Pharmacogenomics-assisted schizophrenia management: A hybrid type 2 effectiveness-implementation study protocol to compare the clinical utility, cost-effectiveness, and barriers.

OBJECTIVES: The response to antipsychotic therapy is highly variable. Pharmacogenomic (PGx) factors play a major role in deciding the effectiveness and safety of antipsychotic drugs. A hybrid type 2 effectiveness-implementation research will be conducted to evaluate the clinical utility (safety and efficacy), cost-effectiveness, and facilitators and barriers in implementing PGx-assisted management compared to standard of care in patients with schizophrenia attending a tertiary care hospital in eastern India. METHODS: In part 1, a randomized controlled trial will be conducted. Adult patients with schizophrenia will be randomized (2: 1) to receive PGx-assisted treatment (drug and regimen selection depending on the results of single-nucleotide polymorphisms in genes DRD2, HTR1A, HTR2C, ABCB1, CYP2D6, CYP3A5, and CYP1A2) or the standard of care. Serum drug levels will be measured. The patients will be followed up for 12 weeks. The primary endpoint is the difference in the Udvalg for Kliniske Undersøgelser Side-Effect Rating Scale score between the two arms. In part 2, the cost-effectiveness of PGx-assisted treatment will be evaluated. In part 3, the facilitators and barriers to implementing PGx-assisted treatment for schizophrenia will be explored using a qualitative design. EXPECTED OUTCOME: The study findings will help in understanding whether PGx-assisted management has a clinical utility, whether it is cost-effective, and what are the facilitators and barriers to implementing it in the management of schizophrenia. TRIAL REGISTRATION: The study has been registered with the Clinical Trials Registry-India (CTRI/2023/08/056210).

Inflammatory Markers in Patients With Major Depressive Disorder: A Prospective, Clinic-Based, Cohort Study From India.

Background Patients with major depressive disorder have varying response rates to treatment. Multiple factors such as non-adherence, comorbidity, chronic stressors, and biological factors may be responsible for this variation. Inflammatory (pro and anti) markers have been well studied as a cause for depression, predisposing factors, and a consequence of depression. Among these, interleukins (ILs), interferons, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) have been studied repeatedly. We conducted a pilot study to assess the levels of these inflammatory markers in patients with major depressive disorder. The specific objectives of this study were to compare and correlate changes in pro- and anti-inflammatory markers throughout different phases of depression, including pretreatment and posttreatment periods, and to evaluate the pattern of pro- and anti-inflammatory markers in patients who experienced remission or showed a positive response to treatment. Methodology This was a prospective, clinic-based, cohort study done for a period of one and a half years. Patients aged 18-65 years with depressive disorder per the International Classification of Diseases Tenth Edition and who scored more than 7 on the Hamilton Depression Rating Scale were included in this study. A total of 81 patients were recruited who were followed up till eight weeks after inclusion. A total of 31 patients completed the eight weeks of follow-up. Levels of IL-10 and TNF-α were assessed at baseline, two weeks, four weeks, and eight weeks of follow-up. Results This study tried to compare the levels of pro- and anti-inflammatory markers across pretreatment and various posttreatment phases of depression. Results showed that the levels of pro-inflammatory cytokine TNF-α increased from baseline till eight weeks of follow-up, and levels of IL-10 decreased from baseline till eight weeks of follow-up. However, these changes were not statistically significant. Conclusions This study supports the hypothesis that inflammatory markers can be trait markers of depression rather than the consequence or result.

Cognitive impairment in 'non-user' first-degree relatives of persons with cannabis dependence syndrome: A pilot, endophenotype study.

