Abstract Objectives Evidence suggests that ketamine’s influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). Methods Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. Results There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. Conclusion There was no significant treatment impact on BDNF serum levels – neither with ketamine nor esketamine – despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion. This clinical trial is registered on the Japan Primary Registries Network: UMIN000032355.

Objectives: Past suicide attempt (SA) is one of the most important risk factors for suicide death. An ideation-to-action framework posits that impulsivity, potentially traumatic events, and mental disorders also play a role in increasing suicide risk. This study aimed to assess the association between trait impulsivity, lifetime exposure to trauma, and post-traumatic stress disorder (PTSD) with SA in a sample of Brazilian college students. Methods: A total of 2,137 participants filled self-reported questionnaires consisting of a sociodemographic and clinical questionnaire, Trauma History Questionnaire, Post-Traumatic Stress Disorder Checklist – Civilian version, and Barratt Impulsiveness Scale. Results: Our findings suggest that trait impulsivity may be interpreted as exerting a distal effect on SA, even in the presence of other variables – such as trauma history, psychological neglect, and PTSD – which also increase the odds of SA. High and medium levels of impulsivity, history of trauma, and PTSD increased the likelihood of SA. Conclusions: Intervention strategies to prevent SA may target trait impulsivity and exposure to traumatic experiences.

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.

Abstract Introduction Anhedonia is defined as the reduced ability to feel pleasure and is a core symptom of various psychiatric disorders such as depression and schizophrenia. The Snaith-Hamilton Pleasure Scale (SHAPS) was developed to assess the presence of anhedonia. The objective of this study was to assess the psychometric properties of the Brazilian Portuguese version of the SHAPS. Methods In this study, the SHAPS (14 items) was translated into Brazilian Portuguese and validated using data obtained from 228 subjects within a clinical sample. Psychometric properties were assessed using item response theory (logistic models) and classical test theory (Cronbach’s alpha). We checked for external validity using a non-parametric correlation with an independent scale: Hospital Anxiety and Depression Scale – Depression subscale (HAD-D). Results The SHAPS presented good internal consistency, with a Cronbach’s α coefficient of 0.759 and adequacy to an IRT 1 parameter logistic (Rasch) model. The SHAPS presented significant correlation with the external measure HAD-D, with Spearman’s ρ = 0.249 (S = 1368914; p < 0.001). Conclusion These results suggest that the Brazilian Portuguese version of the SHAPS is a reliable and valid instrument to assess hedonic tone.

RESUMO. A ETCC (estimulação transcraniana por corrente contínua) é uma tecnologia não-invasiva, indolor e de fácil utilização. Pode ser usada na depressão, esquizofrenia e outros distúrbios neurológicos. Não há orientações ideais sobre o uso de protocolos mais longos quanto à duração e frequência semanal da ETCC. Objetivo: estudar o uso de ETCC duas vezes por semana por 5 semanas em idosos com CCL. Métodos: o estudo foi controlado, randomizado, duplo-cego com ETCC anódica em 58 idosos acima de 60 anos. Uma corrente de 2,0 mA foi aplicada por 30 minutos durante 10 sessões consecutivas, 2 vezes por semana. O ânodo foi colocado no córtex pré-frontal dorsolateral esquerdo (LDLFC). Os pacientes foram avaliados antes e após 10 sessões pelos testes: CAMCOG, Mini-Exame do Estado Mental (MMSE), Trilhas, Fluência Verbal Semântica - Animais, Boston, Relógio, Memória da Lista de Palavras (WLMT), Dígitos - ordem direta e indireta (WAIS-III e WMS-III) e N-back. Resultados: foram encontradas interações significativas (tempo/grupo) para CAMCOG - funcionamento executivo (χ2 = 3,961, p = 0,047), CAMCOG - fluência verbal (χ2 = 3,869, p = 0,049), CAMCOG - recuperação da memória (χ2 = 9.749, p = 0,004), WMLT - recordação (χ2 = 7,254, p = 0,007). Foi observado um declínio no grupo ETCC após a intervenção para CAMCOG - praxia construtiva (χ2 = 4,371, p = 0,037). Não encontramos diferenças significativas entre os grupos ETCC e placebo para outros testes. Conclusão: A ETCC de 2 mA por 30 min, 2x por semana, por 5 semanas consecutivas, é superior ao placebo (Sham) na melhoria da recuperação de memória, fluência verbal e funcionamento executivo em idosos com CCL.

