Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABAB receptor in the ...pathogenesis of schizophrenia. It has been hypothesised that clozapine can mediate its actions via the GABAB receptor. Baclofen is currently recognised as the prototype GABAB receptor agonist. There are some potential clinical similarities between clozapine and baclofen. Indeed, baclofen has been previously proposed for use as an antipsychotic agent. Our analysis of the X-ray crystal structure of GABAB receptor along with molecular docking calculations, suggests that clozapine could directly bind to the GABAB receptor similar to that of baclofen. This finding could lead to a better understanding of the pharmacological uniqueness of clozapine, potential development of a biomarker for treatment resistant schizophrenia and the development of more targeted treatments leading to personalisation of treatment.
Background
‘Pediatric bipolar disorder’ (PBD) is a controversial diagnosis with varying rates of clinical diagnosis. A highly cited meta-analysis (Van Meter et al. 2011) of a dozen epidemiological ...surveys suggested a global community prevalence of PBD of 1.8%. This was updated to 3.9% with eight additional surveys (Van Meter et al. 2019a). In terms of the Cochrane Handbook for Systematic Reviews of Interventions, the heterogenous community surveys were arguably unsuitable for statistical meta-analysis and warranted a narrative analysis. A narrative analysis (Parry et al. 2018) of the original 12 surveys concluded rates of PBD were substantially lower than 1.8% and led to a nine-article debate on the validity, arguable overdiagnosis and iatrogenic aspects of the PBD diagnosis (e.g. Carlson and Dubicka Child Adolesc Mental Health 21:86–87, 2019). This article extends the narrative analysis to include the eight newer community surveys.
Methods
A narrative analysis of the methodologies and the prevalence rates reported by the epidemiological surveys.
Results
Across all twenty surveys there was significant variation in methodologies and reported prevalence rates. Of the eight newer surveys, five (two Brazilian, one English, one Turkish, one United States) provided information of pre-adolescent prevalence rates of bipolar spectrum disorder. These pre-adolescent rates were zero or close to zero. Rates of adolescent hypomania and mania were higher, but follow-up data in two studies suggested hypomania might sometimes achieve prolonged remission or not lead to adult bipolar disorder.
Limitations
Methods in the original surveys vary and criteria used for various bipolar diagnoses were not always fully described. This limitation applies to a narrative analysis but also to a statistical meta-analysis.
Conclusion
Bipolar disorder is very rare in childhood and rare in adolescence. PBD as a diagnostic construct fails to correlate with adult bipolar disorder and the term should be abandoned. Hypomanic syndromes in adolescence may not always progress to adult bipolar disorder. Early diagnosis of bipolar disorder is important, but over-diagnosis risks adverse iatrogenic consequences.
Background:
The hypothesis that bipolar disorder presents before puberty with atypical mania has proved to be controversial. Published academic perspectives on the validity of Paediatric Bipolar ...Disorder (PBD) appear to vary between the United States and the rest of the world.
Methods:
We examined the perspectives of articles citing four seminal articles. The citing articles were grouped as either supportive or non-supportive of the PBD hypothesis, and the perspectives of the articles by US authors were compared with those by non-US authors.
Results:
There were 787 citing articles commenting on PBD, mostly published in US-based journals. Most authors were affiliated with several US institutions. Among the 624 articles with US authorship, the majority (83%) supported PBD. Of the 163 articles by non-US authors, most (60%) supported the traditional view that bipolar disorders are rare before mid-adolescence. Published academic perspectives in favour of the PBD hypothesis are mostly concentrated in several US institutions.
Conclusion:
There is majority support for PBD among citing articles from the United States, whereas the traditional perspective predominates in articles from most other countries.
The required minimum number of psychiatric inpatient beds is highly debated and has substantial resource implications. The present study used the Delphi method to try to reach a global consensus on ...the minimum and optimal psychiatric bed numbers. An international board of scientific advisors nominated the Delphi panel members. In the first round, the expert panel provided responses exploring estimate ranges for a minimum to optimal numbers of psychiatric beds and three levels of shortage. In a second round, the panel reconsidered their responses using the input from the total group to achieve consensus. The Delphi panel comprised 65 experts (42% women, 54% based in low- and middle-income countries) from 40 countries in the six regions of the World Health Organization. Sixty psychiatric beds per 100 000 population were considered optimal and 30 the minimum, whilst 25-30 was regarded as mild, 15-25 as moderate, and less than 15 as severe shortage. This is the first expert consensus on minimum and optimal bed numbers involving experts from HICs and LMICs. Many high-income countries have psychiatric bed numbers that fall within the recommended range. In contrast, the number of beds in many LMIC is below the minimum recommended rate.
