Cannabidiol Recovers Dopaminergic Neuronal Damage Induced by Reserpine or α-synuclein in Caenorhabditis elegans.

Progressive neurodegenerative disorders such as Parkinson Disease (PD) lack curative or long-term treatments. At the same time, the increase of the worldwide elderly population and, consequently, the extension in the prevalence of age-related diseases have promoted research interest in neurodegenerative disorders. Caenorhabditis elegans is a free-living nematode widely used as an animal model in studies of human diseases. Here we evaluated cannabidiol (CBD) as a possible neuroprotective compound in PD using the C. elegans models exposed to reserpine. Our results demonstrated that CBD reversed the reserpine-induced locomotor alterations and this response was independent of the NPR-19 receptors, an orthologous receptor for central cannabinoid receptor type 1. Morphological alterations of cephalic sensilla (CEP) dopaminergic neurons indicated that CBD also protects neurons from reserpine-induced degeneration. That is, CBD attenuates the reserpine-induced increase of worms with shrunken soma and dendrites loss, increasing the number of worms with intact CEP neurons. Finally, we found that CBD also reduced ROS formation and α-syn protein accumulation in mutant worms. Our findings collectively provide new evidence that CBD acts as neuroprotector in dopaminergic neurons, reducing neurotoxicity and α-syn accumulation highlighting its potential in the treatment of PD.

Cannabidiol induces autophagy via ERK1/2 activation in neural cells.

Autophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

Clinical validity and intrarater and test-retest reliability of the Structured Clinical Interview for DSM-5 - Clinician Version (SCID-5-CV).

AIM: The Structured Clinical Interview for the DSM is one of the most used diagnostic instruments in clinical research worldwide. The current Clinician Version of the instrument (SCID-5-CV) has not yet been assessed in respect to its psychometric qualities. We aimed to assess the clinical validity and different reliability indicators (interrater test-retest, joint interview, face-to-face vs telephone application) of the SCID-5-CV in a large sample of 180 non-prototypical and psychiatric patients based on interviews conducted by raters with different levels of clinical experience. METHODS: The SCID-5-CV was administered face-to-face and by telephone by 12 psychiatrists/psychologists who took turns as raters and observers. Clinical diagnoses were established according to DSM-5 criteria and the longitudinal, expert, all data (LEAD) procedure. We calculated the percentage of agreement, diagnostic sensitivity and specificity, and the level of agreement (kappa) for diagnostic categories and specific diagnoses. RESULTS: The percentage of positive agreement between the interview and clinical diagnoses ranged between 73% and 97% and the diagnostic sensitivity/specificity were >0.70. In the joint interview, the levels of positive agreement were high (>75%) and kappa levels were >0.70 for most diagnoses. The values were less expressive, but still adequate, for interrater test-retest interviews. CONCLUSION: The SCID-5-CV presented excellent reliability and high specificity as assessed with different methods. The clinical validity of the instrument was also confirmed, which supports its use in daily clinical practice. We highlight the adequacy of the instrument to be used via telephone and the need for careful use by professionals with little experience in psychiatric clinical practice.

Personality Inventory for DSM-5 (PID-5): cross-cultural adaptation and content validity in the Brazilian context / Inventário de Personalidade para o DSM-5 (PID-5): adaptação transcultural e validade de conteúdo para o contexto brasileiro

Abstract Objective To describe the process of cross-cultural adaptation of the Personality Inventory for DSM-5 (PID-5) to the Brazilian context. Methods Cross-cultural adaptation involved the steps of independent translation of the instrument, synthesis version, and back-translation. Analysis of content validity was conducted by a multidisciplinary expert committee and consisted of quantitative assessment of agreement indicators. The test was then applied to a target population. Results All the steps required for a cross-cultural adaptation were followed and satisfactory agreement values (≥ 4.75) were reached for most of the structures assessed. Most of the changes suggested by the experts were followed; these changes consisted primarily of adjustments to verb tense and agreement and the inclusion of letters and words to allow gender inflection. In the pre-test, no suggestions were made and the instrument was considered comprehensible. Conclusion The Brazilian version of the PID-5 was found to be adequate to the Brazilian context from semantic, idiomatic, cultural, and conceptual perspectives. The Brazilian version assessed here can be freely used, was approved by the publishers who hold the copyright on the instrument, and is considered the official version of the instrument. New studies are underway to determine the validity and reliability of the PID-5.

