Decrease in cognitive performance and increase of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios with higher doses of antipsychotics in women with schizophrenia: a cross-sectional study.

BACKGROUND: We explored the relationship between symptoms, cognitive performance, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) (three markers of inflammation), and antipsychotic dose (in chlorpromazine units) in male and female patients with schizophrenia. METHODS: We conducted a cross-sectional analysis in patients with schizophrenia of the complete blood count and the results of neuropsychological testing, using the Welch t-test to compare groups and the Pearson test for correlations. RESULTS: We found that the NLR and the PLR are higher among women with schizophrenia when compared with men. In women, the NLR and the PLR correlate positively with antipsychotic drug dose and inversely with a working memory test (Direct Digit Span). Higher doses of antipsychotics are associated with worse working and semantic memory and mental flexibility in the women in our sample. CONCLUSION: Higher doses of antipsychotics were associated with worse working and semantic memory and mental flexibility in women with schizophrenia. No such correlations were present in men, suggesting that, in female patients, cognitive performance deteriorates as the antipsychotic dose is increased, a finding that could be mediated by inflammatory mechanisms, given the demonstrated relationship to biomarkers of inflammation - e.g., the NLR and the PLR. TRIAL REGISTRATION: NCT03788759 (ClinicalTrials.gov).

Homeopathy for Major Depressive Disorder: Protocol for N-of-1 Studies.

