Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

PURPOSE: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). METHODS: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. RESULTS: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). CONCLUSION: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats.

Psilocybin (a classic serotonergic psychedelic drug) has received appraisal for use in psychedelic-assisted therapy of several psychiatric disorders. A less explored topic concerns the use of repeated low doses of psychedelics, at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy and often referred to as microdosing. Psilocybin microdose users frequently report increases in mental health, yet such reports are often highly biased and vulnerable to placebo effects. Here we establish and validate a psilocybin microdose-like regimen in rats with repeated low doses of psilocybin administration at a dose derived from occupancy at rat brain 5-HT2A receptors in vivo. The rats tolerated the repeated low doses of psilocybin well and did not manifest signs of anhedonia, anxiety, or altered locomotor activity. There were no deficits in pre-pulse inhibition of the startle reflex, nor did the treatment downregulate or desensitize the 5-HT2A receptors. However, the repeated low doses of psilocybin imparted resilience against the stress of multiple subcutaneous injections, and reduced the frequency of self-grooming, a proxy for human compulsive actions, while also increasing 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These results establish a well-validated regimen for further experiments probing the effects of repeated low doses of psilocybin. Results further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention, while pointing to a possible physiological mechanism.

A facile synthesis of precursor for the σ-1 receptor PET radioligand [18 F]FTC-146 and its radiofluorination.

The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9 GBq/µmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.

Feasibility of using abbreviated scan protocols with population-based input functions for accurate kinetic modeling of [18F]-FDG datasets from a long axial FOV PET scanner.

BACKGROUND: Accurate kinetic modeling of 18F-fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) data requires accurate knowledge of the available tracer concentration in the plasma during the scan time, known as the arterial input function (AIF). The gold standard method to derive the AIF requires collection of serial arterial blood samples, but the introduction of long axial field of view (LAFOV) PET systems enables the use of non-invasive image-derived input functions (IDIFs) from large blood pools such as the aorta without any need for bed movement. However, such protocols require a prolonged dynamic PET acquisition, which is impractical in a busy clinical setting. Population-based input functions (PBIFs) have previously shown potential in accurate Patlak analysis of [18F]-FDG datasets and can enable the use of shortened dynamic imaging protocols. Here, we exploit the high sensitivity and temporal resolution of a LAFOV PET system and explore the use of PBIF with abbreviated protocols in [18F]-FDG total body kinetic modeling. METHODS: Dynamic PET data were acquired in 24 oncological subjects for 65 min following the administration of [18F]-FDG. IDIFs were extracted from the descending thoracic aorta, and a PBIF was generated from 16 datasets. Five different scaled PBIFs (sPBIFs) were generated by scaling the PBIF with the AUC of IDIF curve tails using various portions of image data (35-65, 40-65, 45-65, 50-65, and 55-65 min post-injection). The sPBIFs were compared with the IDIFs using the AUCs and Patlak Ki estimates in tumor lesions and cerebral gray matter. Patlak plot start time (t*) was also varied to evaluate the performance of shorter acquisitions on the accuracy of Patlak Ki estimates. Patlak Ki estimates with IDIF and t* = 35 min were used as reference, and mean bias and precision (standard deviation of bias) were calculated to assess the relative performance of different sPBIFs. A comparison of parametric images generated using IDIF and sPBIFs was also performed. RESULTS: There was no statistically significant difference between AUCs of the IDIF and sPBIFs (Wilcoxon test: P > 0.05). Excellent agreement was shown between Patlak Ki estimates obtained using sPBIF and IDIF. Using the sPBIF55-65 with the Patlak model, 20 min of PET data (i.e., 45 to 65 min post-injection) achieved < 15% precision error in Ki estimates in tumor lesions compared to the estimates with the IDIF. Parametric images reconstructed using the IDIF and sPBIFs with and without an abbreviated protocol were visually comparable. Using Patlak Ki generated with an IDIF and 30 min of PET data as reference, Patlak Ki images generated using sPBIF55-65 with 20 min of PET data (t* = 45 min) provided excellent image quality with structural similarity index measure > 0.99 and peak signal-to-noise ratio > 55 dB. CONCLUSION: We demonstrate the feasibility of performing accurate [18F]-FDG Patlak analysis using sPBIFs with only 20 min of PET data from a LAFOV PET scanner.

