T10. BIOMARKERS IN TREATMENT-RESISTANT SCHIZOPHRENIA; THE BITS STUDY (A STUDY PROTOCOL)

Abstract Background Approximately 30% of patients diagnosed with schizophrenia do not respond to conventional antipsychotic therapy, however, around 30% of these patients will respond to treatment with clozapine. The remaining clozapine non-respondent patients can be defined as ultra-treatment resistant. Special characteristics (biomarkers) may be found in this subgroup of ultra-treatment resistant patients. Recent evidence points to a central role of altered immunological and anti-inflammatory response in schizophrenia. Studies have found that antipsychotic medication affect the immune system and alter levels of different cytokines, but no clear relation between the effect on cytokine levels and improvement in symptoms has been documented. Also increased permeability of the blood brain barrier (BBB) have been linked to psychosis, and a dysfunctional BBB may lead to structural changes in the white matter and neurochemical changes (glutamatergic abnormalities) in CNS. The longitudinal course of BBB alterations in psychosis and how this may influence changes in neuronal structure and function and relate to fluctuation in symptoms have not been examined. The aim of this study is to establish a database with the purpose of identifying biomarkers for treatment resistant schizophrenia (TRS), containing measures of psychopathology and function, treatment variables, brain imaging data, immunological markers from blood and cerebrospinal fluid, BBB-permeability and genetic material. The database will consist of a group of ultra-treatment resistant patients and a group of patients responding to clozapine matched on sex, age and duration of illness (±3 years). Specific aims: Hypothesis Methods The study is a naturalistic longitudinal study including patients with TRS. We plan a thorough examination twice with a three months interval and ultra-treatment resistant patients will be compared with patients stable on clozapine. Between examinations there will be no planned interference with the antipsychotic treatment, but antipsychotic treatment may be changed during the period in the intention to improve symptoms. The primary longitudinal outcome is comparing changes in BBB-permeability along with symptom-fluctuations. This will be done by comparing changes in qAlb, which is the gold standard technique measuring the CSF:serum albumin ratio (QAlb). Results The study has been approved by the regional ethical committee and data collection will begin in 2020. Discussion We expect the obtained results will contribute to a better pathophysiological understanding about illness markers and their progression over time and in relation to functional outcome.

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Increased Homotopic Connectivity in the Prefrontal Cortex Modulated by Olanzapine Predicts Therapeutic Efficacy in Patients with Schizophrenia

Neural Plasticity ◽

10.1155/2021/9954547 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Xiaoxiao Shan ◽

Rongyuan Liao ◽

Yangpan Ou ◽

Yudan Ding ◽

Feng Liu ◽

...

Keyword(s):

Prefrontal Cortex ◽

Support Vector ◽

Individual Treatment ◽

Antipsychotic Treatment ◽

Individual Response ◽

Healthy Controls ◽

Imaging Data ◽

Antipsychotic Therapy ◽

Olanzapine Treatment ◽

Schizophrenic Patients

Background. Previous studies have revealed the abnormalities in homotopic connectivity in schizophrenia. However, the relationship of these deficits to antipsychotic treatment in schizophrenia remains unclear. This study explored the effects of antipsychotic therapy on brain homotopic connectivity and whether the homotopic connectivity of these regions might predict individual treatment response in schizophrenic patients. Methods. A total of 21 schizophrenic patients and 20 healthy controls were scanned by the resting-state functional magnetic resonance imaging. The patients received olanzapine treatment and were scanned at two time points. Voxel-mirrored homotopic connectivity (VMHC) and pattern classification techniques were applied to analyze the imaging data. Results. Schizophrenic patients presented significantly decreased VMHC in the temporal and inferior frontal gyri, medial prefrontal cortex (MPFC), and motor and low-level sensory processing regions (including the fusiform gyrus and cerebellum lobule VI) relative to healthy controls. The VMHC in the superior/middle MPFC was significantly increased in the patients after eight weeks of treatment. Support vector regression (SVR) analyses revealed that VMHC in the superior/middle MPFC at baseline can predict the symptomatic improvement of the positive and negative syndrome scale after eight weeks of treatment. Conclusions. This study demonstrated that olanzapine treatment may normalize decreased homotopic connectivity in the superior/middle MPFC in schizophrenic patients. The VMHC in the superior/middle MPFC may predict individual response for antipsychotic therapy. The findings of this study conduce to the comprehension of the therapy effects of antipsychotic medications on homotopic connectivity in schizophrenia.