ABSTRACT. Transcranial direct current stimulation (tDCS) is a non-invasive, painless and easy-to use-technology. It can be used in depression, schizophrenia and other neurological disorders. There are no studies about longer usage protocols regarding the ideal duration and weekly frequency of tDCS. Objective: to study the use of tDCS twice a week for longer periods to improve memory in elderly with MCI. Methods: a randomized double-blind controlled trial of anodal tDCS on cognition of 58 elderly aged over 60 years was conducted. A current of 2.0 mA was applied for 30 minutes for 10 sessions, twice a week. The anode was placed over the left dorsolateral prefrontal cortex (LDLFC). Subjects were evaluated before and after 10 sessions by the following tests: CAMCOG, Mini-Mental State Examination (MMSE), Trail Making, Semantic Verbal Fluency (Animals), Boston naming, Clock Drawing Test, Word list memory (WLMT), Direct and Indirect Digit Order (WAIS-III and WMS-III) and N-back. Results: After 10 sessions of tDCS, significant group-time interactions were found for the CAMCOG - executive functioning (χ2 = 3.961, p = 0.047), CAMCOG - verbal fluency (χ2 = 3.869, p = 0.049), CAMCOG - Memory recall (χ2 = 9.749, p = 0.004), and WMLT - recall (χ2 = 7.254, p = 0.007). A decline in performance on the CAMCOG - constructional praxis (χ2 = 4.371, p = 0.037) was found in the tDCS group after intervention. No significant differences were observed between the tDCS and Sham groups for any other tasks. Conclusion: tDCS at 2 mA for 30 min twice a week over 5 consecutive weeks proved superior to placebo (Sham) for improving memory recall, verbal fluency and executive functioning in elderly with MCI.

Resumo Introdução A esquizofrenia é um transtorno mental grave. Embora alguns medicamentos antipsicóticos tenham demonstrado eficácia no tratamento de sintomas positivos, não há tratamento amplamente reconhecido para sintomas negativos, o que pode causar sofrimento e prejuízo significativos para pacientes com esquizofrenia. Aqui descrevemos a fundamentação teórica e o design do estudo STARTS (Schizophrenia TreAtment with electRic Transcranial Stimulation), um ensaio clínico destinado a testar a eficácia de um tratamento não farmacológico conhecido como estimulação transcraniana por corrente contínua (ETCC) para tratar os sintomas negativos da esquizofrenia. Métodos O estudo STARTS foi concebido como um ensaio clínico randomizado, controlado por simulação, duplo-cego, avaliando a ETCC para o tratamento dos sintomas negativos da esquizofrenia. Cem pacientes serão incluídos e submetidos a 10 sessões de ETCC sobre o córtex pré-frontal dorsolateral esquerdo (estimulação anódica) e a junção temporoparietal esquerda (estimulação catodal) durante 5 dias consecutivos. Os participantes serão avaliados através de testes clínicos e neuropsicológicos antes e após a intervenção. O desfecho primário é a mudança na pontuação da subescala negativa da Escala da Síndrome Positiva e Negativa (Positive and Negative Syndrome Scale [PANSS]) ao longo do tempo e entre os grupos. Marcadores biológicos, incluindo neurotrofinas e interleucinas do sangue, polimorfismos genéticos e excitabilidade cortical motora, também serão avaliados. Resultados Os resultados clínicos fornecerão informações sobre a ETCC como um tratamento para os sintomas negativos da esquizofrenia, e a investigação dos biomarcadores contribuirá para uma melhor compreensão dos mecanismos de ação da ETCC. Conclusão Nossos resultados podem trazer uma nova técnica terapêutica para o tratamento dos sintomas negativos da esquizofrenia. Registro do ensaio clínico: ClinicalTrials.gov, NCT02535676.

