Herman G.M. Westenberg

Deep Brain Stimulation of the Nucleus Accumbens for Treatment-Refractory Obsessive-Compulsive Disorder

CONTEXT Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Even when the best available treatments are applied, approximately 10% of patients remain severely afflicted and run a long-term deteriorating course of OCD. OBJECTIVE To determine whether bilateral deep brain stimulation of the nucleus accumbens is an effective and safe treatment for treatment-refractory OCD. DESIGN The study consisted of an open 8-month treatment phase, followed by a double-blind crossover phase with randomly assigned 2-week periods of active or sham stimulation, ending with an open 12-month maintenance phase. SETTING Academic research. Patients Sixteen patients (age range, 18-65 years) with OCD according to DSM-IV criteria meeting stringent criteria for refractoriness to treatment were included in the study. INTERVENTIONS Treatment with bilateral deep brain stimulation of the nucleus accumbens. MAIN OUTCOME MEASURES Primary efficacy was assessed by score change from baseline on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Responders were defined by a score decrease of at least 35% on the Y-BOCS. RESULTS In the open phase, the mean (SD) Y-BOCS score decreased by 46%, from 33.7 (3.6) at baseline to 18.0 (11.4) after 8 months (P < .001). Nine of 16 patients were responders, with a mean (SD) Y-BOCS score decrease of 23.7 (7.0), or 72%. In the double-blind, sham-controlled phase (n = 14), the mean (SD) Y-BOCS score difference between active and sham stimulation was 8.3 (2.3), or 25% (P = .004). Depression and anxiety decreased significantly. Except for mild forgetfulness and word-finding problems, no permanent adverse events were reported. CONCLUSION Bilateral deep brain stimulation of the nucleus accumbens may be an effective and safe treatment for treatment-refractory OCD. CLINICAL TRIAL REGISTRATION isrctn.org Identifier: ISRCTN23255677.

Psychopharmacological treatment of social phobia; a double blind placebo controlled study with fluvoxamine

Previous studies have shown selective and non-selective monoamine oxidase inhibitors (MAOIs) to be effective in the treatment of social phobia. In this study we investigated the efficacy of selective serotonin reuptake inhibitors (SSRIs) in social phobia. Thirty patients with social phobia (DSM-IIIR) were treated with the SSRI fluvoxamine (150 mg daily) using a 12-week double-blind placebo controlled design. A substantial improvement was observed in seven (46%) patients on fluvoxamine and in one (7%) on placebo. Statistically significant effects were seen on measures of social anxiety and general (or anticipatory) anxiety in patients treated with fluvoxamine compared with placebo. The level of phobic avoidance decreased also but the difference at endpoint between fluvoxamine and placebo failed to reach statistical significance. It is concluded that treatment with the SSRI fluvoxamine has beneficial effects in patients suffering from social phobia, suggesting that serotonergic mechanisms might be implicated in social anxiety.

Glutamate and anxiety

Although glutamate is a simple molecule, its actions in the limbic system and areas concerning anxiety are complex and widespread. These actions are mediated through different combinations of ionotropic and metabotropic glutamate receptors. Preclinical studies have shown that compounds active at NMDA, AMPA/kaïnate and metabotropic receptors might have anxiolytic properties. The major research effort so far has been directed towards the development of compounds which modulate the function of NMDA receptors. In general, the utility of NMDA and AMPA/kaïnate antagonists is greatly hampered by adverse effects. For the treatment of clinical anxiety disorder a more delicate regulation of the glutaminergic system is required. It is encouraging that different ways to fine-tune the glutaminergic system are emerging, e.g., modulators of the glycine site and compounds acting at the AMPA receptor. Metabotropic glutamate receptor agonists and antagonists are in particular promising in this respect. It can be expected that selective modulators of glutamate activity will be of great clinical significance for the treatment of anxiety disorders.

Dysfunctional Reward Circuitry in Obsessive-Compulsive Disorder

BACKGROUND Obsessive-compulsive disorder (OCD) is primarily conceived as an anxiety disorder but has features resembling addictive behavior. Patients with OCD may develop dependency upon compulsive behaviors because of the rewarding effects following reduction of obsession-induced anxiety. Reward processing is critically dependent on ventral striatal-orbitofrontal circuitry and brain imaging studies in OCD have consistently shown abnormal activation within this circuitry. This is the first functional imaging study to investigate explicitly reward circuitry in OCD. METHODS Brain activity during reward anticipation and receipt was compared between 18 OCD patients and 19 healthy control subjects, using a monetary incentive delay task and functional magnetic resonance imaging. Reward processing was compared between OCD patients with predominantly contamination fear and patients with predominantly high-risk assessment. RESULTS Obsessive-compulsive disorder patients showed attenuated reward anticipation activity in the nucleus accumbens compared with healthy control subjects. Reduced activity of the nucleus accumbens was more pronounced in OCD patients with contamination fear than in patients with high-risk assessment. Brain activity during reward receipt was similar between patients and control subjects. A hint toward more dysfunctional reward processing was found in treatment-resistant OCD patients who subsequently were successfully treated with deep brain stimulation of the nucleus accumbens. CONCLUSIONS Obsessive-compulsive disorder patients may be less able to make beneficial choices because of altered nucleus accumbens activation when anticipating rewards. This finding supports the conceptualization of OCD as a disorder of reward processing and behavioral addiction.