Assessment of perfusion deficit with early phases of [18F]PI-2620 tau-PET versus [18F]flutemetamol-amyloid-PET recordings.

PURPOSE: Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [18F]flutemetamol-amyloid-PET and [18F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease. METHODS: We obtained early-phase PET recordings with [18F]PI-2620 (0.5-2.5 min p.i.) and [18F]flutemetamol (0-10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to ß-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores < - 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests. RESULTS: The z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61-0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16-0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28-0.90). CONCLUSION: The early perfusion phases of [18F]PI-2620 tau- and [18F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity.

Autoradiographic characterization of [18 F]PSMA-1007 binding in rat brain.

Carboxypeptidase II (CBPII) in brain metabolizes the neuroactive substance N-acetyl-L-aspartyl-L-glutamate (NAGG) to yield the elements of glutamate and N-acetyl-aspartate (NAA). In peripheral organs, CBPII is known as prostrate specific membrane antigen (PSMA), which presents an important target for nuclear medicine imaging in prostate cancer. Available PSMA ligands for PET imaging do not cross the blood-brain barrier, and there is scant knowledge of the neurobiology of CBPII, despite its implication in the regulation of glutamatergic neurotransmission. In this study we used the clinical PET tracer [18 F]-PSMA-1007 ([18 F]PSMA) for an autoradiographic characterization of CGPII in rat brain. Ligand binding and displacement curves indicated a single site in brain, with KD of about 0.5 nM, and Bmax ranging from 9 nM in cortex to 19 nM in white matter (corpus callosum and fimbria) and 24 nM in hypothalamus. The binding properties of [18 F]PSMA in vitro should enable its use for autoradiographic investigations of CBPII expression in animal models of human neuropsychiatric conditions.

Static versus Functional PET: Making Sense of Metabolic Connectivity.

Recently, Jamadar et al. (2021, Metabolic and hemodynamic resting-state connectivity of the human brain: a high-temporal resolution simultaneous BOLD-fMRI and FDG-fPET multimodality study. Cereb Cortex. 31(6), 2855-2867) compared the patterns of brain connectivity or covariance as obtained from 3 neuroimaging measures: 1) functional connectivity estimated from temporal correlations in the functional magnetic resonance imaging blood oxygen level-dependent signal, metabolic connectivity estimated, 2) from temporal correlations in 16-s frames of dynamic [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), which they designate as functional FDG-PET (fPET), and 3) from intersubject correlations in static FDG-PET images (sPET). Here, we discuss a number of fundamental issues raised by the Jamadar study. These include the choice of terminology, the interpretation of cross-modal findings, the issue of group- to single-subject level inferences, and the meaning of metabolic connectivity as a biomarker. We applaud the methodological approach taken by the authors, but wish to present an alternative perspective on their findings. In particular, we argue that sPET and fPET can both provide valuable information about brain connectivity. Certainly, resolving this conundrum calls for further experimental and theoretical efforts to advance the developing framework of PET-based brain connectivity indices.

Optimization of a Nucleophilic Two-Step Radiosynthesis of 6-O-(2-[18F]fluoroethyl)-6-O-desmethyl-diprenorphine ([18F]FE-DPN) for PET Imaging of Brain Opioid Receptors.

We have established a method for nucleophilic one-pot, two-step radiosynthesis of the popular opioid receptor radioligand 6-O-(2-[18F]fluoroethyl)-6-O-desmethyl-diprenorphine ([18F]FE-DPN) from the novel precursor 6-O-(2-tosyloxyethyl)-6-O-desmethyl- 3-O-trityl-diprenorphine (TE-TDDPN), which we designate as the Henriksen precursor. We undertook an optimization of the synthesis conditions, aiming to enhance the accessibility of [18F]FE-DPN for positron emission tomography (PET) studies of µ-opioid receptors. Herein, we report an optimized direct nucleophilic 18F-fluorination and the deprotection conditions for a fully automated radiosynthesis of [18F]FE-DPN on a modified GE Tracerlab FX FE synthesis panel. Starting from 1-1.5 GBq of [18F]fluoride and applying an Oasis Max 1cc cartridge for fluorine-18 trapping with a reduced amount of K2CO3 (5.06 µmol K+ ion), [18F]FE-DPN ([18F]11) was produced with 44.5 ± 10.6 RCY (decay-corrected), high radiochemical purity (>99%), and a molar activity of 32.2 ± 11.8 GBq/µmol in 60-65 min.

