Response of symptom dimensions in obsessive- compulsive disorder to treatment with citalopram or placebo Resposta das dimensões dos sintomas no transtorno obsessivo-compulsivo ao tratamento com citalopram ou placebo

Objective: There is increasing evidence that the symptoms of obsessive-compulsive disorder lie on discrete dimensions. Relatively little work has, however, explored the relationship between such factors and response to pharmacotherapy. Method: Data from a multi-site randomized placebo-controlled study of citalopram in obsessive-compulsive disorder were analyzed. Factor analysis of individual items and symptom categories of the Yale-Brown Obsessive-Compulsive Scale Checklist were undertaken, and the impact of symptom dimensions on treatment outcomes was analysed. Results: Factor analysis of Yale-Brown Obsessive-Compulsive Scale Checklist individual items yielded 5 factors (contamination/cleaning, harm/checking, aggressive/sexual/religious, hoarding/symmetry, and somatic/hypochondriacal). Hoarding/symmetry was associated with male gender, longer duration of obsessive-compulsive disorder and early onset, whereas contamination/cleaning was associated with female gender. Citalopram was more effective than placebo, but high scores on the symmetry/hoarding and contamination/cleaning subscales predicted worse outcome at the end of study while high scores on the aggressive/religious/sexual subscale predicted better outcome. Factor analysis of Yale-Brown Obsessive-Compulsive Scale Checklist symptom clusters yielded a 4 factor solution, but confirmed that symmetry/ordering was associated with male gender, early onset, and long duration of obsessive-compulsive disorder while high scores on the hoarding subscale predicted worse response to pharmacotherapy. Conclusion: Citalopram shows good efficacy across the range of obsessive-compulsive disorder symptom dimensions. The relatively worse response of symmetry/hoarding to a selective serotonin reuptake inhibitor is consistent with other evidence that this symptom dimension is mediated by the dopamine system. There may be associations between symmetry/hoarding, male gender, early onset, tics, and particular genetic variants; further work is, however, needed to delineate fully obsessive-compulsive disorder subtypes and their underlying neurobiology. Descriptors: Obsessive-compulsive disorder; Yale-Brown Obsessive-Compulsive Scale; Citalopram; Serotonin; Serotonin uptake inhibitors Resumo Objetivo: Há crescentes evidências de que os sintomas do transtorno obsessivo-compulsivo residem em dimensões discretas. Alguns estudos têm sugerido que esses fatores possuem suportes neurobiológicos específicos. No entanto, poucos trabalhos têm explorado a relação entre tais fatores e a resposta à farmacoterapia. Método: Foi realizada a análise fatorial dos itens individuais e categorias de sintomas do checklist da Escala de Obsessão e Compulsão de Yale-Brown e foi analisado o impacto da dimensão dos sintomas no desfecho dos tratamentos. Resultados: A análise fatorial exploratória dos itens individuais da Escala de Obsessão e Compulsão de YaleBrown produziu cinco fatores (contaminação/limpeza, dano/verificação, agressividade/sexual/religioso, colecionismo/simetria e somático/ hipocondríaco). Colecionismo/simetria foi associado ao sexo masculino, longa duração do transtorno obsessivo-compulsivo e início precoce, ao passo que contaminação/limpeza foi associado ao sexo feminino. O citalopram foi mais eficaz do que placebo, mas altos escores nas subescalas de simetria/colecionismo e de contaminação/limpeza predisseram desfecho pior ao final do estudo, ao passo que altos escores na subescala agressividade/sexual/religioso predisseram melhor desfecho. Uma análise fatorial de sintomas do checklist da Escala de Obsessão e Compulsão de Yale-Brown produziu uma solução com quatro fatores, mas confirmou que simetria/ordenação estava associado ao sexo masculino, início precoce e longa duração do transtorno obsessivo-compulsivo, enquanto altos escores na subescala colecionismo predisseram uma resposta pior à farmacoterapia. Conclusão: O citalopram demonstra boa eficácia ao longo das dimensões do espectro de sintomas do transtorno obsessivo-compulsivo. A resposta relativamente pior de simetria/colecionismo a um inibidor seletivo da recaptação da serotonina é consistente com outras evidências de que essa dimensão de sintomas é mediada pelo sistema dopaminérgico. Pode haver associações entre simetria/colecionismo, sexo masculino, início precoce, tiques e variantes genéticas específicas; porém, mais estudos são necessários para delinear completamente os subtipos de transtorno obsessivo-compulsivo e sua neurobiologia subjacente. Descritores: Transtorno obsessivo-compulsivo; Yale-Brown Obsessive-Compulsive Scale; Citalopram; Serotonina; Inibidores de captação de serotonina Response of symptom dimensions in OCD 304 Rev Bras Psiquiatr. 