Deep brain stimulation in the internal capsule and nucleus accumbens region: responses observed during active and sham programming.

BACKGROUND: Recently, anterior limb of the internal capsule and nucleus accumbens deep brain stimulation (DBS) has been used in the treatment of medication-refractory obsessive-compulsive disorder (OCD). This region has been previously explored with lesion therapy, but with the advent of DBS there exists the possibility of monitoring the acute and chronic effects of electrical stimulation. The stimulation-induced benefits and side effects can be reversibly and blindly applied to a variety of locations in this region. OBJECTIVE: To explore the acute effects of DBS in the anterior limb of the internal capsule and nucleus accumbens region. METHODS: Ten total DBS leads in five patients with chronic and severe treatment-refractory OCD were tested. Patients were examined 30 days after DBS placement and received either "sham" testing or actual testing of the acute effects of DBS (the alternative condition tested 30 days later). RESULTS: Pooled responses were reviewed for comparability of distribution using standard descriptive methods, and relationships between the variables of interest were sought using chi2 analysis. A total of 845 stimulation trials across the five patients were recorded and pooled. Of these 16% were elicited from sham stimulation and 17% from placebo (0 V stimulation). A comparison of active to sham trials showed that sham stimulation was not associated with significant side effects or responses from patients. Non-mood-related responses were found to be significantly associated with the ventral lead contacts (0 and 1) (p = 0.001). Responses such as taste, smell and smile were strongly associated with the most ventral lead positions. Similarly, physiological responses--for example, autonomic changes, increased breathing rate, sweating, nausea, cold sensation, heat sensation, fear, panic and panic episodes--were significantly associated with ventral stimulation (p = 0.001). Fear and panic responses appeared clustered around the most ventral electrode (0). Acute stimulation resulted in either improved or worsened mood responses in both the dorsal and ventral regions of the anterior limb of the internal capsule. CONCLUSION: The acute effects of DBS in the region of the anterior limb of the internal capsule and nucleus accumbens, particularly when obtained in a blinded fashion, provide a unique opportunity to localise brain regions and explore circuitry.

Effect of comorbid tics on a clinically meaningful response to 8-week open-label trial of fluoxetine in obsessive compulsive disorder.

Currently, there are limited published data evaluating the effects of tics on serotonin reuptake inhibitor (SRI) monotherapy responses in treating obsessive-compulsive disorder (OCD). One retrospective case-controlled analysis of OCD patients treated with SRI monotherapy showed lesser improvement in OCD symptoms in patients with tics than those without. However, more recently there were preliminary reports of OCD subjects treated with SRI monotherapy which did not demonstrate poorer response in subjects with tics or Tourette's Syndrome (TS). The specific aim of this study was to investigate whether the presence of comorbid chronic tics affected "clinically meaningful improvement" [McDougle, C.J., Goodman, W.K., Leckman, J.F., Barr, L.C., Heninger, G.R., Price, L.H., 1993. The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. Journal of Clinical Psychopharmacology 13, 354-358] of OCD in an 8-week open-label trial of fluoxetine monotherapy. Seventy-four adult subjects (13 patients with comorbid chronic tics and 61 patients without tics) with a primary DSM-IV OCD diagnosis were treated with up to 40mg fluoxetine for 8 weeks and had at least one post-baseline evaluation. The results indicate that there was a significant response by time in both fluoxetine-with-tic subjects and fluoxetine-without-tic subjects. Additionally, there were 3 (23.0%) OCD subjects with tics who had clinically meaningful improvement versus 16 (26.2%) OCD subjects without tics that demonstrated similar levels of improvement. These findings indicate that OCD patients with or without chronic tic disorders did not have a differential response to an 8-week open-label trial of fluoxetine. Limitations include the relatively low number of tic subjects and the open-label nature of the study. Additional data are needed on how comorbid tics may affect SRI treatment response in OCD.

The neurocircuitry of obsessive-compulsive disorder and disgust.

