Search

Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. Results: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). Discussion: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer’s disease while considering the burden on the healthcare system.

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm

Background Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. Objective The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. Methods ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. Results Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%–96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%–96.9%). Conclusion The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.

Supplemental digital content is available in the text., Purpose/Background Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. Methods/Procedures Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20–70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. Findings/Results All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). Implications/Conclusions The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.

Importance Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality. Objective To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease. Design, Setting, and participants This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included. Interventions Ten milligrams of methylphenidate, twice daily, vs matching placebo. Main Outcomes and Measures The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life. Results Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, −1.25; 95% CI, −2.03 to −0.47;P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91;P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84;P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04;P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups. Conclusions and Relevance This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease. Trial Registration ClinicalTrials.gov Identifier:NCT02346201

To examine the tolerability and efficacy of duloxetine in patients with suspected sphincter of Oddi dysfunction (SOD). An open-label, single-center, 12-week trial of duloxetine 60 mg once daily was conducted in 20 patients with suspected SOD. All patients were evaluated by expert pancreato-biliary specialists. The primary outcome measure was a Patient Global Impression of Change (PGIC) scale. Secondary measures included the pain burden, assessed by the Recurrent Abdominal Pain Intensity and Disability scale, the Short-Form Health Survey, and the Hospital Anxiety and Depression Scale. A positive clinical response was defined as a PGIC score of much or very much improved at 3 months and was estimated using a two-sided 90 % confidence interval. The primary outcome was analyzed using a one-sample binomial test at a significance level of 0.10. Of the 20 screened patients, 18 were enrolled; 14 completed at least one post-baseline evaluation; and 10 patients completed the third month endpoint visit. Patients missing the third month visit were considered non-responders for the primary outcome. Response rates were 90 % for study completers (n = 10; 90 % CI 74–100; p = 0.02) and 64 % for patients who completed at least one post-baseline evaluation (n = 14; 90 % CI 43–85; p = 0.42). Seven patients did not complete the study due to adverse events (mostly fatigue and nausea). Duloxetine showed an indication of efficacy in the treatment of pain in patients with suspected SOD, but adverse events limited its use. These preliminary, open-label results justify definitive placebo-controlled trials.

Introduction Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. Methods S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC). Discussion S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846).

Background Biliopancreatic-type postcholecystectomy pain, without significant abnormalities on imaging and laboratory test results, has been categorized as "suspected" sphincter of Oddi dysfunction (SOD) type III. Clinical predictors of "manometric" SOD are important to avoid unnecessary ERCP, but are unknown. Objective To assess which clinical factors are associated with abnormal sphincter of Oddi manometry (SOM). Design Prospective, cross-sectional. Setting Tertiary. Patients A total of 214 patients with suspected SOD type III underwent ERCP and pancreatic SOM (pSOM; 85% dual SOM), at 7 U.S. centers (from August 2008 to March 2012) as part of a randomized trial. Interventions Pain and gallbladder descriptors, psychosocial/functional disorder questionnaires. Main Outcome Measurements Abnormal SOM findings. Univariate and multivariate analyses assessed associations between clinical characteristics and outcome. Results The cohort was 92% female with a mean age of 38 years. Baseline pancreatic enzymes were increased in 5%; 9% had minor liver enzyme abnormalities. Pain was in the right upper quadrant (RUQ) in 90% (48% also epigastric); 51% reported daily abdominal discomfort. Fifty-six took narcotics an average of 33 days (of the past 90 days). Less than 10% experienced depression or anxiety. Functional disorders were common. At ERCP, 64% had abnormal pSOM findings (34% both sphincters, 21% biliary normal), 36% had normal pSOM findings, and 75% had at least abnormal 1 sphincter. Demographic factors, gallbladder pathology, increased pancreatobiliary enzymes, functional disorders, and pain patterns did not predict abnormal SOM findings. Anxiety, depression, and poorer coping were more common in patients with normal SOM findings (not significant on multivariate analysis). Limitations Generalizability. Conclusions Patient and pain factors and psychological comorbidity do not predict SOM results at ERCP in suspected type III SOD. (Clinical Trial registration number: NCT00688662.)

