Publications by authors named "Brian Dean"
Background And Aims: Glutamate plays a crucial role in cognition, learning, and mood regulation, with studies suggesting glutamatergic dysfunction in chronic schizophrenia. This study explored glutamate levels in the occipital cortex (OCC) and cognitive function in ultra-treatment resistant schizophrenia (uTRS) compared to healthy controls.
Methods: Fifteen uTRS participants and 19 healthy controls underwent 3T proton magnetic resonance spectroscopy (H-MRS) to measure glutamate levels in the OCC.
Cobenfy, a co-formulation of xanomeline and trospium, is the first drug not acting on the dopaminergic system of the CNS approved for the treatment of schizophrenia by the FDA. Xanomeline is a muscarinic M1 and M4 receptor (CHRM1 and CHRM4) agonist whilst trospium is a peripherally active CHRM antagonist that reduces the unwanted peripheral side-effects of xanomeline. Relevant to this exciting development, this review details the human CNS cholinergic systems and how those systems are affected by the molecular pathology of schizophrenia in a way suggesting activating the CHRM1 and 4 would be beneficial in treating the disorder.
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- The study examines genetic variations and gene expression linked to methamphetamine use disorder, focusing on single nucleotide polymorphisms (SNPs) in four candidate genes among 59 participants.
- Findings indicate that specific SNPs are associated with the severity of methamphetamine use and cognitive performance, with certain gene expressions being lower in individuals with the disorder.
- The research suggests novel therapeutic targets due to identified genetic factors and altered mRNA levels in those with methamphetamine use disorder, emphasizing the potential role of these genes in treatment approaches.
Article Synopsis
- The study investigates the differences in receptor binding in the brains of people with schizophrenia, specifically focusing on the Muscarinic Receptor Deficit subgroup (MRDS), which shows reduced binding to the M1 receptor.
- Researchers confirmed MRDS by measuring [H]pirenzepine binding and then examined the binding of other glutamate receptors ([H]kainate, [H]AMPA, [H]NMDA) in Brodmann's areas 9 and 10 to see if there were subgroup-specific differences.
- Results showed that while M1 and kainate receptor binding was lower in BA 9 and BA 10 for MRDS individuals, other glutamate receptors (AMPA and NMDA) did not
Article Synopsis
- This study focuses on a specific subgroup of schizophrenia called the Muscarinic Receptor Deficit subgroup (MRDS), characterized by low levels of cortical M1 muscarinic receptors.
- Researchers analyzed transcriptomic data and predicted changes in the protein AKT interacting protein (AKTIP) in MRDS patients, particularly in Brodmann's area 10.
- The results showed significantly higher levels of AKTIP protein in patients with MRDS compared to controls, indicating a disturbance in the AKT1 signaling pathway in this subgroup.
Objective: Studies using proton magnetic resonance spectroscopy reveal substantial inconsistencies in the levels of brain glutamate, glutamine and glutamate + glutamine across schizophrenia spectrum disorders. This systematic review employs qualitative and quantitative methods to analyse the patterns and relationships between glutamatergic metabolites, schizophrenia spectrum disorders and brain regions.
Methods: A literature search was conducted using various databases with keywords including glutamate, glutamine, schizophrenia, psychosis and proton magnetic resonance spectroscopy.
Article Synopsis
- The study investigates low-volume sampling devices as alternatives to traditional venipuncture for collecting pharmacokinetic (PK) data on various monoclonal antibodies (mAbs) and small molecules.
- The research involved an open-label, non-randomized design with four groups of 10 healthy participants, testing different administration methods for drugs including crenezumab, etrolizumab, hydroxychloroquine, and GDC-X.
- Results showed that while conventional venipuncture and the TassoOne Plus device produced similar PK data, adjustments were needed for some dry blood samples, particularly for hydroxychloroquine, and the study also assessed data quality and patient comfort with the devices.
Article Synopsis
- Research indicates that inflammation-related pathways, particularly TNF-signaling, are crucial in the molecular pathology of mood disorders like bipolar disorder (BPD) and major depressive disorder (MDD).
- The study focused on measuring levels of TRAF1 and tmTNFRSF1B in specific brain areas of individuals with BPD and MDD, finding significantly higher TRAF1 levels in BPD patients, but not in those with MDD.
- Limitations of the study include the effects of prior psychotropic drug treatment on the subjects, and the relatively small sample sizes, which are common in postmortem brain studies.
Objectives: This study sought to identify pathways affected by rat cortical RNA that were changed after treatment with fluoxetine or imipramine.
Methods: We measured levels of cortical RNA in male rats using GeneChip Rat Exon 1.0 ST Array after treatment with vehicle (0.
Article Synopsis
- - A study identified a subset of individuals with schizophrenia, referred to as muscarinic receptor deficit schizophrenia (MRDS), who exhibit significantly lower levels of cortical muscarinic M1 receptors compared to others with schizophrenia.
- - Researchers analyzed gene expression data and found disturbances in a biochemical pathway associated with the processing of the β-amyloid precursor protein (APP), which led them to measure levels of APP-related proteins in the frontal cortex of MRDS and non-MRDS subjects.
