Cognitive remediation in schizophrenia: efficacy and role of neuroplasticity in “top-down” and “bottom-up” mechanisms—a randomized, double-blind, treatment-as-usual-controlled study protocol

Objectives Schizophrenia is characterized by positive, negative and cognitive symptoms, including different degrees of impairment in several neurocognitive domains, such as executive function, processing speed, learning and memory, which impact a patient´s functioning and quality of life. Cognitive remediation can help restore cognitive functioning through repeated exercises, following at least two possible strategies: a “top-down” approach, focused on training executive functions, or perceptual training, a “bottom-up” approach, aimed at first addressing impairments in perceptual processing. This study aims to clarify whether both approaches have comparable efficacy in improving neurocognitive performance, and to explore the timing of their cognitive and molecular effects. It will also examine the relationship between these approaches and changes in BDNF levels, considered a biomarker of neuroplasticity. Materials and methods In order to have a control group, patients will undergo an initial 10-week observation period receiving treatment as usual, followed by randomization into either executive training or perceptual training during the active phase of the trial. Clinical and neurocognitive assessments, as well as blood sampling, will be conducted at the beginning and end of each stage. Finally, assessments will be repeated after a 12-week follow-up period. Discussion The study aims to answer these research questions concerning clinical efficacy and molecular mechanisms and expects to identify possible clinical or molecular biomarkers (such as BDNF levels or the Val66Met polymorphism) that could be helpful as predictors of neurocognitive treatment response for each remediation strategy, thereby contributing to a personalized treatment approach. Study registered on clinicaltrials.gov number NCT06482918.