Preparation of Methyltriazolo[1,4]benzodiazepine via Oxidative Activation of a Thiolactam for the Synthesis of BET Inhibitor Molibresib.

A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.

Aberrant cortical surface and cognition function in drug-naive first-episode schizophrenia.

OBJECTIVE: Impaired cognitive function is a central symptom of schizophrenia and is often correlated with inferior global functional outcomes. However, the role of some neurobiological factors such as cortical structure alterations in the underlying cognitive damages in schizophrenia remains unclear. The present study attempted to explore the neurobiomarkers of cognitive function in drug-naive, first-episode schizophrenia by using structural magnetic resonance imaging (MRI). METHODS: The present study was conducted in patients with drug-naive, first-episode schizophrenia (SZ) and healthy controls (HCs). MRI T1 images were pre-processed using CAT12. Surface-based morphometry (SBM) was utilised to evaluate structural parameters such as cortical thickness and sulcus depth. The positive and negative syndrome scale (PANSS) and Chinese version of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive battery (MCCB) were employed to estimate the psychotic symptoms and cognition, respectively. RESULTS: A total of 117 patients with drug-naive first-episode schizophrenia (SZ) and 98 healthy controls (HCs) were included. Both the cortical thickness and sulcus depth in the frontal lobe were lower in patients with SZ than in the HCs under family-wise error correction (p < 0.05). Attention and visual learning in MCCB were positively correlated with the right lateral orbitofrontal cortical thickness in the patients with SZ (p < 0.01). CONCLUSIONS: The reduced surface value of multiple cortical structures, particularly the cortical thickness and sulcus depth in the frontal lobe, could be the potential biomarkers for cognitive impairment in SZ.

Screening of the college students at clinical high risk for psychosis in China: a multicenter epidemiological study.

BACKGROUND: To investigate a 3-stage screening procedure and explore the clinical features of subjects at Clinical High Risk (CHR) for psychosis in a representative sample of Chinese college students. METHODS: An epidemiological survey of the prevalence of the CHR syndrome in Chinese college students that was selected by stratified random sampling from Shanghai, Nanjing and Nanchang cities was done following a 3-stage procedure. Participants were initially screened with the Prodromal Questionnaire-brief version (PQ-B), and whose distress score of PQ-B exceeded 24 would be invited to a telephone assessment using the subscale for positive symptoms of the Scale of Prodromal Symptoms (SOPS)/Structured Interview for Prodromal Syndromes (SIPS). Lastly, participants who scored 3 or higher in any item of the subscale would be administered with the SIPS interview conducted by trained researchers to confirm the diagnosis of CHR syndrome. RESULTS: Twenty-three thousand sixty-three college students completed the survey during September 2017 to October 2018. Seventy-two students were diagnosed as CHR subjects, and the detection rate in the total sample was 0.3%. The peak age range for the first diagnosis of CHR was 17 to 20 years. Thirteen and forty-six were set as the cutoff points of PQ-B total score and distress score to balance the greatest sensitivity and specificity. Binary logistic regression revealed that 8 items in PQ-B showed significant distinction for detecting CHR subjects. CONCLUSIONS: The 3-stage screening method can be utilized in the detection of CHR subjects for psychosis in the general population, during which delusional ideas, perceptual abnormalities and suspiciousness deserve great attention.

Relationships between abnormal neural activities and cognitive impairments in patients with drug-naive first-episode schizophrenia.

BACKGROUND: Prior resting state functional Magnetic Resonance Imaging studies (rs-fMRI) via the regional homogeneity (ReHo) method have demonstrated inconsistent and conflicting results because of several confounding factors, such as small sample size, medicinal influence, and illness duration. Relationships between ReHo measures and cognitive impairments in patients with drug-naive First-Episode Schizophrenia (dn-FES) are rarely reported. This study was conducted to explore the correlations between ReHo measures and cognitive deficits and clinical symptoms in patients with dn-FES. METHODS: A total of 69 patients with dn-FES and 74 healthy controls were recruited. MATRICS Consensus Cognitive Battery (MCCB), Wechsler Adult Intelligence Scale (WAIS), and Positive And Negative Syndrome Scale (PANSS) were used to assess cognitive function, Intelligence Quotient (IQ), and clinical symptoms, respectively. The correlations between ReHo maps and cognitive deficits and the severity of symptoms were examined using strict correlation analysis. RESULTS: ReHo values in right Middle Frontal Gyrus (MFG) and Superior Frontal Gyrus (SFG) increased in dn-FES group, whereas ReHo values in right cuneus decreased. Correlation analysis showed that the ReHo values in right MFG positively correlated with attention/vigilance impairments, social cognition deficits, and the severity of clinical manifestations. CONCLUSIONS: These findings suggested that abnormal spontaneous activities in right MFG reflect illness severity and cognitive deficits, which also serve as a basis for establishing objective diagnostic markers and might be a clinical intervention target for treating patients with schizophrenia.

Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia.

AIM: The aim of the present study was to evaluate the efficacy and safety of lurasidone for the treatment of Chinese schizophrenic patients. METHODS: Hospitalized schizophrenia patients aged 18-65 were randomized to 6 weeks of double-blind, double-dummy, flexible-dose treatment with lurasidone (40 or 80 mg/day) or risperidone (2, 4 or 6 mg/day). Efficacy was evaluated using a non-inferiority comparison of lurasidone relative to risperidone based on week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score. Safety assessments included adverse events, clinical laboratory measures, and electrocardiograms. RESULTS: Four hundred and forty-four patients were screened to obtain an intent-to-treat sample of 384 patients, of whom 54 patients discontinued treatment prior to 6 weeks. Lurasidone met the criteria for non-inferiority versus risperidone on the PANSS total score. Adjusted mean (SE) change at week 6 on the PANSS total score was -31.2 (1.0) and -34.9 (1.0) in the lurasidone and risperidone group, respectively. The mean difference score was 3.7, and the upper boundary of the 95%-confidence interval (1.0-6.3) was less than the prespecified margin of 7.0. No clinically meaningful between-treatment group differences were evident on secondary efficacy measures, including PANSS positive, PANSS negative, Clinical Global Impression scale - Severity, and Calgary Depression Scale for Schizophrenia scales. The incidence of adverse events was lower for lurasidone vs risperidone for extrapyramidal symptoms (17.0% vs 38.2%), akathisia (7.2% vs 13.6%), prolactin increase (3.1% vs 14.1%), and weight increase (0.5% vs 5.2%). CONCLUSION: Lurasidone was found to be non-inferior to risperidone on the primary endpoint with minimal effects on weight, metabolic parameters, or prolactin levels.

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis.

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.

Prescription practices in the treatment of agitation in newly hospitalized Chinese schizophrenia patients: data from a non-interventional naturalistic study.

BACKGROUND: Data on the pharmacological management of acute agitation in schizophrenia are scarce. The aim of this study is to investigate the prescription practices in the treatment of agitation in Chinese patients with schizophrenia. METHODS: We conducted a large, multicenter, observational study in 14 psychiatry hospitals in China. Newly hospitalized schizophrenia patients with the PANSS-EC total score ≥ 14 and a value ≥4 on at least one of its five items were included in the study. Their drug treatments of the first 2 weeks in hospital were recorded by the researchers. RESULTS: Eight hundred and 53 patients enrolled in and 847 (99.30%) completed the study. All participants were prescribed antipsychotics, 40 (4.72%) were prescribed benzodiazepine in conjunction with antipsychotics and 81 were treated with modified electric convulsive therapy (MECT). Four hundred and 12 (48.64%) patients were prescribed only one antipsychotic, in the order of olanzapine (120 patients, 29.13%), followed by risperidone (101 patients, 24.51%) and clozapine (41 patients, 9.95%). About 435 (51.36%) participants received antipsychotic polypharmacy, mostly haloperidol + risperidone (23.45%), haloperidol+ olanzapine (17.01%), olanzapine+ ziprasidone (5.30%), haloperidol + clozapine (4.37%) and haloperidol + quetiapine (3.90%). Binary logistic regression analysis suggests that a high BARS score (OR 2.091, 95%CI 1.140-3.124), severe agitation (OR 1.846, 95%CL 1.266-2.693), unemployment or retirement (OR 1.614, 95%CL 1.189-2.190) and aggressiveness on baseline (OR 1.469, 95%CL 1.032-2.091) were related to an increased antipsychotic polypharmacy odds. Male sex (OR 0.592, 95%CL 0.436-0.803) and schizophrenia in older persons (age ≥ 55 years, OR 0.466, 95%CL 0.240-0.902) were less likely to be associated with antipsychotic polypharmacy. CONCLUSION: The present study demonstrates that monotherapy and polypharmacy display equally common patterns of antipsychotic usage in managing agitation associated with schizophrenia in China. The extent and behavioral activities of agitation and several other factors were associated with polypharmacy.

