Refractory Obsessive-compulsive Disorder Research Articles

Morphometric brain characterization of refractory obsessive–compulsive disorder: Diffeomorphic anatomic registration using exponentiated Lie algebra

Few studies have used neuroimaging to characterize treatment-refractory obsessive-compulsive disorder (OCD). This study sought to explore gray matter structure in patients with treatment-refractory OCD and compare it with that of healthy controls. A total of 18 subjects with treatment-refractory OCD and 26 healthy volunteers were analyzed by MRI using a 3.0-T scanner and voxel-based morphometry (VBM). Diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL) was used to identify structural changes in gray matter associated with treatment-refractory OCD. A partial correlation model was used to analyze whether morphometric changes were associated with Yale-Brown Obsessive-Compulsive Scale scores and illness duration. Gray matter volume did not differ significantly between the two groups. Treatment-refractory OCD patients showed significantly lower gray matter density than healthy subjects in the left posterior cingulate cortex (PCC) and mediodorsal thalamus (MD) and significantly higher gray matter density in the left dorsal striatum (putamen). These changes did not correlate with symptom severity or illness duration. Our findings provide new evidence of deficits in gray matter density in treatment-refractory OCD patients. These patients may show characteristic density abnormalities in the left PCC, MD and dorsal striatum (putamen), which should be verified in longitudinal studies.

Neurosurgery for mental disorders: a review

Neurosurgical interventions date back to ancient civilization, 5100 BC through a practice known as trephination. Due to past abuse and ethical considerations, neurosurgical interventions in psychiatry remain a controversial issue. This article aims to review the different surgical techniques and their current application in the treatment of psychiatric disorders. The U.S Food and Drug Administration (FDA) gave its approval for vagal nerve stimulation (VNS) for the management of treatment-resistant depression in 2005 and deep brain stimulation (DBS) for refractory obsessive-compulsive disorders (OCD) in 2009. These invasive but non destructive techniques represent the future of neurosurgery for mental disorder.

Deep brain stimulation affects conditioned and unconditioned anxiety in different brain areas

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) has proven to be an effective treatment for therapy refractory obsessive–compulsive disorder. Clinical observations show that anxiety symptoms decrease rapidly following DBS. As in clinical studies different regions are targeted, it is of principal interest to understand which brain area is responsible for the anxiolytic effect and whether high-frequency stimulation of different areas differentially affect unconditioned (innate) and conditioned (learned) anxiety. In this study, we examined the effect of stimulation in five brain areas in rats (NAc core and shell, bed nucleus of the stria terminalis (BNST), internal capsule (IC) and the ventral medial caudate nucleus (CAU)). The elevated plus maze was used to test the effect of stimulation on unconditioned anxiety, the Vogel conflict test for conditioned anxiety, and an activity test for general locomotor behaviour. We found different anxiolytic effects of stimulation in the five target areas. Stimulation of the CAU decreased both conditioned and unconditioned anxiety, while stimulation of the IC uniquely reduced conditioned anxiety. Remarkably, neither the accumbens nor the BNST stimulation affected conditioned or unconditioned anxiety. Locomotor activity increased with NAc core stimulation but decreased with the BNST. These findings suggest that (1) DBS may have a differential effect on unconditioned and conditioned anxiety depending on the stimulation area, and that (2) stimulation of the IC exclusively reduces conditioned anxiety. This suggests that the anxiolytic effects of DBS seen in OCD patients may not be induced by stimulation of the NAc, but rather by the IC.

Bilateral stereotactic anterior capsulotomy for obsessive-compulsive disorder: long-term follow-up

Background and purposePsychosurgery, such as anterior capsulotomy, is a therapeutic option for treatment-resistant obsessive-compulsive disorder (OCD). In this paper, we present a prospective, long-term follow-up study aimed at evaluating both...

