Sex differences in effectiveness and adverse effects of mood stabilizers and antipsychotics: A systematic review.

BACKGROUND: Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically. METHODS: We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk. RESULTS: Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies. LIMITATIONS: Substantial heterogeneity among the studies precluded performing a meta-analysis. CONCLUSION: Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention.

Circulating sex hormones in women with severe anxiety during pregnancy / Hormonas sexuales circulantes en mujeres con ansiedad severa durante el embarazo

Abstract Introduction Anxiety, mood- and stress-related behaviors are regulated by sex hormones in pregnant and non-pregnant women. Very scarce information exists about the role of sex steroids in pregnant women displaying high levels of anxiety. Objective To determine sex hormones serum levels in pregnant women exhibiting high levels of anxiety symptoms. Method The Hamilton Anxiety Rating Scale (HARS/ HAM-A) was used to assess the intensity of anxiety symptoms in third-trimester pregnant women. Two groups were included in the study, pregnant women exhibiting severe anxiety (ANX; HARS scores ≥ 25; n = 101) and healthy control subjects (CTRL; n = 40) displaying lower scores for anxiety (HARS scores ≤ 7). Estradiol (E2), progesterone (P4), and testosterone (T) serum levels were measured using a standard chemiluminescent immunoassay. Bivariate and partial correlations were performed to detect significant associations between groups, clinical measures, biochemical data, and HARS scores. Results The anxiety group (ANX) showed an increase in E2 and T serum levels (p < .001) compared to CTRL. Conversely, significantly lower P4 levels were found in the symptomatic group (p < .001) as compared to the CTRL hormone values. The P4:E2 index was significantly reduced in pregnant women with high levels of anxiety (p < .001). Negative correlations between anxiety (HARS) scores, P4 serum levels (p = .02), and P4:E2 ratio (p = .04) were found in the symptomatic group. Conversely, T serum levels displayed a positive association (p = .001) with high levels of anxiety symptoms in the same group, after adjusting our data by clinical confounders. Discussion and conclusion Serum levels of sex-steroid hormones are altered in pregnant women exhibiting severe anxiety.

Resumen Introducción La ansiedad, el estado de ánimo y el estrés están regulados por diversos esteroides sexuales. Existe poca información sobre el papel que juegan estos esteroides en mujeres embarazadas con niveles elevados de ansiedad. Objetivo Determinar los niveles séricos de hormonas sexuales en mujeres embarazadas con altos índices de síntomas de ansiedad con respecto a mujeres gestantes sanas. Método Determinación de la intensidad de síntomas ansiosos empleando la escala de Hamilton de Ansiedad (HAM-A) en 141 mujeres embarazadas en el tercer trimestre de gestación. Cuantificación de los niveles séricos de estradiol (E2), progesterona (P4) y testosterona (T) por inmunoensayo estándar. Aplicación de las correlaciones de Pearson para detectar asociaciones entre parámetros clínicos y valores hormonales entre los grupos de estudio. Resultados Las mujeres con ansiedad severa (ANX; n = 101; HAM-A ≥ 25) mostraron niveles séricos más altos de E2 y T (p < .001), así como niveles más bajos de P4 (p < .001) en relación con el grupo control (CTRL, n = 40, HAM-A < 7). Se detectó una disminución significativa en el índice P4:E2 en el grupo de ANX (p < .001) y se observaron correlaciones negativas y positivas entre los puntajes elevados de ansiedad con los niveles circulantes de P4 (p = .02), en la taza P4:E2 (p = .04) y en los niveles séricos de T (p = .001) respectivamente, al ajustar nuestros datos con variables confusoras. Discusión y conclusión Los niveles circulantes de los esteroides sexuales se encontraron alterados en mujeres con ansiedad severa.

Efecto del estímulo masticatorio y estrés agudo sobre la interleuquina 6, la memoria y el aprendizaje espacial en ratones Balb/c