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Influence of Ascorbic Acid on the Structure and Function of Alpha-2- macroglobulin: Investigations using Spectroscopic and Thermodynamic Techniques

Protein and Peptide Letters ◽

10.2174/0929866526666191002113525 ◽

2020 ◽

Vol 27 (3) ◽

pp. 201-209

Author(s):

Syed Saqib Ali ◽

Mohammad Khalid Zia ◽

Tooba Siddiqui ◽

Haseeb Ahsan ◽

Fahim Halim Khan

Keyword(s):

Ascorbic Acid ◽

Conformational Changes ◽

Structural Changes ◽

The Body ◽

Titration Calorimetry ◽

Spectroscopic Techniques ◽

Human Beings ◽

Plasma Ascorbic Acid ◽

Dietary Antioxidant ◽

And Function

Background: Ascorbic acid is a classic dietary antioxidant which plays an important role in the body of human beings. It is commonly found in various foods as well as taken as dietary supplement. Objective: The plasma ascorbic acid concentration may range from low, as in chronic or acute oxidative stress to high if delivered intravenously during cancer treatment. Sheep alpha-2- macroglobulin (α2M), a human α2M homologue is a large tetrameric glycoprotein of 630 kDa with antiproteinase activity, found in sheep’s blood. Methods: In the present study, the interaction of ascorbic acid with alpha-2-macroglobulin was explored in the presence of visible light by utilizing various spectroscopic techniques and isothermal titration calorimetry (ITC). Results: UV-vis and fluorescence spectroscopy suggests the formation of a complex between ascorbic acid and α2M apparent by increased absorbance and decreased fluorescence. Secondary structural changes in the α2M were investigated by CD and FT-IR spectroscopy. Our findings suggest the induction of subtle conformational changes in α2M induced by ascorbic acid. Thermodynamics signatures of ascorbic acid and α2M interaction indicate that the binding is an enthalpy-driven process. Conclusion: It is possible that ascorbic acid binds and compromises antiproteinase activity of α2M by inducing changes in the secondary structure of the protein.

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Antipsychotic-induced supersensitivity – A reappraisal

Australian & New Zealand Journal of Psychiatry ◽

10.1177/00048674211025694 ◽

2021 ◽

pp. 000486742110256

Author(s):

William Lugg

Keyword(s):

Tardive Dyskinesia ◽

Significant Proportion ◽

Underlying Mechanism ◽

Antipsychotic Treatment ◽

Physiological Changes ◽

Antipsychotic Therapy ◽

Neurotransmitter Systems ◽

Potential Benefits ◽

Treatment Refractory ◽

Brain Pathways

Objectives: Tardive dyskinesia, psychotic relapse and treatment-refractory psychosis have long been associated. A common underlying mechanism involving antipsychotic-induced ‘supersensitivity’, albeit in different brain pathways, was proposed as early as 1978. This piece seeks to reappraise the concept and potential implications of antipsychotic-induced supersensitivity. Conclusions: Evidence increasingly suggests that chronic antipsychotic exposure induces neuroadaptive physiological changes in dopaminergic, and other, neurotransmitter systems that may render some individuals more vulnerable to psychotic relapse - including those receiving continuous antipsychotic treatment. It is possible that in treating every episode of psychosis with prolonged or indefinite antipsychotic therapy, we paradoxically increase the risk of psychotic relapse in a significant proportion of people. A greater appreciation of supersensitivity may allow us to optimise any potential benefits of antipsychotics while minimising the risk of inadvertent iatrogenic harms. More research is needed to improve our understanding of the underlying neurophysiology of supersensitivity and to better identify which individuals are most vulnerable to its development. It is time we paid more attention to the concept, emerging evidence and potential implications of antipsychotic-induced supersensitivity and, where appropriate, adjusted our practice accordingly.

