Repetitive Störungen manifestieren sich als Leitsymptom in der Zwangsstörung und dem Tourette-Syndrom. Die Symptome werden als enthemmte Stereotypien eines desinhibierten Basalganglien-thalamo-kortikalen (BGTC) Regelkreises verstanden. Überdies wird als neurochemisches Korrelat ein dysregulatives Dopamin (DA)-System innerhalb dieser Kerngebiete nahegelegt, welches über ein überaktives Dopamintransporter (DAT)-System erklärt werden könnte. In der Induktion repetitiver Erkrankungen ist die Interaktion des BGTC Regelkreises und des DA-Systems dennoch unklar. In der vorliegenden Arbeit wurden daher anhand von zwei Pathologiemodellen (Ratte) mit unterschiedlich induzierter Dysregulation des DA-Systems (transgen versus pharmakologisch) die dysfunktionalen Einheiten im BGTC Regelkreises vergleichend untersucht. Im transgenen Modell führte die zentralnervöse DAT-Überexpression: (1) zu einer verstärkten Genexpression des vesikulären Monoamintransporter 2 (VMAT2) sowie des DA-Rezeptors 1 und DA–Rezeptors 2 (DRD1, DRD2), (2) zu einem reduzierten DA-Spiegel mit erhöhter DA-Umsatzrate und veränderten serotonergen- und GABAergen-System, und (3) zu perserverativen Verhalten. Im Gegensatz dazu zeigte die chronische Applikation mit dem D2-Agonisten Quinpirol im pharmakologischen Modell: (1) eine Reduktion des DAT, VMAT2 und DRD2, (2) eine reduzierte DA-Umsatzrate und (3) zwanghaftes Kontrollverhalten. Die Ergebnisse legen nahe, dass die unterschiedlichen klinischen Subtypen der Zwangsstörung unterschiedlichen neurobiologischen Veränderungen zugrunde liegen könnten. Ferner bietet das hier vorgestellte transgene Modell erfolgsversprechende Ansatzpunkte um als neues valides Tiermodell der repetitiven Störungen etabliert zu werden. / Repetitive disorders manifest as the cardinal symptom in obsessive-compulsive disorder and Tourette syndrome. The symptoms are understood as disinhibited stereotypies of a basal ganglia-thalamo-cortical (BGTC) circuit. Furthermore, it is suggested that a dysregulated dopamine (DA) system within this circuit is the underlying neurochemical correlate which could be explained by an overactive dopamine transporter (DAT). At this point, it is still unclear how the BGTC circuit and the DA system interact in the induction of repetitive disorders. Therefore we investigated the dysfunctional unities within the BGTC circuit by comparing two pathological rat models (transgenic versus pharmacologic) with different induced dopaminergic dysregulation. The DAT overexpressing rat model showed: (1) increased gene expression of the vesicular monoamine transporter 2 (VMAT2), DA receptor D1 (DRD1) and DA receptor D2 (DRD2), (2) lower levels of DA with an increased DA metabolism and alterations in the serotonin- and GABA system, and (3) perseverative behavior. In contrast, the chronic application of the D2 receptor agonist quinpirole resulted in the pharmacologic model in: (1) lower gene expressions of the DAT, VMAT2 and DRD2, (2) reduced DA-turnover and (3) compulsive control behavior. These results suggest that different clinical subtypes of obsessive-compulsive disorder caused by different neurobiological alterations. In addition, the presented transgenic model provides the opportunity to be established as a new valid animal model of repetitive disorders.

