Roseli Gedanke Shavitt

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 (χ2 = 16.7, 2df, P = 0.0002) and on the allelic frequencies (χ2 = 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.

Gray matter volumes in obsessive-compulsive disorder before and after fluoxetine or cognitive-behavior therapy: a randomized clinical trial.

Serotonin reuptake inhibitors and cognitive-behavior therapy (CBT) are considered first-line treatments for obsessive-compulsive disorder (OCD). However, little is known about their modulatory effects on regional brain morphology in OCD patients. We sought to document structural brain abnormalities in treatment-naive OCD patients and to determine the effects of pharmacological and cognitive-behavioral treatments on regional brain volumes. Treatment-naive patients with OCD (n=38) underwent structural magnetic resonance imaging scan before and after a 12-week randomized clinical trial with either fluoxetine or group CBT. Matched-healthy controls (n=36) were also scanned at baseline. Voxel-based morphometry was used to compare regional gray matter (GM) volumes of regions of interest (ROIs) placed in the orbitofrontal, anterior cingulate and temporolimbic cortices, striatum, and thalamus. Treatment-naive OCD patients presented smaller GM volume in the left putamen, bilateral medial orbitofrontal, and left anterior cingulate cortices than did controls (p<0.05, corrected for multiple comparisons). After treatment with either fluoxetine or CBT (n=26), GM volume abnormalities in the left putamen were no longer detectable relative to controls. ROI-based within-group comparisons revealed that GM volume in the left putamen significantly increased (p<0.012) in fluoxetine-treated patients (n=13), whereas no significant GM volume changes were observed in CBT-treated patients (n=13). This study supports the involvement of orbitofronto/cingulo-striatal loops in the pathophysiology of OCD and suggests that fluoxetine and CBT may have distinct neurobiological mechanisms of action.

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.

Obsessive-Compulsive Spectrum Disorders and Rheumatic Fever: A Family Study

BACKGROUND Obsessive-compulsive spectrum disorders (OCSDs) are more frequent in patients with active or prior rheumatic fever (RF), suggesting that OCSD and RF may share underlying etiologic mechanisms. Our objective was to estimate the frequency of OCSD in first-degree relatives (FDRs) of RF patients and controls to determine whether there is a familial relationship between OCSD and RF. METHODS This is a case-control family study. Of the 98 probands included in this study, 31 had RF without Sydenhams chorea (SC) and had 131 relatives, 28 had RF with SC and had 120 relatives, and 39 were controls without RF. All probands, 87.9% of the RF FDRs and 93.7% of the control FDRs were assessed directly with structured psychiatric interviews and best-estimate diagnoses were assigned. Odds ratios of morbid risks were estimated using logistic regression by the generalized estimating equations (GEE) method and compared between groups. RESULTS The rate of OCSDs was significantly higher among FDRs of RF probands than among FDRs of controls (n=37; 14.7% vs. n=10; 7.3%, i=.0279). A diagnosis of OCSDs in an RF proband was associated with a higher rate of OCSDs among FDRs when compared to control FDRs (p-GEE=.02). There was a trend for a higher rate of OCSDs among FDRs of RF probands presenting no OCSD, although the difference was not significant (p-GEE=.09). CONCLUSION The results are consistent with the hypothesis that a familial relationship exists between OCSD and RF, since an OCSD in the RF proband was found to increase the risk of OCSDs among FDRs. Additional neuroimmunological and genetic studies involving larger samples are needed to further elucidate this apparent familial relationship between RF and OCSD.

Clinical features of obsessive-compulsive disorder with hoarding symptoms: A multicenter study