[Breakthrough Point of Chinese Medicine and Pharmacy for HIV/AIDS Prevention and Treatment in the Post-HAART Period].

HIV/AIDS is a severe infectious disease with ineffective drug or method found till now. Highly active antiretroviral therapy (HAART) is a treatment method widely internationalized. Its coverage populations are continually expanding due to its definite clinical effect. AIDS prevented and treated by Chinese medicine and pharmacy has ever been reported. Especially early intervention of Chinese medicine syndrome differentiation based treatment can delay the process of HIV-infected subjects' entry into AIDS in AIDS asymptomatic phase. However, it has great significance of clinical and basic researches in the following 4 aspects: (1) attenuating toxic/adverse reactions of HAART; (2) improving clinical effects of HAART; (3) lowering resistance rate of HAART; and (4) treating common opportunistic infections of AIDS in the post-HAART period.

Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A.

HCV NS5B polymerase inhibitor GSK852A (1) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (3) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core 15 from the ß-keto ester in one pot and the efficient conversion of ester 6 to amide 19 via enamine lactone 22. Serendipitous events led to identification of the isolable enamine lactone intermediate 22. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone 22. The hydrogen bond was considered an enabler in the proposed pathway from ester 6 to enamine lactone 22 and its rearrangement to amide 19. GSK852A (1) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of 1. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same ß-keto ester in 5% yield over 13 steps.

[Efficacy and safety of a combined oral contraceptive containing drospirenone 3 mg and ethinylestradiol 20 µg in the treatment of premenstrual dysphoric disorder: a randomized, double blind placebo-controlled study].

OBJECTIVE: To compare the efficacy and safety of a new low-dose oral contraceptive pill (YAZ) containing drospirenone 3 mg and ethinylestradiol 20 µg with placebo in reducing symptoms of premenstrual dysphoric disorder (PMDD). METHODS: This multicenter, double- blind, randomized clinical trial consisted of 2 run- in and 3 treatment cycles (84 days) with daily symptom charting; 187 women with symptoms of PMDD were randomized to either placebo group (n = 94) or YAZ group (n = 93), and assessed with daily record of severity of problems scale (DRSP) and clinical global impressions scale (CGI) before, during and after the treatments. Hormones were administered for 24 days, followed by 4 days of inactive pills. RESULTS: Compared with baseline level of DRSP, both groups got improvement after treatment; the YAZ group (median -28.7, range: -82.5 to 2.3) had greater improvement than that in the placebo group (median -23.7, range: -86.0 to 11.8), while there was not significant difference (P > 0.05). The main adverse effects of YAZ included intermenstrual bleeding [13% (12/93) versus 3% (3/94)], menorrhagia [9% (8/93) versus 1% (1/94)], nausea [5% (5/93) versus 4% (4/94)] and skin rash [4% (4/93) versus 2% (2/94)]. CONCLUSIONS: YAZ could improve symptoms of PMDD better than placebo, while without statistic significance in this study. The most common adverse effects are intermenstrual bleeding, menorrhagia, nausea and rash.

Causal associations between prostate diseases, renal diseases, renal function, and erectile dysfunction risk: a 2-sample Mendelian randomization study.

