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Unified protocol for the discontinuation of long-term serotonin reuptake inhibitors in obsessive compulsive disorder: Study protocol and methods.

ABSTRACT: Obsessive-compulsive disorder (OCD) is chronic psychiatric disorder associated with high rates of functional impairment and decreased quality of life. Although serotonin reuptake inhibitors have demonstrated efficacy in the treatment of OCD, little data is available to guide clinicians on how to manage these medications long-term. Cognitive-behavioral approaches provide a promising avenue for helping OCD patients discontinue maintenance SRIs while minimizing the potential for symptom worsening. This manuscript describes the rationale and methods for pilot feasibility study designed to a unified, cognitive-behavioral strategy for discontinuing long-term SRIs in OCD. The aims of the study are (1) to evaluate the feasibility and acceptability of research procedures and interventions, (2) to test the efficacy of this treatment relative to an enhanced control condition and (3) to investigate the role of distress tolerance in both taper completion and clinical outcome. Our central aim is to investigate whether this approach improves discontinue outcomes relative to an enhanced control condition. Identifying optimal long-term treatment strategies for this population is needed to guide clinicians managing this often-chronic disorder.

SUBMITTER: Boisseau CL

PROVIDER: S-EPMC5803458 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Unified protocol for the discontinuation of long-term serotonin reuptake inhibitors in obsessive compulsive disorder: Study protocol and methods.

Boisseau Christina L CL Rasmussen Steven A SA

Contemporary clinical trials 20180103

Obsessive-compulsive disorder (OCD) is chronic psychiatric disorder associated with high rates of functional impairment and decreased quality of life. Although serotonin reuptake inhibitors have demonstrated efficacy in the treatment of OCD, little data is available to guide clinicians on how to manage these medications long-term. Cognitive-behavioral approaches provide a promising avenue for helping OCD patients discontinue maintenance SRIs while minimizing the potential for symptom worsening. ...[more]

PMID: 29306047

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Project description:Obsessive-compulsive disorder (OCD) is one of the world's most disabling illnesses according to the World Health Organization. Serotonin reuptake inhibitors (SRIs) are the only medications approved by the Food and Drug Administration to treat OCD, but few patients achieve minimal symptoms from an SRI alone. In such cases, practice guidelines recommend adding antipsychotics or cognitive-behavioral therapy consisting of exposure and ritual prevention (EX/RP).To compare the effects of these 2 SRI augmentation strategies vs pill placebo for the first time, to our knowledge, in adults with OCD.A randomized clinical trial (conducted January 2007-August 2012) at 2 academic outpatient research clinics that specialize in OCD and anxiety disorders. Patients (aged 18-70 years) were eligible if they had OCD of at least moderate severity despite a therapeutic SRI dose for at least 12 weeks prior to entry. Of 163 who were eligible, 100 were randomized (risperidone, n?=?40; EX/RP, n?=?40; and placebo, n?=?20), and 86 completed the trial.While continuing their SRI at the same dose, patients were randomized to the addition of 8 weeks of risperidone (up to 4 mg/d), EX/RP (17 sessions delivered twice weekly), or pill placebo. Independent assessments were conducted every 4 weeks.The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) to measure OCD severity.Patients randomized to EX/RP had significantly greater reduction in week 8 Y-BOCS scores based on mixed-effects models (vs risperidone: mean [SE], -9.72 [1.38]; P?<?.001 vs placebo: mean [SE], -10.10 [1.68]; P?<?.001). Patients receiving risperidone did not significantly differ from those receiving placebo (mean [SE], -0.38 [1.72]; P?=?.83). More patients receiving EX/RP responded (Y-BOCS score decrease ?25%: 80% for EX/RP, 23% for risperidone, and 15% for placebo; P?<?.001). More patients receiving EX/RP achieved minimal symptoms (Y-BOCS score ?12: 43% for EX/RP, 13% for risperidone, and 5% for placebo; P?=?.001). Adding EX/RP was also superior to risperidone and placebo in improving insight, functioning, and quality of life.Adding EX/RP to SRIs was superior to both risperidone and pill placebo. Patients with OCD receiving SRIs who continue to have clinically significant symptoms should be offered EX/RP before antipsychotics given its superior efficacy and less negative adverse effect profile.clinicaltrials.gov Identifier: NCT00389493.