BACKGROUND: N-of-1 studies allow the formal assessment of a patient's treatment. A single participant receives different interventions the same number of times in a crossover, double-blind, randomized design. Using this methodology, we will investigate the effectiveness and safety of a standardized homeopathy protocol in treating 10 cases of major depression. METHODS: The method is described below: Design: crossover double-blind placebo-controlled randomized N-of-1 studies, with at most 28 weeks of duration per participant. PARTICIPANTS: women and men at age over 18 years with a diagnosis of a major depressive episode given by a psychiatrist, who have presented a therapeutic response, i.e., a reduction ≥50% of the baseline depressive symptoms, self-assessed by the Beck Depression Inventory - Second Edition (BDI-II), and sustained for at least 4 weeks during an open homeopathic treatment following the protocol of the sixth edition of the Organon, with or without concomitant use of psychotropic drugs. INTERVENTIONS: individualized homeopathy following the same protocol, one globule of the fifty-millesimal potency diluted in 20 mL of 30% alcohol; placebo - 20 mL of 30% alcohol, in the same posology as homeopathy. Crossover study: the participant will go through three consecutive treatment blocks, with two random and masked treatment periods (A or B), corresponding to homeopathy or placebo. Treatment periods will have 2, 4, and 8 weeks in the first, second, and third blocks, respectively. A clinically significant worsening (characterized by an augmentation in BDI-II inclusion score ≥30%) will result in the termination of study participation and resumption of the open treatment. PRIMARY MEASURE: progression of the depressive symptoms, self-assessed by the participant using the BDI-II scale at weeks 0, 2, 4, 8, 12, 16, 20, 24, 28 and analyzed throughout the study concerning homeopathy and placebo partitions. Secondary measures: score of the Clinical Global Impression Scale; mental and physical health scores assessed by the 12-Item Short-Form Health Survey; participant's blind preference for treatment A or B at each block; clinical worsening; and adverse events. DATA ANALYSIS: the participant, assistant physician, evaluator, and statistician will remain blinded for the study treatments until the completion of data analysis of each study. We will follow a 10-step procedure for analyzing N-of-1 observational data of each participant and conduct a meta-analysis of the combined results. DISCUSSION: We understand that each N-de-1 study will be a chapter with its teachings in a book of ten, allowing a broader view of the effectiveness of the homeopathy protocol of the sixth edition of the Organon in treating depression.Einzelpatienten- oder "n = 1"-Studien ermöglichen die formelle Beurteilung der Behandlung eines Patienten. Bei einem einzigen Teilnehmer werden verschiedene Maßnahmen in gleicher Zahl in einem doppelblinden, randomisierten Crossover-Design angewendet. Mit dieser Methode untersuchen wir die Wirksamkeit und Sicherheit eines standardisierten Homöopathie-Protokolls zur Behandlung von Major Depression in zehn Fällen.Aufbau der Studie: Doppelblinde, placebokontrollierte, randomisierte Einzelpatienten- oder "n = 1"-Studie von maximal 28 Wochen Dauer pro Teilnehmer. Teilnehmer: Frauen und Männer ab 18 Jahren mit durch einen Psychiater diagnostizierter Episode einer Major Depression und mit mindestens vier Wochen lang anhaltendem therapeutischem Ansprechen (in Form einer Reduktion der depressiven Symptome um ≥50% gegenüber Baseline laut Selbstbeurteilung mit dem Beck Depression Inventar, zweite Ausgabe [BDI-II]) unter einer offenen homöopathischen Behandlung gemäß dem Protokoll der sechsten Auflage des Organon, mit oder ohne gleichzeitige Anwendung von Psychopharmaka. Interventionen: Individualisierte Homöopathie gemäß demselben Protokoll, ein Globulus der Quinquaginta-Millesimal-Potenz, verdünnt in 20 mL 30%igem Alkohol; Placebo in Form von 20 mL 30%igem Alkohol, nach demselben Dosierungsschema wie die Homöopathie. Crossover-Studie: Der Teilnehmer durchläuft in zwei randomisierten und maskierten Behandlungszeiträumen (A oder B), die Homöopathie oder Placebo enstprechen, je drei aufeinanderfolgende Behandlungsblöcke. Innerhalb der Behandlungszeiträume umfassen der erste, zweite und dritte Block je zwei, vier beziehungsweise acht Wochen. Eine klinisch bedeutsame Verschlechterung (gekennzeichnet durch einen Anstieg des BDI-II-Scores um ≥30% gegenüber der Aufnahme) führt zum Abbruch der Studienteilnahme und zur Wiederaufnahme der offenen Behandlung. Primäre Messgröße: Verlauf der depressiven Symptome laut Selbstbeurteilung des Teilnehmers mit der BDI-II-Skala in Woche 0, 2, 4, 8, 12, 16, 20, 24, 28 und Auswertung im Verlauf der Studie nach Homöopathie-und Placebo-Abschnitten. Sekundäre Messgrößen: Score auf der Clinical Global Impression Scale; Scores für psychische und physische Gesundheit laut 12-Item Short-Form Health Survey; verblindete Teilnehmerpräferenz für Behandlung A oder B in jedem Block; klinische Ver-schlechterung und unerwünschte Ereignisse. Datenauswertung: Der Teilnehmer, behandelnde Arzt, Auswertende und Statistiker bleiben im Hinblick auf die Stu-dienbehandlungen verblindet, bis die Datenauswertung jeder Studie abgeschlossen ist. Wir werden in einem 10-schrittigen Vorgehen die "n = 1"-Beobachtungsdaten der einzelnen Teilnehmer auswerten und eine Metaanalyse der zusammengeführten Ergebnissee durchführen.Unserer Auffassung nach wird jede einzelne "n = 1"-Studie ein Kapitel mit eigenen Lehren innerhalb eines zehnteiligen Buches sein, welches eine umfassende Darstellung der Wirksamkeit des Homöopathie-Protokolls der sechsten Ausgabe des Organon zur Behandlung von Depressionen ermöglicht.

Persistent psychosis associated with extreme delta brush in anti-NMDA receptor encephalitis: a case report.

BACKGROUND: Anti-NMDAR encephalitis is an emerging differential diagnosis of first episode and persistent psychosis in the psychiatric community, as clinical manifestations include psychiatric symptoms, cognitive dysfunction, seizures, decreased consciousness, and dyskinesias. This disease is associated with extreme delta brush (EDB), but the significance and temporal course of this EEG pattern still needs to be determined. Herein, we report a case of anti-NMDAR encephalitis with persistent psychosis associated with EDB occurrence on multiple occasions during a 5-year disease course. CASE PRESENTATION: A 15-year-old girl was diagnosed with anti-NMDAR encephalitis and treated with progressive improvement. Four years after initial manifestations, an EDB pattern was seen on electroencephalogram (EEG) without new neurological symptoms. She had residual symptoms of episodic auditory hallucinations and impulsivity. One year later, the patient had a recurrence of neurological symptoms (seizures, dyskinesias and impaired attention), persisting with EDB on EEG. Clinical symptoms and EDB resolved after second-line treatment with rituximab. CONCLUSION: We describe the first case of persistent psychosis in anti-NMDAR encephalitis associated with extreme delta brush on multiple EEGs on prolonged follow-up. Electroencephalographic patterns such as EDB may serve as markers of residual disease activity, including psychiatric symptoms. Further studies with prolonged EEG monitoring are needed to better understand these findings.

