Nonadherence for first-episode schizophrenia is a major unsolved challenge. The long-acting injectable route is an appealing strategy, but there are concerns about acceptability. We report on acceptance and initial adherence outcomes with risperidone long-acting injection (RLAI) in first-episode schizophrenia patients.
We conducted a prospective randomized controlled trial in which we enrolled patients defined by appropriate Structured Clinical Interview for DSM-IV diagnosis and < or = 16 weeks of lifetime antipsychotic exposure. Participants were randomly assigned (2:1 ratio) to a recommendation of changing to RLAI versus continuing on oral therapy (ORAL). Nonadherence behavior was defined as a medication gap > or = 14 days. Adherence attitudes were determined by the Rating of Medication Influences (ROMI) scale. A priori analysis defined treatment groups as intent-to-treat (ITT) and as-actually-treated (AAT) for the first 12 weeks after initial randomization. Participants were enrolled from December 2004 to March 2007.
Of 46 eligible patients, 37 were randomly assigned, 11 to ORAL and 26 to RLAI. Nineteen of 26 patients (73%) accepted the RLAI recommendation. There were no differences in adherence behavior at 12 weeks based on initial randomization (Kaplan-Meier survival for ITT: 76% [95% CI, 35%-90%] adherent for RLAI vs 72% [95% CI, 55%-89%] for ORAL; log-rank P = .78), but patients accepting RLAI were significantly more likely to be adherent than patients staying on ORAL (AAT: 89% [95% CI, 64%-97%] adherent for RLAI vs 59% [95% CI, 32%-78%] for ORAL; log-rank P = .035). There were no ROMI attitude differences between either treatment group comparison at 12 weeks.
Most first-episode patients taking oral antipsychotics will accept a recommendation of RLAI therapy. On the basis of initial randomization status, an RLAI recommendation did not affect adherence behavior at 12 weeks. However, acceptance of RLAI was associated with significantly better adherence. Regardless of whether RLAI is recommended or accepted, there is no adverse impact on subsequent medication attitudes at 12 weeks. These results support the feasibility and acceptability of introducing RLAI as a treatment option for first-episode schizophrenia patients.
clinicaltrials.gov Identifier: NCT00220714.
"Explanatory Pragmatic Study objectives To determine efficacy and safety in a controlled environment To determine efficacy and safety in a real-world clinical en- vironment Population selection Specific selection criteria may not be fully representative of the population requiring treatment; extensive exclusion criteria Includes all patients who meet basic inclusion criteria; minimal exclusion criteria Site selection Experienced practitioners in an optimal controlled clinical environment Sites are selected broadly from relevant settings that provide treatment to the target population Intervention during trial Limited flexibility; changes in randomized treatment may end study participation Highly flexible; participants retained in treatment even after change of randomized assignment Outcome measures Primary measures are often not applicable to a real-world situation (e.g., use of rating systems or scales not used in routine clinical practice) Include objective measures pertinent to clinicians, patients, and public health officials Adherence Maximized to allow accuracy in analysis of efficacy and safety Allowed to reflect a real-world clinical environment Randomization Random assignment to treatment Often incorporate randomization; completely nonrandomized trials introduce selection bias of an injection allow a definitive assessment of adherence to LAI medications, but adherence to oral treatments can only be determined by less definitive methods. These include self report, pharmacy data, clinical records, family report, pill counts (manual or electronic), or serum medication levels (Valenstein et al., 2002; Weiden et al., 2009; Rosenheck et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: This article reviews key methodological considerations for clinical trials that utilize explanatory and pragmatic trial designs and relates these contrasting approaches to the interpretation of results from comparisons of oral versus long-acting injectable (LAI) antipsychotics in schizophrenia. Explanatory randomized controlled trials (RCTs) generally measure the efficacy of a treatment in a homogeneous population with intensive, frequent, and often clinical trial-specific assessments. In contrast, pragmatic trials measure effectiveness in routine clinical practice and frequently aim to inform choices between treatments. Comparative effectiveness outcomes with pragmatic designs in naturalistic settings for schizophrenia treatments are of increasing interest to healthcare providers because outcomes of treatment (both efficacy and safety) may vary significantly when identified in an explanatory setting compared with a naturalistic pragmatic setting. Indeed, it has been suggested that the inconsistent outcomes observed in trials comparing oral and LAI antipsychotic medications may be a function of the use of explanatory or pragmatic trial designs.
In practice, clinical trial designs are seldom purely explanatory or pragmatic. To identify the predominant orientation of a trial, one must consider multiple features. This paper reviews the relative impact of these features when comparing LAI and oral antipsychotic treatments and makes recommendations for improving these comparative designs.
Schizophrenia Research 07/2014; 156(2-3). DOI:10.1016/j.schres.2014.04.024 · 3.92 Impact Factor
"In fi rst-episode schizophrenia patients, long-acting injectable risperidone was well tolerated and led to more treatment adherence than oral risperidone in a prospective RCT (Weiden et al. 2009). Another longterm 2-year open-label study with fi rst-episode schizophrenia patients revealed that 64% of the patients achieved remission and that 97% of the patients maintained this status until study completion (Emsley et al. 2008). "
[Show abstract][Hide abstract] ABSTRACT: Abstract Objectives. This article presents an overview of the current literature on biological markers for alcoholism, including markers associated with the pharmacological effects of alcohol and markers related to the clinical course and treatment of alcohol-related problems. Many of these studies are well known, while other studies cited are new and still being evaluated. Methods. In this paper we first describe known biomarkers of alcohol-related disorders, review their features and the problems involved in their use. We then consider future developments on biomarkers and their possible impact on the field. Results. More recent findings cited include the work on type 7 adenylcyclase (AC) polymorphism and its lower expression levels in female alcoholics. Neuroimaging studies involving biomarkers have also reported brain volume reductions of gray and white matter, including amygdala and subcortical regions in alcoholic patients, while a high association between the copy number variations (CNVs) in 6q14.1/5q13.2 and alcohol dependence has more recently been identified in genetic studies. Conclusions. In addition to their possible importance for diagnosis, biomarkers may have utility for predicting prognosis, progression of the disorder, the development of new treatments, and monitoring treatment effects. Although such findings should be verified in independent studies, the search for new biomarkers is continuing. Several potential candidate biomarkers have been found recently in blood, imaging, and genetic studies with encouraging results.
The World Journal of Biological Psychiatry 12/2013; 14(8):549-64. DOI:10.3109/15622975.2013.838302 · 4.18 Impact Factor
"Individual patients may discontinue or interrupt treatment as the result of a variety of factors, such as lack of illness insight, forgetfulness, lack of social support, tolerability issues, conscious choice and refractory or non-responsive symptoms [4,5]. Long-acting injectable (LAI) medications can help overcome problems with non-adherence by removing the need for daily dosing and by simplifying treatment; additionally, the healthcare provider can know with certainty whether a patient has received an injection and can make an appropriate intervention if the patient has not . Several studies have shown that switching from an oral to an LAI antipsychotic is both safe and effective [7-10]. "
[Show abstract][Hide abstract] ABSTRACT: Increasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available.
This post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity.
Approximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46--4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59--3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar.
This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.
Annals of General Psychiatry 07/2013; 12(1):22. DOI:10.1186/1744-859X-12-22 · 1.40 Impact Factor
S M Bahr, B C Tyler, N Wooldridge, B D Butcher, T L Burns, L M Teesch, C L Oltman, M A Azcarate-Peril, J R Kirby, C A Calarge
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