Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders – A comprehensive systematic review and meta-analysis

ObjectiveAntipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effect and safety of anti-inflammatory add-on treatment on psychotic disorders is lacking.MethodMultiple databases were searched up until February 2020. Only double-blinded, randomized, placebo-controlled clinical trials (RCTs) were included. Primary outcomes were change in total psychopathology and adverse events. Secondary outcomes included, amongst others, positive and negative symptoms, general psychopathology and cognitive domains. We performed random-effects meta-analyses estimating mean differences (MD) and standardized mean differences (SMD) for effect sizes.ResultsSeventy RCTs (N = 4104) were included, investigating either primarily anti-inflammatory drugs, i.e. drugs developed for immunomodulation, such as NSAIDs, minocycline and monoclonal antibodies (k = 15), or drugs with potential anti-inflammatory properties (k = 55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI = -5.93 to -3.20) points, corresponding to a SMD effect size of -0.29 (95%CI = -0.40 to -0.19). Trials on schizophrenia (MD = -6.80; 95%CI, -9.08 to -4.52) showed greater improvement (p < 0.01) than trials also including other psychotic disorders. However, primarily anti-inflammatory drugs (MD = 4.00; 95%CI = -7.19 to -0.80) were not superior (p = 0.69) to potential anti-inflammatory drugs (MD = 4.71; 95%CI = -6.26 to -3.17). Furthermore, meta-regression found that smaller studies showed significantly larger effect sizes than the larger studies (p = 0.0085), and only 2 studies had low risk of bias on all domains. Small but significant effects were found on negative symptoms (MD = -1.29), positive symptoms (MD = -0.53), general psychopathology (MD = -1.50) and working memory (SMD = 0.21). No differences were found regarding adverse events, but only 26 studies reported hereon.ConclusionsAnti-inflammatory add-on treatment to antipsychotics showed improvement of psychotic disorders; however, no superiority was found in primarily anti-inflammatory drugs, raising the question of the mechanism behind the effect, and treatment effect might be overestimated due to the large number of small studies.     

Are there gender differences in the severity and consequences of sleep disordered in children?

ObjectivesIn adults there is a distinct gender difference in the prevalence and severity of sleep disordered breathing (SDB), however there have been limited studies examining the effects of gender in children with SDB. We aimed to compare the effects of gender on severity of SDB, blood pressure, sleep and respiratory characteristics, quality of life, behavior and executive function.MethodsWe included 533 children aged 3–18 years, who underwent standard pediatric overnight polysomnography (PSG) between 2004 and 2016. Blood pressure was recorded prior to each study. Quality of life, behavior and executive function were assessed with parental questionnaires. Children were grouped by gender and SDB severity based on their obstructive apnea hypopnea index (OAHI) into non-snoring controls, Primary Snoring (PS) (OAHI≤1 event/h), Mild obstructive sleep apnea (OSA) (OAHI>1-≤5 events/h) and moderate/severe (MS) OSA (OAHI>5 events/h) and data compared with 2-way ANOVA.ResultsA total of 298 boys and 235 girls were studied. There were no differences in age, BMI z-score, SDB severity sleep characteristics or blood pressure between genders. Diastolic blood pressure was elevated in females with MS OSA compared to males (P < 0.05). Quality of life, behavior and executive function scores were all elevated in the SDB groups compared to controls. Females with MS OSA exhibited more internalizing behavioral problems compared to males (59.2 ± 2.4 vs. 51.4 ± 2.3, P < 0.05).ConclusionsIn contrast to studies in adults, we identified no gender differences in the severity or consequences of SDB in children, other than females with moderate-severe OSA exhibiting more internalizing problems and higher diastolic blood pressure.     

Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease: an updated meta-analysis

The objective of this study was to provide an updated meta-analysis of the efficacy and safety of huperzine A (HupA) in Alzheimer’s disease (AD). We searched for randomized trials comparing HupA with placebo in the treatment of AD. The primary outcome measures were mini-mental state examination (MMSE) and activities of daily living scale (ADL). Data were extracted from four randomized clinical trials and analyzed using standard meta-analysis and meta-regression methods. Oral administration of HupA for 8–24 weeks (300–500 μg daily) led to significant improvements in MMSE and ADL. The results of meta-regression showed that the estimated effect size of MMSE and ADL was increased over the treatment time. Most adverse events were cholinergic in nature and no serious adverse events occurred. Huperzine A is a well-tolerated drug that could significantly improve cognitive performance and ADL in patients with AD. B.-s. Wang and H. Wang contributed equally to this work.     