Das aktuelle Modell zur Pathophysiologie der Zwangserkrankung (OCD) geht von fronto-striatalen Dysfunktionen aus. Damit werden Beeinträchtigungen im prozeduralen Lernen, das anhand der Serial Reaction Time Task (SRTT) erfasst werden kann, in Verbindung gebracht. Die Befunde zu Defiziten von OCD-Patienten in der SRTT sind widersprüchlich, was auf Unterschiede im methodischen Vorgehen sowie die zusätzliche Auslastung des Arbeitsgedächtnisses durch die Vorgabe einer Gedächtnisaufgabe zurückgeführt wird. Weiterhin ist unklar, ob die vermutete fronto-striatale Dysfunktion und die Defizite im prozeduralen Lernen kennzeichnend für OCD sind oder auch bei anderen Störungsbildern auftreten. Die prozedurale Lernleistung von OCD-Patienten wurde mit der Lernleistung von gesunden Probanden, Patienten mit einer Angststörung und Patienten mit einer Depression verglichen. Weiterhin wurde die prozedurale Lernleistung unter der Vorgabe der SRTT alleine (single-task) und bei gleichzeitiger Vorgabe einer Gedächtnisaufgabe (dual-task) untersucht. OCD-Patienten zeigten im Vergleich zu gesunden Probanden Defizite im prozeduralen Lernen – sowohl unter der single-task als auch unter der dual-task Bedingung. Im Vergleich zu Patienten mit einer Angststörung zeigte sich lediglich in der dual-task Bedingung eine tendenzielle Beeinträchtigung der OCD-Patienten. Keine Unterschiede ergaben sich in der prozeduralen Lernleistung zwischen OCD-Patienten und Patienten mit einer Depression. Die stärkste Beeinträchtigung der prozeduralen Lernleistung in den verschiedenen Symptomdimensionen (Kontrolle, Waschen, Symmetrie, Horten) der OCD zeigte sich in der Dimension Horten. Außerdem waren die Defizite im prozeduralen Lernen stärker bei Patienten mit einem früheren Beginn der Zwangsstörung ausgeprägt. Die Befunde stehen im Einklang mit bisherigen Ergebnissen, wonach bei OCD eine Beeinträchtigung im prozeduralen Lernen vorliegt, was für die Annahme einer fronto-striatalen Dysfunktion bei OCD spricht. / Obsessive-compulsive disorder (OCD) is seen as a disease that implicates fronto-striatal dysfunctions. These dysfunctions are hypothesized to be related to neuropsychological deficits. One of the putative deficits regards procedural learning, which can be assessed by using the serial reaction time task (SRTT). So far, the results regarding procedural learning in OCD patients are inconsistent, which is attributed to differences in methods, like the implementation of a secondary task (dual-task condition) using a concurrent working memory load. Moreover, it is still uncertain whether the fronto-striatal dysfunctions and the deficits in procedural learning are specific to OCD or if they can also be found in other mental illnesses. Procedural learning performance as measured with the SRTT was compared in OCD patients, healthy subjects, patients with anxiety disorder and depression. Additionally, procedural learning was examined under single- (SRTT) and dual-task (SRTT plus a secondary task) conditions. In comparison with healthy subjects, procedural learning was impaired in OCD patients – both in the single- and in the dual-task condition. Yet in the dual task condition, procedural learning was diminished in both groups. Compared to patients with anxiety disorder, OCD patients were impaired in procedural learning only in the dual-task condition, while there was no difference between OCD and depression in procedural learning. Regarding the different symptom dimensions of OCD (checking, washing, symmetry, hoarding), patients high on the dimension hoarding exhibited the most distinct impairment. Moreover, deficits in procedural learning were more pronounced in OCD patients with an earlier age at illness onset. The results confirm previous findings and add supportive evidence for performance deficits in procedural learning and the fronto-striatal dysfunction model of OCD.

Introdução: O Transtorno de Escoriação (TE) é caracterizado pelo comportamento repetitivo e excessivo de escoriar a pele saudável, resultando em dano tecidual e significativo sofrimento, associado a ânsia incontrolável e falha em controlar tal comportamento repetitivo. Atualmente o TE é classificado na seção de transtornos relacionados aos Transtornos Obsessivo-compulsivos (TOC) da 5ª edição do Manual de Diagnóstico e Estatística de Transtornos Mentais (DSM). No entanto, ainda existem debates a respeito da sua classificação, se o mesmo está relacionado a transtornos relacionados ao TOC, ou se é melhor conceituado como uma dependência comportamental. Objetivos: O presente estudo comparou um grupo de indivíduos com TE com dois paradigmas dos transtornos obsessivo-compulsivos, i.e., TOC, e dos transtornos impulsivo-aditivos, i.e., Transtorno do Jogo (TJ), analisando suas características sociodemográficas, clínicas, categorias diagnósticas, perfil de comorbidades, sintomas obsessivo-compulsivos, traços impulsivos e atributos de personalidade. O objetivo de tal comparação foi avaliar se o TE estaria mais relacionado aos transtornos relacionados ao TOC ou ao TJ. Métodos: Participaram do estudo 121 pacientes, que procuraram o tratamento no Instituto de Psiquiatria (IPq) do Hospital das Clínicas da Faculdade de Medicina da Universidade São Paulo (HCFMUSP), Brasil. Do total de 121 participantes, 40 foram diagnosticados com TE, 41 com TOC e 40 com TJ. Foram utilizadas entrevistas clínicas estruturadas para diagnosticar e comparar os três grupos na sobreposição diagnóstica e nas comorbidades psiquiátricas atuais, e escalas