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THU0319 DEVELOPMENT AND OUTCOME OF AORTIC COMPLICATIONS DURING TOCILIZUMAB TREATMENT OF GCA AND HISTOPATHOLOGIC EVIDENCE OF RESIDUAL INFLAMMATION-A CASE SERIES.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4660 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 388.2-389

Author(s):

A. Rubbert-Roth ◽

P. K. Bode ◽

T. Langenegger ◽

C. Pfofe ◽

T. Neumann ◽

...

Keyword(s):

Structural Changes ◽

Case Series ◽

Aortic Aneurysms ◽

Imaging Data ◽

Limited Data ◽

Retrospective Case ◽

Pet Ct ◽

Fdg Pet Ct ◽

Pet Ct Scan

Background:Giant cell arteritis (GCA) may affect the aorta and the large aortic branches and lead to dissections and aortic aneurysms. Tocilizumab (TCZ) treatment has the capacity to control aortic inflammation as has been demonstrated by CRP normalization and imaging data. However, limited data are available on the histopathological findings obtained from patients who underwent surgery because of aortic complications during TCZ treatment.Objectives:We report on 5 patients with aortitis who were treated with TCZ and developed aortic complications.Methods:We describe a retrospective case series of patients with GCA treated with TCZ, who presented in our clinic between 2011 and 2019. Three patients underwent surgery. Histopathologic examination was performed in specimen from all of them.Results:Five female patients were diagnosed with GCA (4/5) or Takaysu arteritis (1/5) involving the aorta, all them diagnosed by MR angiography and/or FDG PET CT scan. Three patients (one with aortic aneurysm, one with dissection) underwent surgery after having been treated with TCZ for seven weeks, nine months and four years, respectively. Imaging before surgery showed remission on MRI and/or PET-CT in all cases. At the time of surgery, all patients showed normalized CRP and ESR values. Histopathological evaluation of the aortic wall revealed infiltrates, consisting predominantly of CD3+CD4+ T cells. Enlargement of pre-existing aneuryms was observed in the other two patients 10 weeks and 4 months after discontinuation of TCZ, respectively. Both patients were not eligible for surgical intervention and died during follow-up.Conclusion:Our case series suggests that during treatment with TCZ, regular imaging is necessary in this patient population to detect development of structural changes such as aneurysms or dissections. Despite treatment, residual inflammation might persist which could contribute to eventual aortic complications.Disclosure of Interests:Andrea Rubbert-Roth Consultant of: Abbvie, BMS, Chugai, Pfizer, Roche, Janssen, Lilly, Sanofi, Amgen, Novartis, Peter Karl Bode: None declared, Thomas Langenegger: None declared, Claudia Pfofe: None declared, Thomas Neumann: None declared, Olaf Chan-Hi Kim: None declared, Johannes von Kempis Consultant of: Roche

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The functional vascular anatomy of the swine for research

Vascular ◽

10.1177/1708538121996500 ◽

2021 ◽

pp. 170853812199650

Author(s):

Joseph Edwards ◽

Hossam Abdou ◽

Neerav Patel ◽

Marta J Madurska ◽

Kelly Poe ◽

...

