuously. The 521 patients remitted at month 6 of a multicenter prospective project were included. Remission was defined as a Quick Inventory of Depressive Symptoms-Self-Report total score of ≤5. Functional impairments were measured with the Sheehan Disability Scale, quality of life with the Quality of Life Enjoyment and Satisfaction Questionnaire - short form, and family burden with the Family Burden Scale of Disease. Visits were scheduled at baseline, weeks 2, 8, 12, and month 6. RESULTS: Difficulty with concentration/decision making was the core residual symptom of MDD, determined with the centrality measure of network analysis. It was positively associated with functional impairments and family burden (r = 0.35, P < 0.01 and r = 0.31, P < 0.01, respectively) and negatively associated with life satisfaction (r = -0.29, P < 0.01). The exhibition of this residual symptom was associated with a family history of psychiatric disorders (OR = 2.610 [1.242-5.485]). CONCLUSIONS: The core residual symptom of MDD, difficulty with concentration/decision making, is associated with poorer social functioning, heavier family burden, and lower life satisfaction. Early detection and intervention of this symptom may be beneficial. CLINICAL TRIALS REGISTRATION NUMBER: (Chinese Clinical Trials.gov identifier) ChiCTR-OOC-17012566 and ChiCTR-INR-17012574.

The novel subtype of major depressive disorder characterized by somatic symptoms is associated with poor treatment efficacy and prognosis: A data-driven cluster analysis of a prospective cohort in China.

BACKGROUND: There is not yet a valid and evidence-based system to classify patients with MDD into more homogeneous subtypes based on their clinical features. This study aims to identify symptom-based subtypes of MDD and investigate whether the treatment outcomes of those subtypes would be different. METHOD: The cohort was established at 12 densely populated cities of China. A total of 1487 patients were enrolled. All participants were 18-65 years old and diagnosed with MDD. Participants were followed up at baseline, weeks 4, 8, and 12, and months 4 and 6. K-means algorithm was used to cluster patients with MDD according to clinical symptoms. The network analysis was adopted to characterize and compare the symptom patterns in the clusters. We also examined the associations between the clusters and the clinical outcomes. RESULTS: The optimal number of the clusters was determined to be 2. Each cluster's maximum Jaccard Co-efficient was calculated to be >0.5 (cluster1 = 0.53, cluster 2 = 0.67). The symptom "depressed mood" and some other affective symptoms were the most prominent in cluster 1. Somatic symptoms, such as weight loss and general somatic symptoms, had the greatest expected influence in cluster 2. Compared with the response rates of the patients in the "somatic cluster", those of the patients in the "affective cluster" were significantly higher (P < 0.05). CONCLUSIONS: Patients with MDD might be classified into two symptom-based subtypes featured with affective symptoms or somatic symptoms. The treatment efficacy and prognosis of the subtype featured with somatic symptoms may be worse.

Low-quality of patient-reported outcome reporting in randomized clinical trials of major depressive disorder-a meta-epidemiological review.

Objective: Our goal was to review current peer-reviewed articles in which the BDI (Beck Depression Inventory), PHQ-9 (Patient Health Questionnaire), or QIDS-SR16 (16-Item Quick Inventory of Depressive Symptomatology) was used as the primary or secondary outcome measure and to evaluate the quality of PRO (Patient-Reported Outcome) reporting in RCTs (Randomized Controlled Trials) according to the 2013 PRO-specific CONSORT (Consolidated Standards of Reporting Trials) extension. Methods: We systematically searched in electronic databases. A study would be included if it included patients diagnosed with major depressive disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases, version 10 (ICD-10) as participants, was a randomized controlled trial, included the BDI, PHQ-9, or QIDS-SR16 as the primary or secondary outcome measure, published between 1990 and 2013, and was in English. Two of the authors evaluated the quality of PRO reporting according to the 2013 CONSORT-PRO. Logistic regression were used to evaluate the association between reporting completeness and trial characteristics. Results: A total of 116 studies were included. These studies were conducted in 25 countries. Sample sizes ranged from 12 to 750. The CONSORT-PRO was not cited in any one of the included studies. Among the 116 studies, 2 (1.72%) studies introduced the rationale for PRO assessment, 60 (51.72%) studies explicitly stated statistical approaches for dealing with missing data, 87 (75.00%) studies reported PRO outcome data at baseline and at subsequent time points. The mean score of reporting completeness was 66.24%. Significantly higher reporting completeness was found for RCTs published after 2013 (OR, 95%CI: 3.81, 1.32-10.99). Studies with a higher sample size were more completely reported than studies with a lower sample size (OR, 95%CI: 1.01, 1.00-1.02). Conclusion: The CONSORT-PRO guidance was rarely cited. The quality of PRO reporting in depression studies requires improvement. This result may be meaningful for the promotion of PRO reporting in RCTs.