Project description:BackgroundAnxiety, obsessive-compulsive, and stress-related disorders frequently co-occur, and patients often present symptoms of several domains. Treatment involves the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), but data on comparative efficacy and acceptability are lacking. We aimed to compare the efficacy of SSRIs, SNRIs, and placebo in multiple symptom domains in patients with these diagnoses over the lifespan through a 3-level network meta-analysis.Methods and findingsWe searched for published and unpublished randomized controlled trials that aimed to assess the efficacy of SSRIs or SNRIs in participants (adults and children) with diagnosis of any anxiety, obsessive-compulsive, or stress-related disorder in MEDLINE, PsycINFO, Embase, and Cochrane Library from inception to 23 April 2015, with an update on 11 November 2020. We supplemented electronic database searches with manual searches for published and unpublished randomized controlled trials registered in publicly accessible clinical trial registries and pharmaceutical companies' databases. No restriction was made regarding comorbidities with any other mental disorder, participants' age and sex, blinding of participants and researchers, date of publication, or study language. The primary outcome was the aggregate measure of internalizing symptoms of these disorders. Secondary outcomes included specific symptom domains and treatment discontinuation rate. We estimated standardized mean differences (SMDs) with 3-level network meta-analysis with random slopes by study for medication and assessment instrument. Risk of bias appraisal was performed using the Cochrane Collaboration's risk of bias tool. This study was registered in PROSPERO (CRD42017069090). We analyzed 469 outcome measures from 135 studies (n = 30,245). All medications were more effective than placebo for the aggregate measure of internalizing symptoms (SMD -0.56, 95% CI -0.62 to -0.51, p < 0.001), for all symptom domains, and in patients from all diagnostic categories. We also found significant results when restricting to the most used assessment instrument for each diagnosis; nevertheless, this restriction led to exclusion of 72.71% of outcome measures. Pairwise comparisons revealed only small differences between medications in efficacy and acceptability. Limitations include the moderate heterogeneity found in most outcomes and the moderate risk of bias identified in most of the trials.ConclusionsIn this study, we observed that all SSRIs and SNRIs were effective for multiple symptom domains, and in patients from all included diagnostic categories. We found minimal differences between medications concerning efficacy and acceptability. This three-level network meta-analysis contributes to an ongoing discussion about the true benefit of antidepressants with robust evidence, considering the significantly larger quantity of data and higher statistical power when compared to previous studies. The 3-level approach allowed us to properly assess the efficacy of these medications on internalizing psychopathology, avoiding potential biases related to the exclusion of information due to distinct assessment instruments, and to explore the multilevel structure of transdiagnostic efficacy.

Project description:Background: Obsessive-compulsive disorder (OCD) is a common chronic mental disorder with a high disability rate. Serotonin reuptake inhibitors (SRIs), including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, such as clomipramine, are the most common choices for the pharmacological treatment of OCD. Optimizing their use is pivotal in guiding clinical practice of OCD. However, there are few studies on the optimal dose of SRIs and there is controversy about their dose-response relationship and optimal target dose. Therefore, the objective of this study was to summarize the relationship between the dose and effect of SRIs, as well as the optimal dose of SRIs for OCD, as to propose future research directions. Methods: Medline, Embase, Biosis, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and CINAHL were searched for relevant publications, and the search was up to February 22, 2020. We used a one-stage, robust error meta-regression (REMR) model to deal with the correlated dose-response data for SRIs from different studies. Doses of SRIs were converted to fluoxetine equivalents when performing dose-response analysis. Review Manager Program Version 5.3 and STATA software package (version 15.1) were applied to analyze data. The study protocol was registered with PROSPERO (number CRD42020168344). Results: Eleven studies involving 2,322 participants were included in final analysis. For SRIs, the dose-efficacy curve showed a gradual increase trend in the 0-40-mg dose range and then had a decreased trend in doses up to 100 mg fluoxetine equivalent. Dropouts due to adverse effects gradually increased throughout the inspected dose slope. The curve of dose of all-cause dropouts suggested no relationship between them. Sensitivity analysis proved that these results were robust. Conclusion: The systematic review found that the optimal dose for efficacy was about 40mg fluoxetine equivalent. Tolerability decreased with increased doses, and there was no significant correlation between acceptability and doses of SRIs. Therefore, the optimal dose of SRIs needs to consider effectiveness and tolerability. Systematic Review Registration: [PROSPERO], identifier [CRD42020168344].