Recent evidence from human research has indicated that discrete regions of the brain control different basic emotions. Whether the recognition and formulation of emotions truly stem from compartmentalized systems or arise from a multidimensional framework has yet to be elucidated, however. Disgust is a basic emotion that has been hypothesized to constitute an evolutionary function of contamination and disease avoidance. Disgust involves the appraisal of objects and events for their potential role in contamination, and OCD conceivably involves a dysfunction of this appraisal process. Disgust sensitivity has been shown to be positively correlated with OCD and to significantly predict contamination fear. Likewise, functional imaging studies of OCD patients with contamination concerns demonstrate activation of the same neural regions with disgust-inducing pictures as symptom relevant stimuli. Therefore, the neurocircuits involved in disgust processing may be relevant to OCD and, in particular, the contamination subtype. This review focuses on describing what is known to date concerning the neurocircuitry of disgust, and its relevance to the apparent neurocircuitry of OCD.

Is speeding a form of gambling in adolescents?

Speeding is a major contributor to motor vehicle accidents, which are the leading cause of death in adolescents. This study compares the extent to which adolescents with gambling behavior and substance use reported driving over the posted speed limits ("speeding"). Florida adolescents ages 13-17 (n = 1051) were surveyed, and asked about gambling activities, problems related to gambling, substance use, demographic questions, and speeding. Of the 562 respondents who were drivers, the gender distribution was 52.1% male and 47.9% female. Of those respondents, 76.9% were Caucasian, 6.8% were African American, 10.1% were Hispanic, and 6.1% were Native American/Asian/Other. Simple correlation analysis revealed that self-reported speeding is significantly related to gambling behavior and substance use. When a linear regression model was used, four factors showed the most significant influence on self-reported speeding: past year gambling tendency, age, trouble with the police due to drinking, and tranquilizer usage. Gambling behavior and high-risk speeding (driving ≥ 10 mph over speed limit) also were noted to be positively correlated. Our data indicate a relationship between risky driving, gambling, and other risk-taking behaviors in adolescents, and support the hypothesis that speeding may be a form of gambling behavior in this age group.

A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder.

BACKGROUND: One of the few combination approaches to the treatment of obsessive-compulsive disorder (OCD) with encouraging support is the addition of an antipsychotic to a serotonin reuptake inhibitor. METHODS: The study consisted of a 6-week, placebo-controlled addition of olanzapine 5-10 mg (6.1 +/- 2.1 mg, mean +/- SD) to fluoxetine in OCD subjects who were partial or nonresponders to an 8-week, open-label fluoxetine trial (40 mg in 43 subjects, 20 mg in 1 subject). RESULTS: Both the fluoxetine-plus-olanzapine (n = 22) and fluoxetine-plus-placebo (n = 22) groups improved significantly over 6 weeks [F(3,113) = 11.64, p <.0001] according to Yale-Brown Obsessive Compulsive Scale scores with repeated-measures analysis of variance; however, the treatment x time interaction was not significant for olanzapine versus placebo addition to fluoxetine. CONCLUSIONS: These findings indicate no additional advantage of adding olanzapine for 6 weeks in OCD patients who have not had a satisfactory response to fluoxetine for 8 weeks, compared with extending the monotherapy trial.

Brain activation by disgust-inducing pictures in obsessive-compulsive disorder.

BACKGROUND: There is growing interest in the role of disgust in the pathogenesis of obsessive-compulsive disorder (OCD). METHODS: Eight OCD subjects with contamination preoccupations and eight gender- and age-matched healthy volunteers viewed pictures from the International Affective Picture System during functional magnetic resonance imaging scans. RESULTS: A different distribution of brain activations was found during disgust-inducing visual stimulation in several areas, most notably the insula, compared with neutral stimulation in both OCD subjects and healthy volunteers. Furthermore, whereas activation during the threat-inducing task in OCD subjects showed a pattern similar to that in healthy volunteers, the pattern of activation during the disgust-inducing task was significantly different, including greater increases in the right insula, parahippocampal region, and inferior frontal sites. CONCLUSIONS: This pilot study supports the relevance of disgust in the neurocircuitry of OCD with contamination-preoccupation symptoms; future studies looking at non-OCD individuals with high disgust ratings, non-contamination-preoccupied OCD individuals, and individuals with other anxiety disorders are needed.

Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial.

