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Objective: Electroconvulsive therapy (ECT) is a well-established therapeutic intervention for major depressive disorder. Recent literature has shown that the anesthetic agent ketamine has some antidepressant properties at low doses and may be an alternative therapy for treatment-resistant major depressive disorder. We hypothesized that the use of low-dose ketamine as an anesthetic adjunct in ECT would more rapidly improve depression while maintaining hemodynamic stability than ECT with propofol alone. Methods: Institutional ethics approval was obtained, and the use of ketamine in this study was approved by Health Canada. This is a randomized, double-blinded, placebo-controlled trial that involved ketamine administration at 0.5 mg/kg IV in addition to propofol anesthesia for ECT. The primary outcome was the number of ECT treatments required to achieve a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included the number of ECT treatments required to achieve a 25% reduction in MADRS score, as well as any differences in the Clinical Global Impression Scale for Severity, hemodynamic variables, and seizure duration. Adverse events were recorded for safety assessment. Results: A total of 45 patients completed the study. No difference was found between groups with respect to the primary or secondary outcomes. The ketamine group showed a trend towards a decreased dose of propofol required to achieve adequate anesthesia. No adverse events were reported. Conclusion: Low-dose ketamine does not improve psychiatric outcomes in the setting of propofol-based anesthesia for ECT. Specifically, ketamine did not reduce the number of ECT sessions necessary to achieve a 50 or 25% reduction in MADRS scores. Reassuringly, the fact that no differences in hemodynamic variables or unexpected adverse events occurred suggests that low-dose ketamine may be safely used in this setting should clinical indications warrant its use. Clinical trial registration: ClinicalTrials.gov, NCT02579642

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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.

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Objective: Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those on continuous treatment for > 1 year who have never had an absolute neutrophil count (ANC) < 2,000/µL has been proposed as a monitoring strategy; however, there are no South American data to support this recommendation. This study sought to investigate whether clozapine use and other variables could explain the occurrence of ANC < 1,000/µL in patients with severe mental disorders. Methods: A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox regression considering the outcome as ANC < 1,000/µL at any time point. Predictors were sex, age, ethnicity, clozapine use, ANC > 2,000/µL during the first year of blood monitoring, and presence of a severe medical condition. Results: In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99, p < 0.05) and ANC > 2,000/µL (HR 0.04; 95%CI 0.01-0.10, p < 0.001) were protective factors, while presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p < 0.001) was a risk factor for ANC < 1,000/µL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI 0.74-2.39, p > 0.05). Conclusions: These findings suggest that clozapine does not increase the risk of neutropenia in subjects with ANC > 2,000/µL during the first year of use and in the absence of a severe medical condition. These results could help guide clinical and public-health decisions regarding clozapine blood monitoring guidelines.

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Objective: To test the hypothesis that genetic variations of cannabinoid receptors contribute to the pathophysiology of cognitive deficits in schizophrenia. Methods: In this genetic association case-control study, cannabinoid receptor polymorphisms CNR1 rs12720071 and CNR2 rs2229579 were tested for association with neurocognitive performance in 69 patients with schizophrenia and 45 healthy controls. Neurocognition was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS). Results: We found a consistent association between CNR1 rs12720071 polymorphism and the cognitive performance of patients in several cognitive domains. Patients with C/C polymorphism presented significantly worse performance in motor speed, verbal fluency, attention/processing speed and reasoning/problem solving. Conclusion: Although limited, our data support the hypothesis that CNR1 variations may be associated with the pathogenesis of cognitive deficits of schizophrenia.