2007;29(4):303-7 Int roduct ion Obsessive-compulsive disorder (OCD) is in many ways a homogeneous disorder. The disorder has a prevalence of around 2% in many different countries, 1 and descriptions of obsessions and compulsions have been remarkably consistent over time and place. 2 Neurobiological studies have consistently found evidence that cortical-striatal-thalamic-cortical (CTSC) circuits play a crucial role in mediating the disorder, 3 and treatment research has invariably demonstrated that serotonin reuptake inhibitors selectively reduce the symptoms of OCD. 4 At the same time, there is growing recognition that OCD is a heterogeneous condition. 5 There are different types of OCD symptoms (e.g.: washing vs checking), and OCD patients differ markedly in their severity of symptoms, degree of insight, and patterns of comorbidity. In some OCD patients the neural substrate of symptoms may include regions other than the CSTC circuits. 6 Although selective serotonin reuptake inhibitors (SSRIs) are the pharmacotherapy of choice, only around 40-60% of OCD patients respond to these agents, a source of variation that remains incompletely understood. Another 50% of patients respond to augmentation of SSRIs with low doses of antipsychotics. 7 Much work attempting to dissect the dimensions of OCD has been limited by not including different symptom subtypes, 812 or by using restricted symptom scales. 13-15 The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) is a clinician-rated measure that has become the most widely used primary efficacy measure in OCD medication trials, and includes a checklist of symptoms which is more comprehensive than the items of earlier scales. Factor analyses of the individual items, or of the symptom clusters, in the Y-BOCS checklist have consistently found 3 to 5 major factors, namely contamination/ cleaning, aggressive/checking, symmetry/ordering, and hoarding symptoms. 16,17-22 There is preliminary evidence that these OCD symptom dimensions are associated with different neuronal substrates 23 and with different genetic variants. 21 Some studies have suggested that washing symptoms do better with exposure therapy, 24,25 and worse with serotonin reuptake inhibitors, 26,27 although not all work is consistent. There is also evidence that hoarding symptoms are associated with worse response to treatment with serotonin reuptake inhibitors. 20,28 Although there have been many multi-site placebo-controlled studies of the pharmacotherapy of OCD, few of these have reported whether symptom factors influence treatment outcome. In this paper we analyzed a trial of the highly selective serotonin reuptake inhibitor (SSRI), citalopram, versus placebo, in order to determine whether symptom factors significantly determined response to medication or placebo. Method 1. Clinical trial The trial on which the analysis is based has been previously described in detail. 29 In brief, the study was a double-blind, placebo-controlled, parallel-group, fixed dose study conducted at 53 centers in 12 countries. Patients were 18-65 years and had been diagnosed according to DSM-IV criteria as suffering from OCD for at least 12 months. Age of onset of OCD was determined by clinical history. Patients with mild depressive symptoms could be included in the study [total MADRS (Montgomery-Åsberg Depression rating scale) score 22], but patients with moderate to severe depression and a range of other comorbid psychiatric or general medical disorders, including Tourette's syndrome, were excluded. Investigators received training on the Y-BOCS at a start-up meeting prior to the study, in order to ensure interrater reliability. The protocol was approved by the institutional review boards of the participating investigators, and subjects gave informed written consent. Patients were randomly assigned to receive fixed daily oral doses of 20, 40 or 60 mg citalopram or placebo for 12 weeks following a 1-week run-in period. At screening, patients received the Y-BOCS symptom checklist, and at baseline and at weeks 1, 3, 5, 7, 9, and 12 OCD symptom severity was assessed using the Y-BOCS. The primary measure of efficacy was change from baseline on the Y-BOCS total score at week 12. As significant effects for citalopram were demonstrated at all doses, the citalopram data were pooled for the current analysis. 2. Statistical analysis An exploratory factor analysis was performed on the individual symptoms from the Y-BOCS checklist (using all available patients, n = 434). A score of 2 was given if the symptom was a principal one, a score of 1 was given if the symptom was present, and otherwise 0 was given. 20 As in previous factor analyses of the Y-BOCS checklist only the current symptoms were used and the two categories 'other obsessions' and 'other compulsions' were not included. 16,17