Abstract Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmaceutical target under investigation for the treatment of several neuropsychiatric conditions. TAAR1 single nucleotide variants ...(SNV) have been found in patients with schizophrenia and metabolic disorders. However, the frequency of variants in geographically diverse populations and the functional effects of such variants are unknown. In this study, we aimed to characterise the distribution of TAAR1 SNVs in five different WHO regions using the Database of Genotypes and Phenotypes (dbGaP) and conducted a critical computational analysis using available TAAR1 structural data to identify SNVs affecting ligand binding and/or functional regions. Our analysis shows 19 orthosteric, 9 signalling and 16 micro-switch SNVs hypothesised to critically influence the agonist induced TAAR1 activation. These SNVs may non-proportionally influence populations from discrete regions and differentially influence the activity of TAAR1-targeting therapeutics in genetically and geographically diverse populations. Notably, our dataset presented with orthosteric SNVs D103 3.32 N (found only in the South-East Asian Region and Western Pacific Region) and T194 5.42 A (found only in South-East Asian Region), and 2 signalling SNVs (V125 3.54 A/T252 6.36 A, found in African Region and commonly, respectively), all of which have previously demonstrated to influence ligand induced functions of TAAR1. Furthermore, bioinformatics analysis using SIFT4G, MutationTaster 2, PROVEAN and MutationAssessor predicted all 16 micro-switch SNVs are damaging and may further influence the agonist activation of TAAR1, thereby possibly impacting upon clinical outcomes. Understanding the genetic basis of TAAR1 function and the impact of common mutations within clinical populations is important for the safe and effective utilisation of novel and existing pharmacotherapies.
Abstract
Suicide rates in the United States (US) reached a peak in 2018 and declined in 2019 and 2020, with substantial and often growing disparities by age, sex, race/ethnicity, geography, veteran ...status, sexual minority status, socioeconomic status, and method employed (means disparity). In this narrative review and commentary, we highlight these many disparities in US suicide deaths, then examine the possible causes and potential solutions, with the overarching goal of reducing suicide death disparities to achieve health equity.
The data implicate untreated, undertreated, or unidentified depression or other mental illness, and access to firearms, as two modifiable risk factors for suicide across all groups. The data also reveal firearm suicides increasing sharply and linearly with increasing county rurality, while suicide rates by falls (e.g., from tall structures) decrease linearly by increasing rurality, and suicide rates by other means remain fairly constant regardless of relative county urbanization. In addition, for all geographies, gun suicides are significantly higher in males than females, and highest in ages 51–85 + years old for both sexes. Of all US suicides from 1999–2019, 55% of male suicides and 29% of female suicides were by gun in metropolitan (metro) areas, versus 65% (Male) and 42% (Female) suicides by gun in non-metro areas. Guns accounted for 89% of suicides in non-metro males aged 71–85 + years old. Guns (i.e., employment of more lethal means) are also thought to be a major reason why males have, on average, 2–4 times higher suicide rates than women, despite having only 1/4—1/2 as many suicide attempts as women. Overall the literature and data strongly implicate firearm access as a risk factor for suicide across all populations, and even more so for male, rural, and older populations.
To achieve the most significant results in suicide prevention across all groups, we need 1) more emphasis on policies and universal programs to reduce suicidal behaviors, and 2) enhanced population-based strategies for ameliorating the two most prominent modifiable targets for suicide prevention: depression and firearms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To provide a brief clinical research update and commentary advice on the practical psychiatric care of patients suffering workplace bullying.
Conclusions
While there is empirical research ...on the prevalence and impacts of workplace bullying, there is a relative dearth of clinical research into psychiatric patient care. Accordingly, we provide commentary on practical considerations that assist in psychiatric care planning and delivery.
Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and ...cognitive impairment. Moreover, newer ‘atypical’ antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp1033.32, TAAR1; Asp1163.32, 5HT1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.
We conducted a systematic review evaluating the efficacy of rivastigmine augmentation for treatment- refractory posttraumatic stress disorder (PTSD). The Preferred Reporting Items for Systematic ...Reviews and Meta-Analyses guidelines were followed. The databases Ovid MEDLINE, PubMed, CINAHL, and EMBASE were searched using key words: 'rivastigmine' OR 'Exelon' OR 'rivastigmine augmentation' OR 'Exelon augmentation' AND 'posttraumatic stress disorder*' OR 'post-traumatic stress disorder*' OR 'PTSD' OR 'combat disorder*' OR 'post-traumatic symptoms'. The asterisk specified plural forms of the relevant word. Four papers were identified, comprising one double-blind randomised controlled trial, one non-controlled open trial, one case series (presenting three case studies), and one paper with two case studies. The randomised controlled trial found no statistically significant difference in efficacy, using the PTSD CheckList-Military Version as the relevant outcomes measure, between the active add-on rivastigmine interventions and placebo or treatment as usual. The open trial, although reporting relatively positive outcomes, had a weak study design and lacked reporting of key information, including participant sex and age and pre-rivastigmine PTSD measures. The assessment of efficacy was based on participants' reporting of subjective benefits, and clinician-rating using a Clinical Global Impression, rather than established PTSD assessments scales. Although the five case studies reported improvement in PTSD symptoms, there were confounding factors and limitations in clinical and demographic data, warranting caution regarding attributed benefits. There is a lack of methodologically robust evidence supporting the efficacy of add-on rivastigmine for the treatment of refractory PTSD. Additional research May help in further evaluating its possible clinical efficacy.
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