Genetic ablation of the isoform γ of PI3K decreases antidepressant efficacy of ketamine in male mice.

About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.

Therapeutic potential of CBD in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior. Despite extensive research, effective pharmacological interventions for ASD remain limited. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has potential therapeutic effects on several neurological and psychiatric disorders. CBD interacts with the endocannabinoid system, a complex cell-signaling system that plays a crucial role in regulating various physiological processes, maintaining homeostasis, participating in social and behavioral processing, and neuronal development and maturation with great relevance to ASD. Furthermore, preliminary findings from clinical trials indicate that CBD may have a modulatory effect on specific ASD symptoms and comorbidities in humans. Interestingly, emerging evidence suggests that CBD may influence the gut microbiota, with implications for the bidirectional communication between the gut and the central nervous system. CBD is a safe drug with low induction of side effects. As it has a multi-target pharmacological profile, it becomes a candidate compound for treating the central symptoms and comorbidities of ASD.

Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications.

BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Effect of two oral formulations of cannabidiol on responses to emotional stimuli in healthy human volunteers: pharmaceutical vehicle matters

Objective: To compare plasma concentrations of cannabidiol (CBD) following oral administration of two formulations of the drug (powder and dissolved in oil), and to evaluate the effects of these distinct formulations on responses to emotional stimuli in healthy human volunteers. Methods: In a randomized, double-blind, placebo-controlled, parallel-group design, 45 healthy male volunteers were randomly assigned to three groups of 15 subjects that received either 150 mg of CBD powder; 150 mg of CBD dissolved in corn oil; or placebo. Blood samples were collected at different times after administration, and a facial emotion recognition task was completed after 150 min. Results: There were no significant differences across groups in the subjective and physiological measures, nor in the facial emotion recognition task. However, groups that received the drug showed statistically significant differences in baseline measures of plasma CBD, with a significantly greater difference in favor of the oil formulation. Conclusion: When administered as a single 150-mg dose, neither formulation of oral CBD altered responses to emotional stimuli in healthy subjects. The oil-based CBD formulation resulted in more rapid achievement of peak plasma level, with an approximate fourfold increase in oral bioavailability.

Increased body sway in phobic patients exposed to images of spiders

Objective: The aim of the present study was to analyze the body sway response in specific phobia (SP) patients and healthy controls while viewing neutral, phobic, and disgusting images. Methods: The participants' heart rate (HR) and skin conductance were also recorded during the procedure. Nineteen patients with arachnophobia and 19 healthy volunteers matched by age, gender, and years of education underwent a postural control test on a stabilometric platform. Results: The platform recorded increased body sway in the SP group when exposed to spider images (SPI). The SP group presented increases in most parameters (SD, velocity, frequency, area, p ≤ 0.05) when viewing pictures of the SPI category. Psychometric measures of subjective anxiety (State-Trait Anxiety Inventory, STAI) and physiological states (HR; skin conductance responses; spontaneous fluctuations in skin conductance) showed increased anxiety (p ≤ 0.05) in the SP group compared to healthy volunteers. High anxiety levels were observed throughout the assessment, including the task of exposure to SPI (p ≤ 0.05). No significant effect or correlation was found between skin conductance and body sway measures (p > 0.05). Conclusions: The results of the postural control test suggest the occurrence of a defensive escape response in SP, in agreement with previous evidence.

Cannabidiol for the treatment of crack-cocaine craving: an exploratory double-blind study

Objective: To assess the efficacy of cannabidiol (CBD) in the management of crack-cocaine craving and the treatment of frequent withdrawal symptoms. Methods: Thirty-one men with a diagnosis of crack-cocaine dependence were enrolled in a randomized, double-blind, placebo-controlled trial. We applied neuropsychological tests and assessed craving intensity, anxiety and depression symptoms, and substance use patterns at baseline and at the end of the trial. The participants were treated with CBD 300 mg/day or placebo for 10 days. During this period, we used a technique to induce craving and assessed the intensity of symptoms before and after the induction procedure. Results: Craving levels reduced significantly over the 10 days of the trial, although no differences were found between the CBD and placebo groups. Craving induction was successful in both groups, with no significant differences between them. Indicators of anxiety, depression, and sleep alterations before and after treatment also did not differ across groups. Conclusion: Under the conditions of this trial, CBD was unable to interfere with symptoms of crack-cocaine withdrawal. Further studies with larger outpatient samples involving different doses and treatment periods would be desirable and timely to elucidate the potential of CBD to induce reductions in crack-cocaine self-administration.

Biological bases for a possible effect of cannabidiol in Parkinson's disease

Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.

Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test

Objective: Cannabidiol (CBD), one of the non-psychotomimetic compounds of Cannabis sativa, causes anxiolytic-like effects in animals, with typical bell-shaped dose-response curves. No study, however, has investigated whether increasing doses of this drug would also cause similar curves in humans. The objective of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers performing a simulated public speaking test (SPST), a well-tested anxiety-inducing method. Method: A total of 57 healthy male subjects were allocated to receive oral CBD at doses of 150 mg (n=15), 300 mg (n=15), 600 mg (n=12) or placebo (n=15) in a double-blind procedure. During the SPST, subjective ratings on the Visual Analogue Mood Scale (VAMS) and physiological measures (systolic and diastolic blood pressure, heart rate) were obtained at six different time points. Results: Compared to placebo, pretreatment with 300 mg of CBD significantly reduced anxiety during the speech. No significant differences in VAMS scores were observed between groups receiving CBD 150 mg, 600 mg and placebo. Conclusion: Our findings confirm the anxiolytic-like properties of CBD and are consonant with results of animal studies describing bell-shaped dose-response curves. Optimal therapeutic doses of CBD should be rigorously determined so that research findings can be adequately translated into clinical practice.

Mental health in medical residents: relationship with personal, work-related, and sociodemographic variables

Objective: To examine association of sociodemographic characteristics, personality traits, social skills, and work variables with anxiety, depression, and alcohol dependence in medical residents. Methods: A total of 270 medical residents completed the following self-report instruments: sociodemographic and work questionnaire, Patient Health Questionnaire-4 (PHQ-4), Alcohol Use Disorders Identification Test-3 (AUDIT-3), Revised NEO-Five Factor Inventory (NEO-FFI-R), and Social Skills Inventory (SSI-Del-Prette). Data were analyzed using descriptive statistics and univariate and multivariate logistic regression analyses. Results: Multivariate analysis showed an association of neuroticism (odds ratio [OR] 2.60, p < 0.001), social skills (OR 0.41, p < 0.01), and number of shifts (OR 1.91, p = 0.03) with anxiety or depression, and of male sex (OR 3.14, p = 0.01), surgical residency (OR 4.40, p = 0.001), extraversion (OR 1.80, p < 0.01), and number of shifts (OR 2.32, p = 0.04) with alcohol dependence. Conclusion: The findings support a multidetermined nature of mental health problems in medical residents, in addition to providing data that may assist in the design of preventive measures to protect the mental health of this group.

Arterial spin labeling in patients with schizophrenia: a systematic review

Abstract Background: Neuroimaging studies are an invaluable source of information about the physiopathology of schizophrenia. Arterial spin labeling (ASL) is a new magnetic resonance technique (MRI) that is able to effectively evaluate brain function without the use of radiation. Objective: To make a systematic review of studies using ASL to compare resting-state regional cerebral blood flow (rCBF) patterns in patients with schizophrenia and healthy controls. Methods: Original articles were searched for on PubMed, Scopus, Web of Science and PsycINFO electronic databases. The search terms used were 'arterial', 'spin', 'labeling', and 'schizophrenia'. Only studies comparing resting-state rCBF were included, a qualitative synthesis was then performed. Results: Ten articles were included in the review among a total of 22. Decreased rCBF in schizophrenia patients was described in the anterior cingulate, cuneus, fusiform gyrus, frontal lobe, left middle frontal gyrus, inferior frontal gyrus, lingual gyrus, middle occipital gyrus, and parietal lobe. The putamen was the only region with increased rCBF in schizophrenia. Discussion: The evidence of the studies reviewed lends support to the concept of hipofrontality in schizophrenia. rCBF alterations were found in regions classically associated with schizophrenia. ASL seems to be valid, and reliable tool to assess schizophrenia.

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

Objectives: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode. Methods: Open-label trial conducted in an inpatient psychiatric unit. Results: Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement. Conclusions: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder. .

Structural and functional neuroimaging findings associated with the use of clozapine in schizophrenia: a systematic review

Objective: Schizophrenia is one of the most severe psychiatric disorders, and its current treatment relies on antipsychotic medications with only partial effectiveness. Clozapine is an atypical antipsychotic with a specific profile of action indicated for treatment-resistant schizophrenia. Neuroimaging studies assessing the effects of clozapine could help shed light on the neural underpinnings of the effects of this drug in the brain. The objective of this study was to review the available literature on the structural and functional neuroimaging findings associated with use of clozapine. Method: We conducted a systematic review of the indexed literature using the PubMed, BIREME, and ISI Web of Knowledge search engines and the following keywords: clozapine, neuroimaging, computed tomography, MRI, functional magnetic resonance, PET, SPECT, and DTI. Results: A total of 23 articles were included in the review. In structural studies, the use of clozapine was associated with volume reductions in the basal ganglia, especially the caudate nucleus, where functional neuroimaging studies also found decreased perfusion. In the frontal lobe, clozapine treatment was associated with increased gray matter volume and reduced perfusion. Conclusion: The results of the studies reviewed suggest that the use of clozapine is associated with distinctive structural and functional neuroimaging findings that are not shared with other antipsychotics. .