Project description:BackgroundMany patients with obsessive-compulsive disorder do not respond adequately to serotonin reuptake inhibitors. Augmentation with antipsychotic drugs can be beneficial in this regard. However, since new relevant randomized controlled trials evaluating new antipsychotics were conducted, a recalculation of the effect sizes appears necessary.MethodsWe meta-analyzed all double-blind, randomized, placebo-controlled trials comparing augmentation of serotonin reuptake inhibitors with antipsychotics to placebo supplementation in treatment-resistant obsessive-compulsive disorder. The primary outcome was mean change in the Yale-Brown Obsessive-Compulsive Scale total score. Secondary outcomes were obsessions, compulsions, response rates, and attrition rates. The data collection process was conducted independently by 2 authors. Hedges's g and risks ratios were calculated as effect sizes. In preplanned meta-regressions, subgroup analyses, and sensitivity analyses, we examined the robustness of the results and explored reasons for potential heterogeneity.ResultsAltogether, 14 double-blind, randomized, placebo-controlled trials (n=491) investigating quetiapine (N=4, n=142), risperidone (N=4, n=132), aripiprazole (N=2, n=79), olanzapine (N=2, n=70), paliperidone (N=1, n=34), and haloperidol (N=1, n=34) were incorporated. Augmentation with antipsychotics was significantly more efficacious than placebo in Yale-Brown Obsessive-Compulsive Scale total reduction (N=14, n=478; Hedges's g=-0.64, 95% CI: -0.87 to -0.41; P=<.01). Aripiprazole (Hedges's g=-1.35), haloperidol (Hedges's g=-0.82), and risperidone (Hedges's g=-0.59) significantly outperformed placebo. Antipsychotics were superior to placebo in treating obsessions, compulsions, and achieving response. There was no between-group difference concerning all-cause discontinuation. The nonsignificant meta-regressions suggest no influence of the antipsychotic dose or baseline symptom severity on the meta-analytic results.ConclusionsAccording to our findings, antipsychotic augmentation of serotonin reuptake inhibitors can be regarded as an evidence-based measure in treatment-resistant obsessive-compulsive disorder.

Project description:Objective: This study aimed to analyze the characteristics and reasons of early discontinuation of obsessive-compulsive disorder (OCD) trials registered on ClinicalTrials.gov. Methods: OCD trials and relevant publications were searched on ClinicalTrials.gov and PubMed, respectively. The characteristics and details regarding the timely publication of trials were recorded. Cox regression analysis was used to explore factors associated with the early discontinuation of OCD trials. Results: The analysis included 298 OCD therapy trials. Most investigations recruited <100 patients and were more likely to involve adults. Of all OCD studies identified, 67.8% were randomized and 61.4% were blind (single- or double-blind). Universities and hospitals were recorded as the two primary locations in the majority of trials. A total of 155 trials (52%) were completed; however, only 29% of those were published. Of the published trials, >70% were published at least 1 year after completion. Behavioral therapy trials were the most common type of major treatment-aimed OCD trials (39%), followed by drug trials (35.1%) and device/procedure trials (24.7%). The univariate Cox regression analysis indicated that drug trials [hazard ratio (HR) = 2.56, 95% confidence interval (CI): 1.21-5.43], absence of collaborators (HR = 3.87, 95% CI: 1.62-9.26), and sponsorship by industry (HR = 3.97, 95% CI: 1.49-10.53) were risk factors for early discontinuation of OCD trials. Further multivariate Cox regression showed that drug trials (HR = 3.93, 95% CI: 1.71-9.08) and absence of collaborators (HR = 5.17, 95% CI: 1.97-13.54) were independent risk factors for early trial discontinuation of OCD trials. The sensitivity analysis confirmed these results. Non-drug trials (OR = 3.32, 95% CI: 1.21-9.11), absence of collaborators (OR = 3.25, 95% CI: 1.10-9.60), and non-blinded trials (OR = 5.23, 95% CI: 1.05-26.2) were independent risk factors for unreported results in registry. Conclusion: The diagnosis and prevention of OCD are rarely investigated in trials. Underreporting and delayed reporting remain major problems. The type of intervention and participation of collaborators are associated with early discontinuation of OCD trials.

Dataset Information

Unified protocol for the discontinuation of long-term serotonin reuptake inhibitors in obsessive compulsive disorder: Study protocol and methods.

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Unified protocol for the discontinuation of long-term serotonin reuptake inhibitors in obsessive compulsive disorder: Study protocol and methods.

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