New anticoagulants in the treatment of stroke： future promise

Recent evidence is leading to the replacement of vitamin K antagonists, the efficacy of which in preventing stroke in patients with atrial fibrillation （AF） is well established, with better tolerated and more manageable new anticoagulant drugs, with a lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments. Among new anticoagulants, dabigatran etexilate is a direct, competitive inhibitor of thrombin. It was evaluated for patients with AF in the RE-LY trial, showing lower rates of stroke and systemic embolism at a dose of 150 mg twice daily with similar rates of major hemorrhage compared with warfarin; and non-inferiority compared with warfarin for the prevention of stroke and systemic embolism at a dose of 110 mg twice daily, with lower rates of major bleeding. Beside dabigatran, oral factor X a inhibitors are also emerging for the prevention of thromboembolic events in AF. Despite the obvious advantages of these new oral anticoagulants over vitamin K antagonists, further information is still needed on how to prioritize the patients deriving the greatest benefit from these novel agents on the basis of patient characteristics or drug pharmacokinetics. There is also a need for assessing their long-term efficacy and safety over decades in the real-world setting.     

How can we improve the assessment of safety in child and adolescent psychopharmacology?

OBJECTIVE: To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents. METHOD: Strengths and limitations of current methodology were reviewed and possible alternatives examined. RESULTS: Research on the validity of safety evaluation has been extremely limited. No evidence-based "gold standard" exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such as mining of large databases, must be considered. CONCLUSION: The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common "core," to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed.     

Efficacy and safety of interferon beta-1b sc in older RRMS patients—a posthoc analysis of the BEYOND study

Evidence of a significant improvement of IFNB-1b in clinical severity in the older population with RRMS has not been established so far. The aim of this exploratory post hoc analysis of the 250 mcg IFNB-1b group of the BEYOND study is to compare the efficacy and safety of older versus younger patients using a cut-off at the age of 50 and at the age of 40, respectively. There was no difference between age groups in adjusted relapse risk (age 50 cut-off: P = 0.482, age 40 cut-off: P = 0.073) nor in adjusted time to confirmed EDSS progression (age 50 cut-off: P = 0.096, age 40 cut-off: P = 0.189). There were no significant differences between patients <50 and ≥50 years in the adjusted annualized relapse rate (P = 0.285), whereas relapse rate was higher in the <40 as compared to the ≥40 group (P = 0.024). The proportion of patients with confirmed disability progression was not significantly different for the 50 cutoff (P = 0.148), whereas significantly fewer <40 than ≥40 patients had disability progression (P = 0.047). Only minor differences in adverse event frequencies between the age groups for the two cut-offs were seen. These results indicate that IFNB-1b is as efficacious and safe in patients ≥50 years as <50 years of age.     

Evaluation of modified hemodilution combined therapy in the treatment of acute ischemic stroke in the elderly

IN T R O D U C T IO N Atpresent, throm bolysis therapy applied atthe early stage is devel- oped in patients w ith acute stroke, and itw orks w elland decreases disability rate.Butthrom bolysis therapy is notsuitable forsom e elder- ly patients w ho delaye…     

Do gender and race impact the use of antithrombotic therapy in patients with stroke/TIA?

The authors examined the relationships between sex and race and antithrombotics prescribed at discharge in the Michigan Medicare population using retrospective medical record abstraction (n = 2,715) for the period January 1, 2001, to June 30, 2001. There were no differences in the use of antithrombotics at discharge by race or sex and no differences in the prescribing of aspirin, warfarin, aspirin/extended release dipyridamole, or clopidogrel by race or sex after adjustment for confounders.     

Sex differences of ischemic stroke in young adults—A single-center Chinese cohort study