Resumo em Inglês:

Objectives: The bipolar spectrum concept has resulted in a paradigm shift that has affected both the diagnosis and therapy of mood disorders, with bipolarity becoming an indicator of treatment resistance in depression. Evening circadian preference has also been linked to affective disorders. The aim of our study was to confirm the relationship between the severity of depressive symptoms, bipolar features, chronotype, and sleep quality among patients with major depressive disorder. Methods: A group of 55 individuals who were recruited from a mental health outpatient clinic completed the following psychometric tools: a Chronotype Questionnaire comprising morningness-eveningness (ME) and subjective amplitude of the rhythm (AM) scales, the Hypomania Checklist 32 (HCL-32), the Beck Depression Inventory (BDI) and the Pittsburgh Sleep Quality Index (PSQI). Results: Factor analysis identified two latent components, accounting cumulatively for 58% of variables: depressive symptoms (BDI and PSQI) and bipolarity (ME, AM, and HCL-32). After rotation, ME loading in the first factor increased the result to a significant level. The correlation between the two components was very low. Conclusions: Evening chronotype appears to be a bipolarity-related marker, with this relationship being independent of its link to depressive symptoms and sleep quality. Eveningness and high circadian rhythm amplitude may offer promise as diagnostic, prognostic, and therapeutic predictors.

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Objective: To analyze the association between physical fitness, cognitive function, and depressive symptoms among older adults in long-term care facilities (LTCFs). Methods: Seventy-six institutionalized male and female elderly individuals (65 years and older) living in LTCFs participated of this study. Physical fitness (aerobic capacity and strength), cognitive functions (global cognition, short-term and working and semantic memories, and executive function), and depressive symptoms were assessed. Linear regression and contingency analyses were performed. Significance was accepted at p-values ≤ 0.05. Results: Aerobic capacity predicted 32% of variance in global cognition (p < 0.01) and 25% of variance in semantic fluency/executive function (p < 0.01). Low levels of upper limb strength, lower limb strength, and aerobic capacity were associated with semantic fluency/executive function (OR = 1.38, p = 0.01, OR = 1.26, p = 0.03, and OR = 1.07, p = 0.01, respectively) and depressive symptoms (OR = 1.06, p < 0.01). Conclusion: Poor physical fitness is associated with cognition and depressive symptoms in institutionalized older adults. Low levels of strength and aerobic fitness increase the odds of presenting with impaired semantic fluency and executive function, possibly denoting an increased risk of developing dementia.

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Objective: To investigate the effects of developing religiosity on abstinence of substance abuse among recovering addicts in a faith-based and a secular-based treatment program. Methods: Religiosity of recovering addicts was measured using the 38-item Brief Multidimensional Measure of Religiousness/Spirituality at three points in time: at initiation of substance addiction treatment (wave 1), discharge from treatment (wave 2), and 6 months after treatment (wave 3). Latent growth curve modeling was used to assess the dynamic and developing effects of religiosity on after-treatment abstinence. Secular-based treatment emphasized the role of biological, psychological, and environmental determinants of substance abuse and provided detoxification interventions, such as counseling and group therapies, skill training, health care, and social support, however also relying on religious and spiritual growth to help recovery. Faith-based treatment fundamentally emphasized the Christian theory of addiction to consider substance abuse a sin caused by one’s spiritual void and separation from God, although it also acknowledged the importance of biological, psychological, and social needs of rehabilitants. Results: Recovering addicts in faith-based treatment had significantly higher levels of religiosity at each wave (intercept factor) and better religious development across the three waves (slope factor). This contributed to after-treatment abstinence and mediated the effect of treatment mode on after-treatment abstinence. Conclusion: Service practitioners and researchers should note the importance of dynamic and developing nature of religiosity in relation to the maintenance of abstinence after treatment is completed.

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Objectives: Although the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a widely used instrument for assessing different obsessive-compulsive symptom dimensions, its factor structure has never been studied in a Brazilian population. Thus, we aimed to assess the goodness-of-fit indexes and factor loadings of two higher-order models of the DY-BOCS using confirmatory factor analysis (CFA) in a large obsessive-compulsive disorder (OCD) sample. Methods: We tested two CFA models in a sample of 955 adults with OCD who had been assessed with the DY-BOCS in a cross-sectional multi-site study. The first model encompassed the symptom checklist (present or absent), whereas the second focused on items related to severity scores. Results: Both models presented adequate goodness-of-fit indexes. The comparative fit index, Tucker-Lewis index, and omega were > 0.9, while the root mean square error of approximation was ≤ 0.06 for both models. Factor loadings for each item of each dimension are presented and discussed. Conclusion: Higher-order factor models showed adequate goodness-of-fit indexes, indicating that they appropriately measured OCD dimensions in this Brazilian population.

