Objectives: To summarize evidence-based cognitive-behavioral therapy (CBT) treatment and propose clinical interventions for adult patients with obsessive-compulsive disorder (OCD). Methods: The literature on CBT interventions for adult OCD, including BT and exposure and response prevention, was systematically reviewed to develop updated clinical guidelines for clinicians, providing comprehensive details about the necessary procedures for the CBT protocol. We searched the literature from 2013-2020 in five databases (PubMed, Cochrane, Embase, PsycINFO, and Lilacs) regarding study design, primary outcome measures, publication type, and language. Selected articles were assessed for quality with validated tools. Treatment recommendations were classified according to levels of evidence developed by the American College of Cardiology and the American Heart Association. Results: We examined 44 new studies used to update the 2013 American Psychiatric Association guidelines. High-quality evidence supports CBT with exposure and response prevention techniques as a first-line treatment for OCD. Protocols for Internet-delivered CBT have also proven efficacious for adults with OCD. Conclusion: High-quality scientific evidence supports the use of CBT with exposure and response prevention to treat adults with OCD.

Objectives: To summarize evidence-based pharmacological treatments and provide guidance on clinical interventions for adult patients with obsessive-compulsive disorder (OCD). Methods: The American Psychiatric Association (APA) guidelines for the treatment of OCD (2013) were updated with a systematic review assessing the efficacy of pharmacological treatments for adult OCD, comprising monotherapy with selective serotonin reuptake inhibitors (SSRIs), clomipramine, serotonin and norepinephrine reuptake inhibitors (SNRIs), and augmentation strategies with clomipramine, antipsychotics, and glutamate-modulating agents. We searched for the literature published from 2013-2020 in five databases, considering the design of the study, primary outcome measures, types of publication, and language. Selected articles had their quality assessed with validated tools. Treatment recommendations were classified according to levels of evidence developed by the American College of Cardiology and the American Heart Association (ACC/AHA). Results: We examined 57 new studies to update the 2013 APA guidelines. High-quality evidence supports SSRIs for first-line pharmacological treatment of OCD. Moreover, augmentation of SSRIs with antipsychotics (risperidone, aripiprazole) is the most evidence-based pharmacological intervention for SSRI-resistant OCD. Conclusion: SSRIs, in the highest recommended or tolerable doses for 8-12 weeks, remain the first-line treatment for adult OCD. Optimal augmentation strategies for SSRI-resistant OCD include low doses of risperidone or aripiprazole. Pharmacological treatments considered ineffective or potentially harmful, such as monotherapy with antipsychotics or augmentation with ketamine, lamotrigine, or N-acetylcysteine, have also been detailed.

RESUMO Os transtornos da ansiedade e o transtorno obsessivo-compulsivo (TOC) e transtornos relacionados são altamente prevalentes e incapacitantes. Apesar disso, ainda existem lacunas a serem exploradas em relação ao tratamento desses transtornos. O medo é um sintoma central desses transtornos e sua aprendizagem é altamente dependente da atividade do fator neurotrófico derivado do cérebro (BDNF). Porém, será que a aprendizagem de medo mediada pelo BDNF deve ser considerada um alvo para o desenvolvimento de novos tratamentos para transtornos da ansiedade, TOC e transtornos relacionados? Revisamos as evidências que sugerem que a expressão de BDNF é necessária para a aquisição do medo condicionado, bem como para a evocação de sua extinção. Descrevemos os resultados relacionados a aprendizagem de medo, manipulação genética e epigenética da expressão de Bdnf em animais e variantes alélicas de BDNF em seres humanos. Posteriormente, discutimos como a manipulação dos níveis de BDNF representa um alvo em potencial para o tratamento, o que pode aumentar os benefícios das terapias que extinguem o medo previamente condicionado.

ABSTRACT Anxiety and obsessive-compulsive related disorders are highly prevalent and disabling disorders for which there are still treatment gaps to be explored. Fear is a core symptom of these disorders and its learning is highly dependent on the activity of the neurotrophin brain-derived neurotrophic factor (BDNF). Should BDNF-mediated fear learning be considered a target for the development of novel treatments for anxiety and obsessive-compulsive related disorders? We review the evidence that suggests that BDNF expression is necessary for the acquisition of conditioned fear, as well as for the recall of its extinction. We describe the findings related to fear learning and genetic/epigenetic manipulation of Bdnf expression in animals and BDNF allelic variants in humans. Later, we discuss how manipulation of BDNF levels represents a promising potential treatment target that may increase the benefits of therapies that extinguish previously conditioned fear.