OBJECTIVE: Binge eating disorder is associated with obesity. Topiramate is an antiepileptic agent associated with weight loss. The objective of this study was to evaluate topiramate in the treatment of binge eating disorder associated with obesity. METHOD: For this 14-week, double-blind, flexible-dose (25-600 mg/day) topiramate trial, 61 outpatients (53 women, eight men) with binge eating disorder who were obese (body mass index >/=30 kg/m(2)) were randomly assigned to receive topiramate (N=30) or placebo (N=31). The primary efficacy measure was binge frequency. The primary analysis of efficacy was a repeated-measures random regression with treatment-by-time as the effect measure. RESULTS: Compared with placebo, topiramate was associated with a significantly greater rate of reduction in binge frequency, binge day frequency, body mass index, weight, and scores on the Clinical Global Impression severity scale and the Yale-Brown Obsessive Compulsive Scale (modified for binge eating). Topiramate was also associated with significantly greater reductions in binge frequency (topiramate: 94%, placebo: 46%) and binge day frequency (topiramate: 93%, placebo: 46%) and with a significantly higher level of response than placebo. The mean weight loss for topiramate-treated subjects who completed the study was 5.9 kg. Median topiramate dose was 212 mg/day (range=50-600). Nine patients (three receiving placebo, six given topiramate) discontinued because of adverse events. The most common reasons for discontinuing topiramate were headache (N=3) and paresthesias (N=2). CONCLUSIONS: Topiramate was efficacious and relatively well tolerated in the short-term treatment of binge eating disorder associated with obesity.

Topiramate in the long-term treatment of binge-eating disorder associated with obesity.

BACKGROUND: This study assessed the long-term effectiveness and tolerability of topiramate in binge-eating disorder (BED) with obesity. METHOD: Sixty-one patients with BED (DSM-IV-TR criteria) and obesity enrolled in a 14-week, single-center, randomized, double-blind, placebo-controlled study. Completers (N = 35) were offered participation in a 42-week, open-label extension trial of topiramate. Fifteen patients who received topiramate and 16 patients who received placebo in the double-blind study entered the open-label trial. Topiramate was titrated from 25 mg/day to a maximum of 600 mg/day. The primary endpoint was change from baseline to final visit in weekly binge frequency using the last observation carried forward for all patients who received topiramate. Baseline for patients receiving double-blind topiramate was the beginning of the controlled study; for patients receiving placebo, baseline was the beginning of the open-label trial. Open-label data were gathered from December 1998 to November 2000. RESULTS: Forty-four patients (31 who received topiramate in the open-label trial plus 13 who received topiramate in the double-blind study only) received at least 1 dose of topiramate; 43 patients provided outcome measures at a median final dose of 250 mg/day. Mean weekly binge frequency declined significantly from baseline to final visit for all 43 patients (-3.2; p < .001), for the 15 patients who received topiramate during the controlled and open-label studies (-4.0; p < .001), and for the 15 patients who received topiramate only during the open-label trial (-2.5; p = .044). Patients also exhibited statistically significant reduction in body weight. The most common reasons for topiramate discontinuation were protocol nonadherence (N = 17) and adverse events (N = 14). CONCLUSION: Topiramate treatment was associated with enduring improvement in some patients with BED and obesity but was also associated with a high discontinuation rate.

A review of the treatment for refractory obsessive-compulsive disorder: from medicine to deep brain stimulation.

This article provides an overview of the etiology, epidemiology, and first-line treatment options for obsessive-compulsive disorder (OCD). The subject of treatment-resistant and treatment-refractory OCD is then discussed, including a definition of these often-debated terms, and the latest treatment options delineated. This includes a review of the latest research concerning the pharmacological agents that have been studied as monotherapy or augmenting agents for the treatment of OCD, the use of experimental medications and procedures, treatment with reversible, minimally invasive procedures, such as vagal nerve stimulation and transcranial magnetic stimulation, invasive but the potentially reversible deep brain stimulation, and irreversible lesioning with ablative psychosurgery. A discussion of the role of psychotherapy in the treatment of OCD is also included.

Effects of topiramate in adults with Prader-Willi syndrome.

