ABSTRACT
The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.
ABSTRACT
INTRODUCTION: We investigated the disease progression rate in patients with progressive supranuclear palsy-Richardson syndrome (PSP-RS) and PSP-parkinsonism (PSP-P) in comparison with Parkinson disease (PD) patients, using MRPI (Magnetic Resonance Parkinsonism Index), and MRPI 2.0. METHODS: Fifteen PSP-RS patients (disease duration, y, mean ± SD: 2.5 ± 1.1), 16 PSP-P patients (disease duration, y, mean ± SD: 6.5 ± 3.2) and 19 PD patients (disease duration, y, mean ± SD: 3.2 ± 2.3) were enrolled. All patients underwent clinical assessment and MRI at baseline, 1-year, and 2-year follow-up. MRPI, MRPI 2.0 and clinical scores over 1 and 2-years were used to evaluate disease progression rate, and to calculate sample sizes required to power placebo-controlled trials. RESULTS: All groups showed increased clinical motor scores over time whereas only PSP groups had increased MRPI and MRPI 2.0 values over T1 and T2 intervals. The percentage increase over 1 and 2-years of MRPI and MRPI 2.0 values was significantly higher in PSP groups than in PD group, and in PSP-RS than in PSP-P patients while no difference between patient groups was observed when clinical motor scores were considered. Sample size estimates showed that MRPI 2.0 performed better than MRPI and clinical scales. Treatment trials with MRPI 2.0 could be performed over 2-years both in PSP-RS and PSP-P with a sample size per treatment arm of 89 and 170 patients, respectively. CONCLUSIONS: Our results demonstrate that MRPI 2.0 was more powerful than MRPI and clinical motor scales in evaluating PSP progression, and in providing the best sample size estimates for clinical trials.