BACKGROUND Factor analyses indicate that hoarding symptoms constitute a distinctive dimension of obsessive-compulsive disorder (OCD), usually associated with higher severity and limited insight. The aim was to compare demographic and clinical features of OCD patients with and without hoarding symptoms. METHOD A cross sectional study was conducted with 1001 DSM-IV OCD patients from the Brazilian Research Consortium of Obsessive-Compulsive Spectrum Disorders (CTOC), using several instruments. The presence and severity of hoarding symptoms were determined using the Dimensional Yale-Brown Obsessive-Compulsive Scale. Statistical univariate analyses comparing factors possibly associated with hoarding symptoms were conducted, followed by logistic regression to adjust the results for possible confounders. RESULTS Approximately half of the sample (52.7%, n = 528) presented hoarding symptoms, but only four patients presented solely the hoarding dimension. Hoarding was the least severe dimension in the total sample (mean score: 3.89). The most common lifetime hoarding symptom was the obsessive thought of needing to collect and keep things for the future (44.0%, n = 440). After logistic regression, the following variables remained independently associated with hoarding symptoms: being older, living alone, earlier age of symptoms onset, insidious onset of obsessions, higher anxiety scores, poorer insight and higher frequency of the symmetry-ordering symptom dimension. Concerning comorbidities, major depressive, posttraumatic stress and attention deficit/hyperactivity disorders, compulsive buying and tic disorders remained associated with the hoarding dimension. CONCLUSION OCD hoarding patients are more likely to present certain clinical features, but further studies are needed to determine whether OCD patients with hoarding symptoms constitute an etiologically discrete subgroup.

How to treat OCD in patients with Tourette syndrome.

Obsessive-compulsive disorder (OCD) constitutes an etiologically heterogeneous set of conditions, including a subtype that seems etiologically related to Tourette syndrome (TS). In order to treat OCD patients optimally, the clinician needs to integrate educational, psychological and pharmacological approaches. The most effective psychological intervention is cognitive-behavior therapy (CBT). Drug treatment includes clomipramine and all selective serotonin reuptake inhibitors (SSRIs). A subgroup of OCD patients, however, shows no significant improvement. Few studies suggest that the presence of tics is associated to a worse treatment response to SSRIs and that such patients benefit from combined therapy of serotonin-reuptake inhibitors plus neuroleptics. Independently of the presence of tics, there are several different augmentation strategies for resistant cases with drugs that interfere in the dopamine, serotonin, opioid and gonadal hormone systems. In addition, new therapies are now being tested against presumed postinfectious autoimmune processes. Finally, new developments are promising in neural circuit-based therapies, including neurosurgery for refractory patients.

Trajectory in obsessive-compulsive disorder comorbidities.

The main goal of this study is to contribute to the understanding of the trajectory of comorbid disorders associated with obsessive-compulsive disorder (OCD) according to the first manifested psychiatric disorder and its impact in the clinical course of OCD and subsequent psychiatric comorbidities. One thousand and one OCD patients were evaluated at a single time point. Standardized instruments were used to determine the current and lifetime psychiatric diagnoses (Structured Clinical Interview for DSM-IV Axis I and for impulse-control disorders) as well as to establish current obsessive-compulsive, depressive and anxiety symptom severity (Yale-Brown Obsessive-Compulsive Scale; Dimensional Yale-Brown Obsessive-Compulsive Scale, Beck Depression and Anxiety Inventories and the OCD Natural History Questionnaire). To analyze the distribution of comorbidities according to age at onset Bayesian approach was used. Five hundred eight patients had the first OC symptom onset till the age of 10 years old. The first comorbidity to appear in the majority of the sample was separation anxiety disorder (17.5%, n=175), followed by ADHD (5.0%, n=50) and tic disorders (4.4%, n=44). OCD patients that presented with separation anxiety disorder as first diagnosis had higher lifetime frequency of post-traumatic stress disorder (p=0.003), higher scores in the Sexual/Religious dimension (p=0.04), Beck Anxiety (p<0.001) and Depression (p=0.005) Inventories. OCD patients that initially presented with ADHD had higher lifetime frequencies of substance abuse and dependence (p<0.001) and worsening OCD course (p=0.03). OCD patients that presented with tic disorders as first diagnosis had higher lifetime frequencies of OC spectrum disorders (p=0.03). OCD is a heterogeneous disorder and that the presence of specific comorbid diagnoses that predate the onset of OCD may influence its clinical presentation and course over the lifetime.