Parameters for screening music performance anxiety

Objective: To assess the discriminative capacity of the Kenny Music Performance Anxiety Inventory (K-MPAI), in its version adapted for Brazil, in a sample of 230 Brazilian adult musicians. Method: The Social Phobia Inventory (SPIN) was used to assess the presence of social anxiety indicators, adopting it as the gold standard. The Mann-Whitney U test and the receiver operating characteristic (ROC) curve were used for statistical analysis, with p ≤ 0.05 set as the significance level. Results: Subjects with social anxiety indicators exhibited higher mean total K-MPAI scores, as well as higher individual scores on 62% of its items. The area under the ROC curve was 0.734 (p = 0.001), and considered appropriate. Within the possible cutoff scores presented, the score -15 had the best balance of sensitivity and specificity values. However, the score -7 had greater specificity and accuracy. Conclusion: The K-MPAI showed appropriate discriminant validity, with a marked association between music performance anxiety and social anxiety. The cutoff scores presented in the study have both clinical and research value, allowing screening for music performance anxiety and identification of possible cases. .

Brazilian Medical Association guidelines for the diagnosis and differential diagnosis of panic disorder

Objective: To present the most relevant findings regarding the Brazilian Medical Association guidelines for the diagnosis and differential diagnosis of panic disorder. Methods: We used the methodology proposed by the Brazilian Medical Association for the Diretrizes Project. The MEDLINE (PubMed), Scopus, Web of Science, and LILACS online databases were queried for articles published from 1980 to 2012. Searchable questions were structured using the PICO format (acronym for “patient” [or population], “intervention” [or exposure], “comparison” [or control], and “outcome”). Results: We present data on clinical manifestations and implications of panic disorder and its association with depression, drug abuse, dependence and anxiety disorders. In addition, discussions were held on the main psychiatric and clinical differential diagnoses. Conclusions: The guidelines are proposed to serve as a reference for the general practitioner and specialist to assist in and facilitate the diagnosis of panic disorder. .

Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain

Objective: To investigate the effects of cannabidiol (CBD) on mitochondrial complex and creatine kinase (CK) activity in the rat brain using spectrophotometry. Method: Male adult Wistar rats were given intraperitoneal injections of vehicle or CBD (15, 30, or 60 mg/kg) in an acute (single dose) or chronic (once daily for 14 consecutive days) regimen. The activities of mitochondrial complexes and CK were measured in the hippocampus, striatum, and prefrontal cortex. Results: Both acute and chronic injection of CBD increased the activity of the mitochondrial complexes (I, II, II-III, and IV) and CK in the rat brain. Conclusions: Considering that metabolism impairment is certainly involved in the pathophysiology of mood disorders, the modulation of energy metabolism (e.g., by increased mitochondrial complex and CK activity) by CBD could be an important mechanism implicated in the action of CBD. .

Quality of life in patients with Charcot-Marie-Tooth disease type 1A / Análise da qualidade de vida de pacientes com a doença de Charcot-Marie-Tooth tipo 1A

We assessed the functional impairment in Charcot-Marie-Tooth resulting from 17p11.2-p12 duplication (CMT1A) patients using the Short-Form Health Survey (SF-36), which is a quality of life questionnaire. Twenty-five patients of both genders aged ≥10 years with a positive molecular diagnosis of CMT1A were selected. Age- and gender-matched Control Group (without family history of neuropathy), and the sociodemographic and professional conditions similar to the patients' group were selected to compare the SF-36 results between them. The results showed that the majority quality of life impairments in CMT1A patients occurred in the social and emotional domains. Functional capacity also tended to be significantly affected; other indicators of physical impairment were preserved. In conclusion, social and emotional aspects are mostly neglected in the assistance provided to CMT1A Brazilian patients, and they should be better understood in order to offer global health assistance with adequate quality of life as a result.

