A single-blinded case-control study of memantine in severe obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a common debilitating psychiatric illness that typically improves but does not remit with first-line medication and behavioral treatments. Serotonergic agents including selective serotonin reuptake inhibitors and clomipramine have provided the mainstay of OCD medication management for decades. Combined dopamine/serotonergic agents such as atypical antipsychotics are presently the only OCD-augmenting strategies proven effective via randomized controlled trials. Despite increasing evidence for a pathogenic role of glutamate in OCD, no controlled trials of glutamatergic augmenting agents have been reported. METHODS: An intent-to-treat sample included 44 subjects receiving standard treatment at the McLean/Massachusetts General Hospital Intensive Residential Treatment (IRT) program, 22 of whom also received memantine augmentation. Admission, monthly and discharge measures of OCD, depression, and psychosocial functioning were collected by raters blinded to augmentation status. Matched controls were selected based on sex, initial OCD severity, psychosocial functioning, and timing of admission. The Clinical Global Improvement Scale captured global clinical change. RESULTS: Mean (SD) Yale-Brown Obsessive Compulsive Scale score decreases were 7.2 (6.4) among the cases and 4.6 (5.9) among the matched controls, reflecting mean clinical improvement among the cases (27.0% decrease) but not the controls (16.5% decrease). Mean (SD) depression severity score decreases were 5.8 (9.5) among the cases and 4.7 (9.9) among the controls. Initial intrusive obsessions were significantly more severe among marked responders compared with limited response or nonresponse cases (4.4 vs 2.9; t = 2.15; P = 0.048). CONCLUSIONS: This study provides preliminary supportive evidence for the effectiveness of memantine as a glutamatergic augmenting agent in severe OCD. Future randomized double-blind placebo-controlled trials are warranted.

A genetic family-based association study of OLIG2 in obsessive-compulsive disorder.

CONTEXT: Obsessive-compulsive disorder (OCD) is a debilitating familial psychiatric illness with associated brain abnormalities in the white matter. The gene for oligodendrocyte lineage transcription factor 2 (OLIG2) is an essential regulator in the development of cells that produce white matter (myelin). The OLIG2 gene is also highly expressed in brain regions implicated in OCD. OBJECTIVES: To examine OLIG2 as a candidate gene for OCD susceptibility and to explore whether comorbidity subtypes of OCD have distinct associations with OLIG2 and the functionally related OLIG1 gene. It was hypothesized a priori that OLIG2 and OLIG1 were associated with OCD regardless of the presence of comorbid Tourette disorder (TD), but not with TD alone. DESIGN: Family-based association candidate gene study. SETTING: Participants and their family members were recruited from tertiary care OCD and TD specialty clinics. PARTICIPANTS: Families of 66 probands with OCD with and without TD and 31 probands with TD without OCD. MAIN OUTCOME MEASURES: Genotypes of single nucleotide polymorphism markers and related haplotypes. RESULTS: The following 3 single nucleotide polymorphism markers on OLIG2 were associated with the OCD without TD phenotype: rs762178 (minor allele frequency, 35%; P<.001), rs1059004 (minor allele frequency, 44%; P = .005), and rs9653711 (minor allele frequency, 44%; P = .004). A 5-marker haplotype (A/C/T/T/G) constituting these single nucleotide polymorphisms and exonic single nucleotide polymorphisms rs6517137 and rs13046814 was undertransmitted (frequency, 32%; permuted P=.004), whereas the G/A/T/T/C haplotype (frequency, 22%; permuted P=.02) was overtransmitted to probands with OCD alone, with a significant global P value (permuted P=.008). CONCLUSIONS: This is the first study reporting an association between OLIG2 and OCD, specifically when TD comorbidity is absent. The findings support a role for white matter abnormalities in the etiology of the disorder.

Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder.