A ansiedade é um componente importante da psicopatologia do transtorno obsessivo-compulsivo (TOC). Até o momento, a maioria das intervenções que provaram ser eficazes para o tratamento de TOC é semelhante àquelas desenvolvidas para outros transtornos de ansiedade. No entanto, estudos que investigaram a neurobiologia do TOC chegaram a conclusões que nem sempre são compatíveis com aquelas anteriormente associadas aos demais transtornos de ansiedade. OBJETIVOS: Neste artigo, revisamos o grau de sobreposição entre as características do TOC e a fenomenologia e fisiopatologia dos demais transtornos de ansiedade com o intuito de dar suporte ao racional que orienta a pesquisa nesse campo. RESULTADOS: Alguns dados sobre os neurocircuitos envolvidos na manifestação dos transtornos de ansiedade foram obtidos a partir do estudo de modelos animais de ansiedade, e da neuroimagem estrutural e funcional em humanos. Esses trabalhos sugerem que no TOC, além da disfunção das vias corticoestriatais, o funcionamento do circuito amigdalocortical, essencial para a apresentação da resposta de medo e processos de extinção dessa resposta, também pode estar prejudicado. CONCLUSÃO: É provável que a ansiedade seja uma dimensão relevante do TOC, com impacto em outras características desse transtorno. Consequentemente, estudos futuros podem se beneficiar da investigação dos fenômenos de medo e ansiedade e de suas relações com os tipos de obsessões e compulsões, idade de início do TOC, comorbidades e padrões de resposta ao tratamento.

Anxiety is an important component of the psychopathology of the obsessive-compulsive disorder (OCD). So far, most interventions that have proven to be effective for treating OCD are similar to those developed for other anxiety disorders. However, neurobiological studies of OCD came to conclusions that are not always compatible with those previously associated with other anxiety disorders. OBJECTIVES: The aim of this study is to review the degree of overlap between OCD and other anxiety disorders phenomenology and pathophysiology to support the rationale that guides research in this field. RESULTS: Clues about the neurocircuits involved in the manifestation of anxiety disorders have been obtained through the study of animal anxiety models, and structural and functional neuroimaging in humans. These investigations suggest that in OCD, in addition to dysfunction in cortico-striatal pathways, the functioning of an alternative neurocircuitry, which involves amygdalo-cortical interactions and participates in fear conditioning and extinction processes, may be impaired. CONCLUSION: It is likely that anxiety is a relevant dimension of OCD that impacts on other features of this disorder. Therefore, future studies may benefit from the investigation of the expression of fear and anxiety by OCD patients according to their type of obsessions and compulsions, age of OCD onset, comorbidities, and patterns of treatment response.

INTRODUCTION: In obsessive-compulsive disorder, early treatment discontinuation can hamper the effectiveness of first-line treatments. OBJECTIVE: This study aimed to investigate the clinical correlates of early treatment discontinuation among obsessive-compulsive disorder patients. METHODS: A group of patients who stopped taking selective serotonin reuptake inhibitors (SSRIs) or stopped participating in cognitive behavioral therapy before completion of the first twelve weeks (total n = 41; n = 16 for cognitive behavioral therapy and n = 25 for SSRIs) were compared with a paired sample of compliant patients (n = 41). Demographic and clinical characteristics were obtained at baseline using structured clinical interviews. Chisquare and Mann-Whitney tests were used when indicated. Variables presenting a p value <0.15 for the difference between groups were selected for inclusion in a logistic regression analysis that used an interaction model with treatment dropout as the response variable. RESULTS: Agoraphobia was only present in one (2.4%) patient who completed the twelve-week therapy, whereas it was present in six (15.0%) patients who dropped out (p = 0.044). Social phobia was present in eight (19.5%) patients who completed the twelve-week therapy and eighteen (45%) patients who dropped out (p = 0.014). Generalized anxiety disorder was present in eight (19.5%) patients who completed the twelve-week therapy and twenty (50%) dropouts (p = 0.004), and somatization disorder was not present in any of the patients who completed the twelveweek therapy; however, it was present in six (15%) dropouts (p = 0.010). According to the logistic regression model, treatment modality (p = 0.05), agoraphobia, the Brown Assessment of Beliefs Scale scores (p = 0.03) and the Beck Anxiety Inventory (p = 0.02) scores were significantly associated with the probability of treatment discontinuation irrespective of interactions with other variables. DISCUSSION AND CONCLUSION: Early treatment discontinuation is a common phenomenon in obsessive-compulsive disorder patients from our therapeutic setting. Psychiatric comorbidities were associated with discontinuation rates of specific treatments. Future studies might use this information to improve management for increased compliance and treatment effectiveness.