Patients with several painful functional gastrointestinal disorders (FGIDs) are reported to have a high prevalence of psychosocial disturbance. These aspects have not been studied extensively in patients with suspected Sphincter of Oddi dysfunction (SOD).A total of 214 patients with post-cholecystectomy pain and suspected SOD were enrolled in seven US centers in a multicenter-randomized trial (Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction). Baseline assessments included pain descriptors and burden, structured psychosocial assessments of anxiety/depression, coping, trauma, and health-related quality of life. Patients with high levels of depression, suicidal ideation, or psychosis were excluded.The study population (92% female, mean age 38) reported anxiety (9%), depression (8%), past sexual trauma (18%), and physical abuse (10%). Of the total screened population (n=1460), 3.9% of the patients were excluded because of the presence of defined severe psychological problems. The mean medical outcomes study short-form-36 (SF-36) physical and mental composite scores were 38.70 (s.d.=7.89) and 48.74 (s.d.=9.60), respectively. Most subjects reported symptoms of other FGIDs. There were no correlations between the extent of the pain burden in the 3 months before enrollment and the baseline anxiety scores or victimization history. However, those with greater pain burden were significantly more depressed. There were no meaningful differences in the psychosocial parameters in subjects with or without irritable bowel, and those who had cholecystectomy for stones or functional gallbladder disease. Those declining randomization were comparable to those randomized.Psychosocial comorbidity in SOD is high. However, it does not appear to differ significantly from that reported in surveys of age- and gender-matched general populations, and may be lower than reported with other FGIDs.

Generalized anxiety disorder (GAD) is a highly prevalent distressing condition for individuals in both community and community primary care settings. However, despite the high prevalence of GAD identified in epidemiological studies, little is known about GAD and its related symptoms and impairments in veteran populations. The present study investigated the prevalence, comorbidity, physical and mental health impairment, and healthcare utilization of veteran participants with GAD, as well as comparing symptoms of GAD and posttraumatic stress disorder (PTSD). Veterans (N = 884) participated in a cross-sectional investigation in primary care clinics in four Veteran Affairs Medical Centers (VAMCs) and completed diagnostic interviews and self-report questionnaires; a chart review was conducted to assess their VAMC healthcare utilization. A large number of participants (12%) met diagnostic criteria for GAD, reporting significantly worse emotional health, pain, and general health, in addition to increased mental healthcare utilization and antidepressant medications. In addition, GAD was found in 40% of participants with PTSD, resulting in more severe symptoms and impairment than in patients with GAD alone. These findings provide evidence of high prevalence and severe impairment associated with GAD in veterans and highlight the need for improved recognition, assessment, and treatments for GAD.

Objectives. We examined suicidality, pain, functioning, and psychiatric disorders among veterans in primary care by using both self-report and clinical measures of pain and mental health to determine correlates that might be clinically useful in primary care settings. Methods. Data were from 884 Veterans Affairs patients enrolled in a regional 4-site cross-sectional study. Patients were administered measures that assessed functioning (including pain) and psychiatric disorders. Data were merged with medical records for clinical pain indicators. Results. Overall, 9.1% (74 of 816) of patients indicated suicidal ideation, with those who were middle-aged, unemployed because of disability, had less than college education, and served in a warzone most likely to consider suicidality. Suicidal patients had worse functioning (measured by the Short Form-36) than did nonsuicidal patients in every domain, including bodily pain, and were more likely to meet criteria for a psychiatric diagnosis. However, when pain and mental health were jointly considered, only mental health (both psychiatric diagnosis and mental health functioning) was related to suicidality. Conclusions. Although providers should be alert to the possibility of suicidality in patients with pain, they should be vigilant when patients have a psychiatric disorder or poor mental health.