de autopreenchimento padronizadas para avaliar os sintomas dimensionais e comparar os três grupos em análise dimensional. Resultados: O grupo TE apresentou maior preponderância de mulheres, mais jovens e com maior instrução acadêmica. Na análise categorial TE se aproximou, significativamente, mais de TOC (n = 14) do que de TJ (n = 3), se sobrepondo ao primeiro. Os grupos TE e TOC também foram mais propensos a apresentar outros Comportamentos Repetitivos Focados no Corpo (CRFC) e transtornos ansiosos em geral. A presença de CRFC diferenciou TE de TJ, por outro lado, TE se diferenciou de TOC pela presença de comportamentos aditivos. A análise dimensional demonstrou que TE se apresenta como um modelo híbrido de obsessividade-compulsividade e impulsividade. Finalmente, a análise de correlação mostrou que os escores de obsessividade-compulsividade e impulsividade não foram correlacionados à gravidade dos sintomas de escoriação da pele. Discussão: Os dados da análise categorial apoiam a classificação de TE como um transtorno correlato ao TOC. Já os achados das análises dimensionais sugerem que uma apresentação psicopatológica híbrida de TE, contendo tanto elementos obsessivo-compulsivos, como com traços impulsivos. No entanto, nenhum desses aspectos foram correlacionados à gravidade dos sintomas de escoriação no grupo TE, sugerindo que o comportamento de escoriação da pele é independente desses fatores nestes indivíduos. O conjunto de tal apresentação sucinta a alocação de TE junto ao grupo dos chamados CRFC. Conclusão: TE apresenta um perfil demográfico e clínico próprios. TE e TOC compartilham mais similaridades no perfil de comorbidades psiquiátricas do que TJ, a maioria baseada nos transtornos ansiosos. Por outro lado, TE se diferencia de TOC, por uma associação mais frequente com os transtornos aditivos. TE apresentou níveis intermediários de compulsividade e impulsividade na abordagem dimensional. O comportamento de escoriação não mostrou correlação relevante com as medidas dimensionais de compulsividade nem impulsividade. TE, de uma forma geral, teve uma associação robusta com os outros CRFC, diferenciando-se de TOC e de TJ. TE poderia ser classificado em uma sessão à parte juntamente com outros CRFC / Introduction: Excoriation Disorder (ED) is characterized by repetitive and excessive picking on healthy skin, resulting in significant skin damage and psychological distress associated with uncontrollable urge and failure to control this repetitive behavior. ED is currently classified under the Obsessive-compulsive and Related Disorders (OCRD) section of the Diagnostic and Statistics Manual of Mental Disorders - 5th edition. Nevertheless, there is still no consensus whether ED is more closely related to OCRDs or it would be better conceptualized as a behavioral addiction. Objectives: Compare ED patients with two paradigms of obsessive-compulsive disorders (OCD) and impulsive-addictive disorders (gambling disorder), analyzing their sociodemographic and clinical characteristics, diagnostic categories, comorbidity profile, obsessive-compulsive symptoms, impulsive traits, and personality features. The purpose of this comparison was to assess whether ED was more related to OCD-related disorders (OCDRD) or to behavioral addictions, e.g., Gambling Disorder (GD). Methods: Study participants were 121 patients seeking treatment at Instituto de Psiquiatria (IPq), Hospital das Clinicas da Faculdade de Medicina da Universidade Sao Paulo (HCFMUSP), Sao Paulo, Brasil. Of the 121 participants, 40 were diagnosed with ED, 41 with OCD, and 40 with GD. Structured clinical interviews were used to diagnose and compare the three groups in diagnostic overlap and current psychiatric-comorbidities, and standardized self-reports were used to evaluate the dimensional variables. Results: Participants in the ED group were more likely to be women, young, and with higher levels of education compared with those of the other groups. In the categorical analysis, ED was more significantly approached to OCD (n=14) than to GD (n=3), overlapping the first. In general, ED and OCD were also more likely to exhibit other body-focused repetitive behaviors (BFRB) and anxiety disorders. The presence of BFRB differentiated ED from GD. In contrast, ED differed from OCD by the presence of addictive behaviors. The dimensional analysis found that ED is a hybrid model of obsessive-compulsivity and impulsivity. Discussion: Categorical analysis supports the classification of ED as OCDRD; however, ED presented differences that may share underlying characteristics with OCD (e.g., compulsivity) and behavioral addiction (e.g., impulsivity). Dimensional analysis suggests a heterogeneous psychopathological in ED with both obsessive-compulsive and impulsive features. Correlation analysis shows that obsessive-compulsivity and impulsivity scores were not correlated to skin excoriation severity symptoms. The overall viewpoints to the allocation of ED points to its own diagnostic category, that is, Body-focused Repetitive Behaviors (BFRB). Conclusion: ED shows a peculiar demographic and clinical profile. ED and OCD share more similarities in the profile of psychiatric comorbidities than GD, mostly based on anxiety disorders. In contrast, ED differs from OCD by a more frequent association with addictive disorders. ED presented intermediate levels of compulsivity and impulsivity between OCD and GD in the dimensional approach. The excoriation behavior showed no relevant correlation with dimensional measures of compulsivity or impulsivity

O transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico freqüentemente crônico caracterizado pela presença de obsessões e/ou compulsões. Tratamentos de primeira linha, que incluem os inibidores seletivos da recaptura de serotonina (ISRS) e a terapia cognitivocomportamental com técnicas de exposição e prevenção de respostas não conseguem melhora satisfatória em até 40% dos pacientes. Para estes casos, existem evidências que apóiam o uso de antipsicóticos como a quetiapina, na potencialização dos ISRS. No entanto, os antipsicóticos são eficazes para apenas um terço dos pacientes e estão associados a eventos adversos preocupantes no longo prazo. Este estudo tem como objetivo comparar a eficácia da potencialização do ISRS fluoxetina com a clomipramina, um inibidor de recaptura da serotonina não-seletivo, ou quetiapina, versus placebo. Para inclusão neste estudo, os pacientes precisavam: relatar os sintomas de TOC como sendo seu problema principal; estar em uso da dose máxima tolerada ou recomendada de fluoxetina por pelo menos oito semanas; ter um escore total na escala Yale Brown Obsessive-Compulsive Disorder Scale (YBOCS) de pelo menos 16; e ter tido uma redução do escore inicial da YBOCS menor do que 35% após tratamento com fluoxetina. Os pacientes (N=54) foram alocados por meio de um método de minimização em três grupos: quetiapina (até 200mg/dia) com fluoxetina (até 40mg/dia) (QTP/FLX) (N=18); clomipramina (até 75mg/dia) com fluoxetina (até 40mg/dia) (CMI/FLX) (N=18); e placebo com dose máxima de fluoxetina (até 80mg/dia) (PLC/FLX) (N=18). Avaliadores cegos obtiveram os escores da YBOCS nas semanas 0 e 12. As análises foram realizadas por intenção de tratar, com imputação do tipo hot-deck para os dados faltantes. Teste de Wald por ANCOVA não paramétrico para medidas ordinais repetidas foi utilizado para avaliar efeitos de grupo, tempo e interação para os resultados da YBOCS e desfechos secundários, tendo as medidas iniciais como co-variáveis. Os resultados da impressão clínica global de melhora (ICG-M) foram utilizados para classificar os pacientes como respondedores ou não-respondedores. O teste qui-quadrado foi utilizado para avaliar a freqüência de respondedores em cada grupo. Foram feitos gráficos de percentis e análises de sensibilidade. Quarenta pacientes (74%) completaram o seguimento. Não foram observados efeitos adversos graves. Pacientes dos grupos PLC/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=49%, DP=0.49) e CMI/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=46%, DP=0.51) melhoraram significativamente e tiveram uma melhor resposta quando comparados aos do grupo QTP/FLX (YBOCS final: média=13, DP=3; redução em relação ao inicial: média=18%, DP=0.20; p=0.001). Não foram encontradas diferenças significativas para as medidas secundárias. Os gráficos de percentis confirmaram que os pacientes do grupo QTP/FLX pioraram com maior freqüência e melhoraram menos do que os pacientes dos outros dois grupos. Análises de sensibilidade demonstraram que outros métodos de análise não modificaram significativamente os resultados. Este é o primeiro estudo duplo-cego controlado de potencialização de ISRS com clomipramina em TOC e também o primeiro a comparar a eficácia de potencialização com quetiapina à de outro potencializador. Limitações deste estudo incluem o uso de doses baixas dos potencializadores, taxas de abandono diferentes para os três grupos e período curto de seguimento. Apesar dessas limitações, nossos resultados apóiam o uso da clomipramina como potencializador (principalmente para aqueles que não toleram doses altas de fluoxetina) e o aumento do período de seguimento com fluoxetina em dose máxima antes de uma potencialização medicamentosa ser tentada / Obsessive-compulsive disorder (OCD) manifests often as a chronic illness and is characterized by the presence of obsessions and compulsions. Firstline treatment options, which include selective serotonin reuptake inhibitors (SSRI) and cognitive-behavior therapy with exposure and response prevention techniques, fail to achieve a satisfactory response in up to 40% of patients. Current evidence supports the augmentation of SSRI with antipsychotics, such as quetiapine. However, anti-psychotics are effective for only one-third of the patients and have been associated with severe long term side effects. This study aimed to compare clomipramine and quetiapine augmentation of the SSRI fluoxetine. Previously to the beginning of this trial all patients had to: report OCD as they primary diagnosis, be taking the highest tolerated or recommended dose of fluoxetine for at least eight weeks, have a current Yale Brown Obsessive-Compulsive Scale (YBOCS) total of at least 16, and have had a reduction of less than 35% of the initial total YBOCS score with fluoxetine treatment. Fifty-four patients were allocated trough a minimization procedure in one of three arms: quetiapine (up to 200 mg/day) plus fluoxetine (up to 40 mg/day) (QTP/FLX) (N=18), clomipramine (up to 75 mg/day) plus fluoxetine (up to 40 mg/day) (CMI/FLX) (N=18) and 18 placebo plus sustained maximum dose fluoxetine (up to 80 mg/day) (PLC/FLX) (N=18). Blinded raters collected YBOCS scores at weeks 0 and 12. Analyses were made with intention-to-treat and hot-deck imputation of missing data. Wald statistics from non-parametric ANCOVA for ordinal categorical repeated measures were used to evaluate group, time and interaction effects for YBOCS scores and secondary