Randomised controlled trial of gradual antipsychotic reduction and discontinuation in people with schizophrenia and related disorders: the RADAR trial (Research into Antipsychotic Discontinuation and Reduction) (original) (raw)
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Frontiers in Psychiatry
Backgrounds: There is a debate regarding the optimal timing of discontinuation of antipsychotic drugs in patients with first episode psychosis (FEP) or schizophrenia. We aimed to provide a review of the literature on which strategy (medication maintenance vs. dose reduction/discontinuation) is more likely to maximize outcomes, such as cognition and social function. Methods: Using PubMed, the Cochrane Library and systematic reviews, articles published between 2007 and 2018 were reviewed, which investigated the effect of dose reduction/discontinuation vs. maintenance treatment on measures of cognition and/or social function in FEP and schizophrenia. Results: Six studies were identified; 2 studies reported on cognition while 4 studies concern social function. All studies except one reported that improvement of functional outcomes in remitted patients with FEP or schizophrenia allocated to a dose reduction/discontinuation arm was equal to or better than that in patients for whom medication doses were maintained. One trial of social function with a 1-year follow-up period found a greater improvement in the medication maintenance group, while no group difference was observed with 3-year and 10-year follow-up periods. On the other hand, a 7-year follow-up study found a superiority for the dose reduction/discontinuation regimen in terms of social outcome. Two studies on cognition with a short follow-up period reported a greater improvement for the dose reduction/discontinuation group. Conclusions: Information on cognition and social function has been relatively sparse. These measures of functional outcome should be considered in deciding which strategy of antipsychotic treatments is beneficial in individual cases with FEP or schizophrenia.
Trials
Background Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition—a finding that was not replicated in another recently published long-term study. Methods/design The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission o...
AIMS: Discontinuation of antipsychotics following remission in first episode psychosis (FEP) is a contentious area of practice. We aimed to investigate the views of early psychosis clinicians on this important clinical question. METHODS: We designed an 11 question online survey on medication discontinuation following remission of symptoms in FEP. The questionnaire was distributed to early intervention team workers in England and Wales via members of the National Early Psychosis Network who were requested to distribute it to their teams. RESULTS: We received 172 questionnaire responses; 37% were nurses, 33% doctors, 11% psychologists and 19% were other allied health professionals. The average years of experience in psychiatry was 16.9. 75.4% of respondents thought that greater than 60% of patients would like to be considered for guided medication reduction/discontinuation. Only 31.4% of respondents said that medication should be continued for over a year following remission. 61.4% of respondents felt that the quality of life of individuals was better in those who stop medication following remission. There was a significant difference in the response of professional groups to this question. 82.6% of respondents said they would be happy to support their patients in participating in a randomized trial of graded antipsychotic reduction/discontinuation versus maintenance medication. CONCLUSIONS: The views of clinicians regarding prophylactic antipsychotic medication following remission in FEP are much less conservative than those in current guidelines; concern was expressed by many about the impact of antipsychotic medication on quality of life. A randomized trial of maintenance antipsychotic medication versus graded reduction/discontinuation is feasible and has considerable clinician support.
Journal of Psychiatric Research, 2009
Data from the 3-year, prospective, observational SOHO study were used to compare the effectiveness (in terms of treatment discontinuation) and the tolerability of olanzapine, risperidone, other atypicals and typical antipsychotics in 1009 previously untreated outpatients with schizophrenia who started monotherapy at baseline. Kaplan-Meier survival analysis estimated the time to treatment discontinuation by the treatment group, Cox proportional hazards regression models identified the variables associated with treatment discontinuation (adjusted for baseline differences between treatment groups), and logistic regression models compared the tolerability profiles of the different treatment groups. Of the 931 patients analyzed, 31.9% discontinued the medication initiated at baseline during the 3-year follow-up. Olanzapine had the lowest rate of discontinuation (28.9%), followed by other atypical (34.0%), risperidone (36.2%) and typical antipsychotics (44.5%). Compared to olanzapine, risk of treatment discontinuation was higher with typical antipsychotics (hazard ratio [HR] 1.75; 95% confidence interval [CI] 1.11, 2.78) or risperidone (HR 1.36; 95% CI 1.02, 1.82). A higher baseline Clinical Global Impression (CGI) positive score was associated with a higher risk of treatment discontinuation (HR 1.18; 95% CI 1.06, 1.30). Olanzapine was associated with a lower frequency of extrapyramidal symptoms than other antipsychotics, fewer prolactin-related adverse events than risperidone and other atypical antipsychotics, but greater weight gain than typicals and risperidone. For all analyses, comparison with the other atypical group is limited due to its small sample size (n = 50). In conclusion, treatment effectiveness and tolerability varied among antipsychotic medications in previously untreated patients with schizophrenia. The results should be interpreted conservatively given the observational study design.