Background: Previous observational studies have found a potential link between prostate disease, particularly prostate cancer (PCa), and kidney disease, specifically chronic renal disease (CKD), in relation to erectile dysfunction (ED), yet the causal relationship between these factors remains uncertain. Aim: The study sought to explore the potential causal association between prostate diseases, renal diseases, renal function, and risk of ED. Methods: In this study, 5 analytical approaches were employed to explore the causal relationships between various prostate diseases (PCa and benign prostatic hyperplasia), renal diseases (CKD, immunoglobulin A nephropathy, membranous nephropathy, nephrotic syndrome, and kidney ureter calculi), as well as 8 renal function parameters, with regard to ED. All data pertaining to exposure and outcome factors were acquired from publicly accessible genome-wide association studies. The methods used encompassed inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode residual sum and outlier techniques. The MR-Egger intercept test was utilized to assess pleiotropy, while Cochran's Q statistic was employed to measure heterogeneity. Outcomes: We employed inverse variance weighting MR as the primary statistical method to assess the causal relationship between exposure factors and ED. Results: Genetically predicted PCa demonstrated a causal association with an elevated risk of ED (odds ratio, 1.125; 95% confidence interval, 1.066-1.186; P < .0001). However, no compelling evidence was found to support associations between genetically determined benign prostatic hyperplasia, CKD, immunoglobulin A nephropathy, membranous nephropathy, nephrotic syndrome, kidney ureter calculi, and the renal function parameters investigated, and the risk of ED. Clinical Implications: The risk of ED is considerably amplified in patients diagnosed with PCa, thereby highlighting the importance of addressing ED as a significant concern for clinicians treating individuals with PCa. Strengths and Limitations: This study's strength lies in validating the PCa-ED association using genetic analysis, while its limitation is the heterogeneity in study results. Conclusion: The results of this study suggest a potential link between PCa and a higher risk of ED.

Gender differences in cognitive improvements after two months of atypical antipsychotic treatment in first episode schizophrenia.

Aims: This study aims to explore the gender differences in cognitive improvements after two months of atypical antipsychotic treatment in first episode schizophrenia (FES). Methods: 82 patients with FES, including 50 male patients and 32 female patients, were enrolled in the present study. Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) were respectively conducted to evaluate the clinical symptoms and cognitive function of patients with FES at baseline and after treatment. Repeated measure ANOVA was performed to compare gender differences in cognitive domains scores between baseline and 2-month follow-up. Stepwise liner regression model was performed to explore the effect factors of cognitive improvements in patients. Results: There was no significant difference in age of onset, education years, PANSS scores, duration of untreated psychosis and Olanzapine equivalent doses between male and female patients (all p > 0.05). In the comparisons of cognition function, male patients exhibited better performance in social cognition compared with female patients at baseline (t = 3.20, p < 0.05). After treatment, improvements of attention/vigilance and working memory were both found in male patients and female patients (attention/vigilance, F = 11.867, p < 0.05; working memory, F = 18.265, p < 0.05). In addition, improvement of speed of information processing was only found in female patients (F = 11.65, p < 0.01). Significant interaction between time and gender was found in speed information of processing (F = 4.140, p = 0.045). Stepwise liner regression model revealed that improvements of negative symptoms promote improvements of cognitive function in female patients (all p < 0.05). Conclusions: Our findings revealed gender differences of cognitive improvements in patients with FES after 2-month treatment. It provides new evidence for gender differences in cognitive symptoms of schizophrenia, and also provides preliminary clues for further individualized cognitive intervention strategies.

Association between increased BMI and cognitive function in first-episode drug-naïve male schizophrenia.

Objective: Although the adverse effects of obesity in schizophrenia are documented, there is limited research exists on the implications for untreated initial schizophrenia. Our investigation aimed to explore the connections between BMI and cognitive function in first-episode drug-naïve (FEDN)schizophrenia. Methods: We enrolled 143 FEDN schizophrenia patients, and collected data on their body mass index, fasting blood glucose and lipid levels. Cognitive function was measured with the MATRICS Consensus Cognitive Battery (MCCB). Using correlation and regression analysis to assess the relationship between BMI and cognitive performance. Results: The prevalence rate of overweight plus obesity in FEDN schizophrenia patients was 33.57%. Patients with FEDN schizophrenia exhibited extensive cognitive impairment, and those who were overweight/obesity demonstrated more severe impairments in working memory and visual learning when compared to normal/under weight counterparts. Correlation analysis indicated a negative association between working memory and BMI and TG, as well as a link between visual learning and BMI and LDL-C. Multiple linear regression analysis revealed that a higher BMI predicted a decrease in working memory in FEDN schizophrenia patients. Conclusion: Our results indicate that the rate of overweight plus obesity is high in FEDN schizophrenia patients, and there is an association between BMI and cognitive function in schizophrenia, particularly in relation to working memory.

Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia.

