Relapse Prevention Trial Research Articles

Efficacy and Safety Of AXS-05 in Agitation Associated with Alzheimer’s Disease: Results from ACCORD, a Phase 3, Double-blind, Placebo-controlled, Relapse Prevention Trial (PL5.004)

Efficacy and Safety Of AXS-05 in Agitation Associated with Alzheimer’s Disease: Results from ACCORD, a Phase 3, Double-blind, Placebo-controlled, Relapse Prevention Trial (PL5.004)

Efficacy and Safety Of AXS-05 in Agitation Associated with Alzheimer's Disease: Results From ACCORD, a Phase 3, Double-Blind, Placebo-Controlled, Relapse Prevention Trial

Efficacy and Safety Of AXS-05 in Agitation Associated with Alzheimer's Disease: Results From ACCORD, a Phase 3, Double-Blind, Placebo-Controlled, Relapse Prevention Trial

Mindfulness mechanisms in alcohol use: Comparing top-down and bottom-up processes.

This study compared two mechanisms by which mindfulness may reduce hazardous drinking: effortful control and craving, "top-down" and "bottom-up" processes, respectively. These relationships were compared in a secondary analysis of a randomized controlled trial of mindfulness-based relapse prevention (MBRP) versus relapse prevention (RP) treatments to explore if they differed based on more explicit versus subtle mindfulness training. A total of 182 individuals (48.4% female; 21-60 years old) who reported drinking > 14/21 drinks/week (for females/males, respectively) in the past 3 months but who wished to quit/reduce their drinking were recruited from Denver and Boulder, CO, United States. Participants were randomly assigned to either 8 weeks of MBRP or RP treatment and completed assessments at baseline, halfway through treatment, and at the end of treatment. The Five-Factor Mindfulness Questionnaire-Short Form, Alcohol Urge Questionnaire, and Effortful Control Scale completed halfway through treatment assessed the predictor, dispositional mindfulness, and mediators, craving and effortful control, respectively. The Alcohol Use Disorder Identification Task was completed after treatment and measured hazardous drinking. Cross-group path analyses were conducted including both mediators/treatments in the same model. Comparing models with and without equality constraints across treatments, no paths significantly differed based on a chi-square test of difference, χ²(5) = 5.11, p = .40, and only the indirect effect of craving was significant (B = -1.01, p = .01). Findings suggest mindfulness may be associated with hazardous drinking reductions through craving but not effortful control and this indirect relationship works similarly across treatments engendering mindfulness explicitly and implicitly. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Consistency checks to improve measurement with the Young Mania Rating Scale (YMRS)

BackgroundMitigating rating inconsistency can improve measurement fidelity and detection of treatment response. MethodsThe International Society for CNS Clinical Trials and Methodology convened an expert Working Group that developed logical consistency (LC) checks for ratings of the Young Mania Rating Scale (YMRS), which is widely used in studies of mood and bipolar disorders. LC and statistical outlier-response pattern checks (SC) were applied to 63,228 YMRS administrations from 14 clinical trials evaluating treatments for bipolar disorder. Checks were also applied to Monte Carlo-simulated data as a proxy for their use under conditions of inconsistency. Results42 LC flags were developed, and four SC flags were created from the data set (n = 14). Almost 20 % of the rating administrations had at least one LC flag, 6.7 % had two or more, 1.7 % had three or more; 17.3 % percent of the administrations had at least one SC flag and 4.6 % percent had two or more. Overall, 31 % of administrations had at least one flag of any type, 12.1 % had two or more and 5.3 % had three or more. In acute antimanic treatment trials (n = 10) there were more flags of any type compared to relapse prevention trials (n = 4). LimitationsFlagged ratings may represent less-common presentations assessed correctly. ConclusionsUsing established methods, we illustrate development and application of consistency flags for YMRS ratings. Applying flags and mitigation during trials may improve the value of YMRS data, help focus attention on rater training, and improve reliability and validity of trial data.

Perspectives on relapse prevention following intensive treatment of anorexia nervosa: A focus group study.

