Increases in functional connectivity between the default mode network and sensorimotor network correlate with symptomatic improvement after transcranial direct current stimulation for obsessive-compulsive disorder.

BACKGROUND: Non-invasive neuromodulation is a promising intervention for obsessive-compulsive disorder (OCD), although its neurobiological mechanisms of action are still poorly understood. Recent evidence suggests that abnormalities in the connectivity of the default mode network (DMN) and the supplementary motor area (SMA) with other brain regions and networks are involved in OCD pathophysiology. We examined if transcranial direct current stimulation (tDCS) alters these connectivity patterns and if they correlate with symptom improvement in treatment-resistant OCD. METHODS: In 23 patients from a larger clinical trial (comparing active tDCS to sham) who underwent pre- and post-treatment MRI scans, we assessed resting-state functional MRI (rs-fMRI) data. The treatment involved 30-minute daily tDCS sessions for four weeks (weekdays only), with the cathode over the SMA and the anode over the left deltoid. We conducted whole-brain connectivity analysis comparing active tDCS-treated to sham-treated patients. RESULTS: We found that active tDCS, but not sham, led to connectivity increasing between the DMN and the bilateral pre/postcentral gyri (p = 0.004, FDR corrected) and temporal-auditory areas plus the SMA (p = 0.028, FDR corrected). Also, symptom improvement was directly associated with connectivity increasing between the left lateral sensorimotor network and the left precuneus (r = 0.589, p = 0.034). LIMITATIONS: Limited sample size (23 participants with resting-state neuroimaging), inability to analyze specific OCD symptom dimensions (e.g., harm, sexual/religious, symmetry/checking, cleaning/contamination). CONCLUSIONS: These data offer novel information concerning functional connectivity changes associated with non-invasive neuromodulation interventions in OCD and can guide new brain stimulation interventions in the framework of personalized interventions.

Comorbidity, age of onset and suicidality in obsessive-compulsive disorder (OCD): An international collaboration.

OBJECTIVES: To collate data from multiple obsessive-compulsive disorder (OCD) treatment centers across seven countries and five continents, and to report findings in relation to OCD comorbidity, age of onset of OCD and comorbid disorders, and suicidality, in a large clinical and ethnically diverse sample, with the aim of investigating cultural variation and the utility of the psychiatric diagnostic classification of obsessive-compulsive and related disorders. METHODS: Researchers in the field of OCD were invited to contribute summary statistics on current and lifetime psychiatric comorbidity, age of onset of OCD and comorbid disorders and suicidality in their patients with OCD. RESULTS: Data from 3711 adult patients with primary OCD came from Brazil (n=955), India (n=802), Italy (n=750), South Africa (n=565), Japan (n=322), Australia (n=219), and Spain (n=98). The most common current comorbid disorders were major depressive disorder (28.4%; n=1055), obsessive-compulsive personality disorder (24.5%, n=478), generalized anxiety disorder (19.3%, n=716), specific phobia (19.2%, n=714) and social phobia (18.5%, n=686). Major depression was also the most commonly co-occurring lifetime diagnosis, with a rate of 50.5% (n=1874). OCD generally had an age of onset in late adolescence (mean=17.9years, SD=1.9). Social phobia, specific phobia and body dysmorphic disorder also had an early age of onset. Co-occurring major depressive disorder, generalized anxiety disorder and psychotic disorders tended to have a later age of onset than OCD. Suicidal ideation within the last month was reported by 6.4% (n=200) of patients with OCD and 9.0% (n=314) reported a lifetime history of suicide attempt. CONCLUSIONS: In this large cross-continental study, comorbidity in OCD was common. The high rates of comorbid major depression and anxiety disorders emphasize the need for clinicians to assess and monitor for these disorders. Earlier ages of onset of OCD, specific phobia and social phobia may indicate some relatedness between these disorders, but this requires further study. Although there do not appear to be significant cultural variations in rates or patterns of comorbidity and suicidality, further research using similar recruitment strategies and controlling for demographic and clinical variables may help to determine whether any sociocultural factors protect against suicidal ideation or psychiatric comorbidity in patients with OCD.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.

Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment / Estudo de associação entre polimorfismos genéticos monoaminérgicos e resposta à clomipramina no tratamento do TOC

In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40 percent or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

No presente estudo, investigaram-se os polimorfismos 5HTTLPR e STin2 da região promotora do gene transportador de serotonina (SLC6A4), o G861C (rs6296) do receptor de serotonina 1D beta (HTR1B), os polimorfismos T102C (rs6113) e C516T (rs6305) do gene do receptor da serotonina subtipo 2A (HTR2A), os polimorfismos UTR, intron 8 e intron 14 do gene transportador de dopamina (SLC6A3), o Val-158-Met (rs4680) da COMT e a mutação G1287A (rs5569) do gene do transportador de norepinefrina (SLC6A2). Foram genotipados 41 pacientes com transtorno obsessivo-compulsivo (TOC), classificados como bons-respondedores (n=27) e maus-respondedores (n=14) ao tratamento com clomipramina, por meio do uso da Escala de Sintomas Obsessivos-Compulsivos Yale Brown (YBOCS). Foram considerados bons-respondedores os pacientes que tiveram redução nos sintomas em 40 por cento ou mais na YBOCS, após 14 semanas de tratamento. A distribuição dos genótipos e alelos estudados foi comparada entre os dois grupos. Não foi encontrada associação entre estes polimorfismos investigados e a resposta à clomipramina na amostra estudada.

Quetiapine versus clomipramine in the augmentation of selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder: a randomized, open-label trial.

After 12 weeks of selective serotonin reuptake inhibitor (SSRI) monotherapy with inadequate response, 10 patients received clomipramine and 11 received quetiapine as augmentation agents of the SSRI. The primary outcome measure was the difference between initial and final scores of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), rated in a blinded fashion, and the score of clinical global improvement (CGI-I). Statistical analyses were performed using nonparametric tests to evaluate treatment efficacy and the difference between treatment groups. Percentile plots were constructed with YBOCS scores from the clomipramine and quetiapine groups. Considering response a >or=35% reduction in the initial Y-BOCS score plus a rating of 'much improved' or 'very much improved' on CGI-I, four of eleven quetiapine patients and one out of ten clomipramine patients were classified as responders. The mean final Y-BOCS score was significantly lower than baseline in the quetiapine augmentation group (P = 0.023), but not in the clomipramine augmentation group (P = 0.503). The difference between groups showed a trend towards significance only at week 4, the mean Y-BOCS score being lower for those receiving quetiapine (P = 0.052). A difference between groups was also observed at week 4 according to percentile plots. These results corroborate previous findings of quetiapine augmentation efficacy in obsessive-compulsive disorder (OCD). Clomipramine augmentation did not produce a significant reduction in Y-BOCS scores. Higher target maximum dosages might have yielded different results.

Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder.

Family and twin studies have supported a strong genetic factor in the etiology of obsessive-compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (chi(2) = 16.7, 2df, P = 0.0002) and on the allelic frequencies (chi(2) = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings.

Adults with early-onset obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a clinically heterogeneous disorder with a bimodal age at onset and range of treatment outcomes. This study attempted to ascertain the importance of the age at OCD symptom onset for a better phenotypic precision. Therefore, the authors compared adult OCD patients with an early symptom onset to OCD patients with a later symptom onset. METHOD: Forty-two adult outpatients with OCD were evaluated with semistructured interviews: 21 with symptom onset before the age of 10 (early-onset group) and 21 with symptom onset after the age of 17 (late-onset group). RESULTS: Early onset was associated with higher scores on the Yale-Brown Obsessive Compulsive Scale, higher frequencies of tic-like compulsions, higher frequency of sensory phenomena, and a higher rate of comorbid tic disorders. The early-onset group also responded less well to treatment with clomipramine and selective serotonin reuptake inhibitors. CONCLUSIONS: The results indicate that age at onset may be an important factor in subtyping OCD and that the phenotypic differences found were not restricted to childhood.

Sintomas obsessivo-compulsivos e tiques vocais em pacientes com coreia de Sydenham: dados preliminares

Coreia de Sydenham (CS) e uma desordem neuropsiquiatrica, considerada uma compilacao da Febre Reumatica (quadro auto-imune pos-infeccao estreptococcica). Uma incidencia mais alta de sintomas compulsivos obsessivos (SOC) e desordem compulsiva obsessiva (TOC) foi documentado em pacientes de CS. TOC tambem foi descrito mais frequentemente em pacientes com o Sindrome de Tourette (ST) e ha varias linhas de pesquisa sugerindo que algumas formas de TOC podem representar uma expressao variante de ST. O estudo presente visa determinar a frequencia de tiques vocais, alem de sintomas obsessivo-compulsivos na Coreia de Sydenham (CS) e na Febre Reumatica sem CS (RF). Metodo: Foram avaliadas trinta e nove criancas com febre reumatica (22 com o CS e 17 com febre reumatica sem CS) (RF). Os pacientes foram diagnosticados de acordo com os criterios Jones. Foram executadas avaliacoes psiquiatricas e neurologicas em todos os pacientes. A Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiological version (K-SADS-E), Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Yale Global Tics Severity Scale (YGTSS) foram administrados a todos os pacientes. Resultados: A amostra de CS apresentou 14 pacientes com tiques vocais (63,64 por cento) e 8 pacientes com SOC (36,36 por cento). A amostra de FR apresentou 5 pacientes com SOC (29,41 por cento) e nenhum com tique vocal. Conclusoes: Os dados sugerem que tiques vocais sao encontrados mais frequentemente em criancas com a Coreia de Sydenham, e SOC sao encontrados, frequentemente, tanto em pacientes com CS como em pacientes com FR sem CS.