Gender specific sexual dysfunction in patients with depression.

Background: This study aims to investigate the factors associated with sexual dysfunction (SD), with a particular focus on the influence of sex on the occurrence and severity of this condition in patients with major depressive disorder (MDD). Method: Sociodemographic and clinical assessments were conducted on 273 patients with MDD (female = 174, male = 99), including the ASEX, QIDS-SR16, GAD-7, and PHQ-15. Univariate analyses, independent samples t-test, Chi-square test, and Fisher's exact test were used as appropriate, and logistic regression analysis was used to identify correlation factors for SD. Statistical analyses were performed using the Statistical Analysis System (SAS 9.4). Result: SD was reported in 61.9% of the participants (ASEX score = 19.6 ± 5.5), and the prevalence of it in females (75.3%, ASEX score = 21.1 ± 5.4) was significantly higher than that in males (38.4%, ASEX score = 17.1 ± 4.6). Factors associated with SD included being female, being aged 45 years or above, having a low monthly income (≤750 USD), feeling more sluggish than usual (a QIDS-SR16 Item 15 score of 1 or above), and having somatic symptoms (evaluated with the total score of PHQ15). Limitation: The use of antidepressants and antipsychotics might be a confounding factor affecting sexual function. Also, the lack of information in the clinical data regarding the number, duration, and time of onset of the episodes limits the richness of the results. Conclusion: Our findings reveal the sex differences in the prevalence and severity of SD in patients with MDD. Evaluated with the ASEX score, female patients showed significantly worse sexual function than male patients. Being female, having a low monthly income, being aged 45 years or above, feeling sluggish, and having somatic symptoms may increase the risk of SD in patients with MDD.

Investigating sleep quality and sleep hygiene awareness among Chinese adults: an association and network analysis study.

PURPOSE: The relationships between sleep quality and sleep hygiene awareness in the Chinese population were unclear. We aimed to investigate the associations and related factors between sleep quality and sleep hygiene awareness in adults and to identify the most central domain for sleep quality using network analysis. METHODS: A cross-sectional survey was conducted from April 22 to May 5, 2020. Adults (18 years old or above) who had access to smartphones were invited to participate in this survey. The Pittsburg Sleep Quality Index (PSQI) and the Sleep Hygiene Awareness and Practice Scale (SHAPS) were used to evaluate the sleep quality and sleep hygiene awareness of the participants. Propensity score matching (PSM) was used as sensitivity analysis to reduce the confounding effects. Multiple logistic regression was performed to evaluate the associations. The R packages "bootnet" and "qgraph" were used to estimate the connection and calculate the network centrality indices between good and poor sleepers. RESULTS: In total, 939 respondents were included in the analysis. Of them, 48.8% (95% CI: 45.6-52.0%) were identified as poor sleepers. Participants with nervous system diseases, psychiatric diseases, and psychological problems were more likely to have poor sleep quality. The notion that using sleep medication regularly was beneficial to sleep was associated with poor sleep quality. Similarly, the notion that waking up at the same time each day disrupted sleep was also associated with poor sleep quality. The findings were consistent before and after PSM. Subjective sleep quality was the most central domain for sleep quality in good and poor sleepers. CONCLUSION: Poor sleep quality was positively associated with certain sleep hygiene notions in Chinese adults. Effective measures such as self-relief, sleep hygiene education, and cognitive behavioral treatment may have been needed to improve sleep quality, especially during the COVID-19 outbreak.