Group cognitive-behavioral therapy versus selective serotonin reuptake inhibitors for obsessive-compulsive disorder: A practical clinical trial

Clinical effectiveness of group cognitive-behavioral therapy (GCBT) versus fluoxetine in obsessive-compulsive disorder outpatients that could present additional psychiatric comorbidities was assessed. Patients (18-65 years; baseline Yale-Brown Obsessive-Compulsive-Scale [Y-BOCS] scores ≥ 16; potentially presenting additional psychiatric comorbidities) were sequentially allocated for treatment with GCBT (n=70) or fluoxetine (n=88). Mean Y-BOCS scores decreased by 23.13% in the GCBT and 21.54% in the SSRI groups (p=0.875). Patients presented a mean of 2.7 psychiatric comorbidities, and 81.4% showed at least one additional disorder. A reduction of at least 35% in baseline Y-BOCS scores and CGI ratings of 1 (much better) or 2 (better) was achieved by 33.3% of GCBT patients and 27.7% in the SSRI group (p=0.463). The Y-BOCS reduction was significantly lower in patients with one or more psychiatric comorbidities (21.15%, and 18.73%, respectively) than in those with pure OCD (34.62%; p=0.034). Being male, having comorbidity of Major Depression, Social Phobia, or Dysthymia predicted a worse response to both treatments. Response rates to both treatments were similar and lower than reported in the literature, probably due to the broad inclusion criteria and the resulting sample more similar to the real world population.

Differential prefrontal gray matter correlates of treatment response to fluoxetine or cognitive-behavioral therapy in obsessive-compulsive disorder

Nearly one-third of patients with obsessive-compulsive disorder (OCD) fail to respond to adequate therapeutic approaches such as serotonin reuptake inhibitors and/or cognitive-behavioral therapy (CBT). This study investigated structural magnetic resonance imaging (MRI) correlates as potential pre-treatment brain markers to predict treatment response in treatment-naïve OCD patients randomized between trials of fluoxetine or CBT. Treatment-naïve OCD patients underwent structural MRI scans before randomization to a 12-week clinical trial of either fluoxetine or group-based CBT. Voxel-based morphometry was used to identify correlations between pretreatment regional gray matter volume and changes in symptom severity on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Brain regional correlations of treatment response differed between treatment groups. Notably, symptom improvement in the fluoxetine treatment group (n=14) was significantly correlated with smaller pretreatment gray matter volume within the right middle lateral orbitofrontal cortex (OFC), whereas symptom improvement in the CBT treatment group (n=15) was significantly correlated with larger pretreatment gray matter volume within the right medial prefrontal cortex (mPFC). No significant a priori regional correlations of treatment response were identified as common between the two treatment groups when considering the entire sample (n=29). These findings suggest that pretreatment gray matter volumes of distinct brain regions within the lateral OFC and mPFC were differentially correlated to treatment response to fluoxetine versus CBT in OCD patients. This study further implicates the mPFC in the fear/anxiety extinction process and stresses the importance of lateral portions of the OFC in mediating fluoxetines effectiveness in OCD. Clinical registration information: http://clinicaltrials.gov-NCT00680602.

Neuropsychological predictors of response to randomized treatment in obsessive-compulsive disorder

OBJECTIVE To identify neuropsychological predictors of treatment response to cognitive-behavioral therapy (CBT) and fluoxetine in treatment-naïve adults with obsessive-compulsive disorder (OCD). METHOD Thirty-eight adult outpatients with OCD underwent neuropsychological assessment, including tasks of intellectual function, executive functioning and visual and verbal memory, before randomization to a 12-week clinical trial of either CBT or fluoxetine. Neuropsychological measures were used to identify predictors of treatment response in OCD. RESULTS Neuropsychological measures that predicted a better treatment response to either CBT or fluoxetine were higher verbal IQ (Wechsler Abbreviated Scale of Intelligence) (p=0.008); higher verbal memory on the California Verbal Learning Test (p=0.710); shorter time to complete part D (Dots) (p<0.001), longer time to complete part W (Words) (p=0.025) and less errors on part C (Colors) (p<0.001) in the Victoria Stroop Test (VST). Fewer perseverations on the California Verbal Learning Test, a measure of mental flexibility, predicted better response to CBT, but worse response to fluoxetine (p=0.002). CONCLUSION In general, OCD patients with better cognitive and executive abilities at baseline were more prone to respond to either CBT or fluoxetine. Our finding that neuropsychological measures of mental flexibility predicted response to treatment in opposite directions for CBT and fluoxetine suggests that OCD patients with different neuropsychological profiles may respond preferentially to one type of treatment versus the other. Further studies with larger samples of OCD patients are necessary to investigate the heuristic value of such findings in a clinical context.