Intramuscular (IM) antipsychotics are preferred for efficient control of agitation symptoms. Previous studies have demonstrated that IM ziprasidone is efficacious and safe for treatment of agitation in schizophrenia. However, clinicians now recognize that racial differences may contribute to altered therapeutic response and tolerability. This study compared the efficacy and tolerability of IM ziprasidone versus IM haloperidol for the management of agitation in Chinese subjects with schizophrenia. Subjects with acute schizophrenia were randomized to either ziprasidone (n = 189, 10 to 20 mg as required up to a maximum of 40 mg/d) or haloperidol (n = 187, 5 mg every 4 to 8 hours to a maximum of 20 mg/d) for 3 days. Psychiatric assessments and adverse events were assessed at baseline, 2, 4, 24, 48, and 72 hours. In the ziprasidone group, 2.1% of subjects discontinued versus 3.7% in the haloperidol group. The least squares mean change (SE) from baseline to 72 hours in Brief Psychiatry Rating Scale total score was -17.32 (0.7) for ziprasidone (n = 167) and -18.44 (0.7) for haloperidol (n = 152), with a 95% confidence interval treatment difference of -0.7 to 2.9. Fewer subjects experienced adverse events after ziprasidone (n = 54, 28.6%) than haloperidol (n = 116, 62.0%), with a notably higher incidence of extrapyramidal symptoms in the haloperidol group (n = 69, 36.9%) compared to the ziprasidone group (n = 4, 2.1%). For controlling agitation in schizophrenia in this Chinese study, ziprasidone had a favorable tolerability profile and comparable efficacy and safety compared to haloperidol.

Synthesis of HCV replicase inhibitors: base-catalyzed synthesis of protected α-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde.

A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1-5 is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a α-hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs 1-5. The bis-BOC α-hydrazino esters 25 and 33 were prepared by addition of ester enolates (from 23 and 32) to di-tert-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li2CO3. A selective aerobic oxidation with catalytic 5% Pt-Bi/C in aqueous KOH was developed to provide the dicarbaldehyde 20 from the diol 27.

[Research on rules of distribution and development of traditional Chinese medicine syndromes of 2,237 HIV/AIDS cases].

HIV/AIDS patients in high prevalence areas with different routes of infection (sexually transmitted 878 cases, 527 cases of intravenous drug user, paid blood donor 652 cases) were choosen for traditional Chinese medicine (TCM) syndrome investigation for one-year clinical follow-up. This paper primarily concluded the nature, location and pathogenesis of AIDS diseases. Deficiency of Yang and Yin, combining deficiency of Qi are the basic deficiency syndromes, while stagnation of dampness, toxic fire are the excess syndromes; the disease location of HIV infector is spleen, main syndrome is deficiency of spleen Qi; the disease location of AIDS patient is kidney, main syndrome is deficiency of spleen and kidney Yang. The pathogenic development tendency is from deficiency of Qi to combining stagnation of dampness and toxic fire, finally to deficiency of Qi and Yin, deficiency of Yang.

Shared and distinct structural brain alterations and cognitive features in drug-naïve schizophrenia and bipolar disorder.

Our study aimed to examine the shared and distinct structural brain alterations, including cortical thickness(CT) and local gyrification index(LGI), and cognitive impairments between the early course stage of drug-naïve schizophrenia(SZ) and bipolar disorder(BD) patients when compared to healthy controls(HCs), and to further explore the correlation between altered brain structure and cognitive impairments. We included 72 SZ patients, 35 BD patients and 43 HCs. The cognitive function was assessed using the MATRICS Consensus Cognitive Battery. Cerebral cortex analyses were performed with FreeSurfer. Furthermore, any structural aberrations related to cognition impairments were examined. Cognitive impairments existed in SZ and BD patients and were much more severe and widespread in SZ patients, compared to HCs. There were no significant differences in LGI among three groups. Compared to HCs, SZ had thicker cortex in left pars triangularis, and BD showed thinner CT in left postcentral gyrus. In addition, BD showed thinner cortex in left pars triangularis, left pars opercularis, left insula and right fusiform gyrus compared to SZ. Moreover, our results indicated that CT in many brain areas were significantly correlated with cognitive function in HCs, but only CT of left pars triangularis was correlated with impaired social cognition found in SZ. The findings suggest that changes of CT in the left pars triangularis and left postcentral gyrus may be potential pathophysiological mechanisms of the cognition impairments in SZ and BD, respectively, and the divergent CT of partly brain areas in BD vs. SZ may help distinguish them in early phases.

A phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to verify the efficacy and safety of ansofaxine (LY03005) for major depressive disorder.