outcome measures considering initial measures as covariates. Clinical Global Impression scores of improvement (CGI-I) were used to classify individuals in responders or non-responders. Chi-square was used to evaluate frequency of responders in each group. Percentile-plots were built and sensitivity analyses were performed. Completion rate was 74% (N=40). No severe adverse events occurred during the trial. Patients from the PLC/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=49%, SD=0.49) and CMI/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=46%, SD=0.51) groups improved significantly and also had a significantly better response than the ones from the QTP/FLX group (final YBOCS score: mean=13, SD=3; reduction from initial YBOCS score: mean=18%, SD=0.20; p=0.001). No significant differences were evident for secondary outcome measures. Percentile plots confirmed that patients in the QTP/FLX group got worse more often or improved less than in the other two groups. Sensitivity analyses showed that other analytical methods did not significantly change results. This is the first double-blind placebo-controlled trial of clomipramine augmentation and the first to compare quetiapine augmentation with another active augmenter. Limitations of our trial include the use of low dose of augmenters, differential drop-out rates for each treatment arm and short period of follow-up. Despite these limitations, our results support the use of clomipramine as an augmentation strategy (mainly for those who do not tolerate higher doses of fluoxetine) and the prorogation of the period of maximum dose of fluoxetine before an augmentation is tried

Introdução: O presente estudo tem como objetivo avaliar a eficácia da estimulação magnética transcraniana de repetição (EMTr) em freqüência excitatória, aplicada ao córtex pré-frontal dorsolateral direito (CPFDLd), quando adicionada ao tratamento vigente de pacientes com transtorno obsessivocompulsivo (TOC) resistente. Método: 30 pacientes com TOC resistente ao tratamento foram alocados aleatoriamente para receber EMTr ativa ou placebo, sendo que a condição de tratamento permaneceu oculta para pacientes e avaliador. O tratamento vigente permaneceu estável por ao menos 8 semanas. A EMTr foi realizada com uma bobina em formato de oito à freqüência de 10Hz, com 110% do limiar motor em 30 sessões diárias de 40 séries de 5 segundos com 25 segundos de intervalo. A gravidade dos sintomas foi avaliada inicialmente, após 2 e 6 semanas de tratamento e 2 e 6 semanas de seguimento com a escala de Yale-Brown para avaliação de sintomas obsessivo-compulsivos (Y-BOCS), Escala de Impressão Clínica Global (CGI), Escala de Hamilton para ansiedade (HAM-A), Escala de Hamilton para depressão com 17 itens (HAM-D17), e inventário SF-36 de qualidade de vida. A medida primária de eficácia foi definida como redução de 30% ou mais nos escores da Y-BOCS e avaliação melhor ou muito melhor na sub-escala de melhora clínica da CGI ao término do seguimento. Resultados: A análise da medida primária de eficácia revelou que apenas um paciente em cada grupo preencheu critérios de resposta para o tratamento com EMTr (P=1.00). A análise de medidas repetidas dos escores de Y-BOCS mostrou um efeito significativo do tempo (F=7.33, P=0.002). Entretanto, não foi observada diferença entre os grupos ou interação grupo/tempo. A análise de medidas repetidas da CGI (gravidade), HAM-D17 e HAM-A também mostrou efeito significativo do tempo (P<0.001, =0.001 e <0.001 respectivamente), novamente sem diferença significativa entre os grupos ou interação. Conclusão: EMTr excitatória aplicada ao CPFDLd de pacientes com TOC resistente ao tratamento não foi diferente de placebo na redução de sintomas obsessivo-compulsivos ou melhora da impressão clínica global. Entretanto, ocorreu uma resposta placebo significativa / Introduction: The present study aims to evaluate the efficacy of added excitatory repetitive transcranial magnetic stimulation (rTMS), applied to the right dorsolateral prefrontal cortex in patients with treatment resistant obsessive-compulsive disorder (OCD). Methods: 30 treatment resistant OCD outpatients were randomized to receive either active or sham rTMS, remaining both patients and rater blind to treatment condition. Baseline treatment was kept stable for at least 8 weeks, and rTMS was performed with a figure-of-eight coil at 10Hz, 110% of motor threshold at 30 daily sessions of 40 trains of 5 seconds with 25 seconds interval. Symptom severity was determined at baseline and after 2 and 6 weeks of treatment and further 2 and 6 weeks of follow-up, using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Clinical Global Impression Scale (CGI), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D17) and SF-36 quality of life inventory. The primary outcome measure was defined as 30% or more improvement in Y-BOCS scores and a much improved or improved score at the CGIimprovement subscale by the end of follow up. Results: The analysis of primary outcome measure revealed that only one patient on each group met response criteria for treatment with rTMS (P=1.00). Repeated-measures analysis of Y-BOCS scores showed a significant effect of time (F=7.33, P=0.002). However, no significant group effect or group by time interaction was observed. Repeated measures analysis of CGI (severity), HAM-D17 and HAM-A also showed a significant effect of time (P<0.001, =0.001 and <0.001 respectively) with no significant group effect or group by time interaction. Conclusion: Excitatory rTMS delivered to the rDLPFC of treatment resistant OCD patients was not different from placebo in reducing obsessive-compulsive symptoms or improving clinical global impression. However, a significant placebo response occurred

O transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico freqüentemente crônico caracterizado pela presença de obsessões e/ou compulsões. Tratamentos de primeira linha, que incluem os inibidores seletivos da recaptura de serotonina (ISRS) e a terapia cognitivocomportamental com técnicas de exposição e prevenção de respostas não conseguem melhora satisfatória em até 40% dos pacientes. Para estes casos, existem evidências que apóiam o uso de antipsicóticos como a quetiapina, na potencialização dos ISRS. No entanto, os antipsicóticos são eficazes para apenas um terço dos pacientes e estão associados a eventos adversos preocupantes no longo prazo. Este estudo tem como objetivo comparar a eficácia da potencialização do ISRS fluoxetina com a clomipramina, um inibidor de recaptura da serotonina não-seletivo, ou quetiapina, versus placebo. Para inclusão neste estudo, os pacientes precisavam: relatar os sintomas de TOC como sendo seu problema principal; estar em uso da dose máxima tolerada ou recomendada de fluoxetina por pelo menos oito semanas; ter um escore total na escala Yale Brown Obsessive-Compulsive Disorder Scale (YBOCS) de pelo menos 16; e ter tido uma redução do escore inicial da YBOCS menor do que 35% após tratamento com fluoxetina. Os pacientes (N=54) foram alocados por meio de um método de minimização em três grupos: quetiapina (até 200mg/dia) com fluoxetina (até 40mg/dia) (QTP/FLX) (N=18); clomipramina (até 75mg/dia) com fluoxetina (até 40mg/dia) (CMI/FLX) (N=18); e placebo com dose máxima de fluoxetina (até 80mg/dia) (PLC/FLX) (N=18). Avaliadores cegos obtiveram os escores da YBOCS nas semanas 0 e 12. As análises foram realizadas por intenção de tratar, com imputação do tipo hot-deck para os dados faltantes. Teste de Wald por ANCOVA não paramétrico para medidas ordinais repetidas foi utilizado para avaliar efeitos de grupo, tempo e interação para os resultados da YBOCS e desfechos secundários, tendo as medidas iniciais como co-variáveis. Os resultados da impressão clínica global de melhora (ICG-M) foram utilizados para classificar os pacientes como respondedores ou não-respondedores. O teste qui-quadrado foi utilizado para avaliar a freqüência de respondedores em cada grupo. Foram feitos gráficos de percentis e análises de sensibilidade. Quarenta pacientes (74%) completaram o seguimento. Não foram observados efeitos adversos graves. Pacientes dos grupos PLC/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=49%, DP=0.49) e CMI/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=46%, DP=0.51) melhoraram significativamente e tiveram uma melhor resposta quando comparados aos do grupo QTP/FLX (YBOCS final: média=13, DP=3; redução em relação ao inicial: média=18%, DP=0.20; p=0.001). Não foram encontradas diferenças significativas para as medidas secundárias. Os gráficos de percentis confirmaram que os pacientes do grupo QTP/FLX pioraram com maior freqüência e melhoraram menos do que os pacientes dos outros dois grupos. Análises de sensibilidade demonstraram que outros métodos de análise não modificaram significativamente os resultados. Este é o primeiro estudo duplo-cego controlado de potencialização de ISRS com clomipramina em TOC e também o primeiro a comparar a eficácia de potencialização com quetiapina à de outro potencializador. Limitações deste estudo incluem o uso de doses baixas dos potencializadores, taxas de abandono diferentes para os três grupos e período curto de seguimento. Apesar dessas limitações, nossos resultados apóiam o uso da clomipramina como potencializador (principalmente para aqueles que não toleram doses altas de fluoxetina) e o aumento do período de seguimento com fluoxetina em dose máxima antes de uma potencialização medicamentosa ser tentada / Obsessive-compulsive disorder (OCD) manifests often as a chronic illness and is characterized by the presence of obsessions and compulsions. Firstline treatment options, which include selective serotonin reuptake inhibitors (SSRI) and cognitive-behavior therapy with exposure and response prevention techniques, fail to achieve a satisfactory response in up to 40% of patients. Current evidence supports the augmentation of SSRI with antipsychotics, such as quetiapine. However, anti-psychotics are effective for only one-third of the patients and have been associated with severe long term side effects. This study aimed to compare clomipramine and quetiapine augmentation of the SSRI fluoxetine. Previously to the beginning of this trial all patients had to: report OCD as they primary diagnosis, be taking the highest tolerated or recommended dose of fluoxetine for at least eight weeks, have a current Yale Brown Obsessive-Compulsive Scale (YBOCS) total of at least 16, and have had a reduction of less than 35% of the initial total YBOCS score with fluoxetine treatment. Fifty-four patients were allocated trough a minimization procedure in one of three arms: quetiapine (up to 200 mg/day) plus fluoxetine (up to 40 mg/day) (QTP/FLX) (N=18), clomipramine (up to 75 mg/day) plus fluoxetine (up to 40 mg/day) (CMI/FLX) (N=18) and 18 placebo plus sustained maximum dose fluoxetine (up to 80 mg/day) (PLC/FLX) (N=18). Blinded raters collected YBOCS scores at weeks 0 and 12. Analyses were made with intention-to-treat and hot-deck