OBJETIVO: Descrever um protocolo integrativo de investigação neurobiológica para melhor compreender as bases patofisiológicas do transtorno obsessivo-compulsivo e apresentar as características clínicas e demográficas da amostra. MÉTODO: Protocolo padronizado que combina diferentes modalidades de investigação (genética, neuropsicologia, ressonância magnética cerebral e imagem molecular do transportador de dopamina) obtidas antes e depois do tratamento em pacientes com transtorno obsessivo-compulsivo nunca expostos à medicação submetidos a um ensaio clínico comparando um inibidor seletivo da recaptação de serotonina (fluoxetina) e terapia cognitivo-comportamental em grupo. RESULTADOS: Cinquenta e dois pacientes com transtorno obsessivo-compulsivo entraram no ensaio clínico (27 no grupo fluoxetina e 25 no grupo de terapia). No início, foram realizadas 47 coletas de sangue para genética, 50 avaliações neuropsicológicas, 50 ressonâncias magnéticas cerebrais e 48 exames de tomografia computadorizada por emissão de fóton único (SPECT) com TRODAT-1. Depois de 12 semanas, 38 pacientes terminaram o protocolo (20 no grupo de fluoxetina e 18 no grupo de terapia). Trinta e oito reavaliações neuropsicológicas, 31 ressonâncias magnéticas de crânio e 34 exames de SPECT foram obtidos após o tratamento. Quarenta e um controles pareados foram submetidos ao mesmo protocolo inicial. CONCLUSÃO: Os dados genéticos, neuropsicológicos, volumétricos e moleculares do transportador de dopamina aliados à resposta a tratamento podem tanto gerar informações importantes a respeito da neurobiologia do transtorno obsessivo-compulsivo quanto ter uma aplicação clínica.

OBJECTIVE: To describe a protocol that was based on an integrative neurobiological model of scientific investigation to better understand the pathophysiology of obsessive-compulsive disorder and to present the clinical and demographic characteristics of the sample. METHOD: A standardized research protocol that combines different methods of investigation (genetics, neuropsychology, morphometric magnetic resonance imaging and molecular neuroimaging of the dopamine transporter) obtained before and after treatment of drug-naïve adult obsessive-compulsive disorder patients submitted to a sequentially allocated 12-week clinical trial with a selective serotonin reuptake inhibitor (fluoxetine) and group cognitive-behavioral therapy. RESULTS: Fifty-two treatment-naïve obsessive-compulsive disorder patients entered the clinical trial (27 received fluoxetine and 25 received group cognitive-behavioral therapy). At baseline, 47 blood samples for genetic studies, 50 neuropsychological evaluations, 50 morphometrical magnetic resonance images and 48 TRODAT-1 single-photon emission computed tomography (SPECT) exams were obtained. After 12 weeks, 38 patients completed the protocol (fluoxetine = 20 and GCBT = 18). Thirty-eight neuropsychological evaluations, 31 morphometrical magnetic resonance images and 34 TRODAT-1 SPECT exams were obtained post-treatment. Forty-one healthy controls matched for age, gender, socioeconomic status, level of education and laterality were submitted to the same research procedures at baseline. CONCLUSION: The comprehensive treatment response protocol applied in this project allowing integration on genetic, neuropsychological, morphometrical and molecular imaging of the dopamine transporter data in drug-naïve patients has the potential to generate important original information on the neurobiology of obsessive-compulsive disorder, and at the same time be clinically meaningful.