Obsessive-compulsive spectrum disorders in patients with obsessive-compulsive disorder and Tourette's syndrome

Introduction: Obsessive-Compulsive Spectrum Disorders include Obsessive-Compulsive Disorder (OCD), Tourette's Disorder (TS), Body Dysmorphic Disorder (BDD) and Trichotillomania (TTM), which, supposedly, share common psychopathological, physiopathological and genetic aspects. To date, the relation of OCD and TS is the most established. Recent studies suggest that patients with OCD and TS have a better response to serotonin reuptake inhibitors (SRI) plus neuroleptics than to SRI alone. Thus, the detection of patients with OCD and tics is important, once it can point to a different psychopharmacological approach. Similarly, the recognition of other psychiatric disorders associated to OCD could indicate important factors in treatment response. This study compares psychiatric comorbidity in patients with OCD and OCD plus TS, with the following hypotheses: 1) The group with both TS and OCD would be at significant risk for greater severity and frequency of associated disorders; 2) TTM would be more frequent in the OCD plus TS group, whereas BDD would be more frequent in the OCD group. Method: Twenty outpatients with OCD and twenty with OCD plus TS (DSM-III-R) were evaluated by the Standar Clinical Interview for the DSM-III-R (SCID) and additional modules designed by the authors for the diagnosis of TS, Chronic Motor Tics, BDD, TTM and Attention Deficit Disorder. Results: 1) Within groups: In the OCD group, the most frequent diagnoses were:...

The association of panic/agoraphobia and asthma. Contributing factors and clinical implications.

The point prevalence of phobic anxiety disorders was determined in 107 asthmatic outpatients through a standardized psychiatric interview and DSM-III-R diagnostic criteria. Agoraphobia and panic disorder were more prevalent (13.1% and 6.5%, respectively) than in the general population. Contributing factors and the clinical implications of this association are discussed. The recognition of specific anxiety syndromes enhances the efficacy of the treatment of anxious asthmatic patients.

[Psychic changes in systemic lupus erythematosus: a multidisciplinary prospective study]. / Alterações psíquicas no lúpus eritematoso disseminado: um estudo prospectivo multidisciplinar.

Despite the high prevalence of psychic symptoms in lupus patients, there are few systematic studies in this area. Through a multidisciplinary approach, the authors developed a prospective study to characterize and correlate psychopathological aspects with clinical and laboratory data concerning neural manifestations of the disease. Out of 23 patients studied, 12 showed psychic alterations, which were interpreted as primary manifestations of the disease. All of them presented organic mental syndromes (DSM-III-R) in which cognitive symptoms were the most prominent, followed by affective, catatonic and hallucinatory features. The neurologic findings (seizure, migraine and muscular atrophy), as well as the ophthalmologic alterations (hemorrhage and soft exudates) were frequent and concomitant with the psychic features. The laboratory findings were: LE cells 50%; anti-Sm: 16%; anti-U1 RNP: 50%; anti-Ro/SS-A: 50%; anti-nDNA: 58%; decreased CH50 or fractions (C3, C4): 67%; anti-P: 18%; antigangliosides IgG: 67%; antigangliosides IgM: 78%. The cerebrospinal fluid analysis showed: increased cellularity: 18%; elevated protein: 36%; antigangliosides IgG: 67%; antigangliosides IgM: 33%; immunocomplexes: 36%. In spite of the absence of an adequate control group and of the small number of patients, the multidisciplinary approach leads to a better characterization of the nervous system involvement in this disease.

[Psychiatric interconsultation: concepts and development]. / Interconsulta psiquiátrica: conceito e evolução.

There has been an important development of consultation-liaison psychiatry in the last fifty years. Psychosocial factors and psychiatric symptoms which can be present in many somatic ilnesses have been considered as deserving of more specialized care. This could be achieved by a multidisciplinary team with the presence of a psychiatrist either permanently (consultation-liaison psychiatry) or episodically (psychiatric consultation). The Brazilian experience in this field can be illustrated describing the "Serviço de Interconsultasa do IPQ HC-FMUSP". Organized in 1979, this clinic has been rendering both psychiatric consultation and liaison work (which, from a practical point of view, are complementary services). The clinic is also involved with research and medical education. There is agreement that psychiatric care in a general hospital brings evident benefits to the patient, to the psychiatrist, to non-psychiatric physicians, and to other team members not only in terms of developing new professional opportunities, but also in terms of broadning the research field and improving medical education.