INTRODUCTION: Cannabis use disorders are global emerging problem nowadays, with high prevalence and morbidity. Cognitive impairments, and also corresponding genetic vulnerability, has been fairly replicated in individuals with cannabis dependence. However, there are few studies that assess cognitive functioning as an endophenotype or a trait marker for cannabis dependence. While the primary objective of this study was to assess the endophenotype pattern of cognitive dysfunction in cannabis dependence, assessing the association between the degree of cognitive functioning, and their socio-demographic and clinical variables in the cannabis dependence patients and their first-degree relatives was the secondary objective. METHODOLOGY: We compared cognitive functioning across three groups- patients with cannabis dependence syndrome, their 'non-user' first-degree relatives and healthy controls, with 30 participants in each group. Five cognitive domains- attention and concentration, verbal fluency, memory, visuospatial ability and executive functions were assessed. We assessed for endophenotype pattern of statistical significance in pairwise analyses of Kruskal-Wallis test, which was corrected for multiple comparisons. Subsequently, correlation analysis to assess association of cognitive impairment with socio-demographic and clinical variables was conducted. RESULTS: Although impairment in attention and executive functions also was seen in patients with cannabis dependence, endophenotype pattern of statistical significance in pairwise analyses, with impairment in first-degree relatives too, was seen in all sub-scores of verbal fluency and verbal memory. None of the correlations were significant. CONCLUSION: 'Non-user' first-degree relatives of patients with cannabis dependence too show significant cognitive impairment. Verbal fluency and verbal memory are possible endophenotypes or trait markers for cannabis dependence syndrome.

First-principles Calculations Reveal Frictional Advantage for C2 N/C6 N6 van der Waals Heterostructures.

Friction at the atomic scale is determined for three different carbon nitride structures namely C2 N/C2 N, C6 N6 /C6 N6 and C6 N6 /C2 N employing ab-initio density functional theory (DFT). The sliding path along the lowest energy corrugations determines the static frictional forces. Both the homo-layer structures (C2 N/C2 N and C6 N6 /C6 N6 ) have higher corrugation energy and correspondingly higher static lateral forces with respect to the hetero-layer structure (C2 N/C6 N6 ). The corrugation energy for the C2 N/C6 N6 heterostructure ( δ c o r r ${{\delta }_{corr}}$ =0.29 meV/atom) is one-order lower than C2 N/C2 N ( δ c o r r ${{\delta }_{corr}}$ =2.08 meV/atom) and C6 N6 /C6 N6 ( δ c o r r ${{\delta }_{corr}}$ =4.37 meV/atom). Such a significantly lower corrugation energy for the heterostructure arises due to the reduced fluctuation in the interfacial charge density along the sliding pathway. Moreover, the change in the interlayer distance along the sliding pathway is only 0.2 Šfor the heterostructure while its 0.3 Šand 0.4 Šfor C2 N and C6 N6 homo-layers respectively. The friction coefficients (FL /FN , FL =static lateral force; FN =normal force) decrease with increasing load for all the systems with the lowest value (0.04) for C2 N/C6 N6 at 2 GPa. The van der Waals heterostructures are, therefore, predicted to be highly efficient lubricant materials for reducing friction at the atomic scale.

External Ear Anomalies and Minor Physical Anomalies in Depressive Disorder Patients and Healthy Controls.

Objective: To determine if external ear anomalies (EEAs) and minor physical anomalies (MPAs) are more prevalent in patients with depressive disorder than in healthy controls.Methods: This cross-sectional study was conducted at a tertiary-level referral center between October 1, 2019, and September 30, 2020, and included 100 patients with depressive disorder (diagnosed per ICD-10 criteria) and 100 aged- and sex-matched healthy controls. The study participants were examined using the External Ear Anomalies Assessment Scale and the extended Waldrop Scale.Results: Independent samples Mann-Whitney U test showed a higher prevalence of mean EEAs and MPAs in patients with depressive disorder. Adherent ear lobe was the most common ear anomaly in both patients (52%) and controls (41%), followed by Darwinian tubercle (21% in the patient group and 19% in the control group).Conclusions: External ear anomalies are more prevalent in patients with depressive disorder, supporting the neurodevelopmental theory of depression. These EEAs need further description and attention for possible inclusion in scales that assess minor physical anomalies and may be used as an endophenotypic marker for depression in the future.Prim Care Companion CNS Disord. 2023;25(4):22m03416. Author affiliations are listed at the end of this article.

Frequency-swept dynamic nuclear polarization.