Introducción. El estrés agudo altera la memoria y aprendizaje espacial y la expresión de la interleuquina 6 (IL-6), mientras que el estímulo masticatorio evitaría dichos efectos. Objetivo. Determinar el efecto del estímulo masticatorio y el estrés agudo sobre la expresión de interleuquina 6, la memoria y el aprendizaje espacial en ratones. Métodos. Experimento con 70 ratones albinos machos de 2 meses de edad de la cepa Balb/c que fueron distribuidos aleatoriamente en grupo A1: estrés agudo 1 hora; grupo A2: estrés agudo 1 hora + estímulo masticatorio 1 hora; grupo B1: estrés agudo 2 horas; grupo B2: estrés agudo 2 horas + estímulo masticatorio 2 horas; grupo C1: estrés agudo 3 horas; grupo C2: estrés agudo 3 horas + estímulo masticatorio 3 horas; y grupo D: sin intervención. Durante 3 días, se evaluó la memoria y el aprendizaje espacial en el laberinto acuático de Morris. La IL-6 fue determinada mediante ELISA. Resultados. La IL-6 fue mayor en el grupo B2 vs los demás grupos (p < 0,001). Además, en el primer día de evaluación, la adquisición de memoria y aprendizaje espacial fue menor en el grupo A1 vs A2 (p = 0,042). Conclusión. Solo en el primer día de evaluación encontramos que el estímulo masticatorio previno la disminución de la adquisición de memoria y aprendizaje espacial en ratones sometidos a estrés agudo de baja intensidad. Los resultados en general no fueron concluyentes sobre el efecto del estímulo masticatorio. Además, la IL-6 fue mayor en el estrés + el estímulo masticatorio (grupo B2) sobre el resto.

Introduction. Acute stress alters memory and spatial learning and the expression of interleukin 6, the chewing stimulus would prevent these effects. Objective. To determine the effect of chewing stimulation and acute stress on the expression of interleukin 6 and memory and spatial learning in mice. Methods. Experiment where 70 male albino mice of the Balb/c of age 2 month were randomly distributed into: Group A1: acute stress 1 hour; Group A2: acute stress 1 hour + chewing stimulus 1 hour; Group B1: acute stress 2 hours; Group B2: acute stress 2 hours + chewing stimulus 2 hours; Group C1: acute stress 3 hours; C2: acute stress 3 hours + chewing stimulus 3 hours; Group D: without intervention. For 3 days, spatial memory and learning were tested in the Morris water maze. Interleukin 6 (IL-6) was analyzed by ELISA test. Results. IL-6 was higher in the B2 group vs the other groups (p<0.0001). In addition, on the first day of evaluation, the acquisition of spatial memory and spatial was lower in the A1 vs. A2 group (p=0.042). Conclusión. Only on the first day of evaluation, we found that the masticatory stimulus prevented the decrease in memory acquisition and spatial learning in mice subjected to low-intensity acute stress. The results were generally inconclusive on the effect of masticatory stimulation. In addition, IL-6 was higher in the stress + masticatory stimulus (group B2) over the rest.

Estrés agudo y crónico en la reparación ósea: un enfoque actualizado desde las neurociencias / Acute and chronic stress in bone repair: an updated approach from the neurosciences

Los mecanismos moleculares fisiológicos asociados a la respuesta ante el estrés agudo y crónico permiten entender los cambios que éstos pueden producir en los diversos tejidos del cuerpo. Diversas investigaciones resaltan el papel del estrés crónico en el desarrollo de disfunciones que afectan el equilibrio corporal; sin embargo, hay que considerar que los mecanismos relacionados con el estrés agudo, también pueden influir en el desarrollo de patologías y de la progresión de las manifestaciones deletéreas del estrés crónico. Por otro lado, uno de los tejidos más estudiados en los últimos años ha sido el tejido óseo, ya que éste se encuentra influenciado por factores nerviosos, endocrinos e inmunológicos. Esta revisión busca analizar las bases neurocientíficas de los mecanismos moleculares del estrés y su relación en el proceso de reparación ósea. Para esto, se realizó una búsqueda de la literatura en las bases de datos de Pubmed, Scopus y ScienceDirect, concluyendo que el estrés modifica la liberación de neurotransmisores, la acción del sistema nervioso autónomo, la liberación de hormonas corticotrópicas y la actividad de diversas citocinas; lo que conlleva al desequilibrio de los procesos de regulación y reparación del tejido óseo sometido a carga o lesión.

The physiological molecular mechanisms associated with the response to acute and chronic stress allow us to understand the changes that these can produce in the various tissues of the body. Various investigations highlight the role of chronic stress in the development of dysfunctions that affect body balance; However, it must be considered that the mechanisms related to acute stress can also influence the development of pathologies and the progression of the deleterious manifestations of chronic stress. On the other hand, one of the most studied tissues in recent years has been bone tissue, since it is influenced by nervous, endocrine and immunological factors. This paper seeks to analyze the neuroscientific bases of the molecular mechanisms of stress and their relationship in the bone repair process. Therefore, a literature search was carried out in the Pubmed, Scopus and ScienceDirect databases. Concluding that stress modifies the release of neurotransmitters, the action of the autonomic nervous system, the release of corticotropic hormones and the activity of various cytokines; which leads to the imbalance of the regulation and repair processes of the bone tissue subjected to load or injury.