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Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. Clinical trial registration: This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

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The notion that schizophrenia is a neuroprogressive disorder is based on clinical perception of cumulative impairments over time and is supported by neuroimaging and biomarker research. Nevertheless, increasing evidence has indicated that schizophrenia first emerges as a neurodevelopmental disorder that could follow various pathways, some of them neuroprogressive. The objective of this review is to revisit basic research on cognitive processes and neuroimaging findings in a search for candidate keys to the intricate connections between neurodevelopment and neuroprogression in schizophrenia. In the complete panorama, schizophrenia is a neurodevelopmental disorder, possibly associated with an additional burden over the course of the disease through pathologically accelerated aging, and cognitive heterogeneity may explain the different trajectories of each patient.

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Social anxiety disorder (SAD) is a highly prevalent psychiatric disorder that presents with an early age of onset, chronic disease course, and increased risk of psychiatric comorbidity. Current treatment options for SAD are associated with low response rates, suboptimal efficacy, and possible risk of adverse effects. Investigation of new neurobiological mechanisms may aid in the identification of more specific therapeutic targets for the treatment of this disorder. Emerging evidence suggests that the endogenous cannabinoid system, also referred to as the endocannabinoid system (ECS), could play a potential role in the pathophysiology of SAD. This review discusses the known pathophysiological mechanisms of SAD, the potential role of the ECS in this disorder, current drugs targeting the ECS, and the potential of these novel compounds to enhance the therapeutic armamentarium for SAD. Further investigational efforts, specifically in human populations, are warranted to improve our knowledge of the ECS in SAD.

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Objective: To examine personality/temperament features and mental health vulnerability in offspring of mothers with bipolar disorders (BD), including dimensions which may impact psychological characteristics or therapeutic measures. Methods: A systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, was conducted to search for original articles that investigated personality/temperament features of offspring of women with BD and emotional factors involved in the mother-child relationship. The electronic search was performed in the PubMed, Web of Science, and PsycINFO databases from February 2010 to February 2017. Results: Ten quantitative studies were included in the analysis: seven from the United States, two from Brazil, and one from Canada. The narrative synthesis was categorized into three dimensions: 1) reliability of instruments for prediction of future psychopathology in offspring; 2) environmental risk factors for offspring; and 3) early interventions. The findings showed impairments in the offspring’s lives, high rates of behavior and temperament problems, and psychiatric disorders. Conclusion: BD is a frequent psychiatric disorder, and the offspring of mothers with this condition are exposed to complex family relationships and psychosocial difficulties. If they are to ensure a good provision of mental health and psychosocial care to this unique population, early interventions must not neglect their contextual specificities. Systematic review registration: PROSPERO CRD-42017039010

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Objective: Conduct a systematic review and meta-analysis to evaluate levels of anger among substance users compared to non-user controls and to analyze the possible association between anger and psychoactive substance use (PSU). Methods: The procedures of this review followed the Meta-Analyzes of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four electronic databases (MEDLINE, EMBASE, BIREME, PsycINFO) were searched. Results: Twelve studies were included in the meta-analysis; 10 used the State-Trait Anger Expression Inventory (STAXI) anger trait subscale and two used the Buss-Perry-Aggression Questionnaire (BPAQ) anger subscale. The sample included 2,294 users of psychoactive substances and 2,143 non-users, all male. The mean difference in anger scale scores between users and non-users was 2.151 (95%CI 1.166-3.134, p ≤ 0.00, inconsistency index [I2] = 98.83) standard deviations. Age and abstinence duration did not moderate the difference in anger between substance users and non-users. Conclusion: Users of psychoactive substances had elevated anger scores compared to non-users, which represents a high risk of relapse. It is suggested that PSU treatment programs include intensive anger management modules, focusing on factors such as dealing with daily stressors, family conflicts, frustrations, and problems.