Dynamic nuclear polarization (DNP) improves the sensitivity of NMR spectroscopy by the transfer of electron polarization to nuclei via irradiation of electron-nuclear transitions with microwaves at the appropriate frequency. For fields > 5 T and using g ∼ 2 electrons as polarizing agents, this requires the availability of microwave sources operating at >140 GHz. Therefore, microwave sources for DNP have generally been continuous-wave (CW) gyrotrons, and more recently solid state, oscillators operating at a fixed frequency and power. This constraint has limited the DNP mechanisms which can be exploited, and stymied the development of new time domain mechanisms. We report here the incorporation of a microwave source enabling facile modulation of frequency, amplitude, and phase at 9 T (250 GHz microwave frequency), and we have used the source for magic-angle spinning (MAS) NMR experiments. The experiments include investigations of CW DNP mechanisms, the advantage of frequency-chirped irradiation, and a demonstration of an Overhauser enhancement of ∼25 with a recently reported water-soluble BDPA radical, highlighting the potential for affordable and compact microwave sources to achieve significant enhancement in aqueous samples, including biological macromolecules. With the development of suitable microwave amplifiers, it should permit exploration of multiple new avenues involving time domain experiments.

Awareness, knowledge, and psycho-emotional aspect of infertility among women seeking fertility assistance at a tertiary care hospital in Chhattisgarh, a cross-sectional study.

BACKGROUND: The lack of fundamental knowledge and awareness about the biological process of reproduction is low worldwide but has reportedly higher incidence rates in under-developed countries. Infertility can have a tremendous effect on a woman's psychological and social well-being, pushing her toward mental stress, anxiety, depression self-blame, self-isolation, feeling of worthlessness, and lack of interest in life. The present study was conducted to determine the level of knowledge and awareness regarding factors affecting fertility and also to ascertain the emotional status of females visiting the Obstetrics and Gynecology out-patient department for fertility assistance. MATERIALS AND METHODS: A cross-sectional study was performed by using a questionnaire which had two parts; the first part had questions about awareness and knowledge of the subject of infertility, and the second part had 12 questions that assessed the psychological and emotional status of the participants, and it also explored prevailing myths about infertility based on a validated questionnaire. RESULTS: There was a significant difference in mean knowledge score; those who were more educated had better knowledge of various aspects of infertility. The overall adequacy for knowledge and awareness revealed that only 62 (47.7%) of the participants had adequate knowledge (score >6) regarding female infertility. The mean score for knowledge among all the respondents was 6.61 ± 1.48. The overall emotional and psychological score suggested that 30 (23%) of the respondents were disturbed because of stress because of infertility. CONCLUSION: Infertility can have a serious impact on the psychological well-being of females, and social pressure and stigma associated with childlessness can further worsen the physical and emotional well-being of couples, which needs to be addressed before starting treatment of infertility for a better response to treatment. The limited knowledge and prevailing mis-conceptions regarding infertility need to be sincerely dealt with to complement the medical treatment of infertility.

External Electric Field Induces a Mechanistic Crossover in the Reactivity of 1,3-Dienes with Sulfur Dioxide: Sulfolene Versus Sultine.

1,3-Dienes (1) react with SO2 to produce sulfolenes (2) and sultines (3). Previous experiments and computational studies have shown that hetero-Diels-Alder (HDA) reaction producing the sultine is kinetically favorable compared to the chelotropic (CE) reaction producing the sulfolene. In this article, DFT calculations for a series of substituted 1,3-dienes show that under the influence of a moderate oriented external electric field (OEEF) of 2.0-4.0 V nm-1 along the reaction axis, the chelotropic reaction becomes the kinetically favorable reaction. In the absence of the OEEF, the destabilizing distortion involved in bringing the 1,3-diene and SO2 to the CE transition-state (TS) exceeds than for the HDA TS. However, under the influence of the OEEF, the strongly stabilizing electrostatic interactions in the CE TS effectively overcome the structural distortion energy. The enhanced dipole moment of the CE TS vis-à-vis the HDA TS under the OEEF accounts for the stabilization of the former.

Prevalence and pattern of mental disorders in the state of West Bengal: Findings from the National Mental Health Survey of India 2016.

