Clinical Trials of Potential Cognitive-Enhancing Drugs in Schizophrenia: What Have We Learned So Far?

Abstract

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website “www.clinicaltrials.gov” using the terms “schizophrenia AND cognition,” “schizophrenia AND neurocognition,” “schizophrenia AND neurocognitive tests,” “schizophrenia AND MATRICS,” “schizophrenia AND MCCB,” “schizophrenia AND BACS,” “schizophrenia AND COGSTATE,” and “schizophrenia AND CANTAB” and “first-episode schizophrenia AND cognition.” The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

“…Cognitive function has been identified as the primary factor determining functional outcome for schizophrenia patients, and efficacies of present treatments are limited (Green, 1996;Keefe and Harvey, 2012;Keefe et al, 2013). In recent years, focus on cognitive domains has increased (e.g., the MATRICS initiative [Measurement and Treatment Research to Improve Cognition in Schizophrenia]; Green et al, 2004;Young et al, 2009), and several animal models have been developed to improve the translational predictability to clinical effects.…”

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

“…Among the 4 studies [59-62] with a duration < 12 weeks, only one was associated with an efficacy signal [59]. Among 118 RCTs on CIAS, a large majority had a duration ≤8 weeks [63]. These findings shed light on the importance of adequate study duration to detect an efficacy signal.…”

Review paper. Neuropsychological dimension of schizophrenia - evaluation possibilities and therapeutic implications

“…In recent years, there have been conducted intensive, multi-center studies to standardize research tools for the evaluation of cognitive deficits in schizophrenia. This research has been done with the hopes of the practical use of these tools to assess neurocognitive deficits and their significance as a predictor of further functioning of patients, as well as to estimate the potential neurocognitive improvement after the application of therapeutic interventions [78,79,80]. The result of these research efforts was to develop within a research program MATRICS a standardized, approved by the FDA (U.S. Food and Drug administation) test battery MCCB (MATRICS Consensus Cognitive Battery).…”

“…Poszukiwania te czyniono z nadziejami praktycznego wykorzystania tych narzędzi do oceny deficytów neuropoznawczych i ich znaczenia jako predyktora dalszego funkcjonowania chorych, a także do szacowania ewentualnej poprawy neuropoznawczej po zastosowaniu oddziaływań terapeutycznych [78,79,80]. Efektem tych poszukiwań badawczych było opracowanie w ramach programu badawczego MATRICS standaryzowanej, zaakceptowanej przez FDA (U.S. Food and Drug Administation) baterii testowej MCCB (MATRICS Consensus Cognitive Battery).…”