Chronobiological Predictors of Depression Relapse: for Prognostic Model Development - a Systematic Review.

BACKGROUND: Depressive disorders are characterized by fluctuating symptom severity, and developing an individual prognostic model for relapse is crucial for effective prevention. Chronobiological factors are poorly understood in this context. METHODS: A systematic search was conducted to identify articles related to the prognosis of depression recurrence based on chronobiological factors. Relevant clinical studies were included, while reviews and case reports were excluded. A total of 14 articles were selected for review. RESULTS: The included articles focused on various chronobiological factors, including circadian biorhythms, individual chronotype, mood swings, seasonal patterns, diurnal cortisol fluctuations, and light therapy. The accuracy of personified prognosis ranged from 22.7% to 93.8%, and the prognostic value of specific predictors in group prognosis varied from 23.9% to 54%. Methodological differences and limitations hindered direct comparison and clinical applicability. CONCLUSIONS: Developing precise and practical models for depression recurrence prognosis remains limited. Parameters of circadian rhythm showed the highest accuracy for short-term prognosis, and the use of digital technologies, including AI, enhanced prognostic value. Relapse seasonality had limited practical applicability. Integrating other chronobiological factors into prognostic models requires further research. Utilizing digital technologies, including AI, can improve the accuracy and range of personified prognosis. Only a few selected parameters of the human chronobiological system were considered in the examined studies. There are indications of the other chronobiological factors that could be included in the integrated prognostic model of recurrence for its further improvement.

Peripheral Blood Mononuclear Cell-Related Biomarkers in Schizophrenia.

INTRODUCTION: Schizophrenia is a severe mental illness causing significant impairment in personal, family, social, educational, occupational, and other important areas of life. While there is no widely accepted endophenotype, peripheral blood cells may serve as an accessible model of intracellular changes in schizophrenia. METHODS: We reviewed the literature on the query "peripheral blood mononuclear cells AND schizophrenia" in Medline (Pubmed), selecting studies that searched for specific biomarkers of schizophrenia. We considered both diagnostic biomarkers and biomarkers of therapeutic response, specific schizophrenia disorders or differential diagnostic biomarkers. RESULTS: We retrieved 41 articles matching the search criteria, among which were studies that considered changes in the production of pro-inflammatory and anti-inflammatory markers, proteins, receptors, enzyme activity, and gene expression as potential biomarkers. CONCLUSION: Approaches analysing a biological axis or a group of related biomarkers may hold the greatest promise for identifying schizophrenia. In addition, pharmacological status, smoking status, inflammatory markers and glucose metabolites, the presence of comorbidities should be considered. Certain biomarkers, while not specific for the diagnosis of schizophrenia, may indicate the prognosis and effectiveness of treatment in the established diagnosis.

Application of SF-36 Health Status Survey in Patients with Arterial Hypertension.

BACKGROUND: To estimate quality of life (QOL) in patients with arterial hypertension (AH) using SF-36 Health Status Survey. SUBJECTS AND METHODS: We included 268 patients (144 men, 124 women) with grade 1-3 AH (subgroup 1 - with coronary stenosis less than 50% (n=158), subgroup 2 - with coronary artery stenosis of 50% or more (n=110)). In the control group - 80 people (47 men, 33 women) without AH. Laboratory and instrumental methods included total cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, creatinine, electrocardiography, echocardiography, Doppler ultrasound of brachiocephalic arteries, stress echocardiography with physical exercises and coronary angiography. For QOL evaluation we used SF-36 Health Status Survey. RESULTS: According to the results of the SF-36 Health Status Survey, when assessing physical (PH) and mental (MH) among the groups, there was a significant decrease in summary points in patients of subgroup 2, in whom, according to coronary angiography, it was revealed stenosis of the carotid arteries 50% and more. Anxiety and depression predominated in men. Patients with corrected cholesterol and LDL-cholesterol levels, as well as after coronary angioplasty, were assessed for QOL with limited physical activity, but with high social functioning. CONCLUSIONS: AH, especially with hemodynamically significant atherosclerosis of the coronary arteries are the predictors for QOL worsening in cardiological patients, mostly in men. Using of the international questionnaire "SF-36 Health Status Survey" is advisable to assess the QOL in patients with cardiovascular diseases. In this sense, the interaction of a cardiologist and a psychotherapist is appropriate and justified for the most optimal management of a patient with this pathology.

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.

Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis.

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

Valproate-Induced Metabolic Syndrome.

