File Name: measurement and treatment research to improve cognition in schizophrenia .zip
- Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis
- Placebo Response and Practice Effects in Schizophrenia Cognition Trials
- Stimulating development of new drugs to improve cognition in schizophrenia
Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis
Unadjusted mean MCCB cognitive composite scores are plotted by study and week of assessment through week The line thickness is proportional to the study sample size, and assessment time points for each study are denoted by markers.
Individual study results are from separate mixed-effects repeated measures models of the change from baseline through week 24, with a fixed categorical effect for visit and a continuous fixed covariate for the baseline score, assuming an unstructured covariance matrix.
In the overall model, visit was nested within a random study effect. Least squares mean change from baseline through week 24 is plotted by level of practice effect as calculated by the T-score change in the cognitive composite from screening to baseline. Results are from a mixed-effect repeated measures model with a continuous fixed covariate for the baseline score and a categorical effect for visit nested within a random study effect, assuming an unstructured covariance matrix.
JAMA Psychiatry. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. A total of patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients.
Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Given that the patients performed 2. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo. Cognitive impairment associated with schizophrenia is severe and a primary cause of poor functional outcomes. Extensive resources have been devoted to developing pharmacologic, 1 - 6 psychosocial, 7 , 8 and cognitive remediation 9 - 13 treatments to reduce cognitive and functional impairment in patients with schizophrenia.
To our knowledge, no treatments to date have had sufficient benefit to warrant regulatory approval. Because there are no effective medical treatments for cognitive impairment associated with schizophrenia, it is challenging to determine whether the lack of success of previous treatment development programs has been due to inadequacies of the treatments being tested or to weaknesses in the methods used.
However, the MCCB validation study used a single test-retest assessment, 17 which does not reflect the complexity of standard clinical trials that have more than 2 assessments performed with the MCCB 1 , 2 , 19 , 20 and multiple treatment conditions.
Patients with schizophrenia manifest consistent cognitive performance over time with a variety of different tests 17 , 21 , 22 and may generate practice effects when they are reassessed. A comparison of the improvement in patients receiving placebo with those who were aware that they were not receiving any treatment would help to determine if expectation bias increases the known improvement due to practice effects.
Regardless of their source, improvements on cognitive tests in patients receiving placebo may be so large that treatment effects are impossible to detect. The opposite speculation has equivalent face validity and has been supported by single studies 1 , 19 , 20 ; if an individual is familiar with being assessed and with the assessment materials, additional assessments are less likely to lead to gains in performance based solely on test exposure.
Furthermore, the magnitude of expected practice and placebo response of the MCCB, which is used in most large multisite clinical trials for cognitive impairment associated with schizophrenia, is unknown.
Finally, while certain patients with schizophrenia and depression who are receiving placebo demonstrate large symptom responses that can be anticipated based on their baseline characteristics, 23 it has not been determined if patients receiving placebo who respond in schizophrenia cognition trials can be similarly identified. There are clear implications in these questions for the interpretation of previous results and the design of future clinical trials.
If individual differences among patients, including differences in their performance change from screening to baseline, are associated with postbaseline retest changes, these measures could be used as factors to be considered in statistical analysis or in patient randomization and stratification.
In this study, we merged data from 12 separate clinical trials, 1 - 3 , 20 , 24 - 29 including patients who were randomized to receive placebo during the course of a double-blind pharmacologic intervention study, and investigated the characteristics of retest-associated improvements in performance on the MCCB.
We compared prerandomization improvements with postrandomization improvements in patients receiving placebo, and we assessed the effect of a number of measures on the magnitude of postbaseline improvement, including the number of retest assessments, the spacing of the retest assessments, the time elapsed since baseline while receiving placebo, and the number of treatment arms of the study.
Finally, we examined a variety of patient demographic and clinical characteristics to determine if they are associated with cognitive placebo response. This review included patients with schizophrenia who were treated with placebo in randomized clinical trials from February 22, , to March 1, The Table describes the demographic and baseline characteristics of the merged data set, with mean SD values for continuous variables and numbers percentages for categorical variables.
Thirty-one patients had 1 or more missing MCCB domain values at the baseline visit, resulting in patients with a cognitive composite score derived from all 7 MCCB domains at baseline.
Three patients did not have at least 1 follow-up score, resulting in a final sample size of An additional 54 patients had test results missing in a domain that had additional tests, so a domain score was able to be calculated.
For all of the trials, patients were treated with a stable dose of antipsychotic medication, and most patients were receiving only 1 antipsychotic.
An improvement of 1 point on the MCCB cognitive composite score reflects a 0. All testers who interacted with patients were first trained on the administration and scoring of the MCCB using video and group training sessions and were individually certified by an MCCB expert. All MCCB data were scored locally or sent to a central site, where they were scored or rescored.
Training, data collection, and data quality assurance were implemented or supervised by an experienced psychologist R. Each standardized measure has a mean SD of 50 The neurocognitive composite is calculated similarly but does not include Social Cognition.