Efecto del estrés crónico y de la masticación sobre los niveles séricos de interleuquina-6 e interferón-gama / Effect of chronic stress and chewing on serum interleukin-6 and interferon-gamma levels

Introducción: el estrés crónico afecta el equilibrio inmunológico alterando los niveles séricos de interleuquina-6 (IL-6) e interferón gama (INF-γ), dicha alteración afecta al sistema nervioso y al comportamiento humano. La masticación adecuada disminuiría dichos efectos. El objetivo del estudio fue determinar el efecto del estrés crónico y de la masticación sobre los niveles séricos de IL-6 e INF-γ. Métodos: experimento donde se emplearon 64 ratones Balb/c de 8 semanas de edad. Se dividieron en 4 tratamientos: Grupo NE: Masticación normal + estrés, Grupo N: masticación normal sin estrés, Grupo DE: Masticación deficiente + estrés, Grupo D: masticación deficiente sin estrés. Mediante test de ELISA se midió IL-6 e IFN-γ alfinal de la 4ta y de la 8va semana de tratamiento. Resultados: tanto la IL-6 como el IFN-γ fueron mayores en el grupo DE (p<0,05) al final de la 4ta semana. Al evaluarlos al término de la 8va semana se observó que en el grupo NE se incrementó la IL-6 respecto al resto de grupos (p<0,0001), y en el grupo DE fue donde se encontró mayor cantidad de IFN-γ (p<0,0001). Conclusión: el estrés crónico y la masticación deficiente incrementan los niveles séricos de IL-6 e IFN-γ. En cambio, la adecuada masticación disminuye el nivel de tales citoquinas al final de la cuarta semana de tratamiento.

Introduction: chronic stress affects the immune balance by altering the serum levels of interleukin-6 (IL-6) and gamma interferon (INF-γ), this alteration affects the nervous system and human behavior. Appropriate chewing would lessen these effects. The aim of this study was to determine the effect of chewing and chronic stress over serum levels of IL-6 and INF-γ. Methods: experiment in which 64 Balb/C mice of 8 weeks of age were used, they were divided into 4 treatments: Group NE: Normal chewing + stress, Group N: normal chewing without stress, Group DE: Chewing poor + stress, Group D: poor chewing without stress. IL-6 and IFN-γ were measured by ELISA after 4 and 8 weeks of treatment. Results: both IL-6 and IFN-γ were higher in the DE group (p < 0,05) at the end of fourth week of treatment. When evaluating the animals at the end of the eighth week of treatment, it was observed that in the NE group, the IL-6 was increased with respect to the rest (p < 0,0001) and the DE group showed more IFN-γ (p < 0,0001). Conclusion: stress and poor chewing increase serum IL-6 and IFN-γ. In contrast, appropriate chewing decreases the effects of stress on the increase of such cytokines at the end of the fourth week of treatment in animals.

[Factors associated with the development of stress, anxiety and depression in the context of COVID-19 pandemic in Peruvian healthcare facilities]. / Factores asociados al desarrollo de estrés, ansiedad y depresión en trabajadores sanitarios en el contexto de la pandemia por COVID-19 en Perú.

OBJECTIVE: To describe the sociodemographic characteristics and determine the factors associated with psychological manifestations of depression, anxiety, and stress in healthcare workers in the context of COVID-19 pandemic in health facilities in Peru during the month of May 2020. METHODS: An analytical cross-sectional study was conducted out in healthcare workers of hospital establishments in Peru. To evaluate the outcome of interest, we administered a structured questionnaire that asked about type of healthcare personnel; sociodemographic characteristics; Generalized Anxiety Disorder scale (GAD-7); Patient Health Questionnaire scale (PHQ-9); and the Revised Stressor Impact scale (IES-R). We used generalized linear Poisson models, with a logarithmic link function and robust variance. RESULTS: Out of 258 respondents, 254 completed the survey; 61.8% were women; the most common work area was emergency department or hospitalization (inpatient) services (62.2%). The median PHQ-9 score was 4 points (IQR: 2-7); for the GAD-7, it was 6 points (IQR: 4-8), and for the IES-R, 16 points (IQR: 8-24). The multivariate analysis showed that being a physician was associated with less anxiety (PR: 0.77; 95% CI: 0.62-0.94), whereas living alone was associated with a greater risk of depression (PR: 1.46; 95% CI: 1.11-1.92). CONCLUSIONS: Healthcare personnel are at risk of manifesting psychological alterations, mainly associated with the female gender, non-medical personnel and living alone.

