Damiaan Denys

Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder

BACKGROUNDnDespite growing evidence for involvement of the dopaminergic system in obsessive-compulsive disorder (OCD), the functional anatomy of the dopaminergic system in the basal ganglia has been investigated sparsely.nnnMETHODSnDopamine D(2) receptor binding was assessed in 10 medication-free OCD patients and 10 healthy control subjects, matched for age, gender, and handedness. The binding potential was measured with single photon emission computerized tomography (SPECT) and infusion of the D(2) receptor radiotracer [(123)I] iodobenzamide. With magnetic resonance imaging as reference, regions of interest (caudate and putamen) were delineated for each hemisphere and coregistered with the corresponding SPECT scans.nnnRESULTSnDopamine D(2) receptor binding in the left caudate nucleus was significantly lower in the patients with OCD than in healthy control subjects [F(1,18) = 7.0, p =.016]. In addition, an interhemispheric difference was observed in the patient sample. Both the D(2) receptor binding potential (df = 9, p =.012), and the volume (df = 9, p =.029) of the left caudate nucleus were statistically significantly reduced relative to the right caudate nucleus.nnnCONCLUSIONSnThis study provides in vivo evidence for abnormalities in the binding potential of the dopamine D(2) receptor, which suggest the direct involvement of the dopaminergic system in the pathophysiology of OCD.

Spatial working memory deficits in obsessive compulsive disorder are associated with excessive engagement of the medial frontal cortex.

Recent studies have shown that obsessive compulsive disorder (OCD) is associated with a specific deficit in spatial working memory, especially when task difficulty (i.e., working memory load) is high. It is not clear whether this deficit is associated with dysfunction of the brain system that subserves spatial working memory, or whether it is associated with a more generalized effect on executive functions. In contrast to studies in healthy volunteers and schizophrenia, spatial working memory in OCD has not been investigated before using functional neuroimaging techniques. We conducted a functional MRI study in 11 treatment-free female patients with OCD and 11 for sex-, age-, education-, and handedness pairwise-matched healthy controls in order to assess performance on a parametric spatial n-back task as well as the underlying neuronal substrate and its dynamics. Patients with OCD performed poorly at the highest level of task difficulty and engaged the same set of brain regions as the matched healthy controls. In this set, the effect of difficulty on magnitude of brain activity was the same in patients and in controls except for a region covering the anterior cingulate cortex. In this region activity was significantly elevated in patients with OCD at all levels of the parametric task. These findings do not provide evidence for a deficit of the spatial working memory system proper, but suggest that the abnormal performance pattern may be secondary to another aspect of executive dysfunctioning in OCD.

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

BACKGROUNDnMounting evidence suggests the involvement of the dopamine system in the pathophysiology of obsessive-compulsive disorder.nnnMETHODnThe relationship of the dopamine D(2) receptor (DRD2) TaqI A, and catechol-O-methyl-transferase (COMT) NlaIII High/Low activity polymorphism to obsessive-compulsive disorder (OCD) was examined in a sample of 150 patients and 150 controls.nnnRESULTSnOCD patients did not show significant differences in genotype distribution and allele frequency for polymorphisms investigated relative to controls. However, when the sample was stratified by gender, there was a trend to a significant predominance of the DRD2 A2A2 genotype (p=0.049), and a higher frequency of the DRD2 A2 allele (p=0.020) and low-activity COMT allele (p=0.035) in male OCD patients compared to male controls. In addition, we observed an association of the DRD2 A2A2 genotype in patients with an early onset of disease (<or=15 years) (p=0.033).nnnCONCLUSIONSnOur findings replicate previous reports and provide support for a potential role of the COMT and DRD2 locus in subgroup of male, early onset patients with OCD.

Decreased TNF-α and NK activity in obsessive-compulsive disorder

Abstract Background : Accumulating evidence points towards the involvement of autoimmune mechanisms in the pathophysiology of some subgroups of obsessive-compulsive disorder (OCD). This study was carried out to investigate whether obsessive-compulsive disorder is associated with altered activity of the immune system, and whether these changes are related to particular clinical characteristics. Methods : Ex vivo production of TNF- α , IL-4, IL-6, IL-10, and IFN- γ in whole blood cultures, and NK-cell activity and peripheral blood NK cell-, monocytes-, T-cell-, and B-cell- percentages were measured in 50 medication-free outpatients with OCD and 25 controls. Results : In OCD patients, we found a significant decrease in production of TNF- α ( p p = 0.002) in comparison with controls. No significant differences were observed in the other immune variables. Patients with first-degree relatives with OCD had significant lower NK-activity than patients who had no relatives with OCD ( p = 0.02), and patients with a childhood onset of OCD had significantly lower number of NK-cells than patients with a late onset ( p = 0.003). Conclusions: Changes in TNF- α and NK activity suggest a potential role of altered immune function in the pathophysiology of obsessive-compulsive disorder.