OBJECTIVE: This paper aims to describe and discuss a minimization procedure specifically designed for a clinical trial that evaluates treatment efficacy for OCD patients. METHOD: Aitchison's compositional distance was used to calculate vectors for each possibility of allocation in a covariate adaptive method. Two different procedures were designed to allocate patients in small blocks or sequentially one-by-one. RESULTS: We present partial results of this allocation procedure as well as simulated data. In the clinical trial for which this procedure was developed, successful balancing between treatment arms was achieved. Separately, in an exploratory analysis, we found that if the arrival order of patients was altered, most patients were allocated to a different treatment arm than their original assignment. CONCLUSION: Our results show that the random arrival order of patients determine different assignments and therefore maintains the unpredictability of the allocation method. We conclude that our proposed procedure allows for the use of a large number of prognostic factors in a given allocation decision. Our method seems adequate for the design of the psychiatric trials used as models. Trial registrations are available at clinicaltrials.gov NCT00466609 and NCT00680602.

OBJETIVO: Descrever o recrutamento de pacientes, instrumentos de avaliação, métodos para o desenvolvimento de estudos colaborativos multicêntricos e os resultados preliminares do Consórcio Brasileiro de Pesquisa em Transtornos do Espectro Obsessivo-Compulsivo, que inclui sete centros universitários. MÉTODO: Este estudo transversal incluiu entrevistas semi-estruturadas (dados sociodemográficos, histórico médico e psiquiátrico, curso da doença e diagnósticos psiquiátricos comórbidos) e instrumentos que avaliam os sintomas do transtorno obsessivo-compulsivo (Escala para Sintomas Obsessivo-Compulsivos de Yale-Brown e Escala Dimensional para Sintomas Obsessivo-Compulsivos de Yale-Brown), sintomas depressivos (Inventário de Depressão de Beck), sintomas ansiosos (Inventário de Ansiedade de Beck), fenômenos sensoriais (Escala de Fenômenos Sensoriais da Universidade de São Paulo), juízo crítico (Escala de Avaliação de Crenças de Brown), tiques (Escala de Gravidade Global de Tiques de Yale) e qualidade de vida (questionário genérico de avaliação de qualidade de vida, Medical Outcome Quality of Life Scale Short-form-36 e Escala de Avaliação Social). O treinamento dos avaliadores consistiu em assistir cinco entrevistas filmadas e entrevistar cinco pacientes junto com um pesquisador mais experiente, antes de entrevistar pacientes sozinhos. A confiabilidade entre todos os líderes de grupo para os instrumentos mais importantes (Structured Clinical Interview for DSM-IV, Dimensional Yale-Brown Obsessive-Compulsive Scale, Universidade de São Paulo Sensory Phenomena Scale ) foi medida após seis entrevistas completas. RESULTADOS: A confiabilidade entre avaliadores foi de 96%. Até março de 2008, 630 pacientes com transtorno obsessivo-compulsivo tinham sido sistematicamente avaliados. A média de idade (±SE) foi de 34,7 (±0,51), 56,3% eram do sexo feminino e 84,6% caucasianos. Os sintomas obsessivo-compulsivos mais prevalentes foram os de simetria e os de contaminação. As comorbidades psiquiátricas mais comuns foram depressão maior, ansiedade generalizada e transtorno de ansiedade social. O transtorno de controle de impulsos mais comum foi escoriação neurótica. CONCLUSÃO: Este consórcio de pesquisa, pioneiro no Brasil, permitiu delinear o perfil sociodemográfico, clínico e terapêutico do paciente com transtorno obsessivo-compulsivo em uma grande amostra clínica de pacientes. O Consórcio Brasileiro de Pesquisa em Transtornos do Espectro Obsessivo-Compulsivo estabeleceu uma importante rede de colaboração de investigação clínica padronizada sobre o transtorno obsessivo-compulsivo e pode abrir o caminho para projetos semelhantes destinados a integrar outros grupos de pesquisa no Brasil e em todo o mundo.