Long-Term Efficacy of Stereotactic Bilateral Anterior Cingulotomy and Bilateral Anterior Capsulotomy as a Treatment for Refractory Obsessive-Compulsive Disorder

Objective: To investigate the long-term efficacy and adverse effects of stereotactic bilateral anterior cingulotomy (BACI) and bilateral anterior capsulotomy (BACA) as a treatment for refractory obsessive-compulsive disorder (OCD) patients. Methods: Seven patients suffering from refractory OCD underwent stereotactic surgery and were followed for 12 months. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess the efficacy. The test was taken before and 6 and 12 months after surgery. Results: The mean Y-BOCS scores decreased significantly from 32.9 ± 4.7 at baseline to 20.6 ± 5.3 after 12 months. Five out of the 7 patients showed a decrease of more than 35%. During the 12-month follow-up, the effective rate had increased from 28.6 to 71.4%. There were no significant adverse effects observed after surgery. Conclusions: The BACI and BACA were effective for the treatment of refractory OCD, and no significant adverse effects on long-term follow-up were found.

In a double-blind, randomized and placebo-controlled trial, adjuvant memantine improved symptoms in inpatients suffering from refractory obsessive-compulsive disorders (OCD)

There is growing evidence that memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, may be applied as an add-on in treating patients suffering from obsessive-compulsive disorders (OCD). The aim of the present study was therefore to assess the effect of adjuvant memantine in a double-blind, randomized, and placebo-controlled study of the treatment of patients suffering from OCD. A total of 40 inpatients (32 females (80%); mean age = 31.25years) suffering from OCD were randomly assigned to a treatment (administration of memantine) or a control group (placebo). Treatment lasted for 12 consecutive weeks. All patients were treated with selective serotonin re-uptake inhibitors or clomipramine. Patients completed the Yale-Brown Obsessive Compulsive Scale four times. Experts' ratings consisted in clinical global impression (clinical global impressions (CGI), illness severity and illness improvement; two to three times). Liver enzymes SGOT and SGPT were also assessed (twice). Of the 40 inpatients approached, 29 completed the 12 consecutive weeks of the study. Of the 11 dropouts, 6 were in the target group and five in the control group. Symptoms significantly decreased across the period of the study, but particularly in the treatment compared with the control group (significant time × group interaction). Illness severity (CGI severity) also significantly decreased over time but more so in the treatment than in the control group (significant time × group interaction). Illness improvements (CGI improvements) were not significant. The pattern of results from the present double-blind, randomized, and placebo-controlled study for the treatment of patients suffering from OCD suggests that adjuvant memantine does significantly and favorably impact on OCD.

Metabolic Imaging of Bilateral Anterior Capsulotomy in Refractory Obsessive Compulsive Disorder: an FDG PET Study

The therapeutic benefits of bilateral capsulotomy for the treatment of refractory obsessive compulsive disorder (OCD) are probably attributed to interruption of the cortico-striato-thalamo-cortical circuitry. We evaluated resting brain metabolism and treatment response in OCD patients using positron emission tomography (PET) imaging. [(18)F]-fluoro-deoxy-glucose PET was performed in eight OCD patients precapsulotomy and postcapsulotomy. We determined metabolic differences between preoperative images in patients and those in eight age-matched healthy volunteers, and postoperative changes and clinical correlations in the patients. The OCD patients showed widespread metabolic increases in normalized glucose metabolism in the bilateral orbitofrontal cortex and inferior frontal gyrus, cingulate gyrus, and bilateral pons/cerebellum, and metabolic decreases bilaterally in the precentral and lingual gyri. Bilateral capsulotomy resulted in significant metabolic decreases bilaterally in the prefrontal cortical regions, especially in the dorsal anterior cingulate cortex (ACC) and in the medial dorsal thalamus and caudate nucleus. In contrast, metabolism increased bilaterally in the precentral and lingual gyri. Clinical improvement in patients correlated with metabolic changes in the bilateral dorsal ACC and in the right middle occipital gyrus after capsulotomy. This study underscores the importance of the internal capsule in modulating ventral prefrontal and dorsal anterior cingulate neuronal activity in the neurosurgical management of OCD patients.

