Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Abnormal semantic processing of threat words associated with excitement and hostility symptoms in schizophrenia.

BACKGROUND: Schizophrenia (SZ) is associated with devastating emotional, cognitive and language impairments. Understanding the deficits in each domain and their interactions is important for developing novel, targeted psychotherapies. This study tested whether negative-threat word processing is altered in individuals with SZ compared to healthy controls (HC), in relation to SZ symptom severity across domains. METHODS: Thirty-one SZ and seventeen HC subjects were scanned with functional magnetic resonance imaging while silently reading negative-threat and neutral words. Post-scan, subjects rated the valence of each word. The effects of group (SZ, HC), word type (negative, neutral), task period (early, late), and severity of clinical symptoms (positive, negative, excitement/hostility, cognitive, depression/anxiety), on word valence ratings and brain activation, were analyzed. RESULTS: SZ and HC subjects rated negative versus neutral words as more negative. The SZ subgroup with severe versus mild excitement/hostility symptoms rated the negative words as more negative. SZ versus HC subjects hyperactivated left language areas (angular gyrus, middle/inferior temporal gyrus (early period)) and the amygdala (early period) to negative words, and the amygdala (late period) to neutral words. In SZ, activation to negative versus neutral words in left dorsal temporal pole and dorsal anterior cingulate was positively correlated with excitement/hostility scores. CONCLUSIONS: A negatively-biased behavioral response to negative-threat words was seen in SZ with severe versus mild excitement/hostility symptoms. The biased behavioral response was mediated by hyperactivation of brain networks associated with semantic processing of emotion concepts. Thus, word-level semantic processing may be a relevant psychotherapeutic target in SZ.

The Effectiveness of Selective Serotonin Reuptake Inhibitors for Treatment of Obsessive-Compulsive Disorder in Adolescents and Children: A Systematic Review and Meta-Analysis.

Background: Obsessive-compulsive disorder (OCD) is a common behavioral disorder among adolescents and children. The selective serotonin reuptake inhibitors (SSRIs) are the first pharmacological choice for this condition due to mild adverse effect profile. Objective: This systematic review was performed to evaluate the efficacy of SSRI for OCD in adolescents and children. Methods: Search terms were entered into PubMed, PsycINFO, Scopus, CINAHL, and Google Scholar. The included studies were randomized, placebo-controlled trials of SSRIs conducted in populations of children and adolescents younger than 18 years. Change from baseline Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), end-treatment CY-BOCS with respective SD, and response and remission rates were collected for continuous and dichotomous outcome assessment, respectively. Cochrane Rev Man software was used for meta-analyses, providing Forest plots where applicable. Results: SSRIs were superior to placebo with a small effect size. There was no additional benefit of combination treatment over cognitive behavioral therapy (CBT) alone, but CBT added substantial benefit to SSRI monotherapy. Fluoxetine and sertraline appear to be superior to fluvoxamine. Conclusion: The results of current systematic review and meta-analysis support the existing National Institute for Health and Care Excellence (NICE) guidelines for choosing CBT as first line of treatment and substituting it with SSRI, depending on patient preference. Adding CBT to current SSRI treatment is effective for non-responders and partial responders, but adding SSRI to ongoing CBT does not prove beneficial. The SSRIs have different effectiveness, and their relative efficacy remains to be investigated.

Adding Psychotherapy to the Naltrexone Treatment of Alcohol Use Disorder: Meta-analytic Review.

Background It remains unclear if naltrexone combined with psychotherapy is superior to naltrexone alone in treating alcohol use disorders (AUD). The current meta-analysis examined the hypothesis that psychotherapy is a significant moderator that influences AUD-related outcomes and that naltrexone combined with psychotherapy is associated with significantly better AUD-related outcomes than naltrexone alone. Methods A total of 30 studies (Nnaltrexone = 2317; Nplacebo = 2056) were included. Random effects model meta-analyses were carried out for each of the studied outcomes. Subsequently, the random effects model pooled estimates from studies with and without psychotherapy were compared using a Wald test. A mixed-effect model, incorporating psychotherapy as a moderator, was used to examine the impact of psychotherapy on treatment outcomes. Results Naltrexone had a significant treatment effect on abstinence relapse and Gamma-Glutamyl Transferase levels, but not cravings. The pooled estimates for studies with and without psychotherapy were not significantly different for any of the studied outcomes. Psychotherapy was not a significant moderator in the mixed effects models for any of the studied outcomes. Conclusions Naltrexone treatment is efficacious in reducing alcohol consumption, but not reducing cravings. Adding psychotherapy on top naltrexone did not result in any significant additional benefit for AUD patients.

Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α antagonists as first-line biologic agents. We determined the overall treatment effect of Th17 pathway inhibitors compared to placebo or active control on American College of Rheumatology (ACR) 20 response at week 12 (primary objective), risk of infections, discontinuation of treatment due to adverse events, and serious adverse events during the placebo-controlled period (12-24 weeks) in adults with active PsA in published randomized controlled trials. METHODS: The SCOPUS database was searched. The Cochrane risk of bias tool was used for assessing quality. The pooled relative risk (RR) was derived from random effects models. RESULTS: Seven randomized controlled trials were included which randomized 1,718 patients to Th17 inhibitors and 840 to placebo. Patients treated with Th17 inhibitors had an RR of 2.04 (95% CI: 1.79-2.33; p < 0.001) for achieving an ACR20 response at week 12 (I2 = 0%; p = 0.89) compared to placebo-treated patients. There was no evidence of publication bias. The result was consistent for study phase and outcome (ACR50/70), mechanism of action and TNF-α naivety. RR of infections was 1.06 (0.91-1.23), that of candida infections was 3.35 (0.75-14.95), that of serious adverse events was 0.82 (0.42-1.59) and that of discontinuation of treatment was 0.54 (0.31-0.93) among treated versus placebo subjects. No incident cases of tuberculosis were reported. CONCLUSION: In patients with active PsA, biologics targeting the Th17 axis produce a clinically significant improvement in joint disease activity with acceptable safety and tolerability for short-term treatment compared to placebo.

Traumatic Brain Injury and Neuropsychiatric Complications.

Traumatic brain injury (TBI) occurs when a blow or jolt to the head or a penetrating injury results in damage to the brain. It is the most frequent cause of hospitalization in young people with a higher prevalence in men. TBI is the leading cause of disability and mortality between the ages 1 and 45. TBI can be caused either by the direct result of trauma or due to a complication of the primary injury. The most common etiological factors for TBI are falls, road traffic accidents, violent physical assaults, and injuries associated with athletic activities. Following TBI, significant neurologic complications may occur which include seizures, dementia, Alzheimer's disease, and cranial nerve injuries. In addition, people may suffer from various psychiatric complications such as depression, posttraumatic stress disorder, generalized anxiety disorder, obsessive-compulsive disorder, and other cognitive and behavioral sequel that might significantly increase the comorbidity of the victims. Considering all of the above complications, TBI is one of the significant public health burdens. Literature has shown that only about 25% of people achieve long-term functional independence following TBI. In this paper, we focused not only on the epidemiology but also the etiology, complications following TBI and understanding their underlying pathogenesis. Further, we focused on analyzing the options to improve the treatment and rehabilitation following TBI in future.

Knowledge and Attitude Towards Pharmacological Management of Acute Agitation: A Survey of Psychiatrists, Psychiatry Residents, and Psychiatric Nurses.

OBJECTIVE: The authors compared the current knowledge and attitude of psychiatrists, psychiatry residents, and psychiatric nurses towards the pharmacological management of acute agitation. METHODS: Questionnaires were electronically distributed to all attending psychiatrists, psychiatry residents, and psychiatric nurses who were either employed by the University Department of Psychiatry and Behavioral Sciences or were staff at a 250-bed affiliated Psychiatric Hospital. Where possible, Fisher's exact test was used to compare responses to questions based on designation. RESULTS: Of the 250 questionnaires distributed, 112 were returned (response rate of 44.8%), of which 64 (57.1%) were psychiatric nurses, 27 (24.1%) were attending psychiatrists, and 21 (18.8%) were psychiatry residents. A significantly higher percentage of attending psychiatrists and psychiatric nurses compared to psychiatry residents thought that newer second- generation antipsychotics (SGAs) are not as effective as older first-generation antipsychotics (FGAs) for managing acute agitation (55.6, 48.4, and 9.5% respectively, p = 0.008). The combination of intramuscular haloperidol, lorazepam, and diphenhydramine was the most preferred option chosen by all designations for the psychopharmacological management of severe agitation. Furthermore, a larger percentage of the psychiatric nurses, in comparison to attending psychiatrists, also chose the combination of intramuscular chlorpromazine, lorazepam, and diphenhydramine as an option for managing severe agitation; no psychiatry resident chose this option. CONCLUSION: Knowledge of evidence-based psychopharmacological management of agitation differs among attending psychiatrists, psychiatry residents and psychiatric nurses. Although the management of agitation should be individualized and context specific, monotherapy should be considered first where applicable.