Prader-Willi syndrome is a multisystem neurogenetic obesity disorder with behavioral manifestations, including hyperphagia, compulsive behavior, self-injury, and mild to moderate mental retardation. In an 8-week open-label study, we evaluated adjunctive therapy with the anticonvulsant topiramate in 8 adults with Prader-Willi syndrome. Appetite was measured by a 1-hour access to food four times throughout the study and quantified with a visual analogue scale. Topiramate did not significantly change calories consumed, Body Mass Index, or increase self-reported appetite. In addition, there were no significant changes in compulsions. Surprisingly, topiramate treatment resulted in a clinically significant improvement in the self-injury (i.e., skin-picking) that is characteristic of this syndrome. Potential benefits of topiramate for self-injury should be evaluated further in controlled trials.

Evaluation of open-label topiramate for scar therapy.

A 3-month open-label pilot study was carried out to assess the safety, tolerability, and effect of the antiepilectic topiramate on the cosmetic appearance of scars. Ten adult subjects with discolored or raised scars at least 2 years old were given an oral dosage of 15 mg per day of topiramate for 1 month. The dosage was then increased to 30 mg per day if there was minimal or no improvement. The safety of topiramate was assessed in this study by reviewing adverse events and vital signs. Efficacy outcomes included a Clinician Global Impression Scale (CGI) to document changes such as thickness and color. Digital photos were taken with consistent variables. In addition, two independent medical reviewers blindly reviewed the photos. The Rosenberg Self-Esteem Scale was done at each visit to measure patients' levels of self-esteem. Side effects were generally mild with the most common being language problems (n = 3) and sleep disturbances (n = 3). All subjects completed the study and experienced at least minimal thinning and decreased coloration (usually redness) of their scars. Based on CGI-assessment data at 3 months, two subjects were very much improved, four were much improved, and four had minimal improvement. One independent medical reviewer arranged before and after treatment picture sets for ten out of ten subjects. The other independent medical reviewer arranged before and after treatment pictures sets for nine out of ten subjects (both p-values less than 0.025). The data indicate that topiramate may be a safe and effective treatment for scar therapy.

Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive-compulsive disorder.

BACKGROUND: From 40% to 60% of obsessive-compulsive disorder (OCD) patients fail to tolerate or respond to selective serotonin reuptake inhibitors (SSRIs). Preclinical and neuroimaging studies have shown abnormally high glutamatergic concentrations in OCD patients and an association between decreased caudate glutamatergic concentrations and reduced OCD symptom severity after SSRI treatment. Topiramate inhibits glutamatergic conduction. METHOD: Thirty-six adult patients with DSM-IV-defined OCD were randomly assigned to topiramate (n = 18) and placebo (n = 18) groups in this 12-week, double-blind, placebo-controlled, parallel-groups trial. Subjects were taking the maximum SSRI dose they could tolerate for at least 12 weeks and their current dose for at least 6 weeks, which was maintained throughout the study. Primary outcome measures were changes in the Yale-Brown Obsessive Compulsive Scale (YBOCS) total score and compulsions and obsessions subscores. Patients were recruited and followed up between April 1, 2003, and April 13, 2006. RESULTS: Using mixed regression models (time [weeks] × treatment), we found a significant treatment effect on the YBOCS compulsions (P = .014) subscale, but not the obsessions (P = .99) subscale or the total score (P = .11). Over the 12-week trial, the topiramate group (mean endpoint dose = 177.8 ± 134.2 mg/d; range, 50-400 mg/d) showed an average linear decrease of 5.38 points on the compulsions subscale compared to 0.6 points in the placebo group. Thirteen topiramate and 14 placebo subjects completed the study. Topiramate was not well tolerated in this trial: 28% (5/18) of the subjects discontinued the drug for adverse effects, and 39% (7/18) had a dose reduction for this reason. CONCLUSIONS: The results of this first double-blind, placebo-controlled trial of topiramate augmentation for treatment-resistant OCD suggest that topiramate may be beneficial for compulsions, but not obsessions. Modifications in glutamatergic function may be responsible, at least in part, for the improved response in compulsions seen with topiramate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00211744.

Deep brain stimulation for intractable obsessive compulsive disorder: pilot study using a blinded, staggered-onset design.