imputation of missing data. Wald statistics from non-parametric ANCOVA for ordinal categorical repeated measures were used to evaluate group, time and interaction effects for YBOCS scores and secondary outcome measures considering initial measures as covariates. Clinical Global Impression scores of improvement (CGI-I) were used to classify individuals in responders or non-responders. Chi-square was used to evaluate frequency of responders in each group. Percentile-plots were built and sensitivity analyses were performed. Completion rate was 74% (N=40). No severe adverse events occurred during the trial. Patients from the PLC/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=49%, SD=0.49) and CMI/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=46%, SD=0.51) groups improved significantly and also had a significantly better response than the ones from the QTP/FLX group (final YBOCS score: mean=13, SD=3; reduction from initial YBOCS score: mean=18%, SD=0.20; p=0.001). No significant differences were evident for secondary outcome measures. Percentile plots confirmed that patients in the QTP/FLX group got worse more often or improved less than in the other two groups. Sensitivity analyses showed that other analytical methods did not significantly change results. This is the first double-blind placebo-controlled trial of clomipramine augmentation and the first to compare quetiapine augmentation with another active augmenter. Limitations of our trial include the use of low dose of augmenters, differential drop-out rates for each treatment arm and short period of follow-up. Despite these limitations, our results support the use of clomipramine as an augmentation strategy (mainly for those who do not tolerate higher doses of fluoxetine) and the prorogation of the period of maximum dose of fluoxetine before an augmentation is tried

No description available.

L’objectif de cette étude était de démontrer que le léchage excessif de surface (LES) chez le chien représente un signe clinique d’un trouble digestif sous-jacent plutôt qu’un trouble obsessionnel compulsif. Vingt chiens présentés pour LES (groupe L) ont été divisés en 2 sous-groupes de 10 chiens chacun : L0, sans, et LD, avec des signes cliniques digestifs concomitants. Dix chiens en santé ont été assignés à un groupe contrôle (groupe C). Une évaluation comportementale complète, un examen physique et neurologique ont été réalisés avant un bilan diagnostic gastro-intestinal (GI) complet (hématologie, biochimie, analyse urinaire, mesure des acides biliaires pré et post-prandiaux et de l’immunoréactivité spécifique de la lipase pancréatique canine, flottaison fécale au sulfate de zinc, culture de selles, échographie abdominale et endoscopie GI haute avec prise de biopsies). En fonction des résultats, un interniste recommandait un traitement approprié. Les chiens étaient suivis pendant 90 jours durant lesquels le comportement de léchage était enregistré. Des troubles GI ont été identifiés chez 14/20 chiens du groupe L. Ces troubles GI sous-jacents incluaient une infiltration éosinophilique du tractus GI, une infiltration lymphoplasmocytaire du tractus GI, un retard de vidange gastrique, un syndrome du côlon irritable, une pancréatite chronique, un corps étranger gastrique et une giardiose. Une amélioration >50% en fréquence ou en durée par rapport au comportement de léchage initial a été observée chez une majorité de chiens (56%). La moitié des chiens ont complètement cessé le LES. En dehors du LES, il n’y avait pas de différence significative de comportement (p.ex. anxiété), entre les chiens L et les chiens C. Les troubles GI doivent être considérés dans le diagnostic différentiel du LES chez le chien. / The objective of this study was to characterize excessive licking of surfaces (ELS) in dogs and demonstrate that it can be a sign of underlying gastrointestinal (GI) pathology rather than an obsessive-compulsive disorder. Twenty dogs presented with ELS (L group) were divided in 2 subgroups of 10 dogs each: L0 without and LD with concomitant digestive signs. Ten healthy dogs were assigned to a control group (C group). Behavioral, physical and neurological examinations were performed prior to a complete work-up of the GI system (CBC, serum chemistry panel, urinalysis, assessment of total serum bile acids and canine specific pancreatic lipase immunoreactivity, fecal flotation by zinc sulfate, fecal culture, abdominal ultrasonography and upper GI endoscopy with biopsies). Based on results, appropriate treatment was recommended. Dogs were monitored subsequently for 90 days during which the licking behavior was recorded. Gastrointestinal disorders were identified in14/20 L dogs. Underlying GI disorders included eosinophilic infiltration of the GI tract, lymphoplasmacytic infiltration of the GI tract, delayed gastric emptying, irritable bowel syndrome, chronic pancreatitis, gastric foreign body and giardiasis. Significant improvement (>50%) in frequency or duration of the basal ELS behavior was observed in the majority of dogs (56%). Resolution of ELS occurred in half of the L dogs. Except for ELS, there was no significant difference in the behavior (e.g. anxiety) of L dogs and C dogs. GI disorders should be considered in the differential diagnosis of ELS in dogs