Attention and cognition in patients with obsessive–compulsive disorder

Abstractu2002 Although a dysfunctional prefrontal‐striatal system is presupposed in obsessive–compulsive disorder (OCD), this is not sustained by neuropsychological studies. The aim of this study was twofold: (i) to investigate the cognitive deficits in patients with OCD compared to matched healthy controls; and (ii) to relate cognitive performance to clinical characteristics in patients with OCD. In this study, 39 patients with primary OCD according to Diagnostic and Statistical Manual, fourth edition criteria were compared to 26 healthy control subjects on a battery measuring verbal memory and executive functioning. Patients with OCD showed slowed learning on the verbal memory task and made more errors on the Wisconsin Card Sorting Test. Errors were failures to maintain set, which were related to severity of OCD symptomatology. The results show that patients with OCD have cognitive deficits. The authors hypothesize that these deficits may be interpreted by attentional deficits caused by a dysfunctional anterior cingulate cortex.

Synergistic dopamine increase in the rat prefrontal cortex with the combination of quetiapine and fluvoxamine

RationaleThe combination of atypical antipsychotic drugs in addition to serotonin reuptake inhibitors has recently proven to be beneficial in a number of neuropsychiatric disorders, such as major depression, schizophrenia, and obsessive–compulsive disorder.ObjectivesTo investigate the effects of an atypical antipsychotic drug in combination with a serotonin reuptake inhibitor on extracellular serotonin [5-HT]ex, and dopamine levels [DA]ex in different brain areas.MethodsThe effects of quetiapine (10xa0mg/kg) with fluvoxamine (10xa0mg/kg) on [5-HT]ex and [DA]ex were compared in the rat dorsal striatum, prefrontal cortex, nucleus accumbens (core and shell), and thalamus by means of microdialysis coupled to HPLC with electrochemical detection.ResultsQuetiapine had no significant effect on [DA]ex and [5-HT]ex levels in the prefrontal cortex and thalamus, but increased [DA]ex and [5-HT]ex levels in the dorsal striatum. In the accumbens, quetiapine increased [DA]ex levels and decreased [5-HT]ex levels. Fluvoxamine increased [5-HT]ex levels in all brain areas, and also increased [DA]ex levels in the striatum. The combination of quetiapine with fluvoxamine increased [DA]ex and [5-HT]ex levels in all brain areas compared with baseline. Although neither quetiapine nor fluvoxamine in monotherapy affected [DA]ex levels in the prefrontal cortex and thalamus, the combination produced a significant increase of [DA]ex levels in these two brain areas.ConclusionsThe combination of quetiapine with fluvoxamine causes a synergistic dopamine increase in the prefrontal cortex and the thalamus.

Electroconvulsive therapy has acute immunological and neuroendocrine effects in patients with major depressive disorder

BACKGROUNDnMajor depressive disorder is associated with alterations in the neuroendocrine as well as immune system. Few studies examined the impact of electroconvulsive therapy (ECT) on these systems in patients with major depressive disorder (MDD).nnnMETHODSnIn this explorative study 12 patients suffering from medication-resistant MDD or MDD with psychotic features were studied during the first, the fifth and eleventh session of ECT. Blood samples were taken immediately prior to the electrostimulus and 5, 15 and 30 min after the electrostimulus to assess various lipopolysaccharide (LPS) stimulated or T-cell mitogen induced cytokines, immune cell numbers, Natural Killer cell activity, cortisol and ACTH.nnnRESULTSnAcute ECT increased the LPS-stimulated production of the cytokines IL-6 and TNF-α by peripheral monocytes but not the production of the anti-inflammatory cytokine IL-10. Acute ECT decreased T cell mitogen-induced levels of IFN-γ but IL-10 and IL-4 levels were left unaffected while NK cell activity increased momentarily but significantly. Cortisol and ACTH rose significantly after electrostimulus. Repeated ECT had no significant effect on any of the parameters.nnnLIMITATIONSnThe study had a small group size. Also the patient group was heterogeneous as it consisted of patients with therapy-resistant depression with or without psychotic features.nnnCONCLUSIONSnResults suggest that acute ECT is associated with transient immunological and neuro-endocrine changes, while repeated ECT does not have an additive effect on the immune and neuroendocrine functions.

Spatial working memory in obsessive–compulsive disorder improves with clinical response: A functional MRI study

To date, only a few studies have examined whether executive dysfunctions in obsessive-compulsive disorder (OCD) are state or trait dependent and almost none of these studies have used functional neuroimaging techniques. We conducted a functional MRI study before and after 12 weeks of pharmacological treatment in 14 psychotropic-free patients with OCD without comorbidity. Subjects performed a spatial variant of a working memory task with four increasing levels of difficulty (n-back task). Responders and non-responders did not differ in clinical and demographical characteristics or brain activation patterns before treatment. Performance improved only in responders and was associated with a change in the overall pattern of brain activity during the task. We found no correlations between (changes in) scores on symptom scales, brain activity and performance. Our preliminary findings suggests that spatial working memory deficits in OCD and their functional anatomical correlates, as assessed with a spatial n-back task, are, at least to some extent, state dependent.