Abstract Introduction Schizophrenia is a severe mental disorder. While some antipsychotic medications have demonstrated efficacy in treating positive symptoms, there is no widely recognized treatment for negative symptoms, which can cause significant distress and impairment for patients with schizophrenia. Here we describe the rationale and design of the STARTS study (Schizophrenia TreAtment with electRic Transcranial Stimulation), a clinical trial aimed to test the efficacy of a non-pharmacological treatment known as transcranial direct current stimulation (tDCS) for treating the negative symptoms of schizophrenia Methods The STARTS study is designed as a randomized, sham-controlled, double-blinded trial evaluating tDCS for the treatment of the negative symptoms of schizophrenia. One-hundred patients will be enrolled and submitted to 10 tDCS sessions over the left dorsolateral prefrontal cortex (anodal stimulation) and left temporoparietal junction (cathodal stimulation) over 5 consecutive days. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in the Positive and Negative Syndrome Scale (PANSS) negative subscale score over time and across groups. Biological markers, including blood neurotrophins and interleukins, genetic polymorphisms, and motor cortical excitability, will also be assessed. Results The clinical results will provide insights about tDCS as a treatment for the negative symptoms of schizophrenia, and the biomarker investigation will contribute towards an improved understanding of the tDCS mechanisms of action. Conclusion Our results could introduce a novel therapeutic technique for the negative symptoms of schizophrenia. Clinical trial registration: ClinicalTrials.gov, NCT02535676 .

Objective: In schizophrenia, scores reflecting deficits in different cognitive processes are strongly correlated, making it difficult to establish a solid relationship between different cognitive mechanisms and other features of this disorder. The objective of this study was to explore whether three frequently postulated executive functions (updating, shifting, and inhibition) could be compared between groups and considered independently in terms of their respective roles in functional outcome. Methods: This study relied on confirmatory factor analysis of schizophrenia patients (n=141) and healthy controls (n=119). The main analyses examined the degree to which three executive functions (updating, set-shifting, and inhibition) could be separated in schizophrenia and compared this model among groups. Structural equation modeling analysis was also performed to examine the extent to which executive function components contribute to functional outcome in schizophrenia. Results: Multiple-group confirmatory factor analysis with unconstrained model parameters indicated that the full three-factor model may fit the data in both groups (χ2 = 61.48, degrees of freedom = 34, p < 0.001, comparative fit index = 0.95; standardized root mean square residual = 0.037; root mean square error of approximation = 0.04; Akaike’s information criteria = 169.49; normed fit index = 0.90), although there was also a good data fit for the patient group with a two-factor model. In the patient group, structural equation modeling suggested that shifting and (principally) updating were associated with the general measure of functional outcome (regression path coefficients: 0.34, p < 0.005; 0.39, p < 0.005, respectively), although when combined the mechanisms fail to contribute. Conclusion: This data suggests that the factor structure may be similar but not identical between groups, and both updating and shifting may play an important role in functional outcome in schizophrenia.

Abstract Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38) were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min). First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

Objective: To investigate if verbal fluency impairment in schizophrenia reflects executive function deficits or results from degraded semantic store or inefficient search and retrieval strategies. Method: Two groups were compared: 141 individuals with schizophrenia and 119 healthy age and education-matched controls. Both groups performed semantic and phonetic verbal fluency tasks. Performance was evaluated using three scores, based on 1) number of words generated; 2) number of clustered/related words; and 3) switching score. A fourth performance score based on the number of clusters was also measured. Results: SZ individuals produced fewer words than controls. After controlling for the total number of words produced, a difference was observed between the groups in the number of cluster-related words generated in the semantic task. In both groups, the number of words generated in the semantic task was higher than that generated in the phonemic task, although a significant group vs. fluency type interaction showed that subjects with schizophrenia had disproportionate semantic fluency impairment. Working memory was positively associated with increased production of words within clusters and inversely correlated with switching. Conclusion: Semantic fluency impairment may be attributed to an inability (resulting from reduced cognitive control) to distinguish target signal from competing noise and to maintain cues for production of memory probes.

Objetivo O estudo descreve o desenvolvimento de duas medidas de atualização da memória de trabalho (MT): Teste de Atualização de Letras (TAL) e Teste de Atualização de Palavras (TAP). Métodos Na etapa 1 foram criados itens e os instrumentos foram analisados por experts e leigos. Na etapa 2, os testes foram aplicados em 15 pacientes com esquizofrenia e 15 controles pareados. Todos foram capazes de compreender e responder aos instrumentos. Na etapa 3, participaram 141 pacientes com esquizofrenia e 119 controles saudáveis com idades entre 18 e 60 anos, avaliados em MT, velocidade de processamento (VP) e funcionalidade. Resultados Os resultados revelaram bons índices de consistência interna para ambas as medidas desenvolvidas, tanto para a amostra total como para cada grupo separadamente, bem como evidências de validade convergente com medidas de MT, validade discriminante com medidas de VP e sensibilidade para discriminar o desempenho entre os grupos. Análise de componentes principais revelou que os testes de atualização apresentaram altas cargas e um fator separado das medidas de VP. Relações positivas, significativas, porém baixas, foram encontradas com medidas de funcionalidade. Conclusão Esses resultados fornecem bons parâmetros psicométricos para as medidas desenvolvidas, aplicáveis em contextos de pesquisa cognitiva da esquizofrenia.

