The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics

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.

Appraising the effectiveness of electrical and magnetic brain stimulation techniques in acute major depressive episodes: an umbrella review of meta-analyses of randomized controlled trials

Electrical and magnetic brain stimulation techniques present distinct mechanisms and efficacy in the acute treatment of depression. This was an umbrella review of meta-analyses of randomized controlled trials of brain stimulation techniques for managing acute major depressive episodes. A systematic review was performed in the PubMed/MEDLINE databases from inception until March 2020. We included the English language meta-analysis with the most randomized controlled trials on the effects of any brain stimulation technique vs. control in adults with an acute depressive episode. Continuous and dichotomous outcomes were assessed. A Measurement Tool to Assess Systematic Reviews-2 was applied and the credibility of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Seven meta-analyses were included (5,615 patients), providing evidence for different modalities of brain stimulation techniques. Three meta-analyses were evaluated as having high methodological quality, three as moderate, and one as low. The highest quality of evidence was found for high frequency-repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, and bilateral rTMS. There is strong clinical research evidence to guide future clinical use of some techniques. Our results confirm the heterogeneity of the effects across these techniques, indicating that different mechanisms of action lead to different efficacy profiles.

Precision non-implantable neuromodulation therapies: a perspective for the depressed brain

Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial

Objective: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. Methods: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. Results: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. Conclusion: Larger, combined datasets are necessary to identify candidate genes for tDCS response.

Psychometric properties of the modified Yale Food Addiction Scale 2 0 in a large Brazilian sample

Objective: The field of food addiction has attracted growing research attention. The modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) is a screening tool based on DSM-5 criteria for substance use disorders. However, there is no validated instrument to assess food addiction. Methods: The mYFAS 2.0 has been transculturally adapted to Brazilian Portuguese. The data for this study was obtained through an anonymous web-based research platform: participants provided sociodemographic data and answered Brazilian versions of the the mYFAS 2.0 and the Barratt Impulsivity Scale (BIS-11). Analysis included an assessment of the Brazilian mYFAS 2.0's internal consistency reliability, factor structure, and convergent validity in relation to BIS-11 scores. Results: Overall, 7,639 participants were included (71.3% females; age: 27.2±7.9 years). The Brazilian mYFAS 2.0 had adequate internal consistency reliability (Cronbach's alpha = 0.89). A single factor solution yielded the best goodness-of-fit parameters for both the continuous and categorical version of the mYFAS 2.0 in confirmatory factor analysis. In addition, mYFAS 2.0 correlated with BIS-11 total scores (Spearman's rho = 0.26, p < 0.001) and subscores. Conclusion: The Brazilian mYFAS 2.0 demonstrated adequate psychometric properties in our sample; however, future studies should further evaluate its discriminant validity.

Validation of the Brazilian Portuguese version of the Premenstrual Symptoms Screening Tool (PSST) and association of PSST scores with health-related quality of life

Objective: To develop and validate a Brazilian Portuguese version of the Premenstrual Symptoms Screening Tool (PSST), a questionnaire used for the screening of premenstrual syndrome (PMS) and of the most severe form of PMS, premenstrual dysphoric disorder (PMDD). The PSST also rates the impact of premenstrual symptoms on daily activities. Methods: A consecutive sample of 801 women aged ≥ 18 years completed the study protocol. The internal consistency, test-retest reliability, and content validity of the Brazilian PSST were determined. The independent association of a positive screen for PMS or PMDD and quality of life determined by the World Health Organization Quality of Life instrument-Abbreviated version (WHOQOL-Bref) was also assessed. Results: Of 801 participants, 132 (16.5%) had a positive screening for PMDD. The Brazilian PSST had adequate internal consistency (Cronbach’s alpha = 0.91) and test-retest reliability. The PSST also had adequate convergent/discriminant validity, without redundancy. Content validity ratio and content validity index were 0.61 and 0.94 respectively. Finally, a positive screen for PMS/PMDD was associated with worse WHOQOL-Bref scores. Conclusions: These findings suggest that PSST is a reliable and valid instrument to screen for PMS/PMDD in Brazilian women.