Valproic acid (VPA) and its salts (sodium calcium magnesium and orotic) are psychotropic drugs that are widely used in neurology and psychiatry. The long-term use of VPA increases the risk of developing adverse drug reactions (ADRs), among which metabolic syndrome (MetS) plays a special role. MetS belongs to a cluster of metabolic conditions such as abdominal obesity, high blood pressure, high blood glucose, high serum triglycerides, and low serum high-density lipoprotein. Valproate-induced MetS (VPA-MetS) is a common ADR that needs an updated multidisciplinary approach to its prevention and diagnosis. In this review, we consider the results of studies of blood (serum and plasma) and the urinary biomarkers of VPA-MetS. These metabolic biomarkers may provide the key to the development of a new multidisciplinary personalized strategy for the prevention and diagnosis of VPA-MetS in patients with neurological diseases, psychiatric disorders, and addiction diseases.

Green Emissive Copper(I) Coordination Polymer Supported by the Diethylpyridylphosphine Ligand as a Luminescent Sensor for Overheating Processes.

Tertiary diethylpyridylphosphine was synthesized by the reaction of pyridylphosphine with bromoethane in a suberbasic medium. The reaction of phosphine with the copper(I) iodide led to the formation of a copper(I) coordination polymer, which, according to the X-ray diffraction data, has an intermediate structure with a copper-halide core between the octahedral and stairstep geometries of the Cu4I4 clusters. The obtained coordination polymer exhibits a green emission in the solid state, which is caused by the 3(M+X)LCT transitions. The heating up of the copper(I) coordination polymer to 138.5 °C results in its monomerization and the formation of a new solid-state phase. The new phase exhibits a red emission, with the emission band maximum at 725 nm. According to the experimental data and quantum chemical computations, it was concluded that depolymerization probably leads to a complex that is formed with the octahedral structure of the copper-halide core. The resulting solid-state phase can be backward-converted to the polymer phase via recrystallization from the acetone or DMF. Therefore, the obtained coordination polymer can be considered a sensor or detector for the overheating of processes that should be maintained at temperatures below 138 °C (e.g., engines, boiling liquids, solar heat systems, etc.).

Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically "non-dopamine" Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of "non-dopamine" Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS.

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.

The Effects of Transcranial Magnetic Stimulation on Cognitive Functioning in Bipolar Depression: A Systematic Review.

BACKGROUND: The features of bipolar affective disorder (BAD) include mood swings, recurring episodes of mania, depression, and mixed states. Numerous studies of people living with BAD have found the presence of cognitive impairments that affect patients' daily social functioning and quality of life. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique recommended for the treatment of bipolar depression (BD). The effect of TMS on cognitive function in BD patients remains mostly unclear. SUBJECTS AND METHODS: We carried out a systematic search in the databases of PubMed and Scopus for the whole publication period until March 30th, 2022. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) was used to identify all data published in English language and related to the use of TMS in the treatment of depression in BAD and its impact on cognitive function. Articles related to TMS, cognition, and BD were identified using predefined term search algorithms. Articles on clinical trials and case reports were included, but reviews were excluded. The PICOS (Population Intervention Comparison Outputs Study) formula in our review included: P - patients with bipolar depression, I - TMS treatment, C - patients without TMS treatment / placebo TMS, O - changes in cognitive functions, S - all types of original studies. RESULTS: Within the primary screening for assessment of full texts, 25 documents met our selection criteria to test the effect of TMS on cognitive functioning in BD. Based on a secondary screening of the full-text analysis, 10 articles (N=259 patients) were included into the current review. Among these, the majority of articles were based on the randomized controlled trials (RCTs, N=6), whereas the remaining four presented a case report, an open unblinded study, an open-label study, and a pilot study, respectively. Most of the studies produced mixed result. However, the limited data strongly suggested that TMS is without detriment to cognition in BD patients and is indeed beneficial in specific domains of cognitive function, namely (i) verbal fluency, (ii) verbal memory, and (iii) executive functioning. Small sample sizes, heterogeneity across the study designs, lack of the control groups data in some of the trials, different TMS protocols parameters and outcome measures represent significant limitations for comparing and analyzing the available results. CONCLUSIONS: Thus, present data on the effects of TMS in improving cognition in BD patients remains limited. To our mind, in order to evaluate properly the effectiveness of TMS in cognitive functioning improvement in BD, there is need for further randomized controlled trials and the corresponding development of the clinical standards for research recommendations. Such studies could define the appropriate methods for valid assessments of cognitive functions, and guide the selection of optimal TMS protocols when planning RCTs. We suggest that efforts should be expended to organize centralized large-scale clinical trials to determine the optimal parameters of TMS procedures and the range of effects of this treatment on various indicators of cognitive functioning in BD. This applies equally to other socially significant mental disorders marked by perturbations in cognitive functioning.