A prospective cohort study of depression (PROUD) in China: rationale and design.

Background: Major depressive disorder (MDD) imposes a heavy global disease burden. However, current etiology, diagnosis and treatment remain unsatisfactory and no previous study has resolved this problem. Building on the strengths and limitations of previous cohort studies of MDD, the prospective cohort study of depression (PROUD) is a 3-year large-scale cohort study designed to collect multidimensional data with a flexible follow-up schedule and strategy. The goal is to establish a nationally representative, high-quality, standardized depression cohort to support precise diagnosis and treatment of MDD and address the gap in current research. Methods: PROUD is a patient-based, nationally representative multicenter prospective cohort study with baseline and 3-year follow-up assessments. It will be carried out from January 2022 to December 2026 in 52 qualified tertiary hospitals in China. A total of 14,000 patients diagnosed with MDD, according to the DSM-5 criteria, and aged ≥ 16 years, will be recruited to PROUD. Participants aged 18-65 years who have not received any treatment during a depressive episode will be included in the precision medicine cohort (PMC) of PROUD (n=4,000). Patients who meet the general eligibility criteria but not the PMC criteria will be included in the naturalistic observation cohort (NOC) of PROUD (n=10,000). A multiple follow-up strategy, including scheduled, remote, telephone, external visits and patient self-reports, will be implemented to collect comprehensive sociodemographic, clinical information, biospecimens, neuroimaging, cognitive function and electrophysiology data and digital phenotypes according to strict standard operating procedures implemented across centers. Trial registration: ChiCTR2200059053, registered on 23 April 2022, http://www.chictr.org.cn/showproj.aspx?proj=165790. Conclusions: PROUD is a prospective cohort study of MDD patients in China. It will provide a comprehensive database facilitating further analyses and aiding the development of homeostatic and precision medicine in China.

Generation and Characterization of ORF55/ORF57-Deleted Recombinant Cyprinid herpesvirus 2 Mutants with Chimeric Capsid Protein Gene of Grouper Nervous Necrosis Virus.

Cyprinid herpesvirus 2 (CyHV-2) is a pathogen that causes significant losses to the global aquaculture industry due to mass mortality in crucian carp and goldfish. This study demonstrates that the ORF55/ORF57 deletion mutants CyHV-2-Δ55-CP and CyHV-2-Δ57-CP obtained through homologous recombination replicate effectively within the caudal fin of Carassius auratus gibelio (GiCF) cells and exhibit morphologies similar to the CyHV-2 wild-type strain. Both mutants demonstrated a decrease in virulence, with CyHV-2-Δ57-CP exhibiting a more significant reduction. This serves as a reference for the subsequent development of recombinant attenuated vaccines against CyHV-2. Additionally, both mutants expressed the inserted RGNNV-CP (capsid protein of Redspotted grouper nervous necrosis virus) fusion protein gene, and inoculation with CyHV-2-Δ57-CP-infected GiCF cell lysates elicited an antibody response in the grouper. These results indicate that, while ORF55 and ORF57 genes of CyHV-2 are not required for viral replication in vitro, they do play a role in virulence in vivo. Additionally, expression of foreign protein in CyHV-2 suggests that the fully attenuated mutant of CyHV-2 could potentially function as a viral vector for developing subunit vaccines or multivalent recombinant attenuated vaccines.

microRNA (miR-KT-635) encoded by Cyprinid herpesvirus 2 regulates the viral replication with targeting to the ORF23.