Comparing the Anti-Depressive Effect of Electroconvulsive Therapy (ECT) Versus Transcranial Magnetic Stimulation (TMS) in the Treatment of Patients with Depression.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for depressive disorders. However, ECT has a number of limitations, such as significant side effects in the neurocognitive domain and the requirement for general anesthesia. Transcranial magnetic stimulation (TMS) is an intervention that applies electric stimulation to the brain without causing convulsions, thus representing an attractive alternative to ECT. The aim of our study is to review systematic reports of the effectiveness of ECT and TMS in the treatment of depressive spectrum disorders. SUBJECTS AND METHODS: We performed search queries in PubMed and eLibrary databases, which retrieved 391 articles, of which 14 met our inclusion criteria for the analysis. The articles comprised three comparisons: TMS vs SHAM, ECT vs sham ECT (SECT), and ECT vs PHARM. The protocol parameters analyzed for TMS were coil type, targeted brain area, amplitude of resting motor threshold, duration of session, number of sessions in total and per week, number and pulses per session and inter-train pause. For ECT, we evaluated the type of ECT device, targeted brain area, type of stimuli, and for ECT vs PHARM we recorded types of anesthesia and antidepressant medication. RESULTS: Three of 6 studies showed a therapeutic effect of TMS compared to placebo; efficacy was greater for TMS frequency exceeding 10 Hz, and with stimulation of two areas of cerebral cortex rather than a single area. There was insufficient data to identify a relationship between the success of TMS and intertrain pause (IP). Three of four studies showed a therapeutic effect of ECT compared to placebo. Three studies of bilateral ECT showed a significant reduction in depression scores compared to the SECT groups. ECT protocols with brief pulses were generally of lesser efficacy. Four of 5 ECT vs PHARM studies showed superior efficacy of ECT compared to PHARM. Among several antidepressants, only the ketamine study showed greater efficacy compared to ECT. CONCLUSIONS: There of six TMS studies and 7 of 9 ECT studies showed efficacy in reducing depressive symptoms. A prospective study of crossover design might reveal the relative efficacies of ECT and TMS.

Genetic Contributors to PTSD: the Role of SNVs, Gene Interactions and Haplotypes for Developing PTSD Prevention Measures. A Comprehensive Review.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a trauma- or stressor-related mental health condition with high socioeconomic burden. We aimed in this review to identify promising genetic markers predisposing for PTSD, which might serve in the design subsequent studies aiming to develop PTSD prevention and remediation measures. SUBJECTS AND METHODS: Our search queries in the PubMed database yielded 547 articles, of which 20 met our inclusion criteria for further analysis: published between 2018 and 2022, original research, containing molecular-genetic and statistical data, containing diagnosis verification methods, PTSD as a primary condition, and a sample of at least 60 patients. RESULTS: Among the 20 analyzed studies were reports of significant associations between PTSD and: FKBP5 variants rs9470080, regardless of the C or T allele; two FKBP5 haplotypes (A-G-C-C and A-G-C-T); gene-gene DRDхANNK1-COMT (rs1800497 × rs6269) and OXTR-DRD2 (rs2268498 × rs1801028); C-allele of CRHR1 (rs1724402). Other findings, such as the association of FKBP5 haplotypes (A-G-C-C, A-G-C-T) and the FKBP5-CRHR1 genotype, were of lesser statistical significance and less extensively studied. CONCLUSIONS: Although our literature analysis implicates certain genetic factors in PTSD, our understanding of the polygenic nature underlying the disorder remains limited, especially considering the hitherto underexplored epigenetic mechanisms. Future research endeavors should prioritize exploring these aspects to provide a more nuanced understanding of PTSD and its genetic underpinnings.