Objective This study describes the development of two updating measures of working memory (WM): Letter Updating Test (LUT) and Word Updating Test (WUT). Methods In stage 1, items were created and the instruments were assessed by experts and laymen. In stage 2, tests were given to 15 patients with schizophrenia and 15 paired controls. All were able to understand and respond to the instruments. In stage 3, 141 patients with schizophrenia and 119 healthy controls aged 18 to 60 took part; they were assessed on WM, processing speed (PS) and functional outcome. Results The results showed adequate rates of internal consistency for both measures developed, for both the total sample and each group separately, as well as evidence of convergent validity, discriminant validity and sensitivity to differentiate performance among the groups. Principal component analysis yielded two components, one for updating tests and other for PS measures, indicating factorial validity. Positive and significant, yet low, correlations were found with functionality measures. Conclusion These results provide adequate psychometric parameters for the measures developed, applicable to cognitive research settings in schizophrenia.

RESUMO Novas evidências sugerem que o cerebelo apresenta alterações estruturais e funcionais nos transtornos psiquiátricos. Objetivo: Medir o volume do cerebelo e de suas sub-regiões em indivíduos portadores de transtornos psiquiátricos e relacionar tais achados aos sintomas. Métodos: Foi realizada a identificação de pacientes com diferentes graus de prejuízo cognitivo proveniente de um estudo populacional (Epidemiologia do Idoso - UNIFESP), pacientes com transtorno do estresse pós-traumático proveniente de outro estudo populacional e portadores de transtorno bipolar proveniente de um ambulatório especializado (Universidade Federal da Bahia). Todos os sujeitos foram submetidos à ressonância magnética estrutural de 1.5T. As medidas de volume, assim como os sintomas medidos por escalas psicométricas foram comparadas entre pacientes e controles. Resultados: Foi observado que o volume do cerebelo está reduzido nos portadores de prejuízo cognitivo sem demência e com demência, no transtorno do estresse pós-traumático e no transtorno bipolar quando comparados aos controles. Na demência e no transtorno do estresse pós-traumático o volume do hemisfério cerebelar esquerdo e do vérmis estão reduzidos. No transtorno bipolar os volumes de ambos os hemisférios e do vérmis estão reduzidos. Nos dois primeiros estudos estas reduções correlacionaram com os sintomas. Conclusão: A natureza exata do envolvimento do cerebelo nos processos mentais ainda não é compreendida. Entretanto, anormalidades na estrutura cerebelar e em suas funções têm sido relatadas em algumas dessas doenças. Pesquisas futuras, com amostras maiores, ainda são necessárias para esclarecer tais achados e investigar se são importantes para o tratamento e prognóstico.

ABSTRACT. New evidence suggests that the cerebellum has structural and functional abnormalities in psychiatric disorders. Objective: In this research, the goal was to measure the volume of the cerebellum and its subregions in individuals with psychiatric disorders and to relate these findings to their symptoms. Methods: Patients with different degrees of cognitive impairment (Epidemiology of the Elderly - UNIFESP) and patients with post-traumatic stress disorder (PTSD) from population studies were analyzed. Also, patients with bipolar disorder from an outpatient clinic (Center for the Study of Mood and Anxiety Disorders, Universidade Federal da Bahia) were recruited for this study. All subjects underwent a 1.5T structural magnetic resonance scan. Volumetric measures and symptom measurements, by psychometric scales, were performed and compared between patients and controls. Results: The cerebellum volume was reduced in patients with cognitive impairment without dementia and with dementia, in patients with PTSD, and in patients with bipolar disorder compared to controls. In dementia and PTSD, the left cerebellar hemisphere and vermis volume were reduced. In bipolar disorder, volumes of both hemispheres and the vermis were reduced. In the first two studies, these cerebellar volumetric reductions correlated with symptoms of the disease. Conclusion: The exact nature of cerebellar involvement in mental processes is still not fully understood. However, abnormalities in cerebellar structure and its functions have been reported in some of these diseases. Future studies with larger samples are needed to clarify these findings and investigate whether they are important for treatment and prognosis.

