Schizophr Res. Such studies were usually conducted in highly selected samples, and were generally designed and financed by the manufacturer of the drug tested. These and other facts have stimulated discussions regarding the effectiveness of the new generation of antipsychotics. AIMS: The aim of the European First Episode Schizophrenia Trial EUFEST is to compare treatment with amisulpride, quetiapine, olanzapine and ziprasidone to a low dose of haloperidol in an unselected sample of first episode schizophrenia patients with minimal prior exposure to antipsychotics. METHODS: patients between the ages of meeting DSM-IV criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder are randomly allocated to one year of treatment with one of the drugs under study. The primary outcome measure is retention in treatment, defined as time to discontinuation of study drug.

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We have combined these two samples to study the predictors and correlates of adherence to treatment. Here we report on adherence to pharmacological treatment at the six and twelve month assessments of these trials with a combined subsample of schizophrenia patients. We used logistic regression to examine the effects of substance use, akathisia, parkinsonism, dyskinesia, hostility, and insight on pharmacological adherence. Furthermore, poor adherence to study medication was associated with earlier discontinuation in the combined data.

Introduction Adherence to medication treatment is critically important for its effectiveness. Non-adherence to antipsychotic treatment increases the risk of hospitalization Weiden et al. Partial non-adherence to medication treatment also increases the likelihood of complete treatment discontinuation Lindenmayer et al. Estimates of frequency and extent of non-adherence vary with the assessment methods Velligan et al.

Improved insight was associated with improved adherence Mohamed et al. Both insight into mental illness and positive attitudes towards treatment were associated with satisfactory adherence Hofer et al. Related to insight, negative attitudes toward medication are associated with non-adherence Lacro et al. Furthermore, negative attitudes towards medication were shown to predict discontinuation of initiated treatment in a subsample of patients participating in the EUFEST trial Gaebel et al.

Younger age, male gender, lower socioeconomic status, minority status, poorer social functioning, and difficulties in building a therapeutic alliance are associated with adherence problems Velligan et al. Combination of substance use problems and non-adherence to medication treatment in severe mental illness is frequent, and it increases the risk of adverse outcomes including violent behavior Swartz et al. Relationships between substance use and treatment non-adherence have been documented in first episode of psychosis Coldham et al.

In a study of patients with first episode of schizophrenia or schizoaffective disorder, individuals with substance abuse stopped medications more than those without substance use, but the difference was not statistically significant Robinson et al. Although the association between substance use and treatment non-adherence in severe mental illness has been established, causation remains unclear. It is possible that substance use causes non-adherence, or that non-adherence causes substance use, or that the relation is not causative and the association is due to other factors, perhaps some personality characteristics.

Parkinsonism but not akathisia predicted discontinuation of antipsychotic treatment after the first relapse of schizophrenia or schizoaffective disorder Robinson et al. Medication adverse effects independently predicted non-adherence to antipsychotic medication in 81 patients with schizophrenia McCann et al.

In a consensus survey, experts agreed that distress associated with persistent side effects or fear of potential side effects was often a very important contributor to medication adherence problem in schizophrenia Velligan et al. On the other hand, only one out of nine older studies looking for an association between severity of side effects and non-adherence to medication in patients with schizophrenia could confirm it.

The other eight studies demonstrated little or no association Lacro et al. A short-term randomized clinical trial has shown that higher hostility levels may be a predictor of non-adherence to medication in schizophrenia patients Lindenmayer et al. Specifically, greater hostility was associated with a greater likelihood of non-adherence at the following visit. However, hostility change from baseline did not predict non-adherence at the following visit. Other risk factors for non-adherence include poor pre-morbid and current cognitive functioning, and less improvement of psychopathology Ascher-Svanum et al.

Thus, the existing literature provides strong support for impaired insight or negative attitudes towards medication and substance abuse as predictors of treatment non-adherence in schizophrenia.

There is limited evidence for an association between non-adherence and the combined effects of increased hostility, substance abuse, and extra-pyramidal adverse effects. These latter correlates of non-adherence have not traditionally been examined in multivariable models in large and generalizable samples. The principal purpose of this study is to investigate insight, substance use, extrapyramidal effects, and hostility in a multivariate analysis using a large sample of schizophrenia patients.

We also aimed to explore the relation between non-adherence and discontinuation of study medication to which the patients had been originally randomized. Experimental procedures 2. Broad inclusion and minimal exclusion criteria were used, allowing the enrollment of patients with coexisting conditions. The participants were randomly assigned to treatment with olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months.