Resumo Objetivo Apresentar o processo de adaptação transcultural do Personality Inventory for DSM-5 (PID-5) para o contexto brasileiro. Métodos A adaptação transcultural envolveu as etapas de tradução independente, versão síntese e retrotradução. A validade de conteúdo foi realizada por um comitê multidisciplinar de especialistas, com avaliação quantitativa dos índices de concordância. Por fim, o pré-teste foi conduzido com a população-alvo. Resultados Todos os estágios da adaptação transcultural foram seguidos, e na maioria das estruturas avaliadas, os valores de concordância foram satisfatórios (≥ 4.75). Grande parte das sugestões de modificações feitas pelos especialistas foram acatadas, sendo as principais relacionadas a ajustes no tempo e concordância verbal e a inclusão de letras e palavras para permitir a flexão de gênero. No pré-teste nenhuma sugestão foi apresentada e o instrumento foi considerado compreensível. Conclusão A versão brasileira do PID-5 mostrou-se adequada ao contexto brasileiro sob as perspectivas semântica, idiomática, cultural e conceitual. A versão brasileira avaliada é de uso livre, foi aprovada pelas editoras responsáveis pelos direitos autorais do instrumento e é considerada oficial. Novos estudos estão sendo conduzidos para aprimorar a busca por evidencias de validade e confiabilidade.

Personality Inventory for DSM-5 (PID-5): cross-cultural adaptation and content validity in the Brazilian context.

OBJECTIVE: To describe the process of cross-cultural adaptation of the Personality Inventory for DSM-5 (PID-5) to the Brazilian context. METHODS: Cross-cultural adaptation involved the steps of independent translation of the instrument, synthesis version, and back-translation. Analysis of content validity was conducted by a multidisciplinary expert committee and consisted of quantitative assessment of agreement indicators. The test was then applied to a target population. RESULTS: All the steps required for a cross-cultural adaptation were followed and satisfactory agreement values (≥ 4.75) were reached for most of the structures assessed. Most of the changes suggested by the experts were followed; these changes consisted primarily of adjustments to verb tense and agreement and the inclusion of letters and words to allow gender inflection. In the pre-test, no suggestions were made and the instrument was considered comprehensible. CONCLUSION: The Brazilian version of the PID-5 was found to be adequate to the Brazilian context from semantic, idiomatic, cultural, and conceptual perspectives. The Brazilian version assessed here can be freely used, was approved by the publishers who hold the copyright on the instrument, and is considered the official version of the instrument. New studies are underway to determine the validity and reliability of the PID-5.

The Influence of Depression on the Psychometric Properties of the Maslach Burnout Inventory-Human Services Survey: A Cross-Sectional Study With Nursing Assistants.

Background: The Maslach Burnout Inventory-Human Services Survey (MBI-HSS) is the most commonly used instrument to assess burnout. Although various factors have been reported to influence its validity, the influence of major depressive disorder (MDD) has not been previously considered. We developed this study to investigate the influence of MDD on the psychometric properties of the MBI-HSS in nursing assistants. Results: From a sample of 521 nursing assistants, we found in those with MDD (n = 138, 24.56%) a degree of data misfit into the model, revealed by non-acceptable values for the root mean square error of approximation (RMSEA; 0.073; p = 0.004) and for the comparative fit index (CFI; 0.912), while in the non-MDD group these indices were acceptable and good, respectively, for RMSEA (0.048; p = 0.639) and for CFI (0.951). Also, we found higher coefficients of correlation among MBI-HSS factors and less items loading properly in their respective factors in the MDD subset, when compared to the non-MDD subset. For the total sample, while original 3-factor solution was an acceptable model, the bifactor model fitted data better. Conclusions: MDD may impair the construct validity of MBI-HSS subscales, by increasing measurement error and decreasing model fitness. Therefore, researchers and health professionals should be aware of potential changes in the psychometric properties of the MBI-HSS when applied in subjects with depression.

Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness.

BACKGROUND: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity. METHODS: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. RESULTS: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. CONCLUSION: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.