In 5 studies, 3 , 25 , 26 the Negative Symptom Assessment 35 , 36 was used to examine negative symptoms in 4 factors: communication, emotion, motivation, and sociality. Data were combined from the intent-to-treat populations of 12 MCCB clinical trials.
Visit schedules varied considerably among the studies, ranging from 2 to 6 MCCB assessments postbaseline reassessments during a period of 4 to 24 weeks. Change from baseline in the MCCB cognitive composite score was investigated using a basic linear mixed model for repeated measures, controlling for baseline value and week of assessment nested within a random study effect.
The ability of patient-level and study-level variables to estimate the magnitude of the placebo effect was analyzed with separate mixed models for each predictor. Complete information on the statistical plan is in the eAppendix in the Supplement.
The mean MCCB composite score at baseline was Figure 1 describes the mean MCCB cognitive composite score over time in all 12 studies. The full week data for 3 studies are available in the eFigure in the Supplement. The overall mean SEM change in the MCCB cognitive composite during receipt of placebo, after adjusting for baseline score, week of assessment, and study, was 1.
To examine the effects of a prebaseline screening assessment on postbaseline placebo effects, the postbaseline changes in the 7 studies 2 , 3 , 24 - 26 with a screening assessment were compared with the changes for the 5 studies 1 , 20 , 27 - 29 without such an assessment.
We also explored the association between postbaseline changes and the numbers of weeks and assessments that had occurred since baseline, adjusting for baseline scores and whether the study had a screening visit.
The increases by assessment were 1. Thus, the points gained per retest assessment during receipt of placebo generally decreased with an increased number of assessments, and the retesting effects were larger than the effects of time of placebo exposure alone. As demonstrated in Figure 3 , there were robust differences between the groups. Patients who manifested negative practice effects mean [SEM], 4. The data from this study were generated from the placebo condition in 12 separate randomized, placebo-controlled clinical trials using the MCCB as the primary end point to assess response to treatment with a pharmacologic intervention in patients with schizophrenia.
The mean amount of total improvement during treatment in patients receiving placebo was approximately 2 T-score points on the MCCB composite score, consistent with a Cohen d effect size of 0.
Studies using a prebaseline assessment did not have smaller postbaseline placebo treatment effects than did studies with the first MCCB assessment at baseline.
The size of the placebo effect was more influenced by the number of postbaseline retest assessments than by the duration of placebo treatment, with the number of reassessments associated with an increase in scores. There are several important implications of these findings. The most obvious conclusion from these data is that the concept of a substantial placebo effect in schizophrenia clinical trials using the MCCB—one that may obscure the detection of meaningful clinical change—is clearly not substantiated.
The data in this report suggest that cognitive performance assessed with the MCCB is 2. Thus, the 0. This amount of postbaseline improvement is almost identical to the amount of prebaseline improvement in these trials and is consistent with the amount of prebaseline improvement reported in a larger sample of patients from 10 trials.
The notion that this magnitude of retest improvement accounts for the negative results in previous cognitive enhancement trials seems unlikely. For the cognitive changes associated with a pharmacologic agent to be of real benefit to patients with schizophrenia, they must exceed the small learning effect represented in the placebo condition in these trials, which is also a part of the cognitive response in patients receiving active treatment.
This amount of improvement with placebo in performance-based cognitive assessments is clearly less than that seen in clinical trials across different neuropsychiatric conditions, including symptom rating scales such as the PANSS and the Hamilton Depression Rating Scale.
Our results can be interpreted to provide recommendations regarding the strategy of testing patients once prior to baseline to expose them to the testing process or to minimize a learning effect. A simple analysis comparing patients who were tested prior to baseline with patients who were not suggests that they had similar improvements in placebo conditions and that this strategy does not systematically lead to reduced postbaseline changes.
Also, a larger number of assessments after baseline was associated with slightly larger MCCB improvements, although the magnitude of between-assessment improvement may diminish as the number of postbaseline assessments increases. These results have implications for study design. First, researchers will need to weigh the value of additional assessments during clinical trials against the potential for an additional learning effect in patients receiving placebo and active treatment, although this effect is small.
Second, important information may be gained from a prebaseline assessment. Patients whose cognitive performance worsened from screening to baseline had the largest placebo effect, and those with the largest improvements from screening to baseline had no placebo effect at all. However, a screening assessment may produce information that can facilitate study design, such as stratification of patients based on potential placebo effects.
It may also allow statistical approaches that adjust for screening values along with the customary baseline values in the primary efficacy model as a method for reducing the noise associated with large fluctuations in patients who may have had exceptionally good or bad days at the baseline visit. Preliminary analyses using this method suggest that it may increase precision of assessing treatment effects in cognitive treatment trials.
The present results raise a more general question of whether cognitive impairments measured by neuropsychological tests are indeed mutable with pharmacologic intervention in schizophrenia, and whether other measures of brain function are better candidates to serve this purpose.