Neurological and Psychiatric Aspects of Biological Markers for the Provision of Medical Care to Patients with Spinal Muscular Atrophy 5q.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic disorder, in which, for the common childhood onset forms, loss of function of the SMA 5q gene leads to disability and death before adulthood. Symptomatic treatment focusses on respiratory and nutritional support, and physical therapy, but there is little consideration of psychiatric manifestations of SMA. The aim of this study was to explore blood biomarker levels, electromyography (EMG) data, and clinical manifestations, including psychiatric impairments, in patients with SMA 5q. Our objectives were twofold: First, to assess the clinical relevance of standard biomarkers, i.e., creatinine, creatine kinase (CK), and lactate dehydrogenase (LDH) levels, and second, to obtain data supporting the development of an effective prognostic algorithm for the course of this disease. RESULTS: We analyzed retrospective data from 112 medical records of 58 registered patients (2008-2022) with SMA. At the time of last registration, the 58 patients had a mean age 38.4 years [13.68; 55.0], of whom 32 (52%) were female. The subgroup of 21 pediatric patients had a mean age 12.32 years [6.57; 13.93], of whom 14 (24%) were girls. The ICD-10 diagnoses were as follows: G12.0 (n=7, 12%, children), G12.1 (n=14, 24% children; n=29, 50% adults), G12.8 (n=6, 10% adults), G12.9 (n=2, 1% adults). The archival data on psychiatric status indicated emotional lability (n=6, 10.3%), fatigue (n=10, 17.2%), and tearfulness (n=3, 5.2%) in some patients. There were no significant subgroup differences in serum creatinine and CK levels, but there were significant differences in LDH levels between the G12.0, G12.1, G12.8, and G12.9 subgroups. Among the serum biomarkers, only LDH levels showed significant differences among the subgroups of SMA 5q patients; higher levels in the G12.1, G12.8, and G12.9 groups compared to the G12.0 (infantile) group related to age, weight, gender, and level of physical activity. Data on psychiatric status were insufficient to identify group differences and associations with biomarker levels. Likewise, longitudinal data on repeat hospitalizations did not indicate associations with biomarker levels. CONCLUSIONS: Creatinine, CK, and LDH levels were insufficient for monitoring and predicting the course of SMA. Further prospective research is needed to elaborate the weak relationships between CK levels, the dynamics of the clinical presentation, and therapeutic interventions, and to investigate psychiatric co-morbidities in SMA 5q patients.

First results on kinetic modelling and parametric imaging of dynamic 18F-FDG datasets from a long axial FOV PET scanner in oncological patients.

PURPOSE: To investigate the kinetics of 18F-fluorodeoxyglucose (18F-FDG) by positron emission tomography (PET) in multiple organs and test the feasibility of total-body parametric imaging using an image-derived input function (IDIF). METHODS: Twenty-four oncological patients underwent dynamic 18F-FDG scans lasting 65 min using a long  axial FOV (LAFOV) PET/CT system. Time activity curves (TAC) were extracted from semi-automated segmentations of multiple organs, cerebral grey and white matter, and from vascular structures. The tissue and tumor lesion TACs were fitted using an irreversible two-tissue compartment (2TC) and a Patlak model. Parametric images were also generated using direct and indirect Patlak methods and their performances were evaluated. RESULTS: We report estimates of kinetic parameters and metabolic rate of glucose consumption (MRFDG) for different organs and tumor lesions. In some organs, there were significant differences between MRFDG values estimated using 2TC and Patlak models. No statistically significant difference was seen between MRFDG values estimated using 2TC and Patlak methods in tumor lesions (paired t-test, P = 0.65). Parametric imaging showed that net influx (Ki) images generated using direct and indirect Patlak methods had superior tumor-to-background ratio (TBR) to standard uptake value (SUV) images (3.1- and 3.0-fold mean increases in TBRmean, respectively). Influx images generated using the direct Patlak method had twofold higher contrast-to-noise ratio in tumor lesions compared to images generated using the indirect Patlak method. CONCLUSION: We performed pharmacokinetic modelling of multiple organs using linear and non-linear models using dynamic total-body 18F-FDG images. Although parametric images did not reveal more tumors than SUV images, the results confirmed that parametric imaging furnishes improved tumor contrast. We thus demonstrate the feasibility of total-body kinetic modelling and parametric imaging in basic research and oncological studies. LAFOV PET can enhance dynamic imaging capabilities by providing high sensitivity parametric images and allowing total-body pharmacokinetic analysis.