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Obsessive–compulsive disorder (OCD) is a psychiatric condition that is characterized by two main symptom cohorts, namely recurrent inappropriate thoughts (obsessions) and seemingly purposeless repetitive motor actions (compulsions). In 70% of cases, the condition only re–sponds to chronic, but not sub–chronic, high dose treatment with the selective serotonin reup–take inhibitors (SSRIs), such as fluoxetine and escitalopram. This indicates a role for hyposero–tonergic functioning in the primary brain areas involved in OCD, namely the components of the cortico–striatal–thalamic–cortical (CSTC) circuit which include the prefrontal cortex, the basal ganglia, and the thalamus. A number of studies have demonstrated a lower serotonin trans–porter (SERT) availability in OCD patients compared with healthy controls, supporting the hy–pothesis of a hyposerotonergic state in OCD. The current study focuses on the validation of the deer mouse (Peromyscus maniculatus bairdii) model of OCD and builds on previous work done in our laboratory. Deer mice that are bred and housed in confinement naturally develop two main forms of stereotypical behaviour, namely vertical jumping and pattern running. Furthermore, these behaviours can be catego–rized into various levels of severity, namely high (HSB), low (LSB) and non–stereotypic (NSB) cohorts. The seemingly purposeless and repetitive nature of these behaviours mimics the com–pulsions that characterize human OCD and constitutes the basis for the face validity of the model. However, although these two forms of stereotypy seem equally repetitive and persis–tent, stereotypical pattern runners do not complete the required number of cage revolutions per 30 minutes compared to the amount of jumps executed by stereotypical vertical jumpers. As only one set of criteria for the appraisal of the different topographies of deer mouse stereotypy has been applied in previous studies, the matter of whether pattern runners do in fact generate stereotypical behaviour of the same persistent and severe nature as opposed to the behaviour expressed by vertical jumpers, is problematic. Therefore, the first objective of the current study was to develop a new classification system for the appraisal of the different forms of behavioural topographies of deer mice and subse–quently to evaluate whether pattern runners can indeed be categorized into non–, low– and high stereotypical cohorts. After an eight–week behavioural assessment period, deer mice express–ing the two different behavioural topographies could be classified into non–, low– and high stereotypical cohorts (NSB, LSB, and HSB respectively), applying different criteria for each be–havioural topography. Based on the weekly mean stereotypy count generated during three 30–minute intervals of highest stereotypical behaviour over the course of a 12–hour assessment period, HSB pattern runners were found to execute on average 296 cage revolutions per 30 minutes, while HSB vertical jumpers executed an average of 3063 jumps per 30 minutes. This discrepancy between the generated numbers of the different topographies of stereotypy indi–cates that one classification system for the appraisal of both behavioural topographies is indeed inappropriate, and hence requires re–evaluation and validation. As patients with OCD present with a lower central SERT availability compared to healthy controls, the second objective of the study was to determine whether a decrease in SERT den–sity could be demonstrated in HSB animals compared to the NSB and LSB controls. After eight weeks of behavioural assessment, animals were sacrificed and frontal–cortical and striatal SERT binding was performed. HSB deer mice presented with significantly lower striatal, but not fron–tal–cortical SERT availability compared to the [NSB/LSB] control animals (p = 0.0009). As far as it concerns a lower SERT availability in HSB animals and involvement of the CSTC circuitry, this data is congruent with that demonstrated in human OCD and strengthens the construct validity of the model. Although previous studies undertaken in our laboratory demonstrated that deer mouse stereotypy is attenuated after chronic (21–day) fluoxetine administration, OCD only responds to chronic, but not sub–chronic treatment with the SSRIs. The lack of response of deer mouse stereotypy to sub–chronic treatment has not been established and therefore the third study ob–jective was to assess the behavioural effects of sub–chronic (7–day) and chronic (28–day) SSRI treatment on expression of deer mouse stereotypy. Chronic, but not sub–chronic treatment with oral escitalopram (50 mg/kg/day) significantly increased the number of intervals over a 12–hour assessment period during which no stereotypical behaviour were expressed by HSB deer mice (p = 0.0241) and decreased the number of intervals during which high–stereotypical be–haviour were executed (p = 0.0054). Neither chronic, nor sub–chronic treatment significantly affected the behaviour of animals in the [NSB/LSB] cohort. The fact that the model demon–strates a lack of response to sub–chronic treatment with high dose SSRIs, positively contributes to the predictive validity of the deer mouse model of OCD. The results from the current study therefore strengthens the construct and predictive valid–ity of the deer mouse model of OCD and confirm the model’s status as a prominent animal model of OCD. Not only is hyposerotonergic functioning in the CSTC circuitry implicated in the behaviour of HSB animals, but the model also demonstrates selective response to chronic SSRI–treatment - two core characteristics of human OCD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.