OBJETIVO: Describir las características sociodemográficas y determinar los factores asociados a manifestaciones psicológicas de depresión, ansiedad y estrés en trabajadores sanitarios en el contexto de la pandemia por COVID-19 en los establecimientos de salud del Perú durante mayo de 2020. Métodos: Se realizó un estudio transversal en trabajadores sanitarios de establecimientos hospitalarios del Perú. Se elaboró un cuestionario estructurado que incluía las características sociodemográficas, la profesión, área y lugar de trabajo, y cuestionarios validados para trastorno de ansiedad generalizada (GAD-7), Salud del paciente (PHQ-9) y la Escala de impacto del estresor revisada (IES-R). Para el análisis se utilizó modelos lineales generalizados de Poisson, función de enlace logarítmico y varianzas robustas. Se calculó el rango intercuartílico (RIC) y la razón de prevalencia ajustada (RPa) y su intervalo de confianza del 95% (IC95%). RESULTADOS: De un total de 258 encuestados, 254 (98%) completaron al cuestionario, siendo el 61,8% mujeres y el área de trabajo más común emergencia u hospitalización (62,2%). La puntuación mediana del PHQ-9 fue 4 (RIC:2-7), del GAD-7 fue 6 (RIC:4-8) y para el IES-R fue 16 (RIC:8-24). El análisis multivariado mostró que ser médico se asocia con una menor prevalencia de ansiedad (RPa: 0,77; IC 95%: 0,62-0,94), mientras que vivir solo se asoció con una mayor prevalencia de depresión (RPa: 1,46; IC 95%: 1,11-1,92). Conclusión: El personal sanitario manifestó alteraciones psicológicas, asociado principalmente al personal no médico y vivir solo.

[Frequency and characterization of self-medication for dental manifestations in patients attending private clinics in Lima in 2021]. / Frecuencia y caracterización de la automedicación ante manifestaciones dentales en pacientes que acudieron a clínicas privadas en Lima en el año 2021.

Introduction: The self-medication is the use of drugs without health professionals' prescription that many times, instead of helping, aggravate the patient's health. Dental pain is the main reason for performing this act in the area of odontology. It is important to know if patients self-medicate in order to develop strategies to reduce the misuse of drugs and avoid this practice. Objective: Establish the frequency and characterization of self-medication in patients who visit to the three private dental clinics between the months of march to July in the year 2021. Materials and methods: Cross-sectional observational study with a sample of 450 patients from three dental clinics in the city of Lima. The assessment tool was a 13-question quiz about the main characteristics of self-medication. Results: The 85,8% of patients use drugs without medical prescription. 41.5% of the patients self-medicated did it with old prescriptions made by the dentist. The age group that more self-medicated was 26-35 years old with 35.5%. The most frequent type of disease was dental pain with 45.6%, The degree of instruction with the highest percentage was complete university superior with 32.9%. Conclusions: The frequency of self-medication of the patients who visited the three dental centers is considerably high.

Genotyping Squamous Cell Lung Carcinoma in Colombia (Geno1.1-CLICaP).

BACKGROUND: Lung cancer is a public health problem, and squamous cell carcinoma (SCC) is the second most prevalent subtype of this neoplasm. Compared to other subtypes, including adenocarcinoma, SCC is less well understood in terms of molecular pathogenesis, limiting therapeutic options among targeted agents approved for other disease subgroups. In this study, we sought to characterize the SCC genomic profile using a validated Next Generation Sequencing (NGS) platform. METHODS: The comprehensive NGS assay (TruSight Tumor 170) was used in order to target the full coding regions of 170 cancer-related genes on SCC samples. PD-L1 expression in tumor cells (TCs) was assessed using clone 22C3 (Dako). Clinical outcomes were correlated with molecular profile, including progression free survival (PFS), overall response rate (ORR), and overall survival (OS). RESULTS: A total of 26 samples were included, median age was 67 years (r, 33-83) and 53.8% were men. Tobacco consumption was identified in all subjects (mean 34-year package). For first-line treatment 80.8% of patients received cisplatin or carboplatin plus gemcitabine. In terms of molecular profile, we identified a high prevalence of inactivating mutations in TP53 (61.5%), PIK3CA (34.6%), MLL2 (34.6%), KEAP1 (38.4%), and NOTCH1 (26.9%). PD-L1 expression ranged from negative, 1, 2-49, and ≥50% in 23.1, 38.5, 26.9, and 11.5%, respectively. Interestingly, the genetic alterations did not have an effect in PFS, OS or ORR in this study. However, PDL1 expression was higher among those who had mutations in TP53 (p = 0.037) and greater expression of PDL1 was related to PIK3CA alterations (p = 0.05). CONCLUSIONS: The genomic profile of SCC encompasses important genes including TP53, PIK3CA and KEAP1. TP53 mutations could be associated with PDL1 expression, generating hypothesis regarding specific treatment options.

Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers vs. Heavy Smokers (Geno1.3-CLICaP).

Objectives: Lung cancer is a heterogeneous disease. Presentation and prognosis are known to vary according to several factors, such as genetic and demographic characteristics. Small-cell lung cancer incidence is increasing in never-smokers. However, the disease phenotype in this population is different compared with patients who have a smoking history. Material and Methods: To further investigate the clinical and genetic characteristics of this patient subgroup, a cohort of small cell lung cancer patients was divided into smokers (n = 10) and never/ever-smokers (n = 10). A somatic mutation profile was obtained using a comprehensive NGS assay. Clinical outcomes were compared using the Kaplan-Meier method and Cox proportional models. Results: Median age was 63 years (46-81), 40% were men, and 90% had extended disease. Smoker patients had significantly more cerebral metastases (p = 0.04) and were older (p = 0.03) compared to their non-smoker counterparts. For never/ever smokers, the main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), and EGFR (30%). Smoker patients had more RB1 (80%, p = 0.04), CDKN2A (30%, p = 0.05), and CEBPA (30%, p = 0.05) mutations. Response rates to first-line therapy with etoposide plus cisplatin/carboplatin were 50% in smokers and 90% in never/ever smokers (p = 0.141). Median overall survival was significantly longer in never smokers compared with smokers (29.1 months [23.5-34.6] vs. 17.3 months [4.8-29.7]; p = 0.0054). Never/ever smoking history (HR 0.543, 95% CI 0.41-0.80), limited-stage disease (HR 0.56, 95% CI 0.40-0.91) and response to first-line platinum-based chemotherapy (HR 0.63, 95% CI 0.60-0.92) were independently associated with good prognosis. Conclusion: Our data supports that never/ever smoker patients with small-cell lung cancer have better prognosis compared to their smoker counterparts. Further, patients with never/ever smoking history who present with small-cell lung cancer have a different mutation profile compared with smokers, including a high frequency of EGFR, MET, and SMAD4 mutations. Further studies are required to assess whether the differential mutation profile is a consequence of a diverse pathological mechanism for disease onset.

EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP).

BACKGROUND: Non-small cell lung cancer (NSCLC) has a 5-year survival of 5-16%. Epidermal growth factor receptor (EGFR) mutations, in most cases, confer sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy. Nonetheless, it is still unclear why clinical outcomes vary among patients with identical EGFR mutations. The amplification of the EGFR gene (EGFRamp) may play a significant role. OBJECTIVE: Compare the complete (CR) and partial response (PR) rates, overall survival (OS), and progression-free survival (PFS) in Hispanic patients with lung adenocarcinoma treated with erlotinib with EGFR mutations (L858R or exon 19 deletion [Del19]) with and without concomitant EGFRamp. PATIENTS AND METHODS: Seventy-two EGFR-positive lung adenocarcinoma patients of Hispanic origin, who underwent first-line treatment with erlotinib, were evaluated for EGFRamp by fluorescence in situ hybridization (FISH). The clinical outcomes were analyzed according to EGFR mutations and EGFRamp status. RESULTS: 30.6% of samples showed EGFRamp, more frequently present in patients with Del19 (p = 0.05). Patients with EGFRamp had a longer PFS (in months) [(28.5, 95% CI 22.3-34.6) vs. (11.0, 95% CI 8.2-16.7); p = 0.002] and OS [(37.8, 95% CI 30.9-44.7) vs. (27.1, 95% CI 12.8-41.3); p = 0.009] than those without. EGFRamp significantly influenced the response to erlotinib (p = 0.0001). EGFRamp+/Del19 had a longer OS, 37.8 (95% CI 31.0-44.6), compared to EGFRamp+/L8585R, 27.5 (95% CI 12.4-42.5) (p < 0.001) and longer PFS (p = 0.043). CONCLUSION: Among Hispanic patients, EGFRamp was present in 30% of patients with EGFR mutations. EGFR mutations and EGFRamp are associated with better OS, PFS, CR, and PR to erlotinib and, hence, could aid in the correct selection of patients that benefit from EGFR TKI treatment.