Cognitive Remediation in Schizophrenia: Efficacy and Role of Neuroplasticity in "Top-down" and "Bottom-up" Mechanisms

Schizophrenia patients have deficits of different degrees in several cognitive domains, impacting their social functioning and quality of life. Cognitive remediation strategies are useful to treat cognitive deficits in patients with schizophrenia. There are at least two different cognitive remediation strategies: one has a "top-down" approach, and is aimed at higher-order cognitive processes, focusing on the training of executive functions. The other one has a "bottom-up" approach, aiming to first recovering the perceptual processing alterations that may affect performance in higher-order cognitive functions. This study addresses in parallel two research questions, one of clinical interest (Are both strategies effective in improving neurocognitive performance?) and another one focused on the psychological / neurobiological mechanisms of neurocognitive remediation (Which cognitive remediation strategies are related to changes in BDNF levels?). The specific objectives are: (1) Evaluate the effectiveness of two cognitive remediation strategies. (2) Study the critical moments of neuroplasticity for each cognitive remediation strategy, observing changes in BDNF levels at the end of the intervention and 12 weeks after the intervention. (3) Identify potential clinical and/or molecular predictors (BDNF levels or val66met polymorphism) of response for each cognitive remediation strategy. For these objectives, two randomized controlled trials with two arms will be carried out in parallel, one where patients will receive cognitive remediation and another consisting of a control group (with usual treatment). The control group subjects will remain on a waiting and observation list for 10 weeks, to later enter the active arm, which will also last 10 weeks. In one of the trials the active arm will consist of cognitive remediation therapy with a "bottom-up" approach (focused on perceptual training), while in the other trial the active arm will consist of cognitive remediation with a "top-down" approach (focused on executive skills training). Neurocognitive and clinical assessments will be carried out along with the measurement of BDNF levels at four evaluation times: one at baseline, one at the end of the observation period with treatment-as-usual, another at the end of cognitive remediation, and another after a 12 week follow-up period.

Schizophrenia is a severe psychiatric illness that has a significant impact on patients, their families, and society. It presents with deficits of different degrees in all cognitive domains, including memory, processing speed, attention and executive functions, which have been consistently demonstrated by different studies across several geographical regions. This has implications for patients' social functioning and quality of life, as cognitive symptoms together constitute the most important predictors of patients' functioning in the community. Antipsychotic drugs, although effective for psychotic symptoms, have little effect on cognition, however, cognitive rehabilitation achieves at least a medium effect size to improve cognition. There are at least two different cognitive remediation strategies, depending on the cognitive processes to which the intervention is targeted. One has a "top-down" approach, and is aimed at higher-order cognitive processes, and focuses on the training of executive functions. The other has a "bottom-up" approach and aims to first recovering the perceptual processing alterations that some patients with schizophrenia have and that would affect performance in higher-order cognitive functions.

This study addresses in parallel two research questions, one of clinical interest, and another focused on the psychological / neurobiological mechanisms of neurocognitive remediation: What neurocognitive remediation strategy, executive skills training ("top-down" approach) or training perceptual approach ("bottom-up" approach), is it effective in improving neurocognitive performance? Which neurocognitive remediation strategies are related to changes in BDNF levels? At what point of the recovery process are these changes observed? The hypothesis is that the "bottom-up" strategy presents observable results at the end of the intervention, whereas the "top-down" strategy results in an observable effect on neurocognitive performance and functioning in the community in a delayed manner, 12 weeks after the intervention. We expect that both strategies will be associated with an increase in BDNF levels compared to the situation prior to the intervention, but that this will occur at the time when the clinical effect is observed. The specific objectives are: (1) Evaluate the effectiveness of two cognitive remediation strategies, one focused on executive skills training (top-down approach) and another on perceptual training (bottom-up approach). (2) Study the critical moments of neuroplasticity for each cognitive remediation strategy, observing changes in BDNF levels at the end of the intervention and 12 weeks after the intervention. (3) Identify potential clinical and/or molecular predictors (BDNF levels or val66met polymorphism) of the response to treatment from the neurocognitive point of view for each cognitive remediation strategy.

In order to achieve this, two randomized controlled trials with two arms will be carried out in parallel, one where patients will receive cognitive remediation and another consisting of a control group (with usual treatment). The control group subjects will remain on a waiting and observation list for 10 weeks, to later enter the active arm, which will also last 10 weeks. In one of the trials the active arm will consist of cognitive remediation therapy with a "bottom-up" approach (focused on perceptual training), while in the other trial the active arm will consist of cognitive remediation with a "top-down" approach (focused on executive skills training). Neurocognitive and clinical assessments will be carried out along with the measurement of BDNF levels at four measurement times: one at baseline, one at the end of the observation period with treatment-as-usual, another at the end of cognitive remediation, and another after a 12 weeks follow-up period.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of schizophrenia according to Diagnostic and Statistical Manual (DSM)-5
* Age between 18 and 59 years
* Clinically stable outpatients
* Current treatment with at least one antipsychotic medication

Exclusion Criteria:

* Significant medical or neurological comorbidity
* Substance use disorder with illegal drugs in active use
* Participation in a cognitive remediation program in the last 6 months