Subacute cytokine changes after a traumatic brain injury predict chronic brain microstructural alterations on advanced diffusion imaging in the male rat.

INTRODUCTION: The process of neuroinflammation occurring after traumatic brain injury (TBI) has received significant attention as a potential prognostic indicator and interventional target to improve patients' outcomes. Indeed, many of the secondary consequences of TBI have been attributed to neuroinflammation and peripheral inflammatory changes. However, inflammatory biomarkers in blood have not yet emerged as a clinical tool for diagnosis of TBI and predicting outcome. The controlled cortical impact model of TBI in the rodent gives reliable readouts of the dynamics of post-TBI neuroinflammation. We now extend this model to include a panel of plasma cytokine biomarkers measured at different time points post-injury, to test the hypothesis that these markers can predict brain microstructural outcome as quantified by advanced diffusion-weighted magnetic resonance imaging (MRI). METHODS: Fourteen 8-10-week-old male rats were randomly assigned to sham surgery (n = 6) and TBI (n = 8) treatment with a single moderate-severe controlled cortical impact. We collected blood samples for cytokine analysis at days 1, 3, 7, and 60 post-surgery, and carried out standard structural and advanced diffusion-weighted MRI at day 60. We then utilized principal component regression to build an equation predicting different aspects of microstructural changes from the plasma inflammatory marker concentrations measured at different time points. RESULTS: The TBI group had elevated plasma levels of IL-1ß and several neuroprotective cytokines and chemokines (IL-7, CCL3, and GM-CSF) compared to the sham group from days 3 to 60 post-injury. The plasma marker panels obtained at day 7 were significantly associated with the outcome at day 60 of the trans-hemispheric cortical map transfer process that is a frequent finding in unilateral TBI models. DISCUSSION: These results confirm and extend prior studies showing that day 7 post-injury is a critical temporal window for the reorganisation process following TBI. High plasma level of IL-1ß and low plasma levels of the neuroprotective IL-7, CCL3, and GM-CSF of TBI animals at day 60 were associated with greater TBI pathology.

Genetic Biomarkers of Antipsychotic-Induced Prolongation of the QT Interval in Patients with Schizophrenia.

Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs' dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.

Diels-Alder Adducts of Morphinan-6,8-Dienes and Their Transformations.

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels-Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.

Cryptogenic Stroke In The Context of Pandemic-Related Stress: The Role of Arterial Hemodynamics.

BACKGROUND: Up to 45% of ischemic strokes are cryptogenic, which is an impediment to proposing preventative measures. In this investigation we aimed to study underlying heart arrhythmias in patients with cryptogenic stroke, taking into consideration the context of the COVID-19 pandemic and stressful lockdown conditions. SUBJECTS AND METHODS: In this cross-sectional study we observed 52 patients with cryptogenic stroke >1 month after acute presentation, and a control group consisting of 88 patients without stroke. All patients undewent the laboratory and instrumental investigation consisting of the following: lipid spectrum; hemostasiograms; hemoglobin A1c; transthoracic or/and transesophageal echocardiography; 24-hours monitoring of ECG; computer tomography or magnetic resonance imaging of the brain. We studied the hemodynamics of the common carotid arteries using Doppler ultrasound imaging and digital sphygmography (SG). RESULTS: The groups were indentical with respect to the preponderance of study parameters (sex, age, comorbidities, instrumental and laboratory data). The ischemic stroke group had a statistically significant difference in the prevalence of the first type of extrasystolic arrhythmia according to our gradation of extrasystoles, which are ventricular systoles of extrasystolic contraction appearing before the transmitral blood flow peak (peak E in echocardiography). We observed that earlier ventricular systoles of extrasystole in the cardiac cycle predicted for greater growth of hemodynamic and kinetic parameters. Calculating the indices of a four-field table established the significant relationship between the moment of appearance of extrasystolic ventricular contraction in the cardiac cycle and the risk for cryptogenic stroke (normalized value of the Pearson coefficient (C`) of the two paramaters was 0.318). CONCLUSIONS: Extrasystolic arrhythmia appeared as an additional risk factor of earlier stroke. The most dangerous type of arrhythmia was when the ventricular contraction of the extrasystole appeared before the transmitral blood flow peak in the cardiac cycle. This observation could present a risk-marker for brain-related cardiovascular complications such as stroke, which might be patients suffering from different internal diseases, especially in the context of environmental stress conditions of the current pandemic and its related lockdown measures.