Herpesviruses have been reported to be able to encode and express functional viral microRNAs that target both viral and cellular transcripts. In our previous studies, we found a new miRNA miR-KT-635 encoded by Cyprinid herpesvirus 2, which is predicted to target viral genes and cellular genes involved in innate immune signalling pathway and apoptosis. However, the function and target gene of miR-KT-635 are not proved. In this study, the regulating target gene of miR-KT-635 was proved as the viral gene ORF23 directly, the target point sequence on gene was verified and miR-KT-635 was identified to regulate the expression of ORF23 protein. According to the bioinformatics analysis, the tRNA domain and ribosome domain in the protein sequence of ORF23 were found to share high homology with R2i and P53R2i, which are related to the ribonucleotide reductase small subunit in the host (transform NTP to dNTP). Within expectations, silencing of viral ORF23 or transfecting miR-KT-635 mimics in Carassius auratus gibelio caudal fin cell line (GiCF) could suppress viral propagation significantly.

Rapid visual detection of Micropterus salmoides rhabdovirus using recombinase polymerase amplification combined with lateral flow dipsticks.

Largemouth bass (Micropterus salmoides) is an important freshwater-cultured species in China. Recently, a lethal and epidemic disease caused by Micropterus salmoides rhabdovirus (MSRV) results in huge economic losses to the largemouth bass industry. Current diagnostics for detecting MSRV are limited in sensitivity and speed and are inconvenient to be used for non-laboratory detection. In this study, three rapid and convenient detection assays of MSRV by recombinase polymerase amplification (RPA) and lateral flow dipsticks (LFD), targeting the conserved sequences of the MSRV-SS N gene, are described. With these RPA methods, the detection could achieve within 50 min at 38°C. Both methods of RPA-AGE and RPA-LFD could detect the viral DNA as low as 170 copies/µl of the MSRV standard plasmid and were 100-fold more sensitive than that in the method of routine PCR. Meanwhile, these RPA methods were highly specific for the detection of MSRV and can be feasibly applied to the diagnostic of MSRV infection. In brief, RPA-AGE, RPA-LFD and RT-RPA-LFD provide convenient, rapid, sensitive and reliable methods that could improve field diagnosis of MSRV with limited machine resources, and would enhance the production of largemouth bass.

Integrated analysis of viral miRNAs, mRNA and protein in the caudal fin cells of C. auratus gibelio with cyprinid herpesvirus 2 infection.

Cyprinid herpesvirus 2 (CyHV-2), a member of the genus Cyprinivirus in the family Alloherpesviridae, has attracted worldwide attention because it causes severe disease and high mortality in crucian carp and goldfish. In this study, we focus on mRNA, protein and viral miRNA expression profiles in C. auratus gibelio caudal fin (GiCF) cells infected with CyHV-2, using high-throughput sequence techniques and TMT-labelled analyses. The results revealed that 156 virus genes were differentially expressed during the infection. Among these differentially expressed genes, 7 viral genes were significantly up-regulated and 28 were significantly down-regulated at 96 hpi (hours post-infection) vs 48 hpi. Besides, a total of 78 viral proteins, including a large number of membrane proteins and capsid proteins associated with the viral assembly, were successfully detected by using proteome analysis. Furthermore, a total of 225,143,474 raw reads were generated from cDNA library of CyHV-2-infected GiCF cells using high-throughput sequencing technology. Following annotation and secondary structure prediction, 10 viral miRNAs were found as significantly modulated in CyHV-2-infected GiCF cells (2 down-regulated and 8 up-regulated). Finally, the CyHV-2 genes (orf19, orf23, orf118, orf121, orf127) targeted by the viral miRNA CyHV-2-KT-635 identified in this study, were predicted and validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and the regulation of CyHV-2-KT-635 on orf121 protein expression was verified by western blotting assay. Taken together, this study provides a valuable basis for further research on the expression of virus genes during CyHV-2 replication and the molecular mechanisms by which miRNA may regulate CyHV-2 virus.

Expression and regulation of ccBAX by miR-124 in the caudal fin cell of C. auratus gibelio upon cyprinid herpesvirus 2 infection.