Psychiatric disorders, spinocerebellar ataxia type 3 and CAG expansion.

Few studies have investigated the association between spinocerebellar ataxia type 3 (SCA3) and psychiatric disorders, using mainly screening scales to assess signs and symptoms of depression and anxiety. With these limitations in mind, we assessed the prevalence of DSM-IV Axis I psychiatric disorders in SCA3 patients and their possible associations with the length of CAG repeats and socio-demographic characteristics, highlighting potential risk factors. DNA samples were collected from 59 adults diagnosed with SCA3 for the quantification of CAG repeats. Next, the patients were assessed in respect to the presence of psychiatric disorders with the Structured Clinical Interview for DSM-IV. Approximately half of the sample had at least one psychiatric disorder (mood disorders 45.2 %), mainly dysthymia and current depression. There were no statistically significant differences in the length of CAG repeats between subjects with and without psychiatric disorders. The perception that SCA3 has a negative impact on life and the subjective assessment of current health status as poor emerged as risk factors for the occurrence of psychiatric disorders in the sample. There is a higher prevalence of psychiatric disorders in SCA3 patients compared to the general population. The lack of association between CAG repeats and occurrence of psychiatric disorders lends support to the hypothesis that psychiatric disorders in this group are associated with adaptive emotional responses to becoming ill.

Effects of pregabalin on behavioral alterations induced by ketamine in rats.

OBJECTIVE: The aim of this study is to investigate the effects of pregabalin on the behavior of rats under the influence of ketamine, an NMDA receptor antagonist that mimics the symptoms of schizophrenia. METHODS: Rats were injected with saline or 25 mg/kg ketamine intraperitoneally. After that, behavior modifications were investigated by the evaluation of stereotypy and hyperlocomotion, after treating rats with pregabalin (at doses of 30 mg/kg or 100 mg/kg) or placebo (saline solution). RESULTS: The administration of pregabalin reduced ketamine-induced hyperlocomotion. However, neither doses of pregabalin had a significant effect on ketamineinduced stereotypy. CONCLUSION: This is the first study to investigate the effects of pregabalin using an animal model of psychosis. Furthermore, our results indicate that behavioral changes induced by ketamine in rats can be reversed with the use of pregabalin, suggesting its potential to treat psychotic symptoms.

Is the highest density of CB1 receptors in paranoid schizophrenia a correlate of endocannabinoid system functioning?

Increased binding of type 1 cannabinoid (CB1) receptor ligands in the dorsolateral prefrontal cortex and other areas has been shown in post-mortem studies, although there are some inconsistent results. The study by Dalton et al. employed a more rigorous control for potentially confounding variables and investigated whether the density of CB1 receptors and their mRNA expression were different in subtypes of schizophrenia patients. They observed an increased density of CB1 receptors in paranoid schizophrenia as compared with nonparanoid schizophrenia patients and controls. This finding strengthens the evidence for the involvement of endocannabinoids in schizophrenia. However, it is difficult to reconcile with previous observations of increased levels of anandamide in the cerebrospinal fluid in paranoid schizophrenia, since CB1 receptor agonists were shown to induce the downregulation of these receptors. The precise role of the endocannabinoid system in the pathophysiology of schizophrenia remains far from understood.

Facial affect processing in social anxiety: tasks and stimuli.

Social anxiety (SA) has as its main feature the fear of social situations, being characterized as social phobia or social anxiety disorder when functional impairment emerges as a result of that fear. Although the recognition of the condition has increased in recent years, it is believed that many patients and physicians still take the symptoms of the disorder for personality traits with no need for treatment. There is evidence that people with SA display abnormal patterns of facial emotion processing that could account for the onset and maintenance of the disorder. The objective of this review is to describe, compare, and discuss the methods used to study facial emotion processing in SA with an emphasis on the tasks and stimuli employed. Articles were searched for on online scientific databases. Forty research articles were selected according to the inclusion and exclusion criteria established. The articles were read and information from them was gathered on a comparative table for analysis. Evidence available to date suggests that SA individuals have abnormal patterns of facial information processing characterized by a bias for negative emotions. The results of the articles analyzed have a high degree of concordance, in spite of the variety of tasks and stimuli employed. The similarity between results from non-clinical samples with SA and patients affected by social phobia speaks in favor of the current view that SA occurs as a continuum of severity, rather than a clearly circumscribed nosological entity.