Background and ObjectiveStroke at a young age is a societal challenge with a rising incidence. Our aim was to investigate sex differences in risk factors, etiology, and diagnostic process of ischemic stroke in Chinese young adults.MethodsWe retrospectively recruited 411 consecutive patients with first-ever ischemic stroke who were 18 to 50 years of age (mean age, 38.2 ± 8.1 years, women 31.4%), admitted to Peking Union Medical College Hospital from 2007 to 2018. Sex differences in demographics, risk factors, etiology, and diagnostic testing were analyzed.ResultsFemales were significantly younger than males (36.9 versus 38.7 years, P<0.05). Hypertension (43.0%), smoking (41.1%), hyperlipidemia (37.2%), and hyperhomocysteinemia (27.9%) were common risk factors, statistically higher among males than females (P<0.05). Stroke etiology showed a significant sex difference that large-artery atherosclerosis and small-vessel diseases were more common among males than females (48.6% versus 19.4%, P<0.001; 9.9% versus 3.1%, P<0.05, respectively). Stroke of other determined etiology was more common among females (50.4% versus 19.1%, P<0.001). Relevant abnormality rates were higher among females on screening for autoimmune diseases and thrombophilia (23.3% versus 11.1%, P<0.05 and 50.0% versus 16.7%, P<0.001, respectively).ConclusionsA high rate of the traditional stroke risk factors and etiological subtype of large artery atherosclerosis in males were found, as well as prominent sex differences in relevant diagnostic testing abnormality rates, providing useful information for developing sex-specific strategies in stroke evaluation and prevention in young adults.     

Patients assessed by the liaison psychiatric team in the emergency department of a regional hospital in Canada – general characteristics and gender differences

Objective: To describe the characteristics of liaison psychiatric patients in the emergency department (ED) of a medium sized hospital in the oil sands region of Northern Alberta.

Methods: ED psychiatry services users were evaluated using a data assessment tool designed to capture all relevant demographic and clinical characteristics.

Results: Overall, 477 patients (48.2% male) were assessed by the psychiatric team over the 12 month period. There was a fairly balanced distribution by age, ethnicity and relationship status between both sexes. The majority of patients with a history of self-harm or childhood sexual abuse were female while male patients were significantly more likely to report medication non-compliance. A higher proportion of female patients had depressive disorders and personality disorders while a higher proportion of male patients had anxiety disorders, bipolar and related disorders, schizophrenia spectrum disorders and substance-related disorders. Nearly one in five patients was admitted for inpatient treatment with a significantly higher proportion of males being admitted involuntarily.

Conclusions: There were sex-specific differences in many of the demographic and clinical measures in our ED psychiatric sample. These differences indicate a potential need for targeted education and service initiatives to promote better access to psychiatric services and treatment outcomes.     

Does self-competence predict gender differences in adolescent depression and anxiety?

This longitudinal study examined 75 young adolescents to explore whether self-competence predicts the emergence of gender differences in depression and anxiety. During both 6th and 7th grade, boys reported significantly higher levels of self-competence than did girls. In addition, boys were significantly less depressed and anxious than girls in 7th grade, but not in 6th grade. Finally, when the variance contributed by self-competence was accounted for, the relationship between gender and trait anxiety weakened and the relationship between gender and depression became non-significant. These results support the hypothesis that self-competence is partially responsible for the emergence of gender differences in depression and anxiety during early adolescence.     

Are gender differences important for the clinical effects of antidepressants?

OBJECTIVE: Gender differences in antidepressant treatment response, side effects, dropout rates, and plasma concentrations were examined in patients with major and predominantly melancholic depression. METHOD: The study included a subgroup of 292 inpatients (96 men, 196 women) from three Danish double-blind, randomized, controlled trials. All patients completed a 5-week treatment period and fulfilled the DSM-III or DSM-III-R criteria for major depression. Clomipramine (150 mg/day) was the reference treatment, and comparable treatments were citalopram (40 mg/day), paroxetine (30 mg/day), and moclobemide (400 mg/day). Assessments were performed by using the 17-item Hamilton Depression Rating Scale and the Udvalg for Kliniske Unders?gelser Side Effect Rating Scale. In a subgroup of 110 patients, weekly measurements of clomipramine plasma concentrations were obtained. Nonparametric statistical tests and multiple linear and logistic regression models were used for statistical evaluations. RESULTS: Both genders had similar remission rates (Hamilton depression scale score <8) when treated with clomipramine and had significantly higher remission rates with clomipramine than with the comparable treatments. The plasma concentrations of clomipramine were significantly higher for female than for male patients. No gender differences were found in posttreatment Hamilton depression scale scores, nor did the therapeutic effects of treatment depend on gender. Rates of dropout and side effects were similar for men and women. No relationship between plasma concentrations, gender, and therapeutic outcome was found. CONCLUSIONS: In a group of patients with major and predominantly melancholic depression, differentiation according to gender was not important in treatment with common antidepressants. Women appeared to have higher plasma concentrations of tricyclic antidepressants than men. The consequences of this difference for clinical effects are unclear. Gender-specific recommendations for dosing of tricyclic antidepressants may be considered.     