1343 – RTMS of the dorsomedial prefrontal cortex achieves robust and durable improvements in refractory obsessive-compulsive disorder

Patients with Obsessive-Compulsive Disorder (OCD) often show minimal response to either pharmacotherapy or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is being explored as a new treatment for OCD. rTMS targeting the dorsolateral prefrontal cortex (DLPFC) has not shown robust efficacy; however, neuroimaging studies of OCD have shown more consistent volumetric grey matter reductions along the medial rather than the lateral prefrontal cortex, specifically in the dorsomedial prefrontal cortex (DMPFC). rTMS targeting medial motor areas such as the supplementary motor area (SMA) and pre-SMA has shown some efficacy in OCD. However, the DMPFC proper, just anterior to the pre-SMA, has not previously been targeted. We have previously used a novel rTMS technique to target DMPFC with robust effects in refractory depression. Here we apply this technique in an open-label series of 10 consecutive patients with refractory OCD. Under MRI-guidance, patients received bilateral DMPFC-rTMS at 10 Hz, 120% resting motor threshold, 6000 pulses per day for 20 - 30 sessions over 4-6 weeks. Robust improvements were achieved, with YBOCS scores dropping by more than half in the large majority of cases and full remission achieved in several cases. Scores continued dropping after treatment in some cases, suggesting durable improvements in capacity to suppress intrusive thoughts and behaviours. Improvements were durable at 3-6 months. Pre- and post-treatment functional MRI revealed changes in resting-state connectivity to DMPFC following treatment. A sham-controlled trial may be warranted as a next step. If successful, DMPFC-rTMS may represent a new, effective therapeutic option in refractory OCD.

Deep Brain Stimulation as a Tool for Improving Cognitive Functioning in Alzheimer’s Dementia: A Systematic Review

Deep brain stimulation (DBS) is an established, in selected cases therapeutically effective, non-lesional treatment method delivering current rectangular pulses into dysfunctional brain structures via chronically implanted stimulation electrodes. DBS is a recognized method applied in movement disorders and is increasingly evaluated as a possible therapeutic option for psychiatric diseases such as refractory obsessive-compulsive disorders, Gilles de la Tourette syndrome, major depression, and substance-related addiction. Latest research indicates that DBS may be a method for improving cognitive functions in Alzheimer’s dementia (AD). Translational data in healthy and AD animals appear to support this notion. Nevertheless, many aspects remain unclear, particularly with regard to the optimal target structure. The objective of this review is to present a systematic overview regarding published research on DBS and cognitive functioning in animal and human studies as well as to provide a systematic overview of the feasibility and efficacy of the treatment. We describe three studies investigating the effects of DBS in patients with dementia, using either the fornix or the nucleus basalis of Meynert (NBM) as a target. In total, we identified 25 animal studies with 10 brain structures being targeted: fornix, NBM, anterior caudate nucleus, dorsal striatum, anterior thalamic nucleus, midline thalamic nuclei, central thalamus, lateral hypothalamus, hippocampus (entorhinal cortex, perforant path), and amygdala. Considering the wide and diverse spectrum of targets, we add to this review a supposition about possible underlying mechanisms of operation and recommendations for further research.

Combined bilateral anterior cingulotomy and ventral capsule/ventral striatum deep brain stimulation for refractory obsessive-compulsive disorder with major depression: Do combined procedures have a long-term benefit?