The Efficacy of Mobile Phone-Based Interventions for the Treatment of Depression: A Systematic Meta-Review of Meta-Analyses of Randomized Controlled Trials.

BACKGROUND: Depression is ranked by the World Health Organization as the single largest contributor to global disability. The shortage of health care resources, conditions of social distancing during the present pandemic, and the continuing need of patients with subclinical depression and in remission for supportive therapies, all together motivate a search for new approaches to deliver appropriate and timeous treatment for depression. SUBJECTS AND METHODS: We conducted a systematic literature search of meta-analyses and systematic reviews on the topic of mobile apps for the treatment of depression using the Medline (Pubmed) database during the period ending March 30th, 2022. This review was managed following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and entailed a search strategy using key-words related to depressive states and mobile phone apps for depression treatment and management. RESULTS: A total of 15 full-text articles met the inclusion criteria for the current systematic review. 13 of the 15 studies reported on the effectiveness of mobile apps for treating depression, finding a significant reduction in depressive symptoms with small-to-medium positive effect size. Patients with severe depression experienced greater benefits from a behavioral activation app, whereas those with mild depression responded better to a mindfulness app. The impact of clinicians' support is difficult to isolated completely from the particular interventions' effects. CONCLUSIONS: Mobile-based intervention apps present a convenient tool for prevention and supportive therapy of depression. The use of mobile apps may act as an efficient intervention to reduce depression in adult patients regardless the potential contributing factors of gender or co-morbidities, but the role of mobile apps should be contrasted with other digital interventions.

Pharmacogenetic Aspects of COVID-19 Management and Post-COVID-19 Depression Treatment with Fluvoxamine.

BACKGROUND: Quarantine measures with self-isolation of varying duration have been significant psychosocial stressors in the context of the COVID-19 pandemic. The serotonin selective reuptake inhibitor fluvoxamine has been considered as a prophylaxis against depression in early COVID-19 patients, with additional benefits apparently arising from its antiviral activity. In this narrative review, we draw attention to the body of evidence showing efficacy of fluvoxamine in protecting against depressive disorders in COVID-19 patients, while also attenuating the severity of COVID-19 disease, with a notable reduction in the need for intubation and lower mortality. We consider this potential two-fold action of fluvoxamine in the light of its pharmacogenetic and pharmacological profiles. SUBJECTS AND METHODS: Full-text publications in English and Russian in Google Scholar, PubMed, NCBI, Web of Science, and E-Library databases were selected by keywords, solitary and in combination (fluvoxamine, COVID-19, depression, anxiety, antidepressants, adverse reactions) for the period from March 01, 2020 to June 06, 2022. We also analyzed the full-text publications in English and Russian language reporting adverse reactions caused by fluvoxamine use for the period from 2012 to 2022. RESULTS: The literature search yielded 10 papers reporting on the efficacy fluvoxamine in relieving depressive symptoms in COVID-19 patients, and 3 papers on its effect on medical outcome. The preponderance of data indicated a dual therapeutic action of fluvoxamine, and our further literature investigation was informative about drug-drug interactions and genetic factors moderating the antidepressant efficacy of fluvoxamine. CONCLUSIONS: Patients with COVID-19 seeking psychopharmacological treatment for depressive symptoms must be informed of the benefits and risks of fluvoxamine use. Several lines of findings indicate this agent to possess an additional antiviral action. However, optimal dosage regimens and the trade-off with drug-drug interactions remain unclear. Pharmacogenetic testing may assist in evidence-based optimization of fluvoxamine dosages in the context of COVID-19 infection with comorbid depression.

