Effect of second-generation antipsychotics on cognition: current issues and future challenges

Abstract

Generalized cognitive impairments are stable deficits linked to schizophrenia and key factors associated with functional disability in the disorder. Preclinical data suggest that second-generation antipsychotics could potentially reduce cognitive impairments; however, recent large clinical trials indicate only modest cognitive benefits relative to first-generation antipsychotics. This might reflect a limited drug effect in humans, a differential drug effect due to brain alterations associated with schizophrenia, or limited sensitivity of the neuropsychological tests for evaluating cognitive outcomes. New adjunctive procognitive drugs may be needed to achieve robust cognitive and functional improvement. Drug discovery may benefit from greater utilization of translational neurocognitive biomarkers to bridge preclinical and clinical proof-of-concept studies, to optimize assay sensitivity, enhance cost efficiency, and speed progress in drug development.

Figure 1. Oculomotor neurophysiological measurements may be more sensitive to the beneficial and adverse neurocognitive changes after acute antipsychotic treatment of first-episode schizophrenia patients when compared with neuropsychological tests

ODR: Oculomotor delayed response; VGS: Visually guided saccades.

Figure 2. Based on larger effect sizes, similar power to detect treatment effects can be achieved with fewer subjects when utilizing neurophysiological biomarker outcomes relative to neuropsychological outcomes

Thus, smaller and less costly proof-of-concept studies with selected drug-relevant neurophysiological measures can be used to evaluate drug outcomes in clinical trials. At a conservative cost of US$20,000–25,000 per subject, the low end of potential savings when using biomarkers in a proof-of-concept study would be US$2–3 million. More importantly, this does not include the value of identifying ill-fated agents during proof-of-concept studies and avoiding costly clinical trial failures. Anti: Antisaccade [75]; NP: Neuropsychological battery [113]; ODR: Oculomotor delayed response [19]; PRED: Predictive saccade test [116]; PRO: Prosaccade [114,115].