Keyword(s):

Translational Research ◽

Functional Anatomy ◽

Three Dimensional ◽

Vascular Anatomy ◽

Review Article ◽

Imaging Data ◽

Preclinical Research ◽

Iodinated Contrast ◽

Translational Research Program ◽

And Function

Objectives Swine ( Sus Scrofa) are utilized broadly in research settings, given similarities to human vessel size and function; however, there are some important differences for clinicians to understand in order to interpret and perform translational research. This review article uses angiograms acquired in the course of a translational research program to present a description of the functional anatomy of the swine. Methods Digital subtraction angiography and computed tomography angiography were obtained throughout the course of multiple studies utilizing power injection with iodinated contrast. Subtracted two-dimensional images and three-dimensional multiplanar reformations were utilized post image acquisition to create maximal intensity projections and three-dimensional renderings of using open-source software (OsiriX). These imaging data are presented along with vessel measurements for reference. Results An atlas highlighting swine vascular anatomy, with an emphasis on inter-species differences that may influence how studies are conducted and interpreted, was compiled. Conclusions Swine are utilized in broad-reaching fields for preclinical research. While many similarities between human and swine vasculature exist, there are important differences to consider when conducting and interpreting research. This review article highlights these differences and presents accompanying images to inform clinicians gaining experience in swine research.

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Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine

BMJ Case Reports ◽

10.1136/bcr-2021-242495 ◽

2021 ◽

Vol 14 (4) ◽

pp. e242495

Author(s):

Nagara Takao ◽

Toshiya Murai ◽

Hironobu Fujiwara

Keyword(s):

Animal Studies ◽

Significant Proportion ◽

Antipsychotic Treatment ◽

High Dose ◽

Receptor Density ◽

Treatment Resistant ◽

Psychomotor Activity ◽

Receptor Blockers ◽

Dopamine Supersensitivity

Dopamine supersensitivity psychosis (DSP) frequently arises with long-term antipsychotic treatment and accounts for a significant proportion of treatment-resistant schizophrenia. The mechanism underlying DSP is thought to be a compensatory increase in dopamine receptor density in the striatum caused by long-term antipsychotic treatment. Previous animal studies have reported that antipsychotics increase serotonin 5-HT2A receptor density in the striatum and that 5-HT2A receptor blockers suppress dopamine-sensitive psychomotor activity, which may be linked to the pathophysiology of DSP. In this paper, we describe a patient who was hospitalised with treatment-resistant schizophrenia. Following treatment with high-dose antipsychotic polypharmacy for 10 weeks, the patient experienced worsening of psychotic and extrapyramidal symptoms. The patient was then started on second-generation antipsychotic asenapine while other antipsychotics were tapered off, resulting in improvement of these symptoms. Retrospectively, we presumed that the high-dose antipsychotic polypharmacy caused DSP, which was effectively treated by the potent 5-HT2A receptor antagonism of asenapine.

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Akt-mTOR hypoactivity in bipolar disorder gives rise to cognitive impairments associated with altered neuronal structure and function

Neuron ◽

10.1016/j.neuron.2021.03.008 ◽

2021 ◽

Author(s):

Amanda M. Vanderplow ◽

Andrew L. Eagle ◽

Bailey A. Kermath ◽

Kathryn J. Bjornson ◽

Alfred J. Robison ◽

...

Keyword(s):

Bipolar Disorder ◽

Cognitive Impairments ◽

Structure And Function ◽

Neuronal Structure ◽

And Function

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Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

Cell Death Discovery ◽

10.1038/s41420-021-00531-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qianshuo Liu ◽

Xiaobai Liu ◽

Defeng Zhao ◽

Xuelei Ruan ◽

Rui Su ◽

...