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

BACKGROUND Despite 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. METHODS Dopamine 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. RESULTS Dopamine 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. CONCLUSIONS This 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.

Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder

BACKGROUND While enhanced cortisol suppression in response to dexamethasone is one of the most consistent biological findings in posttraumatic stress disorder (PTSD), the relative contribution of trauma exposure to this finding remains unclear. METHODS Assessment of diurnal salivary cortisol levels and 1600 h salivary cortisol before and after oral administration of 0.5mg dexamethasone in veterans with PTSD, veterans without PTSD (trauma controls) and healthy controls. Assessment of 1600 h plasma cortisol, ACTH and corticotrophin binding globulin (CBG) in response to dexamethasone in PTSD patients and trauma controls. RESULTS Both PTSD patients and trauma controls demonstrated significantly more salivary cortisol suppression compared to healthy controls. Salivary cortisol, plasma cortisol and ACTH suppression as well as CBG levels did not differ between PTSD patients and trauma controls. PTSD patients showed a reduced awakening cortisol response (ACR) compared to healthy controls that correlated significantly with PTSD symptoms. No significant differences were observed in ACR between PTSD patients and trauma controls. CONCLUSIONS These data suggest that enhanced cortisol suppression to dexamethasone is related to trauma exposure and not specifically to PTSD. The correlation between the ACR and PTSD severity suggests that a flattened ACR may be a result of clinical symptoms.

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder.

γ-Aminobutyric acid (GABAA) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABAA receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABAA receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABAA receptor complex in veterans with and without PTSD using [11C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [11C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [11C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [11C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABAA receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.

Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients

BACKGROUND Disturbances of affect, impulse regulation, and autoaggressive behavior, which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual abuse is reported in these patients. Animal studies indicate that early, sustained stress correlates with a dysfunctional central 5-HT system. Therefore, we hypothesize that sustained traumatic stress in childhood affects the responsivity of the postsynaptic serotonergic system of traumatized BPD patients. METHODS Following Axis I, Axis II, and trauma assessment, a neuroendocrine challenge test was performed with the postsynaptic serotonergic agonist meta-chlorophenylpiperazine (m-CPP) in 12 impulsive and autoaggressive female patients with BPD and 9 matched healthy volunteers. RESULTS The cortisol and prolactin responses to the m-CPP challenge in BPD patients were significantly lower compared to those in controls. Within the group of patients with BPD, the net prolactin response showed a high inverse correlation with the frequency of the physical (r = -.77) and sexual abuse (r = -.60). CONCLUSIONS Our data suggest that severe and sustained traumatic stress in childhood affects the 5-HT system and especially 5-HT(1A) receptors. This finding confirms the data from animal research. The blunted prolactin response to m-CPP appears to be the result of severe traumatization and independent of the BPD diagnosis.

Effects of methylphenidate, desipramine, and l-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder

The objective of this study was to investigate the effects of methylphenidate (MPH) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were. In addition to MPH, two other drugs were administered in order to affect both transmitter systems more selectively, L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task that measures the ability to inhibit an ongoing action, in a double-blind randomized within-subjects design. Each child received an acute clinical dose of MPH, DMI, L-dopa, and placebo; measures of performance and plasma were determined. The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa. The response-time to the stop-signal was marginally shortened after intake of DMI. MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone. No effects of L-dopa whatsoever were noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo. It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms. The improved inhibition under DMI could be serotonergically mediated.

Neurobiology of obsessive-compulsive disorder: serotonin and beyond.

The evidence for the involvement of the serotonergic system in the pathogenesis of obsessive-compulsive disorder (OCD) is circumstantial at best, despite being the focus for most pathophysiological research over the last 2 decades. This hypothesis was initially motivated by the observed differential efficacy of selective serotonin reuptake inhibitors (SSRIs) in alleviating OCD symptoms. Direct evidence that serotonergic perturbations are implicated in the pathophysiology of OCD is still sparse. There is growing evidence, from both preclinical and clinical studies, that the dopamine system may also be involved in the pathogenesis of OCD, and that dopaminergic and serotonergic pathways play a role in the genesis and maintenance of obsessive-compulsive symptoms. The complex interactions between both systems, the phenotypic heterogeneity of the disorder, and the limitations of the available tests to probe both systems, make it as yet impossible to draw firm conclusions as to how these systems are implicated. Further studies with more selective pharmacologic agents and neurocognitive probes in humans, studies using deep brain stimulation in combination with neuroimaging, and the development of better animal models for OCD may further our understanding of this disabling condition