Background Sphincter of Oddi dysfunction (SOD) is a controversial topic, especially in patients with no objective findings on laboratory or imaging studies (SOD type III). The value of ERCP manometry with sphincterotomy is unproven and carries significant risks. Objective To describe the process of planning and initiating a randomized sham-controlled study to establish whether patients with SOD respond to sphincter ablation, and whether the outcomes are predicted by the pain patterns, presence or absence of other functional GI or psychosocial problems, or the results of manometry. Design Planning a trial to establish which patients with "suspected SOD" (if any) respond to endoscopic sphincter ablation. Setting Meetings and correspondence by a planning group of gastroenterologists and clinical research specialists hosted at the Medical University of South Carolina. Patients Clarifying subject characteristics and inclusion and exclusion criteria. Interventions Defining the questionnaires, therapies, randomizations, and numbers of subjects required by outcome measures. Defining the metrics of success and failure. Results The planning resulted in funding for the proposed study as a cooperative agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Limitations Lack of data required several consensus decisions in designing the protocol. Conclusion The planning process was challenging, and some changes were needed after initiation. ⁎ (Clinical trial registration number: NCT00688662.)

This multicenter, double-blind, placebo-controlled, 2-arm, parallel-group study was carried out to determine the effectiveness and safety of the novel anticonvulsant levetiracetam for the treatment of generalized social anxiety disorder (GSAD).After a 1-week, single-blind, placebo run-in period, 217 adult outpatients meeting DSM-IV criteria for social anxiety disorder, generalized type, were randomly assigned (1:1) to 12 weeks of double-blind treatment with either levetiracetam (n = 111) or placebo (n = 106). Participants were required to have scores ofor= 60 on the Liebowitz Social Anxiety Scale (LSAS) and a total score ofor= 17 on the 17-item Hamilton Depression Rating Scale (HDRS). The primary outcome measure was mean change from baseline on LSAS total score. Levetiracetam was initiated at 250 mg/d and flexibly titrated up to a maximum dose of 3,000 mg/d (1,500 mg bid). Dosage was held stable for the last 6 weeks of treatment. The study was conducted from September 2003 to June 2004.No statistically significant difference was found between the adjusted mean changes in LSAS score for levetiracetam (-24.4) and placebo (-28.7) using an efficacy intent-to-treat, last- observation-carried-forward analysis. Rates of response (or= 30% reduction in LSAS score) were similar with 41.3% (levetiracetam) and 46.6% (placebo). No significant between-group differences were found on secondary outcome measures, which included changes in Sheehan Disability Scale, Clinical Global Impression of Change, and HDRS scores.Although well-tolerated, levetiracetam failed to separate from placebo in this trial for the treatment of moderate to severe GSAD.

Objective This study assessed the efficacy and safety of sertraline in the treatment of generalized anxiety disorder (GAD). Method The study was conducted from April 2000 to May 2002. Outpatients with DSM-IV GAD (N = 326) who satisfied inclusion/exclusion criteria and completed a 1-week screening phase were randomly assigned to 10-week double-blind treatment with flexible dosing of sertraline (50-200 mg/day) or placebo. The primary efficacy measure was change from baseline in Hamilton Rating Scale for Anxiety (HAM-A) total score. Response was defined as a 50% or greater decrease in HAM-A total score at endpoint. Results Sertraline produced a statistically significant reduction in anxiety symptoms, as measured by HAM-A total change scores (p = .032), HAM-A psychic anxiety subscale (p = .011), and Hospital Anxiety and Depression Scale-anxiety subscale (p = .001). Response rates were significantly higher (p = .05) for the sertraline group (59.2%) compared to the placebo group (48.2%). Sertraline was well tolerated, with only sexual side effects reported significantly more often by subjects receiving sertraline than those receiving placebo. Conclusion Despite the relatively small between-group differences, study findings suggest a role for sertraline in the acute treatment of GAD.

Clinical and epidemiological data suggest that generalized anxiety disorder (GAD) is a chronic illness causing patients to suffer for many years leading to significant distress in daily life functioning. The literature suggests the several conclusions. GAD is a disorder in need of appropriate treatment and often has a chronic course with comorbid conditions, such as major depression and other anxiety disorders. Benzodiazepines, while effective anxiolytic agents acutely, when prescribed for >4 weeks cause rebound anxiety and following prolonged therapy may lead to withdrawal symptoms. Antidepressants cause significant anxiety relief compared with placebo and for psychosocial treatment cognitive-behavioral therapy is an efficacious psychosocial treatment. Many GAD patients are in need of long-term medication management. Furthermore, there is limited data for patients diagnosed with GAD the treatment outcome with the combination of medication and psychotherapy both acutely and long-term; how to best sequence these treatments; for those patients who do not meet remission criteria what is the ideal approach for augmentation; and for patients with treatment-refractory GAD the empirical evidence is lacking on medication switching and augmentation strategies. Research is needed in the area of developing treatment strategies for patients suffering from treatment-refractory GAD. There is still an urgent need to explore treatment combinations and duration strategies in the management of patients suffering with GAD.

Background: In the medical literature, there is a lack of sex-specific information regarding the efficacy, metabolism, and side effects associated with psychopharmacologic treatment. In part, this lack results from the historic underinclusion of women in clinical trials during early drug development, but it also occurs because investigators of treatment and metabolic studies do not routinely analyze results according to sex. In 1993, the U.S. Food and Drug Administration (FDA) announced changes that encourage the inclusion of women in early pharmacokinetic studies and emphasize the need for subset analyses using sex and age parameters. In conjunction with advances in basic science regarding drug metabolism, these modifications have led to modest increases in information regarding sex differences in drug metabolism and efficacy. In this article, current information regarding potential sex differences in the pharmacotherapy of major depressive disorder is reviewed. Data Sources: A MEDLINE search was conducted using the terms antidepressants, sex-factors, gender differences, and women for the years 1966 to 2000. Data Synthesis and Conclusions: There are data supporting sex differences in the activity of various antidepressant-metabolizing enzymes. However, there is a paucity of investigation regarding how these differences might translate into differences in clinical efficacy. Notably, there is little work using existing databases to perform the subgroup analyses recommended by the FDA. The widespread dissemination of such work is needed, and, if conducted, investigations in this area have the potential to enhance psychopharmacologic treatment for both men and women.

Evidence-based treatment approaches for generalized anxiety disorder (GAD) comprise psychotherapy, pharmacotherapy, or a combination of the two. First-line pharmacotherapy agents include selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, and, in certain European guidelines, pregabalin, which gained European Commission approval. Although short- and long-term efficacy have been established for these agents in controlled trials, response rates of 60–70 % are insufficient, remission rates are relatively modest, and relapse rates considerable. Moreover, questions increasingly arise regarding tolerability and side-effect profiles. As an alternative, antipsychotics have long been of interest for the treatment of anxiety disorders, but investigation had been tempered by their potential for irreversible side effects. With the improved side-effect profiles of atypical antipsychotics, these agents are increasingly being investigated across Axis I disorders. Atypical antipsychotics such as quetiapine, aripiprazole, olanzapine, and risperidone have been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and have since been used in the treatment of a range of mood and anxiety disorders. In this article, we review the efficacy and tolerability of atypical antipsychotics as adjunctive therapy and/or monotherapy for individuals with GAD, a currently off-label indication. The most evidence has accumulated for quetiapine. Findings suggest that approximately 50 % of participants tolerate the side effects, most commonly sedation and fatigue. Among this subset, those who continue treatment demonstrate significant reductions in anxiety when used as adjunctive therapy or monotherapy. The appropriateness of the use of antipsychotics in the treatment of GAD is discussed.

Abdominal pain after cholecystectomy is common and may be attributed to sphincter of Oddi dysfunction. Management often involves endoscopic retrograde cholangiopancreatography (ERCP) with manometry and sphincterotomy.To determine whether endoscopic sphincterotomy reduces pain and whether sphincter manometric pressure is predictive of pain relief.Multicenter, sham-controlled, randomized trial involving 214 patients with pain after cholecystectomy without significant abnormalities on imaging or laboratory studies, and no prior sphincter treatment or pancreatitis randomly assigned (August 6, 2008-March 23, 2012) to undergo sphincterotomy or sham therapy at 7 referral medical centers. One-year follow-up was blinded. The final follow-up visit was March 21, 2013.After ERCP, patients were randomized 2:1 to sphincterotomy (n = 141) or sham (n = 73) irrespective of manometry findings. Those randomized to sphincterotomy with elevated pancreatic sphincter pressures were randomized again (1:1) to biliary or to both biliary and pancreatic sphincterotomies. Seventy-two were entered into an observational study with conventional ERCP managemeny.Success of treatment was defined as less than 6 days of disability due to pain in the prior 90 days both at months 9 and 12 after randomization, with no narcotic use and no further sphincter intervention.Twenty-seven patients (37%; 95% CI, 25.9%-48.1%) in the sham treatment group vs 32 (23%; 95% CI, 15.8%-29.6%) in the sphincterotomy group experienced successful treatment (adjusted risk difference, -15.6%; 95% CI, -28.0% to -3.3%; P = .01). Of the patients with pancreatic sphincter hypertension, 14 (30%; 95% CI, 16.7%-42.9%) who underwent dual sphincterotomy and 10 (20%; 95% CI, 8.7%-30.5%) who underwent biliary sphincterotomy alone experienced successful treatment. Thirty-seven treated patients (26%; 95% CI,19%-34%) and 25 patients (34%; 95% CI, 23%-45%) in the sham group underwent repeat ERCP interventions (P = .22). Manometry results were not associated with the outcome. No clinical subgroups appeared to benefit from sphincterotomy more than others. Pancreatitis occurred in 15 patients (11%) after primary sphincterotomies and in 11 patients (15%) in the sham group. Of the nonrandomized patients in the observational study group, 5 (24%; 95% CI, 6%-42%) who underwent biliary sphincterotomy, 12 (31%; 95% CI, 16%-45%) who underwent dual sphincterotomy, and 2 (17%; 95% CI, 0%-38%) who did not undergo sphincterotomy had successful treatment.In patients with abdominal pain after cholecystectomy undergoing ERCP with manometry, sphincterotomy vs sham did not reduce disability due to pain. These findings do not support ERCP and sphincterotomy for these patients.clinicaltrials.gov Identifier: NCT00688662.

Anxiety symptoms in dementia can be seen as an expression of stress in predisposed patients who become aware of their cognitive decline. In later stages of the disease, when awareness is lost, the presence of anxiety symptoms cannot be explained as a reaction to this type of stress. The presence of anxiety symptoms in the more impaired patients becomes similar and probably as complex in its etiology and clinical manifestations as other behavioral and psychological symptoms of dementia (BPSD). In this review, we will discuss anxiety symptoms in BPSD.

While parenting is a universal human behavior, its neuroanatomic basis is currently unknown. Animal data suggest that the cingulate may play an important function in mammalian parenting behavior. For example, in rodents cingulate lesions impair maternal behavior. Here, in an attempt to understand the brain basis of human maternal behavior, we had mothers listen to recorded infant cries and white noise control sounds while they underwent functional MRI (fMRI) of the brain. We hypothesized that mothers would show significantly greater cingulate activity during the cries compared to the control sounds. Of 7 subjects scanned, 4 had fMRI data suitable for analysis. When fMRI data were averaged for these 4 subjects, the anterior cingulate and right medial prefrontal cortex were the only brain regions showing statistically increased activity with the cries compared to white noise control sounds (cluster analysis with one-tailed z-map threshold of P < 0.001 and spatial extent threshold of P < 0.05). These results demonstrate the feasibility of using fMRI to study brain activity in mothers listening to infant cries and that the anterior cingulate may be involved in mothers listening to crying babies. We are currently replicating this study in a larger group of mothers. Future work in this area may help (1) unravel the functional neuroanatomy of the parent-infant bond and (2) examine whether markers of this bond, such as maternal brain response to infant crying, can predict maternal style (i.e., child neglect), offspring temperament, or offspring depression or anxiety.

Background: Peripheral benzodiazepine receptors (PBRs) are involved in regulating stress responses. Abnormally low numbers of platelet PBRs have been found in patients with panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but not in patients with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). The purpose of this study was to evaluate the PBR density on platelets from patients with generalized social phobia (GSP). Methods: The density (B max ) and dissociation constant (K d ) of platelet PBRs was determined for 53 medication-free patients with GSP and an equal number of control subjects (NC). Results: The GSP group was found to have a significantly lower PBR B max than the NC group (GSF = 2764 ± 1242 vs. NC=4327 ± 1850 fmol/mg protein, df=1,100, F=22.7, p=.00001). Conclusions: GSP shares this PBR abnormality with some other anxiety disorders but not with OCD or MDD. PBRs may play a role in the pathophysiology of some anxiety disorders.

ObjectiveTo compare patients with posttraumatic stress disorder (PTSD) to patients without psychiatric or cognitive disorders on neuropsychological measures of attention.MethodsThe sample included 19 patients with PTSD and 22 participants with no cognitive or psychiatric diagnosis. All had been referred for clinical neuropsychological evaluation at a VA Medical Center. None were diagnosed with dementia, delirium, or current substance dependence except nicotine or caffeine, and none had a history of stroke or of traumatic brain injury with loss of consciousness. Patients were excluded if they failed to exert adequate effort on testing.ResultsPTSD patients performed significantly more poorly than patients without psychiatric diagnoses on Digit Span.ConclusionPTSD patients were impaired relative to participants without psychiatric diagnoses on a measure of focused attention. Several factors, including the small sample size, suggest that the results should be considered preliminary.

The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy for patients with generalized anxiety disorder (GAD). Time-to-event (anxiety symptom recurrence; maximum 52 weeks) multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) following open-label run-in (4-8 weeks) and open-label stabilization (≥ 12 weeks). Primary variable: time from randomization to anxiety event. Secondary variables included: Hamilton Anxiety Rating Scale (HAM-A) total, HAM-A psychic/somatic anxiety factors, Clinical Global Impression-Severity of Illness (CGI-S), and Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scores; adverse events (AE) reporting. Four hundred and thirty-two patients, stabilized on quetiapine XR, were randomized to continue quetiapine XR (N=216) or switch to placebo (N=216). Risk of anxiety symptom recurrence was significantly reduced by 81% for quetiapine XR versus placebo: hazard ratio=0.19 (95% confidence interval 0.12-0.31; P0.001). Fewer patients receiving quetiapine XR (N=22, 10.2%) than placebo (N=84, 38.9%) experienced anxiety symptom recurrence. Significant differences were observed between quetiapine XR and placebo in: HAM-A total, psychic/somatic, CGI-S (all P0.001) and Q-LES-Q (P0.05) scores. AEs (10%) during open-label treatment were dry mouth, sedation, somnolence, dizziness, fatigue, and constipation. During randomized treatment, the most common AEs for quetiapine XR were headache and nasopharyngitis. Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR, with tolerability results consistent with the known profile of quetiapine.

A 12-week, open label flexible dosing study was conducted to evaluate the efficacy of bupropion-SR in the treatment of generalized social phobia. The primary outcome measures include the Clinical Global Impression of Improvement (CGI-I) and the Brief Social Phobia Rating Scale (BSPS). A total of 18 subjects were enrolled. Five of the ten subjects who completed all 12 weeks were considered as responders. Response to treatment was defined as a CGI-I score of 1 or 2, (“much improved” or “very much improved,” respectively) and a >50% decrease in BSPS score. The final doses for the completers ranged between 200 and 400 mg/day (mean 366±68 mg/day). The medication was generally well tolerated. Findings from this open-label trial suggest that bupropion-SR may be useful in treating generalized social phobia. Depression and Anxiety 12:111–113, 2000. © 2000 Wiley-Liss, Inc.

Background Fluoxetine and its active metabolite norfluoxetine have long half-lives of 4-6 days and 4-16 days, respectively. We postulated that, owing to the long elimination half-life, patients diagnosed with panic disorder might be maintained on fluoxetine taken once a week, after being treated initially with daily doses of fluoxetine. Method Ten patients with DSM-III-R panic disorder were treated openly with fluoxetine, 20-40 mg daily. Once panic free, these patients were switched to once-weekly dosing of fluoxetine, and dosage was titrated as needed. Results All 10 patients successfully switched to once-weekly dosing. One patient reported recurrence of panic attacks 18 months after the switch. After a brief treatment for 4 weeks with benzodiazepines and daily fluoxetine, the patient was once again maintained on once-weekly dosing when rechallenged. Patients have been maintained in a panic-free state for up to 26 months with a single weekly dose of fluoxetine ranging from 10 to 60 mg. The medication was well tolerated. Conclusion Fluoxetine at doses ranging from 10 to 60 mg administered once weekly appears to be effective maintenance treatment for patients with panic disorder who were initially treated successfully with daily fluoxetine. A once-weekly regimen may allow for considerable cost savings and may serve as a convenient alternative method for treating panic disorder.

Background: Sleep deprivation has been shown to improve depressive symptoms in some patients with major depressive disorder, but it has not been tested in patients with generalized anxiety disorder (GAD) or social phobia (SP). Methods: To determine if sleep deprivation altered anxiety or depressive symptoms in patients with GAD ( n = 7) or SP ( n = 8), we sleep deprived patients and normal controls ( n = 18) for one night. Results: On one measure of anxiety, GAD patients improved compared with controls, but there were otherwise no significant change differences between controls and SP or GAD patients. Conclusions: The lack of benefit is consistent with previous findings that sleep deprivation provides no benefit to patients with other anxiety disorders. Sleep deprivation may be a biological intervention that distinguishes anxiety from affective disorders.

Objective Although significant advances have been made in recent years in the treatment of generalized anxiety disorder (GAD), many patients remain symptomatic despite ongoing treatment, underscoring the need for adjunctive new treatments to help improve response. Method Forty patients with a primary diagnosis of DSM-IV GAD, who continued to experience GAD symptoms despite current anxiolytic treatment of at least 4 weeks' duration, as evidenced by Hamilton Rating Scale for Anxiety (HAM-A) total score > or = 18 and Clinical Global Impressions-Severity of Illness scale score of moderate or greater, completed a 1-week screening phase and were then randomly assigned to 5 weeks of double-blind adjunctive treatment with placebo or risperidone at flexible doses of 0.5 to 1.5 mg/day. Patients continued to take their anxiolytics throughout the study. The study was conducted from June 2001 through March 2003. Results Adjunctive risperidone was associated with statistically significant improvements in core anxiety symptoms, as demonstrated by greater reductions in HAM-A total scores (p = .034) and HAM-A psychic anxiety factor scores (p = .047) compared with placebo. Although change scores on other outcome variables, including response rates, were higher in the risperidone group, differences did not achieve statistical significance. Conclusion Study findings suggest that risperidone at low doses may represent a useful tool in the management of symptomatic GAD patients.

The authors investigated the types and rates of trauma exposure and differences in symptom endorsement in a clinical sample of patients diagnosed with generalized anxiety disorder (GAD). Fifty-eight patients with GAD were assessed using the Structured Clinical Interview (SCID) and Trauma Assessment for Adults. In order to explore the relationship between specific traumatic event(s) and clinical presentation, the presence of somatic symptoms associated with GAD, including muscle tension, autonomic hyperactivity, and vigilance/scanning clusters (using DSM-III-R criteria), were examined. Patients with a history of sexual assault before 18 years (25.9%) endorsed fewer somatic symptoms, specifically fewer motor tension and autonomic GAD symptoms, than patients with other types of trauma. These findings indicate that early exposure to serious trauma, specifically childhood sexual assault, may lead to a different clinical presentation in GAD patients.

Anxiety disorders are among the most prevalent psychiatric disorders in the general population, found nearly twice as often in women, and estimated to affect 26.9 million individuals in the United States alone. Anxiety disorders are associated with considerable chronicity, morbidity, and disability. Treatment of anxiety disorders includes pharmacologic and nonpharmacologic approaches. The first-line pharmacologic treatments currently include the use of serotonin reuptake inhibitors and selective serotonin reuptake inhibitors. However, despite the general success of the available treatments, no single anxiolytic appears to be effective for all patients suffering from anxiety. Low recovery rates have been reported in all anxiety disorders, underscoring the need for optimizing treatment for these disabling disorders. In recent years, there is increasing interest in the use of atypical neuroleptics in the treatment of anxiety disorders patients. This article discusses the emerging data on the use of these agents in the treatment of anxiety with a focus on treatment-refractory patients and on the implications for the treatment of women suffering from anxiety disorders.

OBJECTIVE The authors evaluated the frequency of body dysmorphic disorder in patients with a primary diagnosis of anxiety disorders and major depression. METHOD Patients with social phobia (N = 54), obsessive-compulsive disorder (N = 53), generalized anxiety disorder (N = 32), panic disorder (N = 47), and major depression (N = 42) and normal comparison subjects (N = 33) were studied. RESULTS Body dysmorphic disorder was most common in patients with social phobia (11%) and obsessive-compulsive disorder (8%); it was less prevalent among patients with panic disorder (2%), generalized anxiety disorder (0%), and major depression (0%) and among normal subjects (0%). CONCLUSIONS These findings suggest that body dysmorphic disorder may share etiologic elements with social phobia and obsessive-compulsive disorder.

The authors compared the distribution of somatic symptoms associated with generalized anxiety disorder in 28 patients with "pure" generalized anxiety disorder and 77 patients with generalized anxiety disorder plus comorbid current or lifetime psychiatric diagnoses. They found no significant differences in individual symptom endorsement between the two groups, indicating that the basic symptoms of generalized anxiety disorder are specific to the disorder itself.

OBJECTIVE The goal of this study was to test the validity of generalized anxiety disorder as an independent diagnostic entity and to evaluate the prevalence and type of other psychiatric disorders coexisting with generalized anxiety disorder. Although a few published studies have addressed the subject, this study presents data from a larger group of subjects and excludes concurrent major depression as a potential confound. METHOD The authors studied patients with a primary diagnosis of generalized anxiety disorder assigned after evaluation with the Structured Clinical Interview for DSM-III-R. Patients with a concurrent major depressive episode were excluded. All diagnoses for which the patient met criteria were determined, including lifetime occurrence of major depressive episode and substance use. RESULTS One hundred nine patients with generalized anxiety disorder were included in the analysis. Twenty-eight (26%) of these patients were not given any other lifetime psychiatric diagnosis. The most prevalent comorbid diagnoses were social phobia (25 [23%] of the patients) and simple phobia (23 [21%] of the patients). Forty-six (42%) of the patients with generalized anxiety disorder had experienced at least one major depressive episode during their lifetime. CONCLUSIONS These results support previous findings of high rates of psychiatric comorbidity in generalized anxiety disorder and validate the usefulness of generalized anxiety disorder as a separate diagnostic entity.