Pathophysiological Mechanisms of Antipsychotic-Induced Parkinsonism.

Among neurological adverse reactions in patients with schizophrenia treated with antipsychotics (APs), drug-induced parkinsonism (DIP) is the most common motility disorder caused by drugs affecting dopamine receptors. One of the causes of DIP is the disruption of neurotransmitter interactions that regulate the signaling pathways of the dopaminergic, cholinergic, GABAergic, adenosinergic, endocannabinoid, and other neurotransmitter systems. Presently, the development mechanisms remain poorly understood despite the presence of the considered theories of DIP pathogenesis.

One-Pot Synthesis of Novel Functionalized Fused Pyridine Derivatives via Consecutive Pyrrolidine Ring-Closure/Ring-Opening/Formal Aza-Diels-Alder Reactions.

In this article, we report a highly regioselective method for the synthesis of new fused pyridine derivatives─2,3-disubstituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives. The method is based on the reaction of 1,1-diethoxybutane derivatives with aromatic and heterocyclic nucleophiles. The isolated compounds are similar to the products formed as a result of the Debner-Miller reaction. However, we have shown that the interaction of 1,1-diethoxybutane derivatives with (hetero)aromatic amines proceeds according to a mechanism different from that of the Doebner-Miller reaction. The proposed method is distinguished by the possibility of obtaining a wide range of substituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives in one step, the absence of the need to use expensive metal-containing catalysts, and a high product yield.

Triple-bridged helical binuclear copper(i) complexes: Head-to-head and head-to-tail isomerism and the solid-state luminescence.

A family of helical dinuclear copper(i) pyridylphospholane complexes [Cu2L3X]X (X = BF4-, Cl- and Br-) was prepared. The family includes the first examples of this type of complex based on copper(i) chloride and copper(i) bromide. The two isomers typical of this class of compounds, namely head-to-head and head-to-tail complexes, were studied in solution by spectroscopic and optical methods, and in the solid state by X-ray diffraction. Furthermore, the solid-state luminescence of the complexes at different temperatures was studied, and the results were interpreted using quantum-chemical calculations. It was shown that the luminescence of the complexes is attributed to the 3(M + X)LCT transitions.

New 2,6-diaminopyridines containing a sterically hindered benzylphosphonate moiety in the aromatic core as potential antioxidant and anti-cancer drugs.

A series of 2,6-diaminopyridines was synthesized for the first time, containing phosphoryl sterically hindered phenolic fragments in the aromatic core. The antioxidant activity of these compounds was investigated, 2,6-diaminopyridine derivatives were shown to exhibit higher activity in comparison with their structural analogues. For dialkyl/diphenyl [(3,5-di-tert-butyl-4-hydroxyphenyl) (2,6-diaminopyridin-3-yl) methyl] phosphonates, their structural analogues based on meta-phenylenediamine, phosphorus-containing sterically hindered phenols and the corresponding cyclohexadienones cytotoxicity against tumor lines of epithelioid carcinoma of the cervix uteri (M-Hela) and breast adenocarcinoma (MCF-7) has been studied in vitro, as well as on normal human Chang liver cell lines. Diphenyl [(3,5-di-tert-butyl-4-hydroxyphenyl) (2,6-diaminopyridin-3-yl) methyl] phosphonate was shown to be the most active against the epithelioid line M-Hela - IC50 comprises 7.4 µM. It was shown that apoptosis induced by the lead compound proceeds along the internal pathway of caspase-9 activation. It was established that all studied compounds do not possess hemolytic activity.

Structure and dynamics of P,N-containing heterocycles and their metal complexes in solution.

Conformations and dynamics of 1,5-diaza-3,7-diphosphacyclooctane (1) with chiral l-menthyl substituents on the phosphorus atoms and several metal complexes thereof were investigated by a variety of DNMR methods. In solution 1 adopts a C(2) symmetrical "crown"-like conformation (CW) and the conformational preference and dynamics of the complexes depend on the type of metal: for the Cu complex the CW form is preferred, whereas the Pd, Pt, or Mo complexes exist in an equilibrium of two "chair-boat"-like conformations (CB/CB*). The barriers of interconversion between these two conformations for the Pd and Pt complexes are about 2 times higher than for the Mo complex. Quantum chemical calculations (B3LYP/6-31G(d)) are in agreement with experimental findings.