Reliability of remote evaluation for the Fugl–Meyer assessment and the action research arm test in hemiparetic patients after stroke

Background Blinding for outcome assessors is considered less possible in rehabilitation treatment trials than in pharmacologic trials. This problem can be solved in part by the standardized remote evaluation system, in which researchers video-record patients for centralized assessment using prospectively standardized shooting procedures, and then outside assessors evaluate the videos using prospectively standardized methods.

Objective To assess the inter-rater reliability of remote evaluation for the Fugl–Meyer assessment (FMA) and the action research arm test (ARAT) in hemiparetic patients after stroke.

Methods A prospective, cross-sectional, single-center study involving 30 patients with mild-to-severe hemiparesis was conducted (Clinical Trial Registration—URL: http://www.umin.ac.jp/. Unique identifier: UMIN000022192). Two assessments (direct observation and video observation) were performed for each participant by trained assessors. The direct observation assessment was video-recorded for the video observation assessment. In the current study, a standardized guidebook for test administration and scoring was used, along with prospectively standardized shooting procedures.

Results Regarding the sum scores of the total/subtests of the FMA and ARAT, the intraclass correlation coefficient ranged from 0.992 to 0.998 (95% confidence interval [CI], 0.960–0.999; p < 0.0001) and Spearman’s rho ranged from 0.949 to 1.000 (95% CI, 0.985–1.000; p < 0.0001). Regarding the individual item scores of the outcome measures, weighted kappa (median of the sum scores of total/subtests) ranged from 0.921 to 1.000.

Conclusions Remote evaluation of the FMA and ARAT reliably assesses the affected upper extremities in patients with mild-to-severe hemiparesis after stroke.     

Efficacy and safety of mitoxantrone use in primary and secondary progressive multiple sclerosis – study site experience based on the therapy of 104 patients

Mitoxantrone (MX) is used in patients with primary and secondary progressive as well as relapsing–remitting type of multiple sclerosis (PPMS, SPMS, RRMS). The objective of our project was to evaluate the efficacy and safety of MX use in patients with PPMS and SPMS. Methods: The retrospective study included 104 patients (mean age 54.2 ± 9.0), with PPMS (13.46%) and SPMS (86.54%) treated with MX. During single cycle of the MX therapy a dose of 12 mg/m² of body surface area was administered and next cycles every three months up to a total dose of 140 mg/m² were realized. Results: The course of the therapy was completed by 95 patients (91.34%) including 73 patients who received a scheduled whole dose. The average cumulative dose per patient was 75.2 mg/m². Thirty-two patients reported nausea after MX administration, 20 revealed increase in the incidence of infection and 19 patients hair loss. Twenty-two patients discontinued therapy (seven patients because of the progress of disability). Independent risk factors for deterioration were: age and the form of PPMS (RR 1.56 [95% CI: 1.17–2.07] and RR 2.8 [95% CI: 1.08–7.21], respectively). Five patients revealed a asymptomatic decrease in EF value <50% or 10% in relation to the previous test. Conclusions: MX therapy enables us to stabilize the disease without causing any significant side effects in most patients with progressive disease as compared to patients with primary progressive disease with a comparable safety profile. Larger benefits of MX therapy are associated with the patients with secondary progressive disease.     

α-MSH: A potential neuroprotective and immunomodulatory agent for the treatment of stroke

Alpha-melanocyte-stimulating hormone (MSH) is a neuropeptide with profound immunomodulatory properties; we evaluated the effects of α-MSH on stroke outcome and its ability to modulate the postischemic immune response. In Lewis rats subjected to 3 hours of middle cerebral artery occlusion (MCAO), plasma concentrations of α-MSH rapidly decreased and returned to baseline over the course of days. Exogenous administration of α-MSH (100 or 500 μg/kg) improved 24 hour outcome in animals subjected to 2 hours MCAO; α-MSH 500 μg/kg also decreased infarct volume at this time point. Both doses of α-MSH were ineffective in improving outcome or decreasing infarct volume in animals subjected to 3 hours MCAO. The splenocyte response to phytohemagglutin in animals treated with α-MSH was attenuated at 24 hours after MCAO. At 1 month after MCAO, treatment with α-MSH 500 μg/kg at the time of stoke was associated with a decrease in TH1 response to myelin basic protein (MBP) in animals subjected to 2 hours MCAO, although treatment was not associated with improved outcome at this time point. Given the early benefits of α-MSH treatment and its effect on immunologic outcome, further studies to evaluate the utility of α-MSH for the treatment of cerebral ischemia are warranted.