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Accelerated evolution of oligodendrocytes in human brain | bioRxiv
> Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell-types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell-types exhibit human-specific upregulation. Moreover, oligodendrocytes have undergone accelerated gene expression evolution in the human lineage compared to neurons. The signature of acceleration is enriched for cell type-specific expression alterations in schizophrenia
oligodendrocytes  schizophrenia  evolution  gene_expression 
10 days ago by porejide
Adderall Has Tighter Links to Psychotic Illness Than Other ADHD Drugs | Inverse
Study links Adderall use to a higher risk of psychosis than Ritalin use. One in every 486 patients on amphetamine-based drugs developed psychosis, whereas only one in 1,146 on methylphenidate-based drugs had the same outcome. (n=221,846)
adderall  schizophrenia  psychosis  brain  health 
29 days ago by mdpatrick
Genetic association study of psychotic experiences in UK Biobank | bioRxiv
> GWAS analyses identified four loci associated with psychotic experiences including a locus in Ankyrin-3 (ANK3, OR=1.16, p=3.06 x 10-8) with any psychotic experience and a locus in cannabinoid receptor 2 gene (CNR2, OR=0.66, p=3.78x10-8) with distressing psychotic experiences. PRS analyses identified associations between psychotic experiences and genetic liability for schizophrenia, major depressive disorder, and bipolar disorder, and these associations were stronger for distressing psychotic experiences. Genetic correlation analysis identified significant genetic correlations between psychotic experiences and major depressive disorder, schizophrenia, autism spectrum disorder and a cross-disorder GWAS. Individuals reporting psychotic experiences had an increased burden of CNVs previously associated with schizophrenia (OR=2.04, p=2.49x10-4) and of those associated with neurodevelopmental disorders more widely (OR=1.75, p=1.41x10-3).
psychosis  schizophrenia  genetics 
29 days ago by porejide
Gluten Triggers Strange Delusions in Woman with Celiac Disease
A recent case report in The New England Journal of Medicine describes a woman whose celiac disease resulted in severe psychosis
glutenfree  celiac  psychosis  schizophrenia 
5 weeks ago by wn
The concept of schizophrenia is coming to an end – here’s why
schizophrenia  mentalillness 
6 weeks ago by SwordQueen
Sci-Hub | Emerging drugs for schizophrenia: an update. Expert Opinion on Emerging Drugs, 19(4), 511–531 | 10.1517/14728214.2014.958148
Introduction: Schizophrenia is one of the most serious mental disorders. Its
treatment remains challenging, as existing antipsychotic antidopaminergic
medications improve only/predominantly positive symptoms, agitation and
aggression but have limited/insignificant efficacy for negative and cognitive
symptoms, which strongly affect functional outcome. Therefore, new therapeutic agents are urgently needed that treat aspects of the spectrum of
schizophrenia symptomatology and improve functional outcome.
Areas covered: The authors review the mechanisms of action and key clinical
results of drug development targets currently in Phase II and III clinical testing
for schizophrenia. They further discuss potential barriers to the successful
development of these targets and summarize the drug development status
of emerging treatments for various aspects of schizophrenia.
Expert opinion: Although modifications and variations of antidopaminergic
mechanisms are expected to be successful, the added benefits will likely
remain small, at least regarding enhanced efficacy for negative symptoms,
cognition and functional outcomes. Greater innovation will likely come
from further and deeper exploration of extra-dopaminergic mechanisms.
Investment is needed to develop clinically meaningful animal paradigms
probing the different symptom domains, to discover more efficient in vivo
screening methods for novel drug targets, to optimize clinical trial design
and trial conduct, and to parse the heterogeneous groups of schizophrenias
into biologically more homogeneous subgroups.
Keywords: agonist, antagonist, dopamine, mechanisms of action, medications,
non-dopaminergic, psychosis, schizophrenia
biochemistry  schizophrenia 
9 weeks ago by whitequark
Sci-Hub | Glutamatergic agents for schizophrenia: current evidence and perspectives. Expert Review of Clinical Pharmacology, 8(3), 335–352 | 10.1586/17512433.2015.1040393
Suboptimal outcomes in schizophrenia are a consequence of lacking insight into the etiology,
biomarkers and treatment-relevant subgroups, the therapeutic restriction to dopaminergicmodulating antipsychotics that fail to significantly improve negative and cognitive
symptoms, non-adherence, and, in the case of treatment-resistance, the underutilization of
clozapine. Evidence suggests additional, extra-dopaminergic abnormalities in amino acid
neurotransmission, particularly the glutamatergic system. Antidopaminergic antipsychotics
modulate this system on several levels, as do mood stabilizers, including lamotrigine,
topiramate and pregabaline. Recently, agonists at metabotropic glutamate receptors and
glycine uptake inhibitors failed in large placebo-controlled trials for schizophrenia. Problems to
overcome for successfully leveraging glutamatergic agents for schizophrenia are patient
selection, focus on positive symptoms and late disease stages, and dose-response relationships.
Because glutamate guides processes of brain development and maturation, clinical research
should focus on the at-risk mental state or first-episode psychosis, address cognition and
negative symptoms and use monotherapy designs in parallel to augmentation strategies.
KEYWORDS: amino acid neurotransmission . antipsychotic . cognition . glutamate . psychosis . schizophrenia
biochemistry  schizophrenia 
9 weeks ago by whitequark
Glutamatergic transmission in schizophrenia: from basic research to clinical practice
Over the past 20 years, attention has turned increasingly to dysfunction of the brain glutamate system as a fundamental underlying pathophysiology in schizophrenia. Attention first turned to glutamatergic systems with the observation that phencyclidine (PCP) and similarly acting psychotomimetic compounds induced their unique behavioral effects by blocking neurotransmission at N-methyl-D-aspartate (NMDA) type glutamate receptors. The glutamatergic hypothesis has since been expanded to include a potential role for dysfunction at other subtypes of glutamatergic receptors, as well as linkages between schizophrenia and glutamate receptor genes. Moreover, accumulating evidence supports a link between the NMDA system, disordered cognition, and sensory (auditory and visual) processing.

