Maria Cristina Cavallini

Clinical predictors of drug response in obsessive-compulsive disorder.

The aim of this study was to evaluate which clinical variables might influence the antiobsessional response to proserotonergic drugs in a sample of patients with obsessive-compulsive disorder (OCD). One hundred fifty-nine patients with DSM-IV OCD underwent a 12-week standardized treatment with fluvoxamine, clomipramine, citalopram, or paroxetine. According to treatment response, defined as a reduction of the Yale-Brown Obsessive Compulsive Scale total score >35%, patients were divided into two groups. Ninety patients (56.6%) responded to treatment and 69 (43.4%) did not. Responders had a significantly higher frequency of positive family history for OCD (FH-OCD) in their first-degree relatives, whereas nonresponders had an earlier onset and a higher frequency of “poor insight” subtype and somatic obsessions. The predictive value of all these variables was tested by a stepwise logistic regression analysis that confirmed poor insight and FH-OCD to be the best predictors of poor and good drug treatment response, respectively. These preliminary findings need additional investigations toward a better definition of the genetic and biological heterogeneity of patients with OCD, and they underlie the importance of collecting the insight score and family history for psychiatric disorders in the pretreatment assessment.

Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case–control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and −270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the −270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.

Serotonin transporter linked polymorphic region in anorexia nervosa and bulimia nervosa.

SIR – Strong genetic liability and common etiopathogenetic background have been suggested for Eating Disorders (ED). Several lines of evidence support a possible involvement of serotonin (5-HT) pathways in modulating eating behavior, since alteration in 5-HT activity has been consistently demonstrated in ED. Moreover, 5-HT disturbances seem to persist after recovery. These findings and the efficacy of 5-HT reuptake inhibitors in the treatment of ED suggest the serotonin transporter (5-HTT) gene as a good candidate for genetic studies. A deletion (short variant = s)/insertion (long variant = l) functional polymorphism has been described within the promoter region of the 5-HTT gene (5-HTTLPR). Studies of transfected cells in culture show that the long and short variants exhibit different transcriptional properties. In particular, basal transcriptional activity of the long variant is more than twice that of the short form. We studied this polymorphism in a sample of 50 bulimic (BN), 56 anorexic (AN) patients (19 restricting and 37 binge-eating type) and 120 healthy controls, closely questioned to exclude any psychiatric disorder. Informed consent was obtained from all the subjects, females, unrelated and of Italian descent. Patients fulfilled DSM-IV diagnostic criteria and were sequentially recruited at the Eating Disorder Clinic and Research Unit at San Raffaele University Hospital, Milan. Genomic DNA was extracted from whole blood and the polymorphism was analyzed as previously described. Statistical analysis was performed with x statistics and power calculation with the EPINFO program (version 6.04b, 1997). Table 1 shows the distribution of 5-HTTLPR alleles and genotypes in our sample. Genotype frequencies in controls and both subtypes of AN patients are in Hardy–Weinberg (H–W) equilibrium, while the BN group shows a significant deviation due to a lowerthan-expected frequency of the l/l genotype.

Executive Dysfunctions in Obsessive-Compulsive Patients and Unaffected Relatives: Searching for a New Intermediate Phenotype

BACKGROUND Evidence in literature suggests that neurocognitive deficits may represent suitable intermediate-phenotype candidates for the dissection of obsessive-compulsive disorder (OCD) genetic heterogeneity. The aim of this study was to search for possible OCD neurocognitive endophenotypes by assessing decision-making, planning, and mental flexibility profiles in OCD probands, healthy control subjects (HC), and their respective relatives. METHODS The sample consisted of 35 pairs of OCD probands without other Axis I comorbidities and unaffected first-degree relatives and 31 pairs of HC subjects without a known family history of OCD and their relatives. Neuropsychological assessment was performed using the Iowa Gambling Task (IGT), the Tower of Hanoi (ToH), and the Wisconsin Card Sorting Test (WCST). RESULTS Obsessive-compulsive disorder patients showed impairments in decision making, planning, and mental flexibility, given that OCD probands performed significantly poorer than HC probands at the IGT, the ToH, and the WCST. Obsessive-compulsive disorder relatives performed poorer at these tests than HC probands and relatives. Symptom severity was found to have no influence on neurocognitive performance. Analysis of proband/relative concordance in task performance was performed for each task. A significant overall difference was found when comparing the percentages of the different concordance profiles of our OCD and HC samples with regard to IGT and ToH performance. No significant difference was found in the WCST. CONCLUSIONS Executive dysfunctions may qualify as a suitable endophenotype candidate for OCD. Concordance rates in neuropsychological task performance suggest that decision-making and planning deficits aggregate in these families and therefore might be a heritable component of OCD.

Obsessive-Compulsive Disorder, 5-HTTLPR polymorphism and treatment response.