The ventral capsule (VC), ventral striatum (VS), and the anterior cingulate gyrus are parts of the obsessive-compulsive disorder (OCD) and depression circuits. We assessed whether a combination of bilateral anterior cingulotomy and VC/VS deep brain stimulation (DBS) had an additive effect in patients with OCD and major depression. Three patients with refractory OCD underwent combined bilateral anterior cingulotomy and VC/VS DBS procedures. All patients met the inclusion criteria for the Korean guidelines of DBS for OCD. Baseline Yale-Brown Obsessive-Compulsive Disorder Scale (Y-BOCS) scores, Hamilton Depression Rating Scale scores, and global assessments of functioning were evaluated. These scores were also serially estimated for more than 24 months after surgery at 3-month intervals. The mean value of the baseline Y-BOCS scores was 34.7 (range 30-38); the mean Y-BOCS value decreased significantly to 23.0 (range 20-25) 3 months after the surgery. This score was maintained 2 years after surgery with a mean value of 19.0 (range 18-20). The combination of the two therapies did not yield superior outcomes, as the clinical outcomes were comparable to those of previous reports for VC/VS DBS alone. Wide-area VC/VS DBS may be sufficient to control refractory OCD.

Treating refractory obsessive-compulsive disorder: what to do when conventional treatment fails?

Obsessive-compulsive disorder (OCD) is a chronic and impairing condition. A very small percentage of patients become asymptomatic after treatment. The purpose of this paper was to review the alternative therapies available for OCD when conventional treatment fails. Data were extracted from controlled clinical studies (evidence-based medicine) published on the MEDLINE and Science Citation Index/Web of Science databases between 1975 and 2012. Findings are discussed and suggest that clinicians dealing with refractory OCD patients should: 1) review intrinsic phenomenological aspects of OCD, which could lead to different interpretations and treatment choices; 2) review extrinsic phenomenological aspects of OCD, especially family accommodation, which may be a risk factor for non-response; 3) consider non-conventional pharmacological approaches; 4) consider non-conventional psychotherapeutic approaches; and 5) consider neurobiological approaches.

Deep Brain Stimulation for the Treatment of Severe, Medically Refractory Obsessive-Compulsive Disorder

Deep Brain Stimulation for the Treatment of Severe, Medically Refractory Obsessive-Compulsive Disorder

N-Acetylcysteine Add-On Treatment in Refractory Obsessive-Compulsive Disorder

This study aimed to evaluate the efficacy and safety of N-acetylcysteine, a glutamate-modulating agent, in patients with treatment-refractory obsessive-compulsive disorder as an adjunct to serotonin reuptake inhibitor treatment. Forty-eight patients (36 women; mean ± SD age, 30.93 ± 4.99) with obsessive-compulsive disorder who failed to respond to a course of serotonin reuptake inhibitor treatment were randomized to a 12-week intervention period of N-acetylcysteine (up to 2400 mg/d) or placebo. Primary outcome measures were the change in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score from baseline to end point and the rate of full response in each group at the end of trial. Full response was defined as 35% or greater reduction in Y-BOCS score from baseline. Changes of Y-BOCS score were different over time (P < 0.001) and between groups (P < 0.001). N-acetylcysteine-assigned patients showed significantly improved mean Y-BOCS score (P = 0.003) and Clinical Global Impression-Severity of Illness scale score (P = 0.01) but not Clinical Global Impression-Improvement scale score at study end point. Of the patients in the N-acetylcysteine group, 52.6% were full responders at the end of the study, which was significantly higher than 15% of the patients in the placebo group (P = 0.013). This trial suggests that N-acetylcysteine may be a safe and effective option to augment standard treatment in patients with refractory obsessive-compulsive disorder.