Sex and the Estrous-Cycle Phase Influence the Expression of G Protein-Coupled Estrogen Receptor 1 (GPER) in Schizophrenia: Translational Evidence for a New Target.

Schizophrenia is a mental disorder with sex bias in disease onset and symptom severity. Recently, it was observed that females present more severe symptoms in the perimenstrual phase of the menstrual cycle. The administration of estrogen also alleviates schizophrenia symptoms. Despite this, little is known about symptom fluctuation over the menstrual cycle and the underlying mechanisms. To address this issue, we worked with the two-hit schizophrenia animal model induced by neonatal exposure to a virus-like particle, Poly I:C, associated with peripubertal unpredictable stress exposure. Prepulse inhibition of the startle reflex (PPI) in male and female mice was considered analogous to human schizophrenia-like behavior. Female mice were studied in the proestrus (high-estrogen estrous cycle phase) and diestrus (low-estrogen phase). Additionally, we evaluated the hippocampal mRNA expression of estrogen synthesis proteins; TSPO and aromatase; and estrogen receptors ERα, ERß, and GPER. We also collected peripheral blood mononuclear cells (PBMCs) from male and female patients with schizophrenia and converted them to induced microglia-like cells (iMGs) to evaluate the expression of GPER. We observed raised hippocampal expression of GPER in two-hit female mice at the proestrus phase without PPI deficits and higher levels of proteins related to estrogen synthesis, TSPO, and aromatase. In contrast, two-hit adult males with PPI deficits presented lower hippocampal mRNA expression of TSPO, aromatase, and GPER. iMGs from male and female patients with schizophrenia showed lower mRNA expression of GPER than controls. Therefore, our results suggest that GPER alterations constitute an underlying mechanism for sex influence in schizophrenia.

Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression.

Doxycycline (DOXY) is a second-generation tetracycline with anti-inflammatory and neuroprotective effects. A proinflammatory profile seems to predict the severity of depressive symptoms. In the present study, we aimed at determining whether the anti-inflammatory action of subantimicrobial-dose doxycycline (SDD) (DOXY, 10mg/kg), alone or combined with the antidepressant escitalopram (ESC), could revert lipopolysaccharide-induced depressive-like alterations in mice. Male Swiss mice received saline or lipopolysaccharide (LPS) for ten consecutive days. From the 6th day of LPS exposure, they were treated with DOXY 10 mg/kg, ESC 4 mg/kg, DOXY 10 mg/kg plus ESC 4 mg/kg (DOXY+ESC), or saline. On the 10th day, we assessed behavioral despair (forced swimming test), anhedonia (sucrose preference test), brain oxidative stress markers, and inflammatory and protective pathways related to depression, such as NF-kB and phospho-CREB. Our results showed that DOXY alone or combined with ESC reduced hippocampal Iba-1 expression and interleukin (IL)-1ß levels. Only DOXY+ESC successfully reversed the LPS-induced increase in NF-kBp65 expression and TNFα levels. DOXY caused a marked increase in the hippocampal expression of phospho-CREB and GSH concentrations. DOXY and DOXY+ESC showed a tendency to modulate the functional status of mitogen-activated kinase p42-44 (Phospho-p44/42 MAPK) and of the phosphorylated form of glycogen synthase kinase 3 beta (GSK3ß), revealing a protective profile against inflammation. In conclusion, SDD, combined with ESC, seems to be a good strategy for reverting inflammatory changes and protecting against depression.

Retrieval-Based Learning in Neuroanatomy Classes / Ensino Baseado na Evocação do Conhecimento em Aulas de Neuroanatomia