Recently, a role for a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR) in conferring susceptibility to Obsessive Compulsive Disorder (OCD) has been suggested. The aim of this study was to test the hypothesis that allelic variation of the 5-HTTLPR could be associated with OCD susceptibility or influence the drug response in OCD. One hundred and eighty-one OCD patients were recruited; 92 patients underwent a standardized treatment with fluvoxamine. No significant differences in allele/genotype distribution of the 5-HTTLPR were found between 191 controls and OCD. No differences in fluvoxamine response in the three genotypes groups in OCD were found, considering Yale–Brown Obsessive Compulsive Scale (YBOCS) total scores. Nevertheless, a significant time per genotype interaction was found for the YBOCS subtotal compulsion scores. Considering patients without tic disorder co-diagnosis, a significant time per genotype interaction for both YBOCS total scores and compulsion scores was found

Obsessive compulsive disorder among idiopathic focal dystonia patients: an epidemiological and family study

BACKGROUND A disturbed function of striato-thalamo-cortical circuitry is hypothesized to underlie idiopathic focal dystonia (IFD) and obsessive compulsive disorder (OCD), two severe and disabling neurologic and psychiatric disorders. Previous studies on small samples showed either higher obsessionality scores or higher frequency of OCD in dystonic patients than in normal control subjects. The aim of this study was to evaluate the frequency and familial loading of OCD in a population of patients with IFD. METHODS We evaluated OCD diagnosis and family history in 76 patients affected by IFD. RESULTS Of our subjects 19.7% satisfied DSM-IV criteria for OCD diagnosis and had a family morbidity risk for OCD of 13.8%, significantly higher than that found in the general population. CONCLUSIONS Our results support the hypothesis of a common pathologic background for OCD and IFD, at least in a subgroup of IFD, indicating basal ganglia dysfunction.

Executive functioning in anorexia nervosa patients and their unaffected relatives

Formal genetic studies suggested a substantial genetic influence for anorexia nervosa (AN), but currently results are inconsistent. The use of the neurocognitive endophenotype approach may facilitate our understanding of the AN pathophysiology. We investigated decision-making, set-shifting and planning in AN patients (n=29) and their unaffected relatives (n=29) compared to healthy probands (n=29) and their relatives (n=29). The Iowa Gambling Task (IGT), the Tower of Hanoi (ToH) and the Wisconsin Card Sorting Test (WCST) were administered. Concordance rates and heritability indices were also calculated in probands/relatives. Impaired performance on the IGT and the WCST were found in both AN probands and their relatives, although planning appeared to be preserved. The IGT heritability index suggested the presence of genetic effects that influence this measure. No evidence for genetic effects was found for the WCST. The results suggest the presence of a shared dysfunctional executive profile in women with AN and their unaffected relatives, characterized by deficient decision-making and set-shifting. Concordance analysis strongly suggests that these impairments aggregate in AN families, supporting the hypothesis that they may constitute biological markers for AN. Decision-making impairment presents a moderate heritability, suggesting that decision-making may be a candidate endophenotype for AN.

Motor inhibition and cognitive flexibility in eating disorder subtypes

Anorexia Nervosa (AN) and Bulimia Nervosa (BN) are complex Eating Disorders (EDs). Even if are considered two different diagnostic categories, they share clinical relevant characteristics. The evaluation of neurocognitive functions, using standardized neuropsychological assessment, could be a interesting approach to better understand differences and similarities between diagnostic categories and clinical subtypes in EDs thus improving our knowledge of the pathophisiology of EDs spectrum. This study explored cognitive flexibility and motor inhibition in patients with AN considering both Restricter and Binge/Purge subtypes, patients with BN and healthy comparisons subjects (HC). Intra-Extra Dimentional Set shifting Test and Stop Signal Task, selected from CANTAB battery, were administered to analyzed set-shifting and motor inhibition respectively. AN patients showed a deficient motor inhibition compared to HC, while no evidence for impaired motor inhibition was found in BN patients; a significant relationship between commission errors in the Stop Signal Task and attentional impulsiveness was found. Moreover, no difference in set-shifting abilities was found comparing all clinician groups and HC. So our results indicated no cognitive impairment in these two cognitive functions in BN patients, while AN and BN showed different performances in motor inhibition. A similar cognitive profile was found in other obsessive compulsive spectrum disorders. Finally, the paper suggests a new interactive approach for the study of cognitive profile in psychiatric disorders; it might be more useful since it is more closely related to the executive functions complexity.

Fat Mass and Obesity-Associated Gene ( FTO ) in Eating Disorders: Evidence for Association of the rs9939609 Obesity Risk Allele with Bulimia nervosa and Anorexia nervosa

Objective: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). Methods: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. Results: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001–∞; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932–∞; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027–1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101–2.541, two-sided p = 0.015,). Conclusion: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN.

Effects of gender and executive function on visuospatial working memory in adult obsessive–compulsive disorder

Visuospatial working memory (VSWM) is the ability of the brain to transiently store and manipulate visual information. VSWM deficiencies have been reported in obsessive–compulsive disorder (OCD), but not consistently, perhaps due to variability in task design and clinical patient factors. To explore this variability, this study assessed effects of the design factors task difficulty and executive organizational strategy and of the clinical factors gender, OCD symptom dimension, and duration of illness on VSWM in OCD. The CANTAB spatial working memory, spatial recognition memory, delayed matching to sample, and stop signal tasks were administered to 42 adult OCD patients and 42 age- and sex-matched healthy controls. Aims were to detect a possible VSWM deficit in the OCD sample, to evaluate influences of the above task and patient factors, to determine the specificity of the deficit to the visuospatial subdomain, and to examine effects of sustained attention as potential neurocognitive confound. We confirmed previous findings of a VSWM deficit in OCD that was more severe for greater memory load (task difficulty) and that was affected by task strategy (executive function). We failed to demonstrate significant deficits in neighboring or confounding neurocognitive subdomains (visual object recognition or visual object short-term memory, sustained attention). Notably, the VSWM deficit was only significant for female patients, adding to evidence for sexual dimorphism in OCD. Again as in prior work, more severe OCD symptoms in the symmetry dimension (but no other dimension) significantly negatively impacted VSWM. Duration of illness had no significant effect on VSWM. VSWM deficits in OCD appear more severe with higher task load and may be mediated through poor task strategy. Such deficits may present mainly in female patients and in (male and female) patients with symmetry symptoms.