Religious coping and its influence on psychological distress, medication adherence, and quality of life in inflammatory bowel disease

Objective:Inflammatory bowel disease (IBD) is associated with elevated levels of anxiety and depression and a reduction in health-related quality of life (HRQoL). Nonadherence to treatment is also frequent in IBD and compromises outcomes. Religious coping plays a role in the adaptation to several chronic diseases. However, the influence of religious coping on IBD-related psychological distress, HRQoL, and treatment adherence remains unknown.Method:This cross-sectional study recruited 147 consecutive patients with either Crohn’s disease or ulcerative colitis. Sociodemographic data, disease-related variables, psychological distress (Hospital Anxiety and Depression Scale), religious coping (Brief RCOPE Scale), HRQoL (WHOQOL-Bref), and adherence (8-item Morisky Medication Adherence Scale) were assessed. Hierarchical multiple regression models were used to evaluate the effects of religious coping on IBD-related psychological distress, treatment adherence, and HRQoL.Results:Positive RCOPE was negatively associated with anxiety (b = 0.256; p = 0.007) as well as with overall, physical, and mental health HRQoL. Religious struggle was significantly associated with depression (b = 0.307; p < 0.001) and self-reported adherence (b = 0.258; p = 0.009). Finally, anxiety symptoms fully mediated the effect of positive religious coping on overall HRQoL.Conclusion:Religious coping is significantly associated with psychological distress, HRQoL, and adherence in IBD.

Development and validation of the Intrinsic Religiousness Inventory (IRI) / Desenvolvimento e validação do Inventário de Religiosidade Intrínseca (IRI)

OBJECTIVE: The role of religious involvement in mental health has been increasingly investigated in psychiatric research; however, there is a shortage of scales on religiousness in Portuguese. The present study aimed to develop and validate a brief instrument to assess intrinsic religiosity (Intrinsic Religiousness Inventory - IRI) in two Brazilian samples. METHOD: The initial version was based on literature review and experts' suggestions. University students (sample 1; n = 323) and psychiatric patients (sample 2; n = 102) completed the Duke Religiosity Index (DUREL), the IRI, an instrument of spirituality measurement (WHOQOL-SRPB), as well as measurements of anxiety and depressive symptoms. RESULTS: The IRI showed adequate internal consistence reliability in sample 1 (Cronbach's α = 0.96; 95 percent CI; 0.95-0.97) and sample 2 (α = 0.96; 95 percent CI; 0.95-0.97). The IRI main component analyses indicated a single factor, which explained 73.7 percent and 74.9 percent of variance in samples 1 and 2, respectively. Strong correlations between IRI and intrinsic subscale of the DUREL were observed (Spearman's r ranging from 0.87 to 0.73 in samples 1 and 2, respectively, p < 0.001). The IRI showed good test-retest reliability (intraclass correlation coefficients > 0.70). CONCLUSION: These data indicate that the IRI is a valid instrument and may contribute to study intrinsic religiosity in Brazilian samples.

OBJETIVO: O papel da religiosidade em saúde mental vem sendo objeto de intensa investigação. Estudos devem ser executados em diferentes locais e culturas. O presente estudo objetiva desenvolver e validar um instrumento breve para mensurar religiosidade intrínseca (Inventário de Religiosidade Intrínseca - IRI) em duas amostras brasileiras. MÉTODO: A versão inicial foi baseada na revisão de literatura e em sugestões de especialistas. Estudantes universitários (amostra 1; n = 323) e pacientes psiquiátricos (amostra 2; n = 102) preencheram o Índice de Religiosidade de Duke (DUREL), o IRI, uma medida de espiritualidade (WHOQOL-SRPB), bem como medidas de sintomas ansiosos e depressivos. RESULTADOS: O IRI apresentou consistência interna adequada nas amostras 1 (α de Cronbach = 0,96; IC 95 por cento; 0,95-0,97) e 2 (α = 0,96; IC 95 por cento; 0,95-0,97). Análises de componentes principais indicaram um único fator que explicou 73,7 por cento e 74,9 por cento da variância nas amostras 1 e 2, respectivamente. Foram observadas fortes correlações entre o IRI e a subescala de religiosidade intrínseca da DUREL (r de Spearman de 0,87 a 0,73 nas amostras 1 e 2, respectivamente, p < 0,001). O IRI apresentou boa validade teste-reteste (coeficientes de correlação intraclasse > 0,70). CONCLUSÃO: Os dados indicam que o IRI é um instrumento válido e pode contribuir para estudar religiosidade intrínseca em amostras brasileiras.

