Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

The Manchester Museum: A case study of a volcano themed public event

It is often difficult to inspire the public about igneous rocks. This case study of apublic activity day shows that through working with a range of partners, innovativeideas can bring the subject alive. Experts with objects to handle talked to the pub-lic about eruptions and volcanoes, with eruption demonstrations, hands on activi-ties, explosions and artists workshops taking place throughout the day

Wild

Press release: New exhibition at Manchester Museum goes ‘wild’ for tackling climate and biodiversity crisisWild Supported by the Garfield Weston Foundation 5 June 2024 to 1 June 2025Press view 4 June 2024, 10am-1pm Wild, an exhibition that explores our relationship with the natural world and unique approaches to environmental recovery, opens at Manchester Museum on 5 June 2024. The exhibition will look at how people are creating, rebuilding and repairing connections with nature, and how we can tackle the climate and biodiversity crisis by making the world more wild.Visitors will be introduced to five wild places across the globe and hear a diverse range of voices, from Aboriginal elders to researchers and community activists, to discover how they are all looking to ‘wild’ for a more positive future. In one case, the restoration of traditional practices is helping to heal both the land and the people. In others, biodiversity has exploded where farmland has been rewilded and the reintroduction of animal species is helping to restore ecological balance.Featuring an immersive installation, audio, film and interactive elements, alongside natural history collections and artworks, the exhibition prompts visitors to notice the biodiversity and heritage of wild places and invites us to question our relationships with the natural world. The featured wild places are Manchester; Knepp Rewilding Project, West Sussex; Lamlash Bay, Arran, North Ayrshire; Noongar Nowanup Boodja, Western Australia; and Yellowstone National Park, USA.These places have historically been shaped by people to support farming, hunting, fishing, housing and industry - frequently to the detriment of the health of land, people and nature, and leading to a significant reduction in biodiversity and kinship connections between plants, animals, people and place.At the Knepp Rewilding Project in West Sussex, a failing farm has been rewilded and transformed into a place of natural abundance. In 2002 free-roaming grazers were introduced to transform the land and recreate dynamic and biodiverse ecosystems. Knepp is one of the UK’s leading rewilding sites and an experiment in land stewardship that prioritises biodiversity.On Arran, a decade-long community-led campaign in direct response to overfishing and dredging, culminated in Scotland’s first No Take Zone being established in 2008. This protected area in Lamlash Bay is enabling the local marine ecosystem to flourish, and highlights the importance of conserving our precious blue spaces to help tackle biodiversity loss and climate change.More than 100 years ago native bushland was cleared by colonial settlers in Western Australia to establish farmland. An Aboriginal-led cultural revegetation project, Nowanup Noongar Boodja, is healing Country to heal people. The Country is being revitalised through planting and the return of traditional practices, showing the importance of making decisions for current and future generations that strengthen cultural connections with the past.Yellowstone National Park, the USA’s first national park established in 1872, played a pivotal role in the birth of ‘fortress conservation’ and the ‘wilderness movement’ and saw the forced removal of Indigenous people. The exhibition explores how the impact of colonial violence wiped out the area’s native wolves and later a government-level decision to reintroduce wolves impacted local communities and their relationships with wildlife. Today, the reintroduction of wolves is contributing to the restoration of ecological balance to the area.The balance between landscaped and abandoned spaces in post-industrial urban landscapes are examined in the context of Manchester’s ambition to become a 'greener' city that embraces nature. The exhibition raises questions about the biodiversity of man-made green spaces and the challenges of coexisting with nature in urban environments.Wild also explores how the natural world has traditionally been presented and idealised through Western art, from pastoral scenes to epic landscapes, and representations in popular culture, from Kenneth Grahame’s The Wind in the Willows to CBeebies’ Octonauts.Curator of Earth Science Collections, David Gelsthorpe, said: “Wild aims to provide hope in the face of a situation that often leaves many of us feeling pessimistic. The exhibition highlights work being done by communities right now, to build stronger relationships with nature and shape their world for the better. This isn't simply theoretical thinking, it is impactful, practical action that is already achieving positive results. We hope Wild inspires visitors to better understand their own relationship with the natural world and empowers them to take action, however big or small."Manchester Museum Director Esme Ward added:“Wild is one of Europe’s first large-scale exhibitions to look at how people are working to make the world around them more ‘wild’. As the world’s first Carbon Literate museum, with a mission to build a more sustainable planet, we set out to share new stories and perspectives, from the local to the global, that could inspire us all to collaborate in creating a fairer future. It is this spirit that sits at the heart of Wild.”<br/

Maximizing Equity in Acute Coronary Syndrome Screening across Sociodemographic Characteristics of Patients

We compared four methods to screen emergency department (ED) patients for an early electrocardiogram (ECG) to diagnose ST-elevation myocardial infarction (STEMI) in a 5-year retrospective cohort through observed practice, objective application of screening protocol criteria, a predictive model, and a model augmenting human practice. We measured screening performance by sensitivity, missed acute coronary syndrome (ACS) and STEMI, and the number of ECGs required. Our cohort of 279,132 ED visits included 1397 patients who had a diagnosis of ACS. We found that screening by observed practice augmented with the model delivered the highest sensitivity for detecting ACS (92.9%, 95%CI: 91.4–94.2%) and showed little variation across sex, race, ethnicity, language, and age, demonstrating equity. Although it missed a few cases of ACS (7.6%) and STEMI (4.4%), it did require ECGs on an additional 11.1% of patients compared to current practice. Screening by protocol performed the worst, underdiagnosing young, Black, Native American, Alaskan or Hawaiian/Pacific Islander, and Hispanic patients. Thus, adding a predictive model to augment human practice improved the detection of ACS and STEMI and did so most equitably across the groups. Hence, combining human and model screening––rather than relying on either alone––may maximize ACS screening performance and equity