Psychiatry Research, 2012
In recent years, measurement of the effectiveness of antipsychotic therapy in schizophrenia has received increasing attention from clinicians and researchers. Several studies have used time to antipsychotic discontinuation for any reason as a global index of antipsychotic effectiveness because it reflects both the physician's and patient's judgment of drug efficacy and tolerability. In this study, we extend this approach by analyzing the rate of discontinuation for different reasons of antipsychotics administered to patients with schizophrenia in a naturalistic setting of care, and explore the determinants of such discontinuation. Ninety-nine patients with schizophrenia who received a first or second generation antipsychotic were followed for 18 months in the Italian outpatient community psychiatric system. We found discontinuation rates for different reasons to be variable and to be influenced by several factors not involving the type of pharmacologic therapy. Some of these factors, such as the frequency of visits to the care unit, underline the need to take into account the role of the care delivery system as potentially influencing the effectiveness of antipsychotics in the ''real world''.
Schizophrenia research, 2017
There is uncertainty about the required duration of long-term antipsychotic maintenance medication after a first episode of psychosis. Robust predictors of relapse after discontinuation are yet to be identified. The present study aimed to determine the proportion of young people who discontinue their antipsychotic medication after a first episode of psychosis, the proportion who experience relapse, and predictors of relapse. A retrospective study of all individuals presenting to the Early Psychosis Prevention and Intervention Centre between 01/01/11 and 31/12/13 was conducted. A Cox regression analysis was conducted to identify predictors of relapse. A total of 544 young people with a FEP were included. A trial of discontinuation was undertaken by 61% of the cohort. Median duration of antipsychotic medication prior to first trial of discontinuation was 174.50days. Amongst those trialing discontinuation, 149 (45.8%) experienced relapse in a median follow-up time post discontinuation ...
Antipsychotic dose reduction compared to dose continuation for people with schizophrenia
The Cochrane library, 2022
BackgroundAntipsychotic drugs are the mainstay treatment for schizophrenia, yet they are associated with diverse and potentially dose‐related side effects which can reduce quality of life. For this reason, the lowest possible doses of antipsychotics are generally recommended, but higher doses are often used in clinical practice. It is still unclear if and how antipsychotic doses could be reduced safely in order to minimise the adverse‐effect burden without increasing the risk of relapse.ObjectivesTo assess the efficacy and safety of reducing antipsychotic dose compared to continuing the current dose for people with schizophrenia.Search methodsWe conducted a systematic search on 10 February 2021 at the Cochrane Schizophrenia Group's Study‐Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, ISRCTN, and WHO ICTRP. We also inspected the reference lists of included studies and previous reviews.Selection criteriaWe included randomised controlled trials (RCTs) comparing any dose reduction against continuation in people with schizophrenia or related disorders who were stabilised on their current antipsychotic treatment. Data collection and analysisAt least two review authors independently screened relevant records for inclusion, extracted data from eligible studies, and assessed the risk of bias using RoB 2. We contacted study authors for missing data and additional information. Our primary outcomes were clinically important change in quality of life, rehospitalisations and dropouts due to adverse effects; key secondary outcomes were clinically important change in functioning, relapse, dropouts for any reason, and at least one adverse effect. We also examined scales measuring symptoms, quality of life, and functioning as well as a comprehensive list of specific adverse effects. We pooled outcomes at the endpoint preferably closest to one year. We evaluated the certainty of the evidence using the GRADE approach.Main resultsWe included 25 RCTs, of which 22 studies provided data with 2635 participants (average age 38.4 years old). The median study sample size was 60 participants (ranging from 18 to 466 participants) and length was 37 weeks (ranging from 12 weeks to 2 years). There were variations in the dose reduction strategies in terms of speed of reduction (i.e. gradual in about half of the studies (within 2 to 16 weeks) and abrupt in the other half), and in terms of degree of reduction (i.e. median planned reduction of 66% of the dose up to complete withdrawal in three studies). We assessed risk of bias across outcomes predominantly as some concerns or high risk. No study reported data on the number