Human pharmacology of current and new treatments for schizophrenia

Abstract

The studies in this thesis together show different ways of studying human pharmacology, give an impression of the current drug development in schizophrenia, and provide examples how human pharmacology can be applied in an early stage of drug development in healthy volunteers. The investigated compounds show that the main pharmacological focus in this area has shifted from psychosis to improvement of individual negative or cognitive symptom complexes, from direct receptor inhibition to indirect receptor modulation, and from single drug strategies to combination therapies, each targeted at different symptoms. We have tried to create a pharmacological fingerprint of the investigated compounds by making use of an intensive CNS test battery to measure effects in different functional domains of the brain and additional 'tools' (i.e. positive controls, dose escalation, PK-PD modeling and pharmacological challenge tests) to improve the reliability of the tests. This diversity of drug development strategies and range of neurotransmitters in schizophrenia reflects the increasing complexity of neuropharmacological hypotheses in this field. Despite these difficulties, incremental changes in drug characteristics and treatment strategies may well lead to the introduction of new classes or combinations of drugs in the future.