ABSTRACT Medical schools are continuously challenged to develop teaching modalities that improve understanding and retention of anatomical knowledge. Traditionally, learning has been regarded as the encoding of new knowledge, whereas retrieval has been considered a means for assessing learning. A solid body of research demonstrates that retrieval practice is a way to promote learning that is robust, durable, and transferable to new contexts. It involves having learners set aside the material they are learning and practice actively reconstructing it on their own. A general challenge is to develop ways to implement retrieval-based learning in educational settings. We developed a pedagogical approach that implements retrieval-based learning in practical neuroanatomy classes, which differs from usual neuroanatomy teaching in that it actively engages students through active learning. It requires students to retrieve anatomical knowledge in oral and written form, as well as to identify structures in cadaveric material. Practical anatomy classes have traditionally relied on students' passive exposure to cadaveric material, with the lecturer pointing to and naming anatomical structures. Since August 2014, we have been applying retrieval practice in neuroanatomy classes. A total of 720 students were included in the study. Student performance one week after the practical lesson was higher in the traditional method group than in the retrieval-based learning group (p < 0.0001, effect size = 0.60). Four weeks after the intervention, however, the performance of students who learned using a retrieval-based approach was higher than that of students passively exposed to the learning material (p < 0.0001, effect size = 0.75). Taken together, our results suggest that retrieval-based learning has a greater effect on long-term retention. Retrieval-based learning is easy to apply and cost-effective. It can be implemented in nearly any educational setting. We hope that our report may inspire educators to adopt retrieval practice approaches and seek ways to apply methods from learning research in actual classrooms.

RESUMO As faculdades de Medicina são continuamente desafiadas a desenvolver modalidades de ensino que melhorem a compreensão e a retenção do conhecimento anatômico. Tradicionalmente, a aprendizagem tem sido considerada como a codificação de novos conhecimentos, enquanto a evocação tem sido considerada apenas um meio para avaliar a aprendizagem. Pesquisas demonstram que a prática da evocação do conhecimento é uma maneira de promover um aprendizado robusto, durável e transferível para novos contextos. Isso implica que os alunos deixem de lado o material que estão aprendendo e pratiquem ativamente reconstruí-lo por conta própria. Um desafio geral é desenvolver maneiras de implementar a aprendizagem baseada em evocação em ambientes educacionais. Desenvolvemos uma abordagem pedagógica que implementa a aprendizagem baseada em evocação em aulas práticas de neuroanatomia, que difere do ensino usual de neuroanatomia, na medida em que envolve ativamente os alunos na aprendizagem. Requer que os estudantes recuperem conhecimentos anatômicos em forma oral e escrita, bem como identifiquem estruturas em material cadavérico. As aulas práticas de anatomia tradicionalmente se baseiam na exposição passiva dos estudantes ao material de cadáveres, com o professor apontando e nomeando estruturas anatômicas. Desde agosto de 2014, aplicamos a prática da evocação em aulas de neuroanatomia. Um total de 720 alunos foi incluído no estudo. O desempenho dos alunos uma semana após a aula prática foi melhor no grupo submetido ao método de ensino tradicional do que no grupo de aprendizagem baseada em evocação (p < 0,0001, tamanho do efeito = 0,60). Quatro semanas após a intervenção, no entanto, o desempenho dos alunos que aprenderam usando uma abordagem baseada na evocação foi melhor do que o dos estudantes passivamente expostos ao material de aprendizagem (p < 0,0001, tamanho do efeito = 0,75). Em conjunto, nossos resultados sugerem que o aprendizado baseado em evocação tem um efeito maior na retenção a longo prazo. A aprendizagem baseada em evocação é fácil de aplicar e econômica. Pode ser implementada em praticamente qualquer ambiente educacional. Esperamos que nosso relato possa inspirar os educadores a adotarem abordagens de práticas de aprendizagem por evocação e a buscarem maneiras de aplicar métodos de ensino e aprendizagem derivados da pesquisa sobre educação em salas de aula reais.

Transtorno de Ansiedade Social no Contexto da Aprendizagem Baseada em Problemas / Social Anxiety Disorder in the Context of Problem Based-Learning