Polypharmacy with antidepressants in children and adolescents

The aim of this study was to review current epidemiological data on the use of antidepressants in co-prescription with other psychotropic drugs in children and adolescents, as well as available efficacy and safety information. A Medline search from inception until February 2012 was performed to identify epidemiological and clinical studies, reviews and reports containing potentially relevant information on polypharmacy with antidepressants in young people. There has been an increase in polypharmacy in children and adolescents involving antidepressants in recent years. Antidepressants have become one of the drug classes most frequently prescribed in combination and are commonly co-prescribed with stimulants and antipsychotics. Most information regarding efficacy and safety of polypharmacy patterns was provided by case series and open-label studies. Efficacy studies gave some support for the use of a combination of antidepressants and antipsychotics in the management of refractory obsessive-compulsive disorder and some residual symptoms in major depressive disorder. Even less empirical support was found for a combination of stimulants and antidepressants in co-morbid attention deficit hyperactivity disorder and mood or anxiety disorders. Adverse events were similar to those found with individual medication groups, with severe adverse events mostly reported by individual case reports. The use of polypharmacy with antidepressants has become a regular practice in clinical settings. Although there is still little efficacy and safety information, preliminary evidence points to the potential clinical usefulness of some polypharmacy patterns. Further research on patients with co-morbidities or more severe conditions is needed, in order to improve knowledge of this issue.

Buprenorphine augmentation in the treatment of refractory obsessive–compulsive disorder

OCD is often refractory to treatment. There is a need for the development of new, non-invasive treatments for severe OCD. There is evidence that opiates can be a useful adjunctive treatment in OCD. We summarise our experience with sublingual buprenorphine augmentation of standard pharmacological management of severe OCD. Patients were recruited from a standard psychiatric outpatient clinic and gave their consent to the treatment trial. The severity of the OCD was rated with the Y-BOCS. The buprenorphine was introduced to their existing medication regime at a low dose and the dose increased according to response. In order to gauge the reproducibility of the response the buprenorphine was withdrawn and then reintroduced once symptoms had returned. 4 out of 7 patients with treatment resistant OCD showed a 30% reduction in the Y-BOCS score following buprenorphine augmentation. 3 of the responders were comorbid for other Axis 1 diagnoses. All of the responders had shown some improvement with SSRIs or clomipramine. Non-responders had not shown any improvement with either antidepressant or antipsychotic drugs. Typically improvement appeared within 2 days of initiating buprenorphine and waned within 1 to 2 days of its discontinuation. The dose of buprenorphine required varied between 400 µg and 600 µg a day. One responder managed on alternate day dosing. Reintroduction of buprenorphine resulted in symptom control within 2 to 3 days. The buprenorphine treatment was not associated with significant side-effects and the improvement was maintained without progressive dose escalation. Buprenorphine augmentation of standard treatment for OCD can result in clinically meaningful improvement in a proportion of refractory OCD cases. Further treatment trials are indicated.

Brain-Behavior Relationship in a Case of Successful ECT for Drug Refractory Catatonic OCD

This case report describes the successful response to electroconvulsive therapy (ECT) in a patient with an unusual presentation of catatonia, whose onset occurred in the context of an extremely severe form of refractory obsessive-compulsive disorder (OCD). We correlated the clinical improvement in catatonic and OCD symptoms with specific changes in brain function as shown by regional cerebral blood flow scans, neurological soft signs examination, and neuropsychological testing. All assessments were conducted before and after the ECT course. The results strongly suggest that a right hemisphere dysfunction was the neural correlate of our patient's symptoms, and that ECT, by reverting this abnormality, may serve as an effective therapeutic approach for refractory catatonic OCD.

How should we measure delayed sleep phase shift in severe, refractory obsessive-compulsive disorder?