First, neuropsychological tests have demonstrated sensitivity to changes under a variety of different conditions in schizophrenia. They are highly sensitive to the effects of alcohol, 41 nicotine, 42 anticholinergic medications, 43 and stimulants, 44 as well as other drugs. Second, because they have consistently demonstrated a clinically significant magnitude of improvement in response to cognitive remediation strategies in schizophrenia, 13 the possibility that neuropsychological tests could be a plastic attribute in response to behavioral intervention but a stable trait in response to pharmacologic intervention does not seem reasonable.
Third, although it is often assumed that the effects of drugs on other, more biologically proximal measures of brain function, such as brain imaging or electrophysiology, are more powerful than on neuropsychological tests, there is little evidence to support this assumption. It is not at all clear whether the inability of later studies to replicate these findings were due to inefficacy of the pharmacologic intervention, insensitivity of the cognitive tests, or other weaknesses of study design and implementation.
In 12 double-blind, placebo-controlled, clinical trials for cognitive impairment associated with schizophrenia, the magnitude of placebo effects on the MCCB was small and not different from the retesting effects during the pretreatment screening period when patients knew that they were not receiving treatment. The magnitude of the placebo effect was not large enough to obscure a treatment effect with a small to medium effect size. There are patient and study characteristics that have a modest influence on postbaseline retest changes, and the number of reassessments is minimally associated with changes in performance on the MCCB.
Figure 2. Figure 3. Demographic and Baseline Characteristics.
Placebo Response and Practice Effects in Schizophrenia Cognition Trials
Cognitive deficits are core features of schizophrenia that are critical determinants of poor functional outcome. Until recently, the development of novel pharmacologic treatments that specifically target these deficits has been impeded by a lack of consensus about which domains of cognition should be covered and how they should be measured in clinical trials. This review summarizes the rationale for the MATRICS Initiative, some of its achievements to date, and promising pharmacologic targets for the cognitive deficits of schizophrenia. This is a preview of subscription content, access via your institution. Schizophr Res , 72 :1—3. Geyer MA, Tamminga CA: Measurement and treatment research to improve cognition in schizophrenia: neuropharmacological aspects.
Stimulating development of new drugs to improve cognition in schizophrenia
Schizophrenia is a psychiatric disorder characterized by continuous or relapsing episodes of psychosis. About 0. About half of those diagnosed with schizophrenia will have a significant improvement over the long term with no further relapses, and a small proportion of these will recover completely.
Investigation of cognition in schizophrenia: psychometric properties of instruments for assessing working memory updating. Arthur A. Tatiana P.
Language: English Spanish French. The US National Institute of Mental Health supported an initiative to facilitate the development of pharmacological agents for enhancing neurocognition in patients with schizophrenia. This has been accomplished through a consensus-building process that has included representatives from academia, the pharmaceutical industry, and government. The group has addressed obstacles to drug development that include i the lack of a well-accepted instrument for measuring neurocognition in clinical trials; ii the lack of a consensus on the best molecular target or targets for drug development; iii the lack of a consensus regarding the optimal trial design for either comedication that improves cognition when added to an antipsychotic or a broad spectrum agent that improves cognition and treats psychosis; and iv the approaches of regulatory agencies such as the US Food and Drug Administration to approving and labeling a new agent. The US National Institute of Mental Health NIMH developed the Measurement and Treatment Research to Improve Cognition in Schizophrenia MATRICS initiative for a number of reasons: i there is a widespread belief that too few innovative new drugs are being developed for illnesses that affect, the central nervous system CNS in comparison to other areas of medicine 1 ; ii drugs for CNS disorders have often been accidental discoveries rather than the products of well-developed scientific strategies 2 ; and iii there is dissatisfaction with the effectiveness of drugs for schizophrenia. Evidence for this comes from the recent publication of a large trial comparing the effectiveness and side effects of several second-generation antipsychotics known as the Clinical Antipsychotic Trials of Intervention Effectiveness CATTE trial.
Though effective interventions have proven elusive, the literature continues to grow rapidly. To date, lengthy, multifaceted interventions have shown the most promise. The literature on cognitive deficits in schizophrenia has been growing rapidly since the s [ 1 ]. This paper reviews the most recent literature on cognitive deficits in schizophrenia; however, rather than duplicate the reviews and meta-analyses that have been published this year, this paper will place the most recent studies in the broader context of the evolution of knowledge concerning the way in which domains of cognition are defined, how cognitive deficits may be related to performance and real-world functioning with particular emphasis on social functioning , and the implications of the persistence of cognitive deficits into old age.
Unadjusted mean MCCB cognitive composite scores are plotted by study and week of assessment through week The line thickness is proportional to the study sample size, and assessment time points for each study are denoted by markers. Individual study results are from separate mixed-effects repeated measures models of the change from baseline through week 24, with a fixed categorical effect for visit and a continuous fixed covariate for the baseline score, assuming an unstructured covariance matrix. In the overall model, visit was nested within a random study effect. Least squares mean change from baseline through week 24 is plotted by level of practice effect as calculated by the T-score change in the cognitive composite from screening to baseline. Results are from a mixed-effect repeated measures model with a continuous fixed covariate for the baseline score and a categorical effect for visit nested within a random study effect, assuming an unstructured covariance matrix. JAMA Psychiatry.
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