OBJETIVO: Avaliar a combinação de dois fatores: clinical dementia rating sum of boxes scores (CDR-SB) e volume hipocampal (VH) como preditores de conversão de ditúrbio cognitivo leve (DCL) em demência. MÉTODO: Vinte e oito indivíduos (9 normais e 19 com DCL) foram classificados de acordo com a soma dos escores CDR-SB em 3 grupos. RESULTADOS: O volume do hipocampo foi significativamente menor no grupo de alto risco e naqueles que desenvolveram demência depois de dois anos. A taxa de conversão foi crescente entre os três grupos. CONCLUSÃO: Propusemos uma medição adicional do volume do hipocampo que pode ser útil no prognóstico. No entanto, notou-se que a CDR-SB é um método tão eficiente quanto neuroimagem para prever demência com a vantagem de ser um processo de baixo custo e de fácil implementação, mais consistente com a política pública.

OBJECTIVE: To evaluate the combination of two factors: clinical dementia rating sum of boxes scores (CDR-SB) and hippocampal volume (HV) as predictors of conversion from mild cognitive impairment (MCI) to dementia. METHODS: Twenty-eight individuals (9 normal and 19 with MCI) were classified according to their CDR sum of boxes scores into 3 groups. RESULTS: The hippocampal volume was significantly lower in the high-risk group and in those who developed dementia after two years. The rate of conversion was crescent among the three groups. CONCLUSION: We were proposed an additional measurement of the hippocampal volume which may be helpful in the prognosis. However, we noted that the CDR-SB is a method as efficient as neuroimaging to predict dementia with the advantage of being a procedure for low cost and easy implementation, more consistent with public policy.

OBJETIVO: Relatar estudos de neuroimagens estruturais e funcionais explorando o papel potencial do córtex orbitofrontal (COF) na fisiopatologia dos transtornos psiquiátricos (TP) mais prevalentes. MÉTODO: Foi realizada uma revisão não sistemática da literatura no MEDLINE, usando como parâmetros os seguintes termos: "córtex orbitofrontal", "esquizofrenia", "transtorno bipolar", "depressão maior", "transtornos ansiosos", "transtornos de personalidade" e "dependência a drogas". A pesquisa eletrônica foi feita até julho de 2011. DISCUSSÃO: Foram relatadas anormalidades estruturais e funcionais do COF em muitos TP, particularmente esquizofrenia, transtornos afetivos, transtornos ansiosos, transtornos de personalidade e dependência a drogas. Estudos de aquisição de imagens estruturais por ressonância magnética relataram a redução do volume do COF em pacientes portadores de esquizofrenia, transtornos afetivos, TEPT, transtorno do pânico, transtornos de personalidade do grupo B e dependência a drogas. Além disso, estudos de aquisição de imagens funcionais por ressonância magnética empregando paradigmas cognitivos demonstraram alterações na atividade do COF em todos os TP anteriormente relacionados. CONCLUSÃO: Estudos de neuroimagens observaram um envolvimento importante do COF em vários TP. Entretanto, estudos futuros são claramente necessários para caracterizar o papel específico do COF em cada TP, assim como para a compreensão de seu papel tanto no comportamento normal como no patológico, na regulação do humor e no funcionamento cognitivo.

OBJECTIVE: To report structural and functional neuroimaging studies exploring the potential role of the orbitofrontal cortex (OFC) in the pathophysiology of the most prevalent psychiatric disorders (PD). METHOD: A non-systematic literature review was conducted by means of MEDLINE using the following terms as parameters: "orbitofrontal cortex", "schizophrenia", "bipolar disorder", "major depression", "anxiety disorders", "personality disorders" and "drug addiction". The electronic search was done up to July 2011. DISCUSSION: Structural and functional OFC abnormalities have been reported in many PD, namely schizophrenia, mood disorders, anxiety disorders, personality disorders and drug addiction. Structural magnetic resonance imaging studies have reported reduced OFC volume in patients with schizophrenia, mood disorders, PTSD, panic disorder, cluster B personality disorders and drug addiction. Furthermore, functional magnetic resonance imaging studies using cognitive paradigms have shown impaired OFC activity in all PD listed above. CONCLUSION: Neuroimaging studies have observed an important OFC involvement in a number of PD. However, future studies are clearly needed to characterize the specific role of OFC on each PD as well as understanding its role in both normal and pathological behavior, mood regulation and cognitive functioning.