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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. [ABSTRACT FROM AUTHOR] more...

Psychotomimetics like the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and the 5-hydroxytryptamine2A receptor (5-HT2AR) agonist psilocybin induce psychotic symptoms in healthy volunteers that resemble those of schizophrenia. Recent theories of psychosis posit that aberrant encoding of prediction errors (PE) may underlie the expression of psychotic symptoms. This study used a roving mismatch negativity (MMN) paradigm to investigate whether the encoding of PE is affected by pharmacological manipulation of NMDAR or 5-HT2AR, and whether the encoding of PE under placebo can be used to predict drug-induced symptoms. Using a double-blind within-subject placebo-controlled design, S-ketamine and psilocybin, respectively, were administrated to two groups of healthy subjects. Psychological alterations were assessed using a revised version of the Altered States of Consciousness (ASC-R) questionnaire. As an index of PE, we computed changes in MMN amplitudes as a function of the number of preceding standards (MMN memory trace effect) during a roving paradigm. S-ketamine, but not psilocybin, disrupted PE processing as expressed by a frontally disrupted MMN memory trace effect. Although both drugs produced positive-like symptoms, the extent of PE processing under placebo only correlated significantly with the severity of cognitive impairments induced by S-ketamine. Our results suggest that the NMDAR, but not the 5-HT2AR system, is implicated in PE processing during the MMN paradigm, and that aberrant PE signaling may contribute to the formation of cognitive impairments. The assessment of the MMN memory trace in schizophrenia may allow detecting early phases of the illness and might also serve to assess the efficacy of novel pharmacological treatments, in particular of cognitive impairments. [ABSTRACT FROM AUTHOR] more...

Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D2-like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebo-controlled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D2-like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance.Neuropsychopharmacology (2008) 33, 497–512; doi:10.1038/sj.npp.1301421; published online 25 April 2007 [ABSTRACT FROM AUTHOR] more...

Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT2A receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT2A receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 μg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120–2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.Neuropsychopharmacology (2007) 32, 1876–1887; doi:10.1038/sj.npp.1301324; published online 14 February 2007 [ABSTRACT FROM AUTHOR] more...