Validity of the Mood Disorder Questionnaire in a Brazilian psychiatric population / Validação da versão em português do Questionário de Transtornos do Humor em uma população brasileira de pacientes psiquiátricos

OBJECTIVE: Bipolar spectrum disorders are prevalent and frequently underdiagnosed and undertreated. This report describes the development and validation of the Brazilian version of the Mood Disorder Questionnaire, a screening instrument for bipolar spectrum disorders, in an adult psychiatric population. METHOD: A total of 114 consecutive patients attending an outpatient psychiatric clinic completed the Brazilian version of the Mood Disorder Questionnaire. A research psychiatrist, blind to the Mood Disorder Questionnaire results, interviewed patients by means of the mood module of the Structured Clinical Interview for DSM-IV ('gold standard'). RESULTS: The internal consistency of the Brazilian Mood Disorder Questionnaire, evaluated with Cronbach's alpha coefficient was 0.76 (95 percent CI; 0.69-0.92). Principal component analysis with varimax rotation indicated an 'irritability-racing thoughts' factor and 'energized-activity' factor, which explained 39.1 percent of variance. On the basis of the SCID, 69 (60.5 percent) individuals received a diagnosis of bipolar disorders. A Brazilian Mood Disorder Questionnaire screening score of 8 or more items yielded sensitivity of 0.91 (95 percent CI; 0.85-0.98), specificity of 0.70 (95 percent CI; 0.62-0.75), a positive predictive value of 0.82 (95 percent CI; 0.75-0.88) and a negative predictive value of 0.84 (95 percent CI; 0.77-0.90). CONCLUSION: The present data demonstrate that the Brazilian Mood Disorder Questionnaire is a valid instrument for the screening of bipolar disorders. The instrument needs to be validated in other settings (e.g., in general practice).

OBJETIVO: Transtornos do espectro bipolar são prevalentes e comumente subdiagnosticados e subtratados. O presente trabalho descreve o desenvolvimento e a validação da versão brasileira do questionário de transtornos do humor, um instrumento de rastreio para transtornos bipolares, em uma população psiquiátrica adulta. MÉTODO: 114 pacientes consecutivos de um ambulatório psiquiátrico completaram a versão brasileira do questionário de transtornos do humor. Um psiquiatra pesquisador, cego para os escores da versão brasileira do questionário de transtornos do humor, entrevistou os participantes por meio do módulo de transtornos do humor da entrevista clínica estruturada para o DSM-IV ("padrão-ouro"). RESULTADOS: A consistência interna da versão brasileira do questionário de transtornos do humor, avaliada por meio do coeficiente alfa de Cronbach, foi de 0,76 (IC 95 por cento; 0,69-0,92). Uma análise de componentes principais com rotação ortogonal indicou fator de "irritabilidade-pensamentos acelerados" e outro de "energia-atividade", que explicaram 39,1 por cento da variação dos escores. De acordo com o padrão-ouro, 69 (60,5 por cento) dos participantes tiveram um diagnóstico de transtornos bipolares. Um escore do questionário de transtornos do humor de 8 ou mais itens apresentou uma sensibilidade de 0,91 (IC 95 por cento; 0,85-0,98), especificidade de 0,70 (IC 95 por cento; 0,62-0,75), valor preditivo positivo de 0,82 (IC 95 por cento; 0,75-0,88) e valor preditivo negativo de 0,84 (IC 95 por cento; 0,77-0,90). CONCLUSÃO: Os resultados do presente estudo demonstram que a versão brasileira do questionário de transtornos do humor é um instrumento válido para o rastreio de transtornos bipolares. O instrumento necessita de validação em outros contextos (p.ex., serviços primários).

Validity of the Brazilian Portuguese version of the bipolar spectrum diagnostic scale / Validade da versão brasileira em português da escala diagnóstica do espectro bipolar

