S74. Exploring Participant-Level Trajectories of Cognitive Performance Among Patients With Schizophrenia in a Multi-National Trial

Abstract

BackgroundIt remains unclear whether the lack of clinical trial success and drug approval for cognitive impairment associated with schizophrenia (CIAS) is due to compounds being ineffective, or whether trial methodology itself has been a limiting factor in successfully demonstrating the efficacy of these agents. Schizophrenia is a heterogeneous disorder and whilst cognitive deficits are a core feature, the profile and degree of neuropsychological impairment can vary across patients. Though most individuals with schizophrenia exhibit some general cognitive impairment compared to antecedent expectations, such as premorbid intelligence, up to a quarter display cognitive performance in the ‘normal’ range. This may pose a problem for pro-cognitive drug trials in this population given that it potentially inflates baseline scores and reduces the scope to see improvement between treatment and placebo groups. In order to examine this potential issue, we investigated participant-level trajectories of cognitive performance among patients with schizophrenia enrolled in a multi-national, phase II clinical trial.MethodsWe conducted a post-hoc analysis of existing trial data from 463 patients with schizophrenia who participated in a randomized, double-blind, placebo-controlled trial. Patients met established diagnosis for schizophrenia (DSM-5), were clinically stable (non-acute) and had no more than moderate severity ratings on the Positive and Negative Syndrome Scale (PANSS). During the trial, participants completed two different neurocognitive test batteries, the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the MATRICS Consensus Cognitive Battery (MCCB), at 4 separate time points (screening, baseline, week 6 & week 12). Participant data were pooled across placebo and treatment groups to explore trajectories of cognitive performance, at the participant-level, across the course of the study.ResultsLinear mixed model analyses revealed that participants who performed within the ‘normal range’ at screening on cognitive tasks as measured by CANTAB, continued to perform well at baseline, week 6 and week 12, showing no significant change in their performance. By contrast, participants who performed below the normal range at screening, showed a significant improvement in their test performance across the remainder of the study. When compared in the context of MCCB, those participants who performed a standard deviation (SD) above the MCCB normative mean at screening, were also the participants who performed within the normal range on CANTAB. Approximately 25% of the overall sample were performing within a clinically normal cognitive range at screening.DiscussionSubstantial variability was evident in cognitive performance among the current sample of patients with schizophrenia. We identified a subsample of patients whose performance fell within a clinically normal range. Cognitive improvement was observed only in those who exhibited a deficit at screening, bringing into question whether the inclusion of unimp...

Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study

“…These findings may not generalise to other cognitive batteries. However, studies with other assessment batteries, such as the Brief Assessment of Cognition in Schizophrenia, Cambridge Neuropsychological Test Automated Battery, and MATRICS™ Consensus Cognitive Battery, have shown similar effects to those reported here, including in successful cognitive training studies [26,30].…”

“…Evaluable patients were separated into two groups based on cognitive impairment at study baseline using a CBB composite Z-score cutoff of -1 SD, relative to the normative mean. This cutoff was selected based on its previous use to differentiate clinically significant cognitive impairment from non-/minimal impairment in both patients with schizophrenia and more broadly in clinical neuropsychological assessment [30][31][32]. Patients with CBB composite Z-scores equal to or above this cutoff (Z-score ≥ -1) were designated as minimally impaired, whereas patients below the cutoff (Z-score < -1) were designated as clinically impaired.…”

The Use of Cognitive Screening in Pharmacotherapy Trials for Cognitive Impairment Associated With Schizophrenia

“…For the purposes of demonstrating efficacy, pro-cognitive intervention trials should be powered to detect a “clinically meaningful” difference between treatment groups, typically equating to an effect size in the small-medium range (e.g., Cohen’s d ≥ 0.3). However, recent evidence has suggested that it is unlikely that one would expect to see gains in cognition this large in up to a quarter of patients who score similarly to healthy controls on cognitive tasks (9–13). This means that the poorer performing patients would need to exhibit substantially greater cognitive gains in order to meet the pre-specified average group-based level of improvement.…”

“…Though the majority of patients with schizophrenia exhibit some general cognitive dysfunction compared to antecedent expectations, such as premorbid intelligence (7, 8), there is evidence that approximately a quarter of patients display cognitive performance comparable to healthy controls (9–12). Recent evidence has indicated that these “normally” performing patients are significantly less likely to exhibit changes in cognition when participating in CIAS trials (13, 14), suggesting that inclusion of these individuals may limit the scope to detect a pro-cognitive efficacy signal. Contemporary evidence has also reported that there is no association between cognitive performance and measures of social, vocational or everyday functioning in these cognitively “normal” patients (15), suggesting that other illness-related variables are the primary drivers of functional disability among these individuals.…”