Perhaps most importantly, glutamatergic receptors include multiple modulatory sites that are actively being studied as potential treatment targets. Receptors for glutamate are divided into two broad families, ionotropic and metabotropic. Ionotropic receptors are differentiated based upon sensitivity to the synthetic glutamate derivatives NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate. In particular, NMDA receptors contain several allosteric modulatory sites that are treatment targets, including a site for the endogenous brain amino acids glycine and D-serine (Fig. 1) and a redox site that is sensitive to glutathione (GSH). Metabotropic receptors, which are G protein coupled and mediate longer-term neuromodulatory effects of glutamate, are divided into groups on the basis of effector coupling and ligand sensitivity.
biochemistry  schizophrenia 
9 weeks ago by whitequark
Glutamate in Schizophrenia: A Focused Review and Meta-Analysis of 1H-MRS Studies
Schizophrenia is a severe chronic psychiatric illness, characterized by hallucinations and delusions. Decreased brain volumes have been observed in the disease, although the origin of these changes is unknown. Changes in the n-methyl-d-aspartate (NMDA)-receptor mediated glutamatergic neurotransmission are implicated, since it is hypothesized that NMDA-receptor dysfunction in schizophrenia leads to increased glutamate release, which can have excitotoxic effects. However, the magnitude and extent of changes in glutamatergic metabolites in schizophrenia are not clear. With 1H magnetic resonance spectroscopy (1H-MRS), in vivo information about glutamate and glutamine concentrations can be obtained in the brain. A systematic search through the MEDLINE database was conducted to identify relevant 1H-MRS studies that examined differences in glutamate and glutamine concentrations between patients with schizophrenia and healthy control subjects. Twenty-eight studies were identified and included a total of 647 patients with schizophrenia and 608 healthy-control subjects. For each study, Cohen’s d was calculated and main effects for group analyses were performed using the random-effects model. Medial frontal region glutamate was decreased and glutamine was increased in patients with schizophrenia as compared with healthy individuals. Group-by-age associations revealed that in patients with schizophrenia, glutamate and glutamine concentrations decreased at a faster rate with age as compared with healthy controls. This could reflect aberrant processes in schizophrenia, such as altered synaptic activity, changed glutamate receptor functioning, abnormal glutamine-glutamate cycling, or dysfunctional glutamate transport.

Keywords: magnetic resonance spectroscopy, glutamatergic system, aging
biochemistry  schizophrenia 
9 weeks ago by whitequark
Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning | Nature Neuroscience
> Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records
microglia  schizophrenia  roy_perlis 
10 weeks ago by porejide

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