RESUMO Objetivo Investigar os sintomas de transtorno de ansiedade social (TAS) entre os estudantes de Medicina do Centro Universitário Christus (Unichristus), instituição que adota o método de Aprendizagem Baseada em Problemas (ABP). Métodos Estudo transversal com 431 estudantes do primeiro ao quarto ano do curso de Medicina, por meio da aplicação da Escala de Ansiedade Social de Liebowitz (LSAS-SR), do Inventário de Ansiedade de Beck de Avaliação de Ansiedade, além de questionário com perguntas referentes a questões sociodemográficas, história familiar de doenças psiquiátricas, acompanhamento psicoterápico e psiquiátrico, nível de ansiedade para se expressar na tutoria e percepção de como a ansiedade variou ao longo dos semestres da faculdade. Resultados Utilizando-se a LSAS-SR como instrumento de triagem para casos de TAS, encontraram-se escores sugestivos do transtorno em 59,2% (255) dos estudantes. Em relação ao nível de ansiedade, o Inventário de Ansiedade de Beck (BAI) evidenciou que 59,3% (258) dos estudantes apresentaram nível de ansiedade mínimo; 26,6% (115), nível leve; 9,7% (42), nível moderado; e 4,4% (19), nível grave. Observou-se uma correlação significativa entre os escores obtidos nas escalas BAI e LSAS-SR: estudantes com sintomas sugestivos de ansiedade social apresentaram maior grau de ansiedade. Além disso, estudantes com sintomas de ansiedade social relataram maior nível de ansiedade para se expressar durante as sessões de tutoria. Conclusão A elevada prevalência de TAS apontada nesta investigação já justifica o estímulo à adoção de medidas psicoeducativas e estratégias pedagógicas que venham a auxiliar os estudantes com manifestações de ansiedade social a reduzir esses sintomas, favorecendo o processo de ensino-aprendizagem.

ABSTRACT Objective To investigate the symptoms of social anxiety disorder (SAD) among medical students of the Christus University Center (Unichristus), an institution that adopts the problem-based learning (PBL) method. Methods A cross-sectional study with 431 students in their first to fourth years of Medical School, through the application of the Liebowitz Social anxiety scale (LSAS-SR), Beck's anxiety Inventory, and a questionnaire with questions concerning sociodemographic issues, family history of psychiatric disorders, psychiatric appointments, level of anxiety when expressing themselves in tutorials, and the perception of how their anxiety varied throughout the college semesters. Results Using the LSAS-SR as a screening tool for cases of SAD, there were indications of the disorder in 59.2% (255) of the students. In relation to the level of anxiety, the Beck's anxiety inventory (BAI) showed that 59.3% (258) of the students presented minimal anxiety, 26.6% (115) presented light anxiety, 9.7% (42) presented moderate anxiety, and 4.4% (19) presented severe anxiety. A significant correlation was observed between the scores obtained in the BAI and LSAS-SR scales: students with symptoms suggesting social anxiety showed a greater degree of anxiety. Also, students with symptoms of social anxiety reported higher levels of anxiety when expressing themselves during tutorials. Conclusions The high prevalence of SAD pointed out in this research justifies stimulating the adoption of psycho-educational measures and pedagogical strategies that will help students with the manifestations of social anxiety, reduce these symptoms, and promote the teaching-learning process.

Fator V de Leiden na doença de Legg-Calvé-Perthes / Leiden's V-factor in Legg-Calvé-Perthes disease

Trobofilias hereditárias têm sido implicadas na patogênese da doenca de Legg-Calvé-Perthes. Uma investigação do fator de risco hereditário mais comum para hipercoagulabilidade - a mutação no gene do fator V (fator V de Leiden) - foi conduzida em 20 pacientes com Legg-Calvé-Perthes e 214 controles sadios. A prevalência do fator V de Leiden foi maior nos pacientes com Legg-Calvé-Perthes que no grupo controle (30 vs. 1,87 por cento). A razão de chances (odds ratio) para o desenvolvimento de Legg-Calvé-Perthes foi de 22,5 (p<0,05; intervalo de confiança: 5,68- 89.07). Estes dados sugerem, o fator V de Leiden como fator de risco hereditário para hipercoagulabilidade associada ao desenvolvimento da doença de Legg-Calvé-Perthes.

Inherited tendency to hypercoagulability has been suggested as a cause of vascular thrombosis resulting in Legg-Calvé-Perthes disease. An investigation of the most common inherited risk factor for hypercoagulability - the mutation in the V-factor gene (Leiden's V-factor) - was carried out among 20 Patients diagnosed with Legg- Calvé-Perthes disease. Patients were compared with 214 healthy controls. The prevalence of the Leiden's V-factor was higher in patients with Legg-Calvé-Perthes disease than in controls (30 percent vs. 1,87 percent). The odds ratio for the development of Legg-Calvé-Perthes disease in the presence of the Leiden's V-factor mutation was 22,5 (p<0,05; confidence interval: 5,68-89.07). These data suggest the Leiden's V-factor as an inherited risk factor for hypercoagulability associated with the development of Legg-Calvé-Perthes disease.