Influence of aripiprazole, risperidone, and amisulpride on sensory and sensorimotor gating in healthy 'low and high gating' humans and relation to psychometry

Abstract

Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.

Figure 1

The influence of the AAPs aripiprazole (a), risperidone (b), and amisulpride (c) and negative control treatments lorazepam (d), modafinil (e), and valproate (f) on sensory gating, expressed as percent P50 suppression. All AAPs significantly increased P50 suppression in low-gating healthy volunteers. Lorazepam and modafinil reduced percent P50 suppression independently of low- and high-gating subgroups. Differences in placebo gating within one cohort originate from the exclusion of invalid data sets in a nonpairwise manner. *Significant difference between active drug and placebo. Error bars refer to SEM.

Figure 2

The influence of the AAPs aripiprazole (a), risperidone (b), and amisulpride (c) and negative control treatments lorazepam (d), modafinil (e), and valproate (f) on sensorimotor gating expressed as percent PPI. Aripiprazole increased PPI in the low-gating subgroup and decreased PPI in the high-gating subgroup. Risperidone and amisulpride did not significantly influence sensorimotor gating. Whereas valproate did not significantly modulate PPI, lorazepam and modafinil attenuated sensorimotor gating independently of high- and low-gating group. Differences in placebo gating within one cohort originate from the exclusion of invalid data sets in a nonpairwise manner. *Significant difference between active drug and placebo. Error bars refer to SEM.

Figure 3

SCL-90 symptom scales (a) and global severity index (b) in the low (n=44) and the high (n=44) P50 subgroups. SO, somatization; OC, obsessive–compulsive; IS, interpersonal sensitivity; DE, depression; AN, anxiety; HO, hostility; PA, phobic anxiety; PI, paranoid ideation; PS, psychoticism. *Significant difference between low- and high-gating subgroups. Error bars refer to SEM.