Objective. A previous study, based upon direct nursing observations, showed almost half of a cohort of inpatients with severe, enduring OCD also suffered from delayed sleep phase shift. Males, younger patients and those with more severe symptoms were most likely to be affected. However, the ward environment may have had a direct effect on sleeping patterns. In this study we compared the accuracy of actigraphic measurements with that of the “gold standard” of direct nursing observation, and other clinical sleep scales. We postulated that actigraphy would prove a reliable, acceptable, and valid alternative. Methods. All patients admitted over 29 months to a specialized treatment unit for severe, chronic refractory OCD were invited to participate. We collected demographic data, clinical measures of OCD and depressive symptom severity, self-rated measures of social and occupational disability and sleep, nursing records based upon direct observation of sleep onset and duration, and actigraphy records. Results. Evaluable data was obtained from 36 patients (22 males) with an average age of 37 years and profound OCD symptoms measured by the Yale-Brown Obsessive-Compulsive Scale. According to direct nursing observation, 12 patients (33%) showed delayed sleep phase shift. Actigraphic recordings demonstrated good agreement (kappa = 0.63) with nursing observation as did the St George's Insomnia Questionnaire (kappa = 0.66). Conclusion. This study demonstrates that actigraphy is a reliable method of recording sleep/activity cycles in severe, enduring OCD.

Long-term follow-up of deep brain stimulation for refractory obsessive-compulsive disorder

We studied the 2-year outcome of deep-brain stimulation at the ventral anterior limb of the internal capsule and ventral striatum for 4 patients with treatment-resistant OCD. There were prolonged improvement of obsessive-compulsive symptoms and depressive symptoms along with notable functional improvement in all participants with no battery depletion.

Pilot study of deep brain stimulation in refractory obsessive–compulsive disorder ethnic Chinese patients

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is a promising alternative to ablative surgery in treatment of refractory obsessive-compulsive disorder (OCD). A pilot study was conducted to assess 15-month outcomes of DBS in patients with refractory OCD in Taiwan. Four adult patients with a 3-year or more history of refractory OCD (Yale-Brown Obsessive-Compulsive Scale [Y-BOCS] score of at least 28) met the criteria for DBS surgery. DBS electrodes were implanted bilaterally in the VC/VS. Stimulation was adjusted for therapeutic benefit and absence of adverse effects. Psychiatric evaluation was conducted preoperatively, postoperatively, and at follow up at every 3 months for 15 months. Primary outcome measure was Y-BOCS. Secondary outcomes included the Hamilton Depression Rating Scale (HAM-D), and the Global Assessment of Function Scale. Mean severity of OCD was a Y-BOCS score of 36.3 ± 2.1. At the end of 15 months' follow up, there was a 33.06% decrease in OCD severity (P = 0.001). Similar findings were seen for HAM-D (32.51% reduction, P = 0.005), and Global Assessment of Function Scale (31.03% increase, P = 0.026). In terms of adverse effects, two patients suffered from hypomania episodes after several weeks of DBS stimulation, and one had transient hypomania-like syndrome during DBS initial programming. One patient (Case 1) had an allergic reaction to implantation of the pulse generator in the chest, and another patient (Case 3) exhibited vertigo. We confirm that DBS of the VC/VS appears to be beneficial for improvements in function and mood among patients with treatment-resistant OCD. Compared to previous studies examining the therapeutic effects of DBS, no serious adverse effects were observed.

N-of-1 trial following deep brain stimulation in a patient with obsessive–compulsive disorder

N-of-1 trials are an effective evidence-based approach in individual patient management. It has been suggested that deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is effective in the treatment of refractory obsessive–compulsive disorder (OCD). However, it has not been documented in the literature whether a perioperative acute stimulation test can provide substantial information for chronic stimulation. A 21-year-old man with a 6-year history of medication-refractory OCD underwent bilateral DBS on the VC/VS. Two weeks after surgery, an acute stimulation test was performed in an N-of-1 trial. Olfactory hallucinations, laughter, and euphoria were observed during the acute stimulation test. At follow-up after 17 months, the patient's scores improved from 34 at baseline to 14 on the Yale–Brown Obsessive Compulsive Scale, from 34 to 20 (41.2% improvement) on the Hamilton Anxiety Rating scale, and from 41 to 71 (75% improvement) on the Global Assessment of Functioning scale. According to our N-of-1 trial, olfactory hallucinations, in addition to laughter, induced by a perioperative acute stimulation test may be an indicator of good outcome in OCDDBS during chronic stimulation.