- - The results indicated that while those with MRDS had notably low muscarinic receptor levels, individuals with schizophrenia overall had lower levels of soluble APP (sAPP) compared to control subjects, suggesting that APP might play a role in the underlying mechanisms
Article Synopsis
- Phelan-McDermid syndrome (PMS) is a rare genetic disorder linked to deletions or variants in the 22q13 region, leading to conditions like autism, intellectual disability, and seizures.
- The complexity of PMS arises from varied deletion sizes, making it hard to pinpoint specific gene effects on symptoms such as language impairment and hypotonia.
- The study utilized genomic data mining and brain network analysis to identify candidate genes associated with PMS, offering insights into disease mechanisms and potential new treatment approaches.
Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal.
Expert Opin Investig Drugs
December 2023
Article Synopsis
- * The review discusses the journey from developing drugs that activate muscarinic M1 and M4 receptors to clinical use, explaining how these receptors can influence various schizophrenia symptoms.
- * The effectiveness of muscarinic receptor-targeting drugs may vary among individuals with schizophrenia, suggesting a need for further research to identify which patients are most likely to benefit from this type of treatment.
During bioanalytical assay development and validation, maintaining the stability of the parent drug and metabolites of interest is critical. While stability of the parent drug has been thoroughly investigated, the stability of unanalyzed metabolites is often overlooked. When an unstable metabolite is known or suspected to interfere with measurement of the parent drug or other metabolites of interest through back-conversion or other routes, additional tests with these unstable metabolites should be conducted.
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- Matrix effect (ME) occurs when compounds coelute with target analytes, affecting their ionization and thus the accuracy, precision, and sensitivity of bioanalytical methods.
- The review focuses on the evaluation and control of ME in supercritical fluid chromatography-mass spectrometry (SFC-MS), highlighting how its impact differs from other chromatographic techniques.
- Key factors influencing ME in SFC-MS-based methods are examined, along with a literature review on ME evaluation in these targeted bioanalytical approaches, underscoring the importance of robust instruments and effective sample preparation.
Objectives: We have postulated that common changes in gene expression after treatment with different therapeutic classes of psychotropic drugs contribute to their common therapeutic mechanisms of action.
Methods: To test this hypothesis, we measured levels of cortical coding and non-coding RNA using GeneChip Rat Exon 1.0 ST Array after treatment with vehicle (chow only), chow containing 1.
In pharmacokinetic studies for respiratory diseases, urea is a commonly used dilution marker for volume normalization of various biological matrices, owing to the fact that urea diffuses freely throughout the body and is minimally affected by disease states. In this study, we developed a convenient liquid chromatography-tandem mass spectrometry (LC-MS/MS) surrogate matrix assay for accurate urea quantitation in plasma, serum and epithelial lining fluid. Different mass spectrometer platforms and ionization modes were compared in parallel.
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- Ipatasertib (GDC-0068) is a targeted cancer treatment being developed by Genentech/Roche, focusing on inhibiting the Akt protein kinase, with studies examining its effects both alone and with other therapies.
- An open-label study with radiolabeled ipatasertib assessed how the drug is absorbed, metabolized, and excreted, showing a bioavailability of 34.0% and similar terminal half-lives for oral and intravenous forms.
- The majority of the drug recovered was metabolized, primarily through hepatic pathways, with the main metabolic process being -dealkylation facilitated by the CYP3A enzyme.
This chapter outlines some of the general principles that need to be considered when developing a radioligand binding assay to measure the affinity and density of radioligand binding to a receptor in tissue or on cells. In addition it describes an innovative step forward in using radioligand binding assays to measure levels of muscarinic M1 receptors in human postmortem CNS, using both membrane binding and in situ radioligand binding. These examples show how, using receptor-specific allosteric modulators, it is possible to gain an estimate of the density of a single receptor using a radioligand that is not totally specific to the target site of interest.
View Article and Find Full Text PDFSchizophrenia is a disabling disorder involving genetic predisposition in combination with environmental influences that likely act via dynamic alterations of the epigenome and the transcriptome but its detailed pathophysiology is largely unknown. We performed cell-type specific methylome-wide association study of neonatal blood (N = 333) from individuals who later in life developed schizophrenia and controls. Suggestively significant associations (P < 1.
View Article and Find Full Text PDFMultiple lines of evidence argue for lower levels of cortical muscarinic M1 receptors (CHRM1) in people with schizophrenia which is possibly due to a sub-group within the disorder who have a marked loss of CHRM1 (muscarinic receptor deficit sub-group (MRDS)). In this study we sought to determine if the lower levels of CHRM1 was apparent in older people with schizophrenia and whether the loss of CHRM1 was associated with symptom severity by measuring levels of cortical [H]pirenzepine binding to CHRM1 from 56 people with schizophrenia and 43 controls. Compared to controls (173 ± 6.
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- Research indicates that muscarinic receptors, specifically M1 and M4, play a significant role in the molecular issues related to schizophrenia.
- Clinical trials show that activating these receptors can help reduce various symptoms of schizophrenia, including positive, negative, and cognitive symptoms.
- Advances in neuroimaging have allowed for better visualization of these receptors in the brain, highlighting a potential subgroup of schizophrenia patients who may benefit from targeted drug therapies aimed at restoring muscarinic M1 receptor function.
Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs.
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