Actions and interactions of two antidepressants and diazepam on human skilled performance and mood were studied in a randomized double-blind cross-over trial with single oral doses of 50 mg amitriptyline (AMI), 15 mg Org 3770 (ORG) and placebo, given alone and in combination with 15 mg diazepam (DZ) to 12 young healthy subjects at one-week intervals. Objective tests (digit substitution, tapping, flicker fusion, Maddox wing, tracking, choice reactions, body sway, memory) and subjective assessments (visual analogue scale) were performed at baseline and 1.5, 3, 4.5 and 6 hours after drug administration. Side-effects were reported, blood pressure and heart rate measured and blood samples taken after each testing run. Placebo was nearly inert on performance and mood. DZ impaired some objective skills and showed sedative effects in the subjective tests. AMI produced sedation and impaired coordination as well as cognitive performance (digit substitution), most clearly at 3 to 4.5 hr. ORG resembled AMI in impairing objective and subjective performance, however, not necessarily in the same tests. Their combined effects with DZ were additive in objective tests but less additive in subjective tests. The drug combinations, but not any single drug, impaired learning acquisition. Plasma concentrations of the drugs given alone were about as expected, without important interactions. We conclude that the combinations of benzodiazepines with the antidepressants used impair skilled performance but may not cause major hazards.

It has been suggested that a combined blockade of 5-HT2A and D2-dopamine receptors improves efficacy and reduces the risk for extrapyramidal symptoms when treating schizophrenic patients with antipsychotic drugs. ORG 5222 is a new potential antipsychotic drug which has high affinity for 5-HT2A, D2-dopamine and alpha 1 adrenergic receptors in vitro. The objective of this study was to examine if ORG 5222 occupies 5-HT2A and D2-dopamine receptors in human subjects in vivo. Central receptor occupancy was measured by positron emission tomography (PET) in three healthy subjects after sublingual administration of 100 micrograms ORG 5222. [11C]N-methylspiperone ([11C] NMSP) was the radioligand used to measure 5-HT2A receptor binding in the neocortex and [11C]raclopride to measure D2-dopamine receptor binding in the striatum. The 5-HT2A occupancy was 15-30% and the D2-dopamine receptor occupancy was 12-23%. The study confirms that ORG 5222 binds to 5-HT2A and D2-dopamine receptors in human brain. Since receptor occupancy of ORG 5222 is rather low, doses higher than 100 micrograms are suggested in future clinical trials to evaluate the antipsychotic drug effect of ORG 5222.

Summary The effects of the catecholamine reuptake blocker methylphenidate (Ritalin @, 20 mg) and the benzodiazepine diazepam (Valium 8, 10 mg) on the acoustic eye blink reflex were investigated in healthy volunteers. Stand alone as well as prepulse trials were presented and three intensities of stand-alone stimuli and three intensities of prepulses were used in an double blind cross-over study (n=12). Measured were the amplitude, area under the curve, onset and peak latencies of the blink reflex. It was found that the amplitude, area under the curve, and the onset latency were dependent on the intensity of the stand-alone and prepulse trials. The amplitude of the startle reflex was not changed by methylphenidate, diazepam showed a large reduction in the amplitude. The amplitude of prepulse trials was not reduced by methylphenidate, but strongly by diazepam. The onset latencies were prolonged in loud prepulse trials and after diazepam. The diazepam data not only suggest that firm reductions in stand-alone trials might have major consequences for the amplitude in prepulse inhibition trials, they equally show that sedation may affect the reflex amplitude in prepulse inhibition trials and that large reduction of the amplitude in prepulse inhibition trials are not exclusive for DA agents.

Differences (if any) were found to meet strict bioequivalence requirements and were so small that they are of no clinical consequences.