of participants with a clinically important change in quality of life or functioning, and only eight studies reported continuous data on scales measuring quality of life or functioning. There was no difference between dose reduction and continuation on scales measuring quality of life (standardised mean difference (SMD) −0.01, 95% confidence interval (CI) −0.17 to 0.15, 6 RCTs, n = 719, I2 = 0%, moderate certainty evidence) and scales measuring functioning (SMD 0.03, 95% CI −0.10 to 0.17, 6 RCTs, n = 966, I2 = 0%, high certainty evidence).Dose reduction in comparison to continuation may increase the risk of rehospitalisation based on data from eight studies with estimable effect sizes; however, the 95% CI does not exclude the possibility of no difference (risk ratio (RR) 1.53, 95% CI 0.84 to 2.81, 8 RCTs, n = 1413, I2 = 59% (moderate heterogeneity), very low certainty evidence). Similarly, dose reduction increased the risk of relapse based on data from 20 studies (RR 2.16, 95% CI 1.52 to 3.06, 20 RCTs, n = 2481, I2 = 70% (substantial heterogeneity), low certainty evidence). More participants in the dose reduction group in comparison to the continuation group left the study early due to adverse effects (RR 2.20, 95% CI 1.39 to 3.49, 6 RCTs with estimable effect sizes, n = 1079, I2 = 0%, moderate certainty evidence) and for any reason (RR 1.38, 95% CI 1.05 to 1.81, 12 RCTs, n = 1551, I2 = 48% (moderate heterogeneity), moderate certainty evidence).Lastly, there was no difference between the dose reduction and continuation groups in the number of participants with at least one adverse effect based on data from four studies with estimable effect sizes (RR 1.03, 95% CI 0.94 to 1.12, 5 RCTs, n = 998 (4 RCTs, n = 980 with estimable effect sizes), I2 = 0%, moderate certainty evidence). Authors' conclusionsThis review synthesised the latest evidence on the reduction of antipsychotic doses for stable individuals with schizophrenia. There was no difference between dose reduction and continuation groups in quality of life, functioning, and number of participants with at least one adverse effect. However, there was a higher risk for relapse and dropouts, and potentially for rehospitalisations, with dose reduction. Of note, the majority of the trials focused on relapse prevention rather potential beneficial outcomes on quality of life, functioning, and adverse effects, and in some studies there was rapid and substantial reduction of doses. Further well‐designed RCTs are therefore needed to provide more definitive answers.
Second-Generation Antipsychotic Discontinuation in First Episode Psychosis: An Updated Review
Clinical Psychopharmacology and Neuroscience, 2011
All-causes discontinuation" refers to discontinuation of treatment for any reason, and medication adherence is an important component of this measure. Similar to our previous results, we found that almost 30% of patients with first-episode psychosis (FEP) discontinue medication in the first 9 months of treatment, a finding that has important implications for long-term outcomes. Many newer second-generation antipsychotics have not been studied in FEP. The self-reported Drug Attitude Inventory may help identify patients at heightened risk for medication discontinuation. In addition to vigilant monitoring for and adequate treatment of psychopathology and medication side effects, Relapse Prevention Therapy and the use of long-acting injectable agents may be effective interventions decrease discontinuation rates in FEP. There is currently no consensus on how long a patient should remain on an antipsychotic medication following remission of FEP. Studies are needed to identify predictors of which patients in remission from FEP are less likely to relapse when medication is discontinued. Taken together, our findings presented here underscore the importance of addressing medication discontinuation both as a means of preventing long-term morbidity and enhancing remission and functional recovery in FEP.
BMC medicine, 2005
Stopping antipsychotic treatment can interrupt improvement and exacerbate the illness. The reasons for discontinuing treatment during controlled clinical trials were analyzed to explore this phenomenon. A post-hoc, pooled analysis was made of 4 randomized, double-blind clinical trials, 24-28 weeks in duration, involving 1627 patients with schizophrenia or a related disorder. Analyses combined all the atypical antipsychotic treatment groups in the studies. The majority of patients (53%) stopped their treatment at an early stage. Poor psychiatric response along with worsening symptoms was the most frequently given reason for discontinuing the course (36%), which was substantially more common than discontinuation due to poor tolerability of the medication (12%). This phenomenon was corroborated by less improvement in patients who discontinued treatment compared with those who completed, based on the PANSS total scores. Discontinuation due to poor response was, apparently, more predomin...