Background: West Bengal, situated in eastern India, comprising 19 districts as of 2016 and consisting of 9.13 crore population, had been one of the participating states in the National Mental Health Survey, 2015-16. Aim: To estimate the prevalence and pattern of mental disorders in a representative population in West Bengal. Materials and Methods: Based upon a multi-stage stratified random cluster sampling with probability proportionate to each stage, 2646 eligible individuals were interviewed. Standard validated instruments in Bengali like socio-demographic profiles and Mini International Neuropsychiatric Interview (MINI) version 6 were used by trained data collectors with quality monitoring as per a standardized protocol. Results: The current prevalence of mental illness in the state of West Bengal is 13.07% (12.9-13.24 95% CI), which is more than the current national average of 10.56% (10.51-10.61 95% CI). The prevalence of severe mental illness of 2.32% and suicide risk of 1.75% (1.68-1.81 95% CI) is higher than the national average. The common mental illness prevalence is 11.29 (11.13-11.45 95% CI), which is similar to the national weighted average. In West Bengal, severe mental illness is more concentrated in the rural areas in contrast to the national trend. Also, the prevalence of alcohol use disorder is 3.04 (2.96-3.13 95% CI) and epilepsy is 0.03 (0.27-0.29 95% CI), which is less than the national average. Conclusion: The prevalence of mental disorders in the state of West Bengal is higher than the national average, and for severe mental illness, the prevalence is the highest as compared to the national average.

EEG-ERP Correlates of Cognitive Dysfunction in Polycystic Ovarian Syndrome.

Background: Polycystic ovarian syndrome (PCOS) has been shown to affect the psychological and cognitive status of a woman. However, amidst various conflicting reports in this regard, very few studies attempted to assess these aspects objectively using electroencephalography (EEG) and event-related potential (ERP). Purpose: To assess changes in neurocognitive and psychological parameters of PCOS women without any other comorbidities. Methods: PCOS women aged 18 years to 35 years, diagnosed from obstetrics and gynecology OPD who are otherwise free of any other comorbidities, were assessed for psychological status (anxiety and depression using the State-Trait Anxiety Inventory and Beck Depression Inventory, respectively). Thereafter, a cognitive assessment was done subjectively by the Montreal Cognitive Assessment (MoCA) questionnaire and objectively by using EEG [absolute and relative power of alpha, beta, and theta waves along with theta/beta ratios (TBR) and theta/alpha ratio (TAR)] and P300 amplitude and latency of ERP during a visual oddball paradigm task in control (n = 30) and PCOS (n = 37) subjects. Results: PCOS women showed significantly higher anxiety and depression scores along with low MoCA scores. Significantly reduced absolute alpha, increased frontal beta, and markedly increased theta (relative) power with increased TAR in the PCOS group were seen. Also, a significant reduction in P300 amplitude with prolonged latency during the visual oddball paradigm task was evident in them. Conclusion: Reduced alpha and higher theta activity with increased TAR are indicative of poor neural processing ability. Reduced P300 amplitude with more latency also suggests a cognitive decline, which is corroborated by reduced MoCA scores. Our study objectively indicates the presence of subclinical cognitive impairment in PCOS patients even without any comorbidities.

Harnessing Noncovalent Interactions for a Directed Evolution of a Six-Component Molecular Crystal.

Building up on weak orthogonal interactions in supramolecular chemistry, a six-component crystal is designed. Using five distinctly different noncovalent forces, namely, hydrogen bonding, halogen bonding, cation-π, anion-π, and ion-pair interactions, three six-component crystals were designed with crown-ether (I), thiourea (II), 2,3,5,6-tetrafluoro-1,4-dibromobenzene (III), lone-pair donating anion (IV), ammonium cation (V), and electron-rich aromatic ring (VI). The M06-2X functional which is highly suitable in describing other weak interactions fails for ion-pairs. Tuned range-separated (RS)-DFT calculations are found to be capable in describing the ionic interactions in molecular solids. Molecular dynamics simulations show that the predicted multicomponent crystals are stable at room temperature and reducing the ionic charges for the ion-pairs destabilizes them. The strong electrostatic interactions between the three ion-pairs, NH4+···ClO4-, NH4+···HSO4-, and NH4+···HCO3- is the primary driving force for the stabilization of the six-component crystal. Using a hybrid of strong and weak intermolecular interactions, one may generate exotic molecular complexity like n-component crystals.

Sexual Dysfunction and Satisfaction in Males With Alcohol Dependence: A Clinic-Based Study From Central India.