CONTEXT: Obsessive-Compulsive Disorder (OCD) is a debilitating illness with putative glutamatergic abnormalities. Two separate proximal haplotypes in the glutamate transporter gene, SLC1A1, were recently reported to be associated with OCD among males, but replication is required. OBJECTIVES: This study examines SLC1A1 as a candidate gene for OCD and explores gender influences. It was hypothesized that a significant association between SLC1A1 and OCD would be replicated in an independent sample of males but not females. DESIGN: Family-based association candidate gene study. SETTING: Participants were recruited from tertiary care OCD specialty clinics. PARTICIPANTS: OCD probands and their first degree relatives. MAIN OUTCOMES MEASURES: Association of OCD with genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes. RESULTS: Association between OCD and the three-marker haplotype rs12682807/ rs2072657/ rs301430, with overtransmission of A/T/T, was observed in both genders combined (global P = 0.0015) and in males (global P = 0.0031). Single-marker associations with OCD in the region (rs3780412 and rs2228622) demonstrated modest significance (permuted P = 0.045). CONCLUSIONS: This study identifies a significant association between the SLC1A1 glutamate transporter gene and OCD in a haplotype overlapping with that recently reported.

Aberrant error processing in relation to symptom severity in obsessive-compulsive disorder: A multimodal neuroimaging study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is characterized by maladaptive repetitive behaviors that persist despite feedback. Using multimodal neuroimaging, we tested the hypothesis that this behavioral rigidity reflects impaired use of behavioral outcomes (here, errors) to adaptively adjust responses. We measured both neural responses to errors and adjustments in the subsequent trial to determine whether abnormalities correlate with symptom severity. Since error processing depends on communication between the anterior and the posterior cingulate cortex, we also examined the integrity of the cingulum bundle with diffusion tensor imaging. METHODS: Participants performed the same antisaccade task during functional MRI and electroencephalography sessions. We measured error-related activation of the anterior cingulate cortex (ACC) and the error-related negativity (ERN). We also examined post-error adjustments, indexed by changes in activation of the default network in trials surrounding errors. RESULTS: OCD patients showed intact error-related ACC activation and ERN, but abnormal adjustments in the post- vs. pre-error trial. Relative to controls, who responded to errors by deactivating the default network, OCD patients showed increased default network activation including in the rostral ACC (rACC). Greater rACC activation in the post-error trial correlated with more severe compulsions. Patients also showed increased fractional anisotropy (FA) in the white matter underlying rACC. CONCLUSIONS: Impaired use of behavioral outcomes to adaptively adjust neural responses may contribute to symptoms in OCD. The rACC locus of abnormal adjustment and relations with symptoms suggests difficulty suppressing emotional responses to aversive, unexpected events (e.g., errors). Increased structural connectivity of this paralimbic default network region may contribute to this impairment.

Long-term outcome following Intensive Residential Treatment of Obsessive-Compulsive Disorder.

BACKGROUND: IRT has been demonstrated as an effective treatment for severe, refractory OCD. METHODS: Consecutive IRT subjects were ascertained over a 12 month period (female N=26, male N=35). Psychometric measures were completed at admission and discharge from the McLean/MGH OCD Institute IRT, including the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Beck Depression Inventory (BDI) and the Work and Social Adjustment Scale (WSA)(N=61). These measures were repeated at one (N=57), three (N=42) and six months (N=36) following discharge. This study was IRB approved. RESULTS: OCD mean severity did not significantly worsen from discharge to the one (17.4, SD 6.5), three (16.5, SD 7.4) or six month (16.2, SD 7.3) follow-up (p>0.25). Furthermore, the significant improvement from admission was maintained at each of the one (17.4, SD 6.5), three (16.5, SD 7.4) and six month (16.2, SD SD 7.3) follow-up time points (p<0.001). Relapsers were significantly more likely to be living alone following discharge (p=0.01), and were less likely to have comorbid illnesses (p=0.02). There were no significant differences found between study dropouts and completers with regards to YBOCS scores (P>0.47). CONCLUSION: In the first OCD IRT long-term follow-up study to date, findings have indicated that mean treatment gains were maintained at one, three, and six months post-discharge. This finding is important as it suggests that improvements of OCD severity were subsequently retained in home and work environments. Improvement of depression severity from admission was also maintained.

Body dysmorphic disorder and obsessive-compulsive disorder: similarities, differences and the classification debate.

Obsessive-compulsive disorder and body dysmorphic disorder have many similarities in clinical presentation. Obsessive-compulsive disorder has historically been considered an anxiety disorder, whereas body dysmorphic disorder has been grouped among the somatoform disorders. Researchers in these areas are currently debating whether the similarities warrant the inclusion of body dysmorphic disorder within a proposed category of obsessive-compulsive spectrum disorders. This article describes the association between obsessive-compulsive disorder and body dysmorphic disorder as evidenced by the emerging literature, and presents theoretical and clinical implications of this association.