Including the perspectives of individuals with lived experience of mental health issues is a critical step in research and treatment development. Focus groups with patients with a history of treatment for anorexia nervosa (AN) were conducted in anticipation of a clinical trial of Relapse Prevention and Changing Habits (REACH+). Seven female adults (23-51 years) who had previously received inpatient treatment for AN, now in remission, participated in one of two semistructured focus groups. Rapid qualitative analysis was used to examine participants' contributions and identify common topics. Transcript analysis yielded three topics related to relapse prevention: (1) recovery aids, including a sense of agency in treatment decisions and finding new interests/passions, (2) recovery hindrances, such as lack of access to care, and (3) identification of members of support system. Aspects of REACH+ received positive feedback, such as continuity of care from the inpatient setting and the use of telehealth. Viewpoints differed with respect to the helpfulness of obtaining patient weights in treatment. The REACH+ online platform received positive comments regarding content and usability, as well as suggestions for additional content. Qualitative feedback from patients with a history of AN highlighted the value of engaging patients in their own treatment decisions, as well as in treatment design and innovation. Within this small group, there were differences of opinion about treatment components, specifically weight assessment, that suggest the need for further data. User-centered design provides opportunities to improve the acceptability and, therefore, dissemination of novel treatments. Relapse prevention is a critical treatment need for patients with anorexia nervosa, as this illness too often follows a protracted course. There are challenges in both obtaining specialized care and in retaining patients in treatment. Here, patient perspectives on these challenges offer input to allow for optimization of relapse prevention treatment. Shared decision-making may be particularly valuable to support an individual's sense of agency and engagement in care.

Pilot randomized controlled trial of mindfulness-based relapse prevention vs cognitive behavioral therapy for smoking and alcohol use

BackgroundThe combined use of cigarettes and alcohol is associated with a synergistic increase in the risk of morbidity and mortality. Continued alcohol use during a smoking quit attempt is a considerable risk factor for smoking relapse. As such, there is a need for interventions that address both behaviors concurrently. Mindfulness-based interventions hold much promise for simultaneously addressing tobacco and alcohol use. MethodThis pilot study evaluated the feasibility and acceptability of a mindfulness-based intervention using a two-arm randomized controlled trial of Mindfulness-Based Relapse Prevention for Smoking and Alcohol (MBRP-SA) vs Cognitive Behavioral Therapy (CBT). Interventions were delivered via telehealth in a group setting; all participants received a 6-week supply of the nicotine patch. Participants (N = 69) were adults who smoked cigarettes who reported binge drinking and were motivated to both quit smoking and change their alcohol use. Primary outcomes were feasibility and acceptability of MBRP-SA compared to CBT. Changes in tobacco and alcohol use are also presented. ResultsParticipants in MBRP-SA and CBT indicated that the treatments were highly acceptable, meeting a priori benchmarks. Feasibility was mixed with some outcomes meeting benchmarks (e.g., recruitment) and others falling below (e.g., retention). Participants in both conditions demonstrated significant reductions in tobacco and alcohol use at the end of treatment. ConclusionsIn sum, MBRP-SA had comparable outcomes to CBT on all metrics measured. Future research should evaluate the efficacy of MBRP-SA on smoking abstinence and drinking reductions in a large-scale, fully powered trial. This study was registered on clinicaltrials.gov (NCT03734666).

Longitudinal study of inflammation and relapse in schizophrenia

IntroductionThe clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. MethodsWe analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design. Results70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse. ConclusionAlthough there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.

Optimizing relapse prevention and changing habits (REACH+) in anorexia nervosa.

Relapse rates in anorexia nervosa (AN) are high, even after full weight restoration. This study aims to develop a relapse prevention treatment that specifically addresses persistent maladaptive behaviors (habits). Relapse Prevention and Changing Habits (REACH+) aims to support patients in developing routines that promote weight maintenance, encourage health, and challenge habits that perpetuate illness. The clinical trial design uses the Multiphase Optimization STrategy (MOST) framework to efficiently identify which components of treatment contribute to positive outcomes. Participants will be 60 adults with AN who have achieved weight restoration in an inpatient setting. Treatment will consist of 6months of outpatient telehealth sessions. REACH+ consists of behavior, cognitive, and motivation components, as well as food monitoring and a skill consolidation phase. A specialized online platform extends therapy between sessions. Participants will be randomly assigned to different versions of each component in a fractional factorial design. Outcomes will focus on maintenance of remission, measured by rate of weight loss and end-of-trial status. Interventions that contribute to remission will be included in an optimized treatment package, suitable for a large-scale clinical trial of relapse prevention in AN.

Contingency planning and risk mitigation strategies for a schizophrenia relapse prevention trial during the COVID-19 pandemic

Contingency planning and risk mitigation strategies for a schizophrenia relapse prevention trial during the COVID-19 pandemic

Time course of adverse events – descriptive data analysis of a schizophrenia relapse prevention trial of cariprazine

Time course of adverse events – descriptive data analysis of a schizophrenia relapse prevention trial of cariprazine

Is extended release naltrexone superior to buprenorphine-naloxone to reduce drinking among outpatients receiving treatment for opioid use disorder? A secondary analysis of the CTN X:BOT trial.

The comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT) trial showed that following induction, treatment with the sublingual agonist (buprenorphine-naloxone, BUP-NX) or injected antagonist (extended release naltrexone, XR-NTX) produced similar reductions in opioid relapse in injection users with opioid use disorder (OUD). Because XR-NTX reduces drinking in alcohol use disorder (AUD), we conducted a secondary analysis of the X:BOT sample of patients successfully inducted onto treatment to determine whether XR-NTX (n=204) was superior to BUP-NX (n=270) in reducing drinking or heavy drinking in patients with OUD. Standard drink units consumed were measured using the Timeline Follow-back method. Mixed-models regression was used to examine the monthly frequency of any drinking and heavy drinking over 6months of treatment. We used a proportional hazard survival analysis to examine the time to first drink. Both treatment groups reduced drinking from baseline to posttreatment (small to medium effect), but no differences between groups were detected. However, only 29% (n=136) of the sample had AUD and 19% (n=26/136) of those were abstinent before treatment. Analysis of a subsample enriched for possible drinking included 136 individuals with an AUD diagnosis plus 43 who did not have AUD, but reported at least one day of heavy drinking prior to the study. However, this subsample reported only 32% of days of any drinking with a median of only 13% of days designated as "heavy." Within this subsample, at baseline, the BUP-NX group reported more mean drinks per drinking day than the XR-NTX group (p=0.03); however, there were no other significant group differences on drinking observed before, during, or at the end of treatment. There was an overall reduction in drinking during treatment of OUD using both agonist and antagonist medications, so that the hypothesis that XR-NTX would be superior to BUP-NX was not supported. The study is limited by low levels of comorbid AUD or heavy drinking observed in X:BOT trial participants seeking treatment for OUD.

Prophylactic effects or withdrawal reactions? An analysis of time-to-event data from antidepressant relapse prevention trials submitted to the FDA.

Background:Relapse prevention trials build the scientific foundation for recommendation of antidepressant continuation and maintenance therapy. However, the validity of the evidence is disputed and may be biased due to withdrawal confounding.Methods:We analysed survival curves from all antidepressant relapse prevention trials submitted to the United States (US) Food and Drug Administration (FDA) between 1987 and 2012 for 13 approved drugs. The main outcome was the percent of the drug effect (placebo-antidepressant difference in relapse events) at any week of the maintenance phase in relation to the total drug effect at the endpoint of the randomised maintenance phase.Results:Altogether, 14 studies with a mean observation period of 38.9 weeks (Kaplan–Meier estimators) were analysed. At week 3, a mean of 20.6% [95% confidence interval (CI) = 10.9–30.3%] of the total drug effect was achieved. At weeks 6 and 12, the corresponding figures were 50.3% (37.3–63.3%) and 69.0% (55.1–82.8%). No further antidepressant–placebo separation was observed as of week 24 [101.0% of total drug effect (94.6–107.3%)]. This means that censoring relapse events that occurred in the first 3, 6, 12 and 24 weeks would reduce the total drug effect at study endpoint by 20.6%, 50.3%, 69.0% and 101.0%, respectively. Assuming antidepressants had a constant prophylactic effect over 38.9 weeks, we further showed that, around week 6, the antidepressant–placebo separation was about three times larger than expected.Conclusion:The placebo–antidepressant separation was disproportionally large between weeks 3 and 6 of the randomised maintenance phase. The benefits of continuing antidepressants relative to abrupt/rapid discontinuation declined sharply after week 6. This indicates an excess of relapse events in the placebo arms during the early maintenance phase that may be due to withdrawal reactions caused by abrupt/rapid discontinuation of active treatment. If these early relapse events are due to a direct pharmacological effect, then antidepressants’ true prophylactic long-term effects are substantially overestimated.