Possible Clinical and Pharmacogenetic Predictors of the Efficacy and Safety of Carbamazepine in Post-COVID-19 Depression.

BACKGROUND: Individuals who have suffered from novel coronavirus disease (COVID-19) are at risk for developing post-COVID neuropsychiatric disorders, which are an integral part of the Long COVID syndrome. Depression and/or anxiety are considered the most common psychiatric disorders after experiencing COVID-19. Certain antiepileptic drugs, notably, carbamazepine (CMZ), are effective in the treatment of mood disorders, especially as mood stabilizers in bipolar affective disorder (BAD), but the efficacy of CMZ in Long COVID remains to be established. The aim of the review was to investigate pharmacogenetic predictors of safety and efficacy of CMZ in patients with depressive symptoms of Long COVID during the post-infection period. SUBJECTS AND METHODS: We carried out a systematic search for publications in English and Russian on the safety and efficacy of CMZ in depressive disorders of different etiologies in the PubMed, Web of Science, Springer, Clinical Keys, Google Schooler, E-Library databases using keywords and combined word searches (carbamazepine, COVID-19, depression, epilepsy, post-COVID-syndrome) for the period from January 01,2020 to June 10, 2022. RESULTS: We review the main adverse drug reactions (ADRs) associated with CMZ, drug-drug interactions, and genetic predictors of the development of ADR. Here, we consider as risk factors, candidate genes for CMZ metabolism, CMZ transport, immunohistocompatibility genes, and candidate genes for QT prolongation. CONCLUSIONS: The choice of antidepressant treatment for patients with Long COVID is fraught because of the frequent occurrence of subclinical (interictal) epileptiform activity in the EEG. Consequently, antidepressant medications with a proconvulsant effect are contraindicated for Long COVID patients. CMZ may be a promising alternative for the treatment of depressive disorders in Long COVID states, given its mood-stabilizer, antidepressant, and antiepileptic profile.

Association between Neuropathic Pain and Depression: Focusing on the Transcranial Magnetic Stimulation As a Promising Treatment Approach.

BACKGROUND: Neuropathic pain (NP) affects approximately 7% of the general population and is often accompanied by depressive symptoms with up to 85% of NP patients are suffering from comorbid depression (CD). The noninvasive neuromodulation technique of transcranial magnetic stimulation (TMS) is an established proven clinically effective nonpharmacological treatment for depression, and considered a highly promising option also for reducing the burden of NP by relieving pain perception and increasing patients' quality of life. In this article, we systematically review the various clinical protocols used in TMS treatments in patients suffering from NP and comorbid depression. SUBJECTS AND METHODS: Using Scopus, Elsevier, and PubMed databases, our keyword search identified 639 articles, of which 22 were selected for detailed analysis based on the inclusion criteria and in consideration of the heterogeneous study design of the majority of small trials. We evaluated the clinical efficacy in NP and comorbid depression, in relation to various TMS protocol parameters including coil type, target brain area, locus of increased evoked motor potential, amplitude of stimulation, duration of session, number of sessions per day/month, as well as inter-session-intervals, number and frequency of trains, and number and frequency of pulses. RESULTS: The most effective TMS protocols for treating comorbid NP and depression, as marked by decreased pain and depression scores proved to entail figure-of-8 coils targeting the primary motor area (M1), and applying at least ten daily rTMS sessions using high frequency stimulation (10-20 Hz) with a sub threshold intensity of 80-90% RMT and a total number of pulses of at least 1500 per session. Performing an additional maintenance phase after the acute treatment phase may strengthen and prolong the therapeutic effects of rTMS. CONCLUSIONS: Our database analysis suggests that a specific combination of TMS parameters is most effective for treating NP and comorbid depression. Although results are promising, the heterogeneity within the literature is such that many underpowered studies contribute rather little to the outcome, as evident by our inclusion / exclusion analysis. Moreover, we see a need for consensus on clinical protocols and inclusion of much larger clinical samples. Furthermore, we conclude that future research should entail advanced TMS procedures with multiple brain region stimulation (sequential or concurrent), and address issues of TMS maintenance and improved coil engineering for targeting deeper structures.