Clozapine enhances prepulse inhibition in healthy humans with low but not with high prepulse inhibition levels

Background: Atypical antipsychotics have been assessed for normalization effects on deficient sensory gating as indexed by prepulse inhibition (PPI) in schizophrenics with generally positive, although somewhat conflicting, results. Methods: We tested the acute effect of clozapine on startle, PPI, and attention, working memory, and executive functioning in 28 healthy male volunteers with low versus high PPI levels using a placebo-controlled within-subject design. Results: Clozapine significantly increased PPI levels obtained at short lead intervals of 60 and 120 msec in subjects with low PPI performance but showed no effect in subjects with high PPT Clozapine also caused a mild cognitive impairment on attention and pattern recognition memory tests. No correlations between cognitive measures and PPI performance were found. Moreover, low and high PPI performers were shown to exhibit stable levels of PPI across three separate nondrug testing days. Conclusions: Clozapine increases sensorimotor gating in healthy subjects with low but not high PPI levels in a manner comparable to that seen in dozapine-treated schizophrenia patients. Healthy subjects with low PPI level in combination with genetic studies may provide a translational model to elucidate the neuronal basis of PPI deficits and to test the efficacy of novel antipsychotic medication.