Abstract
Cognitive dysfunction is a core feature of schizophrenia spectrum disorders and a major determinant of functional outcomes. This study aimed to: (a) systematically review randomized controlled trials (RCTs) evaluating the cognitive effects of third-generation antipsychotics (TGAs: brexpiprazole, cariprazine, lumateperone, and lurasidone) and xanomeline-trospium; and (b) perform a network meta-analysis (NMA) including additional second-generation antipsychotics with potential procognitive effects. A systematic literature search identified eligible RCTs, which were combined with trials on aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone from a previous meta-analysis. A frequentist NMA (random-effects model) was conducted using standardized mean differences (SMDs) in pre-post cognitive scores. Associations between cognitive outcomes, follow-up duration, and SMDs for psychotic symptoms were examined; metaregression controlled for age and psychosis severity. Fourteen RCTs ( n = 2464) met the inclusion criteria. Lurasidone (Hedges' g = 0.46) and xanomeline ( g = 0.30) outperformed placebo in improving global cognitive performance, whereas quetiapine ( g = 0.64) and cariprazine ( g = 0.20) had the most favorable impacts on attention. Cognitive SMDs were unrelated to follow-up duration or improvements in psychotic symptoms. Age and baseline psychosis severity did not influence cognitive response. In conclusion, selected second and TGAs, including M1/M4 receptor agonists such as xanomeline, may offer promising treatment options for cognitive dysfunction. Further research should personalize pharmacological strategies based on cognitive profiles.