BACKGROUND: Prior promising results have been reported with deep brain stimulation (DBS) of the anterior limb of the internal capsule in cases with severe obsessive compulsive disorder (OCD) who had exhausted conventional therapies. METHODS: In this pilot study, six adult patients (2 male; 4 female) meeting stringent criteria for severe (minimum Yale-Brown Obsessive Compulsive Scale [Y-BOCS] of 28) and treatment-refractory OCD had DBS electrode arrays placed bilaterally in an area spanning the ventral anterior limb of the internal capsule and adjacent ventral striatum referred to as the ventral capsule/ventral striatum. Using a randomized, staggered-onset design, patients were stimulated at either 30 or 60 days following surgery under blinded conditions. RESULTS: After 12 months of stimulation, four (66.7%) of six patients met a stringent criterion as "responders" (> or =35% improvement in the Y-BOCS and end point Y-BOCS severity < or =16). Patients did not improve during sham stimulation. Depressive symptoms improved significantly in the group as a whole; global functioning improved in the four responders. Adverse events associated with chronic DBS were generally mild and modifiable with setting changes. Stimulation interruption led to rapid but reversible induction of depressive symptoms in two cases. CONCLUSIONS: This pilot study suggests that DBS of the ventral capsule/ventral striatum region is a promising therapy of last resort for carefully selected cases of severe and intractable OCD. Future research should attend to subject selection, lead location, DBS programming, and mechanisms underpinning therapeutic benefits.

Pulse-loaded intravenous clomipramine in treatment-resistant obsessive-compulsive disorder.

INTRODUCTION: Small studies have suggested that intravenous clomipramine (CMI) may be more effective and induce faster improvement in obsessive-compulsive disorder than do orally administered serotonin reuptake inhibitors. OBJECTIVE: To test these hypotheses, we conducted a randomized, double-blind, double-dummy study of pulse-loaded intravenous versus oral CMI, followed by open-label oral CMI for 12 weeks. METHODS: We enrolled a volunteer and referred group of 34 adults with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition obsessive-compulsive disorder of > or =1-year duration and Yale-Brown Obsessive Scale score of > or =20. Eligible subjects had failed > or =2 adequate serotonin reuptake inhibitor trials. Subjects received pulse loaded CMI 150 mg by vein or by mouth on day 1 and 200 mg on day 2. Oral CMI began on day 6 at 200 mg/d and was increased by 25 mg every 4 days to 250 mg/d, as tolerated, for 12 weeks. RESULTS: Adverse events led to one withdrawal during oral pulse loading and 5 during open-label oral treatment. Intravenous pulse loading did not induce a more rapid or greater Yale-Brown Obsessive Scale score decrease than oral pulse loading at day 6 or by week 12. Day 6 and week 12 improvement were unrelated to plasma drug or metabolite concentrations. Pulse loading itself seemed to induce more rapid and greater improvement than expected in treatment-resistant obsessive-compulsive disorder. CONCLUSIONS: Further investigation of oral pulse-loading regimens in treatment-resistant obsessive-compulsive disorder is warranted.

Long-term habituation of the smile response with deep brain stimulation.

Human and animal research has shown that the ventral striatum, including the nucleus accumbens, may play a critical role in mediating positive emotions. Recently we described a subject with obsessive-compulsive disorder who intra-operatively exhibited the acute onset of an asymmetric smile and acute positive emotional change with contralateral deep brain stimulation (DBS) in either the right or left nucleus accumbens and anterior limb of the internal capsule region. The purpose of the present study was to examine the stability of the stimulation-induced smile(s) over a 12-month period. Custom computer software objectively quantified left and right facial movement during DBS. Although stimulation-induced smiles were elicited at one and two months post-surgery, they were no longer present from 3-12 months following chronic high frequency DBS. The smiles could not be elicited even with long washout periods. These findings imply potential long-term habituation and changes in the neural chemistry (possibly neuroplasticity) induced by chronic DBS.

Clinical predictors of early fluoxetine treatment response in obsessive-compulsive disorder.

Despite wide use, relatively little is known about sociodemographic and clinical characteristics that predict early fluoxetine response. What research has been conducted has produced inconsistent findings, which may be due to the statistical procedures used, and no studies to date have examined predictors of early fluoxetine treatment response. Sixty adults with obsessive-compulsive disorder (OCD) completed an open-label fluoxetine trial for 8 weeks (up to 40 mg) after a 1-week, single-blind, placebo run-in before baseline assessment. The baseline and posttreatment assessment battery included the Yale-Brown Obsessive Compulsive Scale, the Hamilton Rating Scale for Depression, and the Yale Global Tic Severity Scale. Patient characteristics included illness duration, age, age of onset, gender, and pharmacological treatment history. Independent t-tests and multiple logistic regression analysis showed that longer illness duration, older age, and greater symptom severity were associated with nonresponse. Our findings highlight the impact of functional psychiatric impairment on determining those who may respond to treatment. Furthermore, findings suggest early predictors of patients with certain characteristics who may ultimately need adjunctive care to facilitate response.

Topiramate attenuates self-injurious behaviour in Prader-Willi Syndrome.

Self-injurious behaviour (SIB), most notably skin picking, has been described by various terms in the literature ranging from neurotic/psychogenic excoriations to compulsive/pathological skin picking. Prader-Willi Syndrome (PWS) is a neurogenetic multisystem disorder characterized by infantile hypotonia, mental retardation, short stature, hypogonadism, dysmorphic features, and hyperphagia with a high risk of obesity. Psychiatric manifestations include SIBs in the form of skin picking, nail biting and rectal gouging. Topiramate is a novel anti-epileptic medication without significant liability of weight gain. There are no published reports of topiramate being utilized in PWS or SIB. We report attenuation of SIB with resultant lesion healing in three PWS adults treated with topiramate in an 8-wk open-label trial. Although our findings should be treated with caution, they suggest that double-blind or cross-over studies with topiramate are warranted to establish the possible role of topiramate in attenuating SIB in PWS and other disorders that involve SIB.

Problematic internet use: proposed classification and diagnostic criteria.

Since the mid-1990s, there have been frequent reports of individuals whose use of the computer and internet is problematic. Given the recent expansion and the expected increase in internet availability and usage in the coming years, it is important that healthcare professionals be informed about this behavior and its associated problems. Recently, psychological and psychiatric literature has described individuals that exhibit problematic internet use who often suffer from other psychiatric disorders. In the face of this comorbidity, it is essential to evaluate whether these individuals represent a distinct class of disorder, or a manifestation/coping mechanism related to other underlying diagnosis. In either event, problematic internet use negatively impacts social and emotional functioning. Based on the current limited empirical evidence, problematic internet use may best be classified as an impulse control disorder. It is therefore imperative that problematic internet use be appropriately identified among symptomatic individuals. For these reasons, we propose specific diagnostic criteria that will allow for consistent identification and assist in further study of this behavior.

What's in a "smile?" Intra-operative observations of contralateral smiles induced by deep brain stimulation.

OBJECTIVE: To describe smiling and euphoria induced by deep brain stimulation (DBS). BACKGROUND AND SIGNIFICANCE: The brain systems inducing emotional experiences and displays are not entirely known, but the ventral striatum including the nucleus accumbens has been posited to play a critical role in mediating emotions with positive valence. DBS has been successfully employed for the treatment of movement disorders, and most recently obsessive compulsive disorder (OCD). The purpose of this report is to describe the emotional changes associated with stimulation of the ventral striatum. METHODS: A single patient with intractable OCD had electrode arrays placed in the right and left anterior limbs of the internal capsule and region of the nucleus accumbens. Changes in facial movement during stimulation were quantified by video recording. Ten video segments, time locked to the onset of stimulation, were digitized and changes in pixel intensity that occurred over both sides of the lower face, on a frame by frame basis, following stimulation onset were computed. These summed changes in pixel intensity represented the dependent variable of "entropy" and directly corresponded to changes in light reflectance that occur during facial movement. RESULTS: During stimulation on both the right and left side, the patient consistently developed a half smile on the side of the face contralateral to the stimulating electrode, and also became euphoric. The effect ceased when DBS was discontinued. CONCLUSIONS: DBS in the region of the nucleus accumbens produced smile and euphoria suggesting that alterations in the ventral striatum may result in emotional experience and displays. We hypothesize the existence of a limbic-motor network responsible for such changes. This observation suggests that DBS may be useful as a therapy for mood disorders.