Study protocol for a randomized controlled trial of mindfulness-based relapse prevention for opioid use disorders

The opioid misuse epidemic has reached a crisis level in the United States. Though mindfulness-based relapse prevention (MBRP) has been shown as effective in treating substance use disorders, there is limited research on its application to opioid use disorders specifically, and there is a need to understand the underlying mechanisms. This paper outlines a protocol for a randomized controlled trial of MBRP for opioid use disorders. MBRP is a group aftercare program that integrates mindfulness skills training with cognitive-behavioral relapse prevention strategies. We will recruit 240 participants who have completed opioid use disorder treatment, and randomize them to an 8-week MBRP group intervention or treatment as usual (TAU) control group. The TAU control group will complete the intervention after 8 weeks. Assessments will take place at baseline, 8 weeks, and 16 weeks. The primary outcome is frequency of opioid use. The secondary outcomes include craving and withdrawal symptoms, time to first opioid use, adherence to medication-assisted treatment plans, perceived stress, quality of life, posttraumatic stress symptoms, and chronic pain. We will also examine the following potential moderators and correlates of intervention outcomes: comorbid diagnoses, life events history, and MBRP intervention adherence. In addition, we will examine the following mediators of intervention outcome: mindfulness skills, emotion regulation skills, executive functioning skills, savoring, and positive and negative affect. This study will contribute to the evidence base regarding MBRP's efficacy in reducing opioid use, as well as contribute to the understanding of the causal mechanisms and factors that modify treatment outcome for MBRP for substance use disorders.

How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding.

The aim of this article is to discuss the validity of relapse prevention trials and the issue of withdrawal confounding in these trials. Recommendations for long-term antidepressant treatment are based almost exclusively on discontinuation trials. In these relapse prevention trials, participants with remitted depression are randomised either to have the antidepressant abruptly discontinued and replaced by inert placebo or to continue active treatment. The drug–placebo difference in relapse rates at the end of the maintenance phase is then interpreted as a prophylactic drug effect. These trials consistently produce remarkable benefits for maintenance treatment. However, the internal validity of this trial protocol is compromised, as research has shown that abruptly stopping antidepressants can cause severe withdrawal reactions that lead to (or manifest as) depression relapses. That is, there is substantial withdrawal confounding in discontinuation trials, which renders their findings uninterpretable. It is not clear to what degree the drug–placebo separation in relapse prevention (discontinuation) trials is due to withdrawal reactions, but various estimations suggest that it is presumably the majority. A review of findings based on other methodologies, including real-world long-term effectiveness trials like STAR*D and various naturalistic cohort studies, do not indicate that antidepressants have considerable prophylactic effects. As absence of evidence does not imply evidence of absence, no definitive conclusions can be drawn from the literature. To enable a thorough risk–benefit evaluation, real-world effectiveness trials should not only focus on relapse prevention, but also assess antidepressants’ long-term effects on social functioning and quality of life. Thus far, reliable long-term data on these outcome domains are lacking.

Withdrawal effects confounding in clinical trials: another sign of a needed paradigm shift in psychopharmacology research.

Randomized controlled trials’ ability to produce evidence useful for people to decide whether to take, continue taking, or stop taking psychotropic drugs has been intensely critiqued, along with the trials’ commercial, ideological, and regulatory contexts. This article applies the critique to the topic of withdrawal effects confounding the outcomes of relapse-prevention trials where prescribed psychotropic drugs are discontinued. Until recently, the complexity and reach of withdrawal and post-withdrawal effects were neglected by mainstream psychiatry, but not by lay users of prescribed psychotropics. This article discusses withdrawal effects as part of the pharmacology of psychotropic drugs but shaped by psychosocial factors, and possibly shaping the presentation of psychological distress generally. It outlines biases and misconceptions in assumptions, design, and reporting of general efficacy trials and findings from a recent review of 80 discontinuation trials. In theory, relapse-prevention trials are tautological and exaggerate efficacy. In publications, they pay little attention to the central feature of their design, favor abrupt or rapid discontinuations, do not attend to environmental factors, and provide insufficient data to allow re-analyses. Thus, relapse-prevention RCTs likely confound the detection of their main outcome of interest: “relapse.” Using slower tapers, active placebo controls, and specific covariates in analyses would reduce the risk of withdrawal confounding, and better reporting would reduce the opaqueness of trials. The crisis in psychopharmacology is fueled partly by the disconnect between claims of therapeutic efficacy from so-called best-evidence methods despite unchanging population-level indicators of psychiatric sickness. Only by “stacking the deck” against trial sponsors’ hoped-for outcomes can psychopharmacology trials regain scientific credibility.

Personality as a Predictor of Treatment Response to Escitalopram in Adults With Body Dysmorphic Disorder.

