TY - JOUR
T1 - A validation of cognitive biomarkers for the early identification of cognitive enhancing agents in schizotypy
T2 - a three-center double-blind placebo-controlled study
AU - Koychev, Ivan
AU - McMullen, Katrina
AU - Lees, Jane
AU - Dadhiwala, Rukiya
AU - Grayson, Lois
AU - Perry, Charlotte
AU - Schmechtig, Anne
AU - Walters, James
AU - Craig, Kevin J
AU - Dawson, Gerard R
AU - Dourish, Colin T
AU - Ettinger, Ulrich
AU - Wilkinson, Lawrence
AU - Williams, Steven
AU - Deakin, John Francis William
AU - Barkus, Emma
N1 - Copyright © 2011 Elsevier B.V. All rights reserved.
PY - 2012/7
Y1 - 2012/7
N2 - A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia.
AB - A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia.
KW - Adult
KW - Amisulpride
KW - Analysis of Variance
KW - Biomarkers/metabolism
KW - Cognition Disorders/diagnosis
KW - Double-Blind Method
KW - Female
KW - Follow-Up Studies
KW - Humans
KW - Male
KW - Memory, Short-Term/drug effects
KW - Neuropsychological Tests
KW - Nootropic Agents/therapeutic use
KW - Personality Inventory
KW - Reproducibility of Results
KW - Risperidone/therapeutic use
KW - Schizotypal Personality Disorder/complications
KW - Sulpiride/analogs & derivatives
KW - Surveys and Questionnaires
KW - United Kingdom
KW - Verbal Behavior/drug effects
KW - Young Adult
U2 - 10.1016/j.euroneuro.2011.10.005
DO - 10.1016/j.euroneuro.2011.10.005
M3 - Article
C2 - 22137565
SN - 0924-977X
VL - 22
SP - 469
EP - 481
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 7
ER -