Biomarkers for the effects of antipsychotic drugs in healthy volunteers

Studies of novel antipsychotics in healthy volunteers are traditionally con cerned with kinetics and tolerability, but useful information may also be o btained from biomarkers of clinical endpoints. A useful biomarker should me et the following requirements: a consistent response across studies and ant ipsychotics; a clear response of the biomarker to a therapeutic dose; a dos e-response relationship; a plausible relationship between biomarker, pharma cology and pathogenesis. In the current review, all individual tests found in studies of neuroleptics in healthy volunteers since 1966 were progressiv ely evaluated for compliance with these requirements. A MedLine search yiel ded 65 different studies, investigating the effects of 23 different neurole ptics on 101 different (variants of) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objectiv e measures of alertness, and of visual-visuomotor-auditory and motor skills were most sensitive to antipsychotics, although over half of all the studi es failed to show statistically significant differences from placebo. The m ost consistent effects were observed using prolactin response and saccadic eye movements, where 96% and 83% of all studies resp. showed statistically significant effects. The prolactin inducing dose equivalencies relative to haloperidol of 19 different antipsychotic agents correlated with the lowest recommended daily maintenance dose (r(2)=0.52). This relationship could re flect the clinical practice of aiming for maximum tolerated levels, or it c ould represent a common basis behind prolactin release and antipsychotic ac tivity (probably D-2-receptor antagonism). The number of tests used in huma n psychopharmacology appears to be excessive. Future studies should look fo r the most specific and sensitive test within each of the domains that are most susceptible to neuroleptics.