Serotonin reuptake inhibitors (SRIs) are the first-line pharmacotherapy for body dysmorphic disorder (BDD), a common and severe disorder. However, predictors and correlates of treatment response are not well understood. A closer examination of baseline personality dimensions and disorders and of changes in personality during SRI treatment is needed to advance knowledge of this clinically important issue. We conducted a secondary analysis of data from a pharmacotherapy relapse prevention trial of the SRI escitalopram in adults with BDD to examine personality dimensions and traits, as well as whether these variables predict and correlate with treatment response. A total of 65 participants with BDD completed the Revised NEO Personality Inventory (NEO PI-R) before starting open-label treatment with escitalopram and 42 participants completed the NEO PI-R after treatment. At baseline, participants with BDD displayed higher levels of neuroticism and lower levels of extraversion than a normed reference group. Higher baseline neuroticism was a significant predictor of nonresponse to escitalopram treatment, even when baseline depression severity was controlled for. Changes in neuroticism were not associated with treatment response. Our findings underscore the relationship between BDD and neuroticism, and they suggest a link between neuroticism and SRI treatment response.

Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy.

The purpose of this review is to describe the available data for brexpiprazole in the maintenance treatment of schizophrenia. This objective was completed by searching the databases PubMed, Embase, and ClinicalTrials.gov to identify relevant study results presented as papers or abstracts. In summary, brexpiprazole is a new agent in the D2 partial agonist class that has a unique receptor-binding profile, based in part on high affinity for serotonin 5HT1A and 5HT2A receptors, paired with lower intrinsic activity at dopamine D2 receptors. The average dose used in efficacy and safety studies for the maintenance treatment of schizophrenia ranged from 3.0 and 3.1 mg in the open-label safety studies to 3.6 mg in the double-blind randomized relapse-prevention study. Highlights from the 52-week double-blind placebo-controlled relapse-prevention trial evidenced rates of relapse in the brexpiprazole group of 13.5% vs 38.5% in the placebo group (number needed to treat 4, 95% CI 3–8; P<0.0001). Safety data indicate that brexpiprazole is tolerated well, with rates of discontinuation due to treatment-emergent adverse events that ranged from 5.2% of those taking brexpiprazole in the double-blind maintenance phase of the relapse-prevention trial to 15.3% in a 52-week open-label safety study. In the available trials, there were relatively low rates of akathisia, and the degree of weight gain was similar to that seen in studies with aripiprazole for the treatment of schizophrenia. Positive and Negative Syndrome Scale scores also remained relatively stable in the open-label safety studies. Available data indicate that brexpiprazole is an effective agent for the maintenance treatment of schizophrenia that is overall well tolerated.

Factors Associated With Successful Medication Discontinuation After a Randomized Clinical Trial of Relapse Prevention in First-Episode Psychosis

Factors Associated With Successful Medication Discontinuation After a Randomized Clinical Trial of Relapse Prevention in First-Episode Psychosis

An open trial of rolling admission mindfulness-based relapse prevention (Rolling MBRP): feasibility, acceptability, dose-response relations, and mechanisms.

Mindfulness-based relapse prevention (MBRP) is an effective treatment for substance use disorders (SUD). However, evidence is primarily based on studies of closed groups, and few studies support flexible formats of MBRP, such as rolling groups. This nonrandomized, open trial evaluated feasibility, acceptability, dose-response relations, and mechanisms of rolling admission MBRP ("Rolling MBRP") offered as part of short-term residential treatment for SUD. Rolling MBRP was developed prior to the trial through an iterative process over several years. Participants included 109 adults (46% female, 74.3% racial/ethnic minorities, mean age=36.40). Rolling MBRP was offered to all patients in the program 2x/week and attendance was tracked. Outcomes were craving, self-efficacy, mental health, mindfulness, and self-compassion at discharge. Self-reported out-of-session mindfulness practice was examined as a mediator of attendance-outcome relations. Analyses involved multiple regression and mediation models. Feasibility was demonstrated by good attendance rates. Acceptability was demonstrated by high engagement in mindfulness practice and high satisfaction ratings. Total sessions attended did not predict outcomes at discharge. However, attending 2+ sessions (versus 1 or none) significantly predicted better mental health and higher mindfulness at discharge, and these effects were mediated by informal and formal mindfulness practice. Total sessions attended had significant indirect effects on craving, self-compassion, mindfulness, and mental health, via mindfulness practice. Results support the feasibility and acceptability of Rolling MBRP and suggest mindfulness practice may be a key mechanism driving effects of MBRP on other key mechanisms during the recovery process, such as decreased craving and improved mental health.

Characteristics of Romanian women who enrolled in a postpartum tobacco smoking relapse prevention trial

Characteristics of Romanian women who enrolled in a postpartum tobacco smoking relapse prevention trial