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Rna Binding ◽

Vital Role ◽

Brain Barrier ◽

Blood Brain ◽

Bbb Permeability ◽

Novel Target ◽

And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

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Environmental–biomechanical reciprocity and the evolution of plant material properties

Journal of Experimental Botany ◽

10.1093/jxb/erab411 ◽

2021 ◽

Author(s):

Karl J Niklas ◽

Frank W Telewski

Keyword(s):

Physical Environment ◽

Structural Changes ◽

Abiotic Factors ◽

Biotic Interactions ◽

Cellular Solids ◽

Form And Function ◽

Evolutionary Innovation ◽

Plant Form ◽

And Function ◽

Abiotic Environmental Factors

Abstract Abiotic–biotic interactions have shaped organic evolution since life first began. Abiotic factors influence growth, survival, and reproductive success, whereas biotic responses to abiotic factors have changed the physical environment (and indeed created new environments). This reciprocity is well illustrated by land plants who begin and end their existence in the same location while growing in size over the course of years or even millennia, during which environment factors change over many orders of magnitude. A biomechanical, ecological, and evolutionary perspective reveals that plants are (i) composed of materials (cells and tissues) that function as cellular solids (i.e. materials composed of one or more solid and fluid phases); (ii) that have evolved greater rigidity (as a consequence of chemical and structural changes in their solid phases); (iii) allowing for increases in body size and (iv) permitting acclimation to more physiologically and ecologically diverse and challenging habitats; which (v) have profoundly altered biotic as well as abiotic environmental factors (e.g. the creation of soils, carbon sequestration, and water cycles). A critical component of this evolutionary innovation is the extent to which mechanical perturbations have shaped plant form and function and how form and function have shaped ecological dynamics over the course of evolution.

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Abnormalities in Glucose Blood Level during Antipsychotic Treatment in Schizophrenia Patients

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2021.6294 ◽

2021 ◽

Vol 9 (T3) ◽

pp. 340-344

Author(s):

Faisal Idrus ◽

Theodorus Singara ◽

Dwiwahyu Sunarto ◽

Saidah Syamsuddin ◽

Sonny T. Lisal

Keyword(s):

Side Effects ◽

Blood Sugar ◽

Blood Sugar Level ◽

Fasting Blood Glucose ◽

Antipsychotic Treatment ◽

Antipsychotic Therapy ◽

Potential Health ◽

Sugar Levels ◽

Risperidone Group ◽

Haloperidol Group

Background: Schizophrenia is one of the mental disorder with many problematic issues, in both psychologically and socially. This disease requires provision of long-term antipsychotic therapy, hence could rise other potential health problems. Antipsychotic treatment can cause serious glucometabolic side-effects, including type 2 diabetes and hyperglycemic emergency. Recent attention has also been focused on antipsychotic-induced hyperglycemic emergencies experienced by new users of typical and atypical antipsychotic. Patients treated with atypical APDs have ~10 times higher risk in developing hyperglycaemic emergencies. In our pre-eliminary study, hyperglycemia condition in new patients occurs in four in seven patients who received typical and atypical antipsychotics. This condition is often overlooked and is not routinely evaluated. Moreover, it can develop into diabetes and increase the risk of morbidity and mortality in schizophrenia patients. In this study, we would like to determine the acute effects of metabolic (hyperglycemia) in patients treated with antipsychotic (Risperidone and Haloperidol) Measurement of blood sugar levels was performed in groups treated with haloperidol (N = 15) and treated with risperidone (N = 15). Plasma samples were taken at the beginning of treatment, in week IV, and in week VIII. The measurement of glucose levels was performed after meal and in early morning before breakfast (fasting blood glucose level 8 hours). Results: The blood sugar level after meals was significantly higher in the Risperidone group compared to the Haloperidol group (p <0.001) after IV and VIII weeks. Meanwhile, the fasting blood sugar level was significantly higher in the Risperidone group compared to the Haloperidol group after VIII weeks of treatment ( p <0.001). Conclusions: Both antipsychotics can cause an increase in blood sugar levels. Treatment with Risperidone significantly increased the blood sugar levels compared to treatment with haloperidol. Measurement of blood sugar level is needed to monitor the metabolic effect of antipsychotic, especially in patients treated with Risperidone. It is necessary to have dietary regulation and physical activities to prevent undesired metabolic side effects.

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