OBJECTIVE: Bipolar spectrum disorders (BSDs) are prevalent and frequently unrecognized and undertreated. This report describes the development and validation of the Brazilian version of the bipolar spectrum diagnostic scale (B-BSDS), a screening instrument for bipolar disorders, in an adult psychiatric population. METHOD: 114 consecutive patients attending an outpatient psychiatric clinic completed the B-BSDS. A research psychiatrist, blind to the B-BSDS scores, interviewed patients by means of a modified version of the mood module of the Structured Clinical Interview for DSM-IV ("gold standard"). Subthreshold bipolar disorders were defined as recurrent hypomania without a major depressive episode or with fewer symptoms than those required for threshold hypomania. RESULTS: The internal consistency of the B-BSDS evaluated with Cronbach's alpha coefficient was 0.89 (95 percent CI; 0.86-0.91). On the basis of the modified SCID, 70 patients (61.4 percent) of the sample received a diagnosis of BSDs. A B-BSDS screening score of 16 or more items yielded: sensitivity of 0.79 (95 percent CI; 0.72-0.85), specificity of 0.77 (95 percent CI; 0.70-0.83), a positive predictive value of 0.85 (95 percent CI; 0.78-0.91) and a negative predictive value of 0.70 (95 percent CI; 0.63-0.75). CONCLUSION: The present data demonstrate that the B-BSDS is a valid instrument for the screening of BSDs.

OBJETIVO: Transtornos do espectro bipolar (TEB) são prevalentes e comumente subdiagnosticados e subtratados. O presente trabalho descreve o desenvolvimento e a validação da versão brasileira da escala diagnóstica do espectro bipolar (B-EDEB), um instrumento de rastreio para transtornos bipolares, em uma população psiquiátrica adulta. MÉTODO: 114 pacientes consecutivos de um ambulatório psiquiátrico completaram a versão brasileira da B-EDEB. Um psiquiatra pesquisador, cego para os escores do B-EDEB, entrevistou os participantes por meio de uma versão modificada do módulo de transtornos do humor da entrevista clínica estruturada para o DSM-IV ("padrão-ouro"). RESULTADOS: A consistência interna da B-EDEB, avaliada mediante o coeficiente alfa de Cronbach, foi de 0,89 (IC 95 por cento; 0,86-0,91). De acordo com o padrão-ouro, 70 (61,4 por cento) participantes tiveram diagnóstico de TEB. Um escore da B-EDEB de 16 ou mais itens apresentou sensibilidade de 0,79 (IC 95 por cento; 0,72-0,85), especificidade de 0,77 (IC 95 por cento; 0,70-0,83), valor preditivo positivo de 0,85 (IC 95 por cento; 0,78-0,91) e valor preditivo negativo de 0,70 (IC 95 por cento; 0,63-0,75). CONCLUSÃO: Os resultados do presente estudo demonstram que a B-EDEB é um instrumento válido para o rastreio de TEB.

Tratamento farmacológico do transtorno de personalidade limítrofe: revisão crítica da literatura e desenvolvimento de algoritmos / Pharmacological treatment of borderline personality disorder: critical review of the literature and development of algorithms

INTRODUÇÃO: O transtorno de personalidade limítrofe (TPL) é uma síndrome psiquiátrica que causa significativa morbidade e mortalidade para pacientes internados e ambulatoriais tratados por profissionais de saúde mental. Dada a sua alta prevalência na população de pacientes psiquiátricos, esforços são necessários para tratar esse grupo apropriadamente. OBJETIVO: O objetivo do presente artigo é revisar evidências atuais acerca da efetividade das diversas abordagens farmacológicas empregadas como parte do plano de tratamento produzido para indivíduos que enfrentam essa doença. MÉTODOS: Para esse propósito, os autores revisaram o banco de dados MEDLINE em busca de ensaios clínicos publicados entre 1986 e 2003. Borderline personality disorder e clinical trials foram usados com descritores. RESULTADOS: Numerosos trabalhos foram encontrados, mas poucos estudos controlados estavam disponíveis. Notável é o fato de que virtualmente todas as classes de psicofármacos foram testadas nesse grupo de pacientes, comumente com desfechos modestos ou variáveis. Devido a limitações metodológicas na vasta maioria dos ensaios clínicos envolvendo drogas específicas nesse grupo de pacientes, foi difícil estimar o benefício real dos vários agentes testados. A evidência mais forte existe para os inibidores seletivos de serotonina, antipsicóticos e divalproato. DISCUSSÃO: Claramente, mais ensaios clínicos bem delineados são necessários, mas os dados revisados sugerem que psicofármacos são efetivos para tratar sintomas-alvo nesses pacientes. Conclui-se que psicotrópicos são adjuntos úteis às abordagens psicoterapêuticas usualmente empregadas para tratar pacientes limítrofes.