Patients exhibiting tardive dyskinesia were not assigned to perphenazine. Phase 1 was a double-blind trial Lieberman et al. The participants were followed for up to 18 months as outpatients. Information on adherence to study medication was obtained using the pill count and inputs from other sources. We used the monthly pill count as the measure of adherence in our analyses.

We quantified adherence as the proportion of the assigned amount of medication number of tablets that was actually used.

The Insight item on the PANSS also is scored on a scale ranging from 1 no impairment of insight of psychiatric illness to 7 emphatic denial of past and present psychiatric illness. For analytic purposes, a dichotomous variable side effect present or absent was created for each of the extrapyramidal side effects. The resulting dichotomous variable no use v. All-cause treatment discontinuation was the primary outcome variable to assess effectiveness Lieberman et al. The primary outcome measure was all-cause treatment discontinuation.

Adherence was assessed using a one-item, 7-point rating scale sometimes referred to as Hayward scale where complete refusal of treatment is scored as 1, and ready acceptance of treatment is scored as 7 Kemp et al. Extrapyramidal syndromes parkinsonism, akathisia and dyskinesia were assessed using the St.

Hans Rating Scale Gerlach et al. Unlike CATIE, use of alcohol or substances was not captured by this variable unless it reached the level of abuse or dependence. Data on all assessments were available at a minimum of three time points: at baseline, 6 months, and 12 months data at 3 and 9 months were also available for some assessments. Statistical procedures We applied multivariate logistic regression analyses in the combined sample of CATIE and EUFEST patients to investigate concurrent and predictive associations between medication non-adherence on one hand and a set of potentially important variables pinpointed by prior studies on the other hand.

For concurrent associations, the dependent and independent variables were assessed at the same period in the study first 6 or 12 months whereas in the predictive analyses of treatment non-adherence during the study, the assessment of predictors occurred at baseline. Adherence was used as the dependent variable. Since adherence was measured as a polychotomous variable 7-point scale , with higher scores indicating better adherence, the multinomial distribution with the log-link function was specified for the logistic model.

The set of principal independent variables of interest included hostility; lack of judgment and insight; substance abuse; extrapyramidal adverse effects; and basic demographic measures such as age and sex. Side effects were rated by different scales in the two studies; to increase comparability of the side effect measures from the two studies, we applied them as dichotomous variables in the analyses.

A score of 1 was assigned to a variable if a constituting item had a non-zero entry; otherwise, the value of the variable was set to 0. In order to investigate whether the association was specific with regard to the above predictors, symptom severity on the PANSS Positive Subscale excluding the hostility item was used in the analysis as a covariate.

Furthermore, Study i. The odds ratio statistic was adopted to characterize the strength of the association between the dependent and each of the independent variables. A separate analysis was performed for each of the concurrent 6 and 12 month and predictive associations of interest baseline vs. The investigation of concurrent association at 6 months in the pooled sample of patients from both studies was considered as the primary analysis in order to increase statistical power and limit the impact of missing data.

In addition, we conducted sensitivity analyses using the multiple imputation approach for missing data. We adopted the fully conditional specification FCS approach that allows for data sets with an arbitrary pattern of missing data. We used the logistic regression method to impute missing values since it makes allowance for classification variables which have a binary or ordinal response van Buuren, , We used the Hochberg procedure for statistical adjustment to avoid inflation of Type 1 error due to multiple comparisons.

Results 3. Table 1 Basic demographic and clinical characteristics of the study sample at baselinea.


The European First Episode Schizophrenia Trial (EUFEST): rationale and design of the trial.

Kikinos The presence of one or more of the contra-indications against any of the study drugs. The primary outcome measure is retention in treatment, defined as time to discontinuation of study drug. Results and Publications Publication and dissemination plan Not provided at time of registration Intention to publish date Participant level data Not provided at time of registration Basic results scientific Eeufest list 1. Study information Scientific title The European study of the effectiveness of haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on loss of retention in first episode schizophrenia Acronym EUFEST Study hypothesis What is the effectiveness of low doses of haloperidol and regular doses of amisulpride, olanzapine, quetiapine, and ziprasidone on loss of xtudy year retention in patients with recent onset of schizophrenia, schizoaffective, and schizophreniform disorder? The aim of the European First Episode Schizophrenia Trial EUFEST is to compare treatment with amisulpride, quetiapine, olanzapine and ziprasidone to a low dose of haloperidol in an unselected sample of first episode schizophrenia patients with minimal prior exposure to antipsychotics. These and other facts have stimulated discussions fufest the effectiveness of the new generation of antipsychotics.








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