OBJECTIVE: To describe the recruitment of patients, assessment instruments, implementation, methods and preliminary results of The Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders, which includes seven university sites. METHOD: This cross-sectional study included a comprehensive clinical assessment including semi-structured interviews (sociodemographic data, medical and psychiatric history, disease course and comorbid psychiatric diagnoses), and instruments to assess obsessive-compulsive (Yale-Brown Obsessive-Compulsive Scale and Dimensional Yale-Brown Obsessive-Compulsive Scale), depressive (Beck Depression Inventory) and anxious (Beck Anxiety Inventory) symptoms, sensory phenomena (Universidade de São Paulo Sensory Phenomena Scale), insight (Brown Assessment Beliefs Scale), tics (Yale Global Tics Severity Scale) and quality of life (Medical Outcome Quality of Life Scale Short-form-36 and Social Assessment Scale). The raters' training consisted of watching at least five videotaped interviews and interviewing five patients with an expert researcher before interviewing patients alone. The reliability between all leaders for the most important instruments (Structured Clinical Interview for DSM-IV, Dimensional Yale-Brown Obsessive-Compulsive Scale, Universidade de São Paulo Sensory Phenomena Scale) was measured after six complete interviews. RESULTS: Inter-rater reliability was 96%. By March 2008, 630 obsessive-compulsive disorder patients had been systematically evaluated. Mean age (±SE) was 34.7 (±0.51), 56.3% were female, and 84.6% Caucasian. The most prevalent obsessive compulsive symptom dimensions were symmetry and contamination. The most common comorbidities were major depression, generalized anxiety and social anxiety disorder. The most common DSM-IV impulsive control disorder was skin picking. CONCLUSION: The sample was composed mainly by Caucasian individuals, unmarried, with some kind of occupational activity, mean age of 35 years, onset of obsessive-compulsive symptoms at 13 years of age, mild to moderate severity, mostly of symmetry, contamination/cleaning and comorbidity with depressive disorders. The Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders has established an important network for standardized collaborative clinical research in obsessive-compulsive disorder and may pave the way to similar projects aimed at integrating other research groups in Brazil and throughout the world.

OBJETIVO E MÉTODO: Apesar de existirem terapêuticas eficazes para o tratamento do transtorno obsessivo-compulsivo, uma parcela significativa dos pacientes acometidos por tal condição não alcança ou não mantém a remissão dos sintomas mesmo com tratamento adequado. O alívio do sofrimento destes pacientes com os tratamentos existentes representa um desafio para o clínico, que, nestas situações, se vê, freqüentemente, sem respostas satisfatórias. O objetivo desta revisão da literatura é avaliar os conceitos e critérios de resistência e refratariedade ao tratamento, abordar os aspectos intrínsecos e extrínsecos à fenomenologia descritiva do transtorno obsessivo-compulsivo que possam influenciar a resposta aos tratamentos convencionais preconizados, e propor um fluxo de alternativas terapêuticas para casos resistentes e refratários às diversas abordagens. CONCLUSÃO: A literatura evidencia que tanto aspectos intrínsecos à fenomenologia do transtorno obsessivo-compulsivo, quanto aspectos extrínsecos podem colaborar para que pelo menos 30% dos pacientes não obtenham o resultado desejado. Várias alternativas de tratamento e/ou de potencialização, sejam psicofarmacológicas, biológicas ou psicoterápicas, estão disponíveis, mas vários estudos ainda são necessários para que as evidências apontem na direção mais adequada para a remissão dos sintomas.

OBJECTIVE AND METHOD: Despite the existence of effective therapeutic alternatives for obsessive-compulsive disorder, a significant number of patients does not achieve or does not maintain remission after adequate treatment. The relief of these patients’ suffering with the available treatments is a clinical challenge related to many unanswered questions. The objective of this literature review is to evaluate the current concepts of treatment resistance and refractoriness, to describe the intrinsic and extrinsic factors of obsessive-compulsive disorder’s phenomenology that might influence treatment response to conventional treatment, and to present a fluxogram of therapeutic alternatives for resistant or refractory obsessive compulsive disorder patients. CONCLUSION: The literature evinces that intrinsic and/or extrinsic phenomenological aspects of obsessive-compulsive disorder may collaborate to the fact that, at least 30% of obsessive-compulsive disorder patients do not respond to conventional treatment. Several therapeutic or augmentation alternatives, psychopharmacological, biological or even psychotherapeutical exists, but more studies are necessary to evince the correct way to symptom remission.