Bcl2 family proteins play a critical role in cell death or survival. BAX, the death-promoting protein of bcl2 family, mediated mitochondrial pathway inducing cells' apoptosis in mammal. MiRNAs have been implicated as negative regulators down-regulating genes' expression after post-transcriptional level. At present, little is known about the regulatory mechanism of miRNA on the Bcl2 family proteins during CyHV-2 infection in silver crucian carp (Carassius auratus gibelio). In this study, the ccBAX (silver crucian carp BAX) gene was cloned and expressed, and polyclonal antibodies were raised in mouse against the purified ccBAX-GST fusion protein. The structure analysis indicated that ccBAX protein included four conserve domains (BH1, BH2, BH3 and transmembrane domains) and the expression of ccBAX protein occurred throughout the cells. Furthermore, two miRNAs (miR-124 and miRNA-29b) were identified to negatively regulate ccBAX gene expression in GiCF cell. miR-124 was found to suppress the expression of WT-ccBAX (wild type), but not the MT-ccBAX (mutant). Overall, the results demonstrated that the expression of the ccBAX gene was significantly down-regulated by miR-124 in silver crucian carp (Carassius auratus gibelio) during CyHV-2 infection.

Transcriptomic and proteomic analyses reveal new insights into the regulation of immune pathways during cyprinid herpesvirus 2 infection in vitro.

Carassius auratus gibelio is susceptible to the herpesviral hematopoietic necrosis (HVHN) disease caused by cyprinid herpesvirus 2 (CyHV-2) infection during the breeding process. Nevertheless, the report on biological response of CyHV-2 with C. auratus gibelio was limited, especially in vitro. In this study, host gene expression profiling was mostly analyzed in caudal fin cells of Carassius auratus gibelio (GiCF) underlying CyHV-2 infection. Transcriptomics and proteomics were employed to study the differential expression gene and revealed the host genes involved in pathway during the CyHV-2 infection. Transcriptome analysis revealed that compared with the control group, there were 11 335 and 19 421 differentially expressed unigenes at 48 h and at 96 h, respectively. Furthermore, proteome analysis showed that there were a total of 9008 proteins, among which 169 proteins were differential expression in the 48 h group and 502 proteins in the 96 h group. Notably, 10 and 158 differentially co-expressed genes at mRNA and protein levels (cDEGs) were reliably quantified at 48 h and 96 h, respectively. Interestingly, significantly different expressed genes both in the transcriptome and the proteome were identified, including GNG7, Hsp90a, THBS1 and RRM2. The result suggested that PI3k-AKT pathway was activated, but the p53 signaling pathway was suppressed. The above result will lay the foundation for understanding the mechanisms of host defense virus invasion during CyHV-2 infection.

MicroRNA expression profiling of caudal fin cell of C. auratus gibelio upon cyprinid herpesvirus 2 infection.

As a member of the genus Cyprinivirus in the family Alloherpesviridae, Cyprinid herpesvirus 2 (CyHV-2) has caused great economic loss in the aquaculture industry, mainly in C. auratus gibelio and goldfish. However, the molecular mechanisms underlying the pathogenicity of CyHV-2 remain elusive. In this study, high-throughput sequencing technology was employed to explore the miRNA expression profiles of C. auratus gibelio (GiCF) caudal fin cells in response to Cyprinid Herpesvirus-2 (CyHV-2) infection. A total of 631 novel miRNAs and 409 known miRNAs were identified. The expression levels of 7 miRNAs were found as significantly modulated (5 down-regulation and 2 up-regulation; P < 0.01, |logFC|>1, TPM>10) in CyHV-2 infected cells. 7 miRNA and their potential mRNA targets were validated by Real-time PCR (qRT-PCR), respectively. Targets prediction and functional analysis of these 7 miRNAs revealed significant enrichment for several signaling pathways, including PPAR, p53 and FoxO pathways. These studies provided more valuable basis for further study on the roles of miRNAs in CyHV-2 replication and pathogenesis.