Treatment with cannabidiol reverses oxidative stress parameters, cognitive impairment and mortality in rats submitted to sepsis by cecal ligation and puncture.

Oxidative stress plays an important role in the development of cognitive impairment in sepsis. Here we assess the effects of acute and extended administration of cannabidiol (CBD) on oxidative stress parameters in peripheral organs and in the brain, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent either sham operation or CLP. Rats subjected to CLP were treated by intraperitoneal injection with "basic support" and CBD (at 2.5, 5, or 10mg/kg once or daily for 9days after CLP) or vehicle. Six hours after CLP (early times), the rats were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus, striatum, and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day (late times), the rats were submitted to the inhibitory avoidance task. After the test, the animals were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus) were obtained and assayed for TBARS formation and protein carbonyls. The acute and extended administration of CBD at different doses reduced TBARS and carbonyl levels in some organs and had no effects in others, ameliorated cognitive impairment, and significantly reduced mortality in rats submitted to CLP. Our data provide the first experimental demonstration that CBD reduces the consequences of sepsis induced by CLP in rats, by decreasing oxidative stress in peripheral organs and in the brain, improving impaired cognitive function, and decreasing mortality.

Social anxiety disorder women easily recognize fearfull, sad and happy faces: the influence of gender.

BACKGROUND: It has been suggested that individuals with social anxiety disorder (SAD) are exaggeratedly concerned about approval and disapproval by others. Therefore, we assessed the recognition of facial expressions by individuals with SAD, in an attempt to overcome the limitations of previous studies. METHODS: The sample was formed by 231 individuals (78 SAD patients and 153 healthy controls). All individuals were treatment naïve, aged 18-30 years and with similar socioeconomic level. Participants judged which emotion (happiness, sadness, disgust, anger, fear, and surprise) was presented in the facial expression of stimuli displayed on a computer screen. The stimuli were manipulated in order to depict different emotional intensities, with the initial image being a neutral face (0%) and, as the individual moved on across images, the expressions increased their emotional intensity until reaching the total emotion (100%). The time, accuracy, and intensity necessary to perform judgments were evaluated. RESULTS: The groups did not show statistically significant differences in respect to the number of correct judgments or to the time necessary to respond. However, women with SAD required less emotional intensity to recognize faces displaying fear (p=0.002), sadness (p=0.033) and happiness (p=0.002), with no significant differences for the other emotions or men with SAD. CONCLUSIONS: The findings suggest that women with SAD are hypersensitive to threat-related and approval-related social cues. Future studies investigating the neural basis of the impaired processing of facial emotion in SAD using functional neuroimaging would be desirable and opportune.

Confiabilidade da entrevista clínica estruturada para o DSM-IV - versäo clínica" traduzida para o português / Reliability of the structured clinical interview for DSM-IV - clinical version translated into portuguese

Objetivos: Verificar a confiabilidade da "Entrevista Clínica Estruturada para o DSM-IV - Versäo Clínica (SCID-CV)" traduzida para o português. Métodos: Foram submetidos, a duas entrevistas independentes (teste-reteste), 45 pacientes psiquiátricos em seguimento no Hospital das Clínicas da Faculdade de Medicina de Ribeiräo Preto da Universidade de Säo Paulo (HC-FMRP/USP). Os dados foram analisados pelo Coeficiente Kappa (K). Resultados: O Kappa ponderado foi excelente (Kw=0,83). A confiabilidade foi estatisticamente significante em transtorno do humor (K=0,87); transtornos psicóticos (K=0,90); transtornos relacionados ao uso de substância (K=0,76); transtornos de ansiedade (K=0,61); e nas categorias diagnósticas específicas analisadas, exceto em agorafobia sem história de transtorno do pânico (K=0,04). Conclusões: A SCID-CV traduzida e adaptada para o português apresenta, em geral, boa confiabilidade, mas a ausência de questões e critérios diagnósticos específicos no próprio instrumento em diagnósticos, como agorafobia sem história de transtorno de pânico, diminuiu sua confiabilidade