Background Apart from the alcohol effects on various domains of health, the effect on sexual health is the most concerning aspect to the individual. Chronic alcohol intake leads to sexual dysfunction leading to interpersonal difficulties which further worsens alcohol dependence creating a vicious cycle. Methodology This is a cross-sectional study done at an inpatient psychiatry ward of a tertiary care hospital after taking institutional ethical clearance and due informed consent from the participants. The study sample comprised of 50 alcohol dependent subjects and 50 healthy controls taken by purposive sampling based on the inclusion criteria. Subjects were rated on the Arizona sexual experiences (ASEX) scale for various aspects of sexuality and on the New sexual satisfaction scale (NSS) for the degree of sexual satisfaction. WHO-Quality of Life (WHOQOL)-BREF was used to assess the quality of life in both groups. Data was collected and analyzed using MS Excel and SPSS version 23 (IBM Corp., Armonk, USA),  Results The prevalence of sexual dysfunction in the study was about 40% with an inability to reach and satisfaction with orgasm (38% and 28% respectively) the most common followed by erectile dysfunction (26%). The patients with alcohol dependence had a significantly higher degree of sexual dysfunction, poor sexual satisfaction, and low quality of life compared to controls. With correlation analysis, the total scores on ASEX were positively correlated with the duration of alcohol use and dependence. Conclusions This study concludes that sexual dysfunction is common and seen in nearly half of the patients with alcohol dependence affecting desire, erection, and satisfaction with orgasm. Alcohol dependence further impairs the sexual satisfaction and quality of life of the individual. This information can be utilized in motivational interviewing of patients with alcohol dependence by addressing both the problems simultaneously to improve sexual functioning and quality of life.

Water-soluble BDPA radicals with improved persistence.

1,3-Bis(diphenylene)-2-phenylallyl (BDPA) radicals are promising polarizing agents for increasing the sensitivity of NMR spectroscopy through dynamic nuclear polarization (DNP), but have low persistence and solubility in aqueous media. New tetraalkyl/aryl-ammonium derivatives of BDPA are soluble in polar solvents and are highly persistent, with 5-20-fold lower initial rates of degradation than BDPA.

On the Limited Stability of BDPA Radicals.

1,3-Bis(diphenylene)-2-phenylallyl (BDPA)-based radicals are of interest as polarizing agents for dynamic nuclear polarization (DNP). For this purpose, a BDPA-nitroxide biradical, employing a phosphodiester linkage, was synthesized. Contrary to what is commonly assumed, BDPA-derived radicals were observed to have limited stability. Hence, the effects of various factors on the stability of BDPA radicals were investigated. Solvent polarity was found to play a significant role on degradation; a polar BDPA radical was observed to degrade faster in a non-polar solvent, whereas non-polar radicals were more unstable in polar solvents. The rate of decomposition was found to increase non-linearly with increasing radical concentration; a 2-fold increase in concentration led to a 3-fold increase in the rate of degradation. Collectively, these results indicate that the dimerization is a significant degradation pathway for BDPA radicals and indeed, a dimer of one BDPA radical was detected by mass spectrometry.

Perspectives, attitude, and practice of lithium prescription among psychiatrists in India.

INTRODUCTION: Lithium "the magic pill" past its discovery remained the respite for patients with bipolar disorders for decades. The prescriptions of lithium were replaced by other drugs because of the cumbersome monitoring, adverse effect profile, narrow therapeutic index, and frequent comorbidities in patients. The objectives of this study were to understand the knowledge, attitude, and practice of lithium by a subset of psychiatrists in India, which will help us understand the theory-practice gap and for devising strategies to bridge the existing gap. MATERIALS AND METHODS: The current study was an online survey which included 103 psychiatrists from India of either gender and any age group. Predesigned questionnaire about the knowledge, attitude, and practice of lithium use was circulated for 1 month (March 2018). We received 135 responses (31% response rate), of which 32 were incomplete. Hence, the total sample of psychiatrists included in the study was 103. RESULTS: The results suggest that most practitioners included in the survey had knowledge about the effects, adverse effects, and the monitoring protocols and were comfortable in using lithium in patients on outpatient basis. Despite being aware of the indications, the psychiatrists were skeptical in starting lithium due to multitude of perceived barriers such as comorbidities, patient's low adherence to blood monitoring, and adverse effects. CONCLUSIONS: Clinicians should be well aware of the adverse effects, monitoring protocols, which will help them to use lithium in a more appropriate manner.