Avaliou-se o comprometimento funcional de pacientes com Charcot-Marie-Tooth provenientes da duplicação 17p11.2-p12 (CMT1A), utilizando o SF-36, que é um questionário para medir a qualidade de vida. Vinte e cinco pacientes de ambos os sexos com idades ≥10 anos e diagnóstico molecular de CMT1A foram selecionados. Idade, sexo, condições sociodemográficas e profissionais foram pareados com o Grupo Controle (sem histórico familiar de neuropatia). Os resultados mostraram que o maior impacto da CMT1A na qualidade de vida ocorreu nos domínios social e emocional dos pacientes avaliados. A capacidade funcional também tende a ser significativamente afetada, enquanto outros indicadores de deficiência física foram preservados. Por fim, os aspectos sociais e emocionais dos pacientes acometidos por CMT1A costumam ser negligenciados na assistência médica prestada aos pacientes brasileiros, e devem ser melhor compreendidos a fim de oferecer uma assistência global à saúde, resultando em adequada qualidade de vida.

A humanistic gift from the Brazilian Emperor D. Pedro II (1825 - 1891) to the Brazilian nation: the first lunatic asylum in Latin America / Um presente humanitário do Imperador D. Pedro II (1825 - 1891) à nação brasileira: o primeiro asilo para lunáticos da América Latina

Until the beginning of the 19th century, psychiatric patients did not receive specialized treatment. The problem that was posed by the presence of psychiatric patients in the Santas Casas de Misericórdia and the social pressure from this issue culminated in a Decree of the Brazilian Emperor, D. Pedro II, on July 18, 1841. The “Lunatic Palace” was the first institution in Latin America exclusively designed for mental patients. It was built between 1842 and 1852 and is an example of neoclassical architecture in Brazil, located at Saudade Beach in the city of Rio de Janeiro. In the 1930s and 1940s, the D. Pedro II Hospital was overcrowded, and patients were gradually transferred to other hospitals. By September of 1944, all the patients had been transferred and the hospital was deactivated. Key words: psychiatry, history, madness.

Até o início do século 19, os pacientes psiquiátricos não recebiam nenhum tipo de tratamento específico. A pressão social da época decorrente do problema representado pela presença dos pacientes psiquiátricos nas Santas Casas de Misericórdia culminou no Decreto do Imperador brasileiro, D. Pedro II, em 18 de julho de 1841. O “Palácio dos Loucos” foi a primeira instituição na América Latina voltada exclusivamente para a assistência aos doentes mentais. Foi construído entre 1842 e 1852, na Praia da Saudade na cidade do Rio de Janeiro, e é um dos expoentes da arquitetura neoclássica do Brasil. Nas décadas de 1930 e 1940, o então Hospital D. Pedro II estava superlotado, tendo sido os pacientes gradualmente transferidos para outros hospitais. Em setembro de 1944, concluiu-se a tranferência de todos os pacientes e o hospital foi desativado.

Animal models for predicting the efficacy and side effects of antipsychotic drugs

The use of antipsychotic drugs represents an important approach for the treatment of schizophrenia. However, their efficacy is limited to certain symptoms of this disorder, and they induce serious side effects. As a result, there is a strong demand for the development of new drugs, which depends on reliable animal models for pharmacological characterization. The present review discusses the face, construct, and predictive validity of classical animal models for studying the efficacy and side effects of compounds for the treatment of schizophrenia. These models are based on the properties of antipsychotics to impair the conditioned avoidance response and reverse certain behavioral changes induced by psychotomimetic drugs, such as stereotypies, hyperlocomotion, and deficit in prepulse inhibition of the startle response. Other tests, which are not specific to schizophrenia, may predict drug effects on negative and cognitive symptoms, such as deficits in social interaction and memory impairment. Regarding motor side effects, the catalepsy test predicts the liability of a drug to induce Parkinson-like syndrome, whereas vacuous chewing movements predict the liability to induce dyskinesia after chronic treatment. Despite certain limitations, these models may contribute to the development of more safe and efficacious antipsychotic drugs.

Transtornos de ansiedade: terapia com estimulação magnética transcraniana / Anxiety disorders: treatment with transcranial magnetic stimulation

Dentre os transtornos psiquiátricos, os transtornos de ansiedade (TAs) são os mais comuns, com prevalência em torno de 20% na população e, portanto, provocam grande prejuízo a pacientes e familiares. São vários os subtipos de transtornos de ansiedade e um diagnóstico correto se baseia em uma avaliação clínica cuidadosa. No presente artigo apresentamos os diagnósticos e os achados mais recentes sobre o tratamento com estimulação magnética transcraniana repetitiva (EMTr) para o transtorno de pânico, transtorno obsessivo-compulsivo, transtorno de estresse pós-traumático e fobia social.

Among psychiatric disorders, anxiety disorders (ATs) are the most common, with a prevalence of around 20% in the population and with great harm to patients and families. There are several subtypes of anxiety disorders and a correct diagnosis is based on a careful clinical assessment. In this paper we present the findings and the latest findings about treatment with repetitive transcranial magnetic stimulation (rTMS) for panic disorder, obsessive-compulsive disorder, post-traumatic stress and social phobia.