Major depressive disorder (MDD) is the most prevalent form of depression and is becoming a great challenge for public health and medical practice. Although first-line antidepressants offer therapeutic benefits, about 35% of depressed patients are not adequately treated, creating a substantial unmet medical need. A multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial was conducted in patients with MDD in China to assess the efficacy and safety of ansofaxine (LY03005), a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. Eligible 588 MDD patients were included and randomly assigned (1:1:1) to 8-week treatment with ansofaxine 80 mg/day(n = 187), ansofaxine 160 mg/day(n = 186), or placebo(n = 185). The primary efficacy endpoint was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to the end of the study. Safety indexes included adverse events, vital signs, physical examination, laboratory tests, 12-lead electrocardiogram (ECG), and evaluation of suicide tendency and sexual function. Significant differences were found in mean changes in MADRS total score at week 8 in the two ansofaxine groups (80 mg, -20.0; 160 mg, -19.9) vs. placebo (-14.6; p < 0.0001). All doses of ansofaxine were generally well-tolerated. Treatment-emergent adverse events (TEAEs) were reported by 137 (74.46%) patients in ansofaxine 80 mg group, 144 (78.26%) patients in ansofaxine 160 mg and 125 (67.93%) patients in the placebo group. The incidence of treatment-related adverse events (TRAEs) was 59.2% (109 patients), 65.22% (120 patients) in the 80, 160 mg ansofaxine groups, and 45.11% (83 patients) in the placebo group. The initial results of this trial indicate that ansofaxine at both the 80 mg/day and 160 mg/day was effective and safe in adult patients with MDD. ClinicalTrials.gov Identifier: NCT04853407.

Data-driven learning to identify biomarkers in bipolar disorder.

BACKGROUND AND OBJECTIVE: Bipolar disorder (BD) is one of the primary causes of disability globally and can be easily misdiagnosed as schizophrenia or major depression due to their similar symptoms. Hence, it is of great significance to explore the pathogenesis of BD. Statistical analysis is currently the most common method for exploring the neuropathological mechanisms of psychiatric disorders. However, this method only considers the relationship between groups and does not reflect the individual-level diagnosis. Therefore, we developed machine learning algorithms to measure pathological brain changes in psychiatric disorders. METHODS: An autoencoder and a feature selection method are proposed to identify the abnormal structural patterns of BD in this study. The autoencoder was constructed using structural imaging data from 1113 healthy controls, which aims to define the normal range of anatomical deviations to distinguish healthy individuals from BD patients. The biomarkers of BD were identified by the reconstruction errors in each brain region. The proposed feature selection (FS)-select framework aimed to determine the optimal FS method and identify the most reproducible feature associated with BD. RESULTS: We found that the left orbital region of the middle frontal gyrus had the greatest difference between healthy controls and BD patients using a trained autoencoder. The most reproducible feature was the left orbital region of the middle frontal gyrus by FS-select framework when using the different cross-validation strategies. CONCLUSIONS: A consistent result was obtained from the above two proposed methods wherein a significant difference between healthy controls and BD patients was identified in the left orbital region of the middle frontal gyrus.

Global functioning, cognitive function, psychopathological symptoms in untreated patients with first-episode schizophrenia: A cross-sectional study.

Although many studies have been conducted on the relationship between cognitive functioning, psychopathological symptoms, and global functioning in patients with schizophrenia, these studies frequently suffer from a lack of control for confounding variables, high attrition rates, and a lack of cognitive domains completed at each assessment point. The purpose of this study is to select patients with untreated first-episode schizophrenia to investigate the relationship between psychopathological symptoms, cognitive functioning, and global functioning. A total of 117 untreated first-episode schizophrenia patients were evaluated using the global assessment functions (GAF), the Positive And Negative Syndrome Scale (PANSS), the MATRICS Consensus Cognitive Battery (MCCB), and some social and role functional parameters. The GAF, PANSS, and MCCB scores of 117 patients were significantly lower than normal. Multiple stepwise linear regression analysis revealed that the negative symptom factor, positive symptom factor, excitation-hostility factor, and attention/vigilance were all independent factors influencing global functioning. Our findings show that the negative symptom factor, the positive symptom factor, the excitement hostility factor, and attention/vigilante are all independent risk factors for GAF in first-episode schizophrenia. The negative symptom factor had the most noticeable effect among these influencing factors, followed by the positive symptom factor, the excitement hostility factor, and attention/vigilance in that order.