All effective antipsychotic drugs work by blocking post-synaptic dopamine D2 receptors; no new mechanism of action has emerged
since they were discovered 70 years ago. The action is desirable since it acts to oppose the excessive release of dopamine that occurs
in schizophrenia. However side-effects are problematic and response is often partial. There is therefore a strong need to find nondopamine
acting antipsychotics; I will describe 3 approaches to finding them - some successful.
1) Sunovion SEP-363856 is one of a series was discovered by screening compounds for a behavioural profile in rodents that matched
clozapine, our most effective antipsychotic. It does not block dopamine receptors but can oppose dopamine-mediated behaviour in
rodents. To determine its possible efficacy in humans we assessed its effects on dopamine functions using fMRI to monitor its actions
on reward processing and brain connectivity in healthy volunteers.
2) Autifony AUT00206 in contrast, was discovered by screening thousands of compounds for a specific molecular property, the ability to
potentiate the activity of a potassium channel. Promoting the Kv3.1 channel on GABA inter-neurons could restore GABA function in
schizophrenia. We tested whether it would restore experimentally impaired GABA function induced by ketamine in healthy volunteers.
3) Minocyline is a well known antibiotic that also has anti-inflammatory properties including reducing activation of the brain’s
inflammatory microglial cells. The evidence of brain inflammation in schