Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial.

OBJECTIVE: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. DESIGN: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. SETTING: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. PARTICIPANTS: Alzheimer's disease patients with clinically significant apathy. MEASUREMENTS: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). RESULTS: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. CONCLUSION: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

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.

Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial.

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.

Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

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 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the rivastigmine and placebo groups, respectively (p = 0.41). A mixed-effect model including treatment, time, and treatment-by-time interaction indicated no significant difference in treatment effect over time between the groups (p = 0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments.

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.

Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate.

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.

A 12-Month Open-Label Extension Study of the Safety and Tolerability of Lisdexamfetamine Dimesylate for Major Depressive Disorder in Adults.

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.

The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial.

BACKGROUND: Alzheimer's disease (AD) is characterized not only by cognitive and functional decline, but also often by the presence of neuropsychiatric symptoms. Apathy, which can be defined as a lack of motivation, is one of the most prevalent neuropsychiatric symptoms in AD and typically leads to a worse quality of life and greater burden for caregivers. Treatment options for apathy in AD are limited, but studies have examined the use of the amphetamine, methylphenidate. The Apathy in Dementia Methylphenidate Trial (ADMET) found that treatment of apathy in AD with methylphenidate was associated with significant improvement in apathy in two of three outcome measures, some evidence of improvement in global cognition, and minimal adverse events. However, the trial only enrolled 60 participants who were followed for only 6 weeks. A larger, longer-lasting trial is required to confirm these promising findings. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a phase III, placebo-controlled, masked, 6-month, multi-center, randomized clinical trial targeted to enroll 200 participants with AD and apathy. Participants are randomly assigned 1:1 to 20 mg methylphenidate per day prepared as four over-encapsulated tablets or to matching placebo. The primary outcomes include (1) the mean difference in the Neuropsychiatric Inventory Apathy subscale scores measured as change from baseline to 6 months, and (2) the odds of having a given rating or better on the modified AD Cooperative Study Clinical Global Impression of Change ratings at month 6 compared with the baseline rating. Other outcomes include change in cognition, safety, and cost-effectiveness measured at monthly follow-up visits up to 6 months. DISCUSSION: Given the prevalence of apathy in AD and its impact on both patients and caregivers, an intervention to alleviate apathy would be of great benefit to society. ADMET 2 follows on the promising results from the original ADMET to evaluate the efficacy of methylphenidate as a treatment for apathy in AD. With a larger sample size and longer follow up, ADMET 2 is poised to confirm or refute the original ADMET findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02346201 . Registered on 26 January 2015.

Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies.

BACKGROUND: The efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy in adults with major depressive disorder (MDD) from two phase 3 studies are reported. METHODS: Across study 1 (placebo, n=201; LDX, n=201) and study 2 (placebo, n=213; LDX, n=211), most participants (placebo and LDX) in the safety analysis set were female (study 1: 66.2% and 64.2%; study 2: 67.1% and 66.8%); mean±SD ages were 41.8±12.04 with placebo and 42.2±12.32 with LDX in study 1 and 42.6±11.41 with placebo and 42.0±11.63 with LDX in study 2. Participants (18-65 y) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores ≥24. Eight-week antidepressant lead-in phases prospectively assessed antidepressant response. Then, 8 weeks of randomized (1:1), double-blind treatment with dose-optimized LDX (20-70mg) or placebo in participants exhibiting inadequate antidepressant monotherapy responses (augmentation baseline MADRS total scores ≥18 and <50% MADRS total score reductions from lead-in baseline to augmentation baseline) was initiated. The primary endpoint was MADRS total score change from augmentation baseline to week 16. Safety and tolerability measures included the occurrence of treatment-emergent adverse events (TEAEs). RESULTS: Least squares mean (95% CI) treatment differences (LDX-placebo) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 (0.1 [-1.7, 2.0], P=0.883) or study 2 (-0.5 [-2.3, 1.3], P=0.583). The only TEAE reported by >5% of LDX participants at twice the placebo rate in both studies was dry mouth. LIMITATIONS: Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders, the inability to assess specific MDD symptom domains (eg, anhedonia, cognition) or subtypes, the use of telephone-based depression assessments, and the potential influence of placebo response. CONCLUSION: Contrary to expectations, LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy.

Duloxetine for the Treatment of Patients with Suspected Sphincter of Oddi Dysfunction: A Pilot Study.

OBJECTIVE: To examine the tolerability and efficacy of duloxetine in patients with suspected sphincter of Oddi dysfunction (SOD). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Role of atypical antipsychotics in the treatment of generalized anxiety disorder.

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.

Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial.

IMPORTANCE: 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. OBJECTIVE: To determine whether endoscopic sphincterotomy reduces pain and whether sphincter manometric pressure is predictive of pain relief. DESIGN, SETTING, AND PATIENTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00688662.

Can patient and pain characteristics predict manometric sphincter of Oddi dysfunction in patients with clinically suspected sphincter of Oddi dysfunction?

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.).

Psychosocial characteristics and pain burden of patients with suspected sphincter of Oddi dysfunction in the EPISOD multicenter trial.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prevalence and features of generalized anxiety disorder in Department of Veteran Affairs primary care settings.

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.

Attentional functioning in patients with posttraumatic stress disorder: a preliminary study.

OBJECTIVE: To compare patients with posttraumatic stress disorder (PTSD) to patients without psychiatric or cognitive disorders on neuropsychological measures of attention. METHODS: The 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. RESULTS: PTSD patients performed significantly more poorly than patients without psychiatric diagnoses on Digit Span. CONCLUSION: PTSD 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 role of pain, functioning, and mental health in suicidality among Veterans Affairs primary care patients.

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.

Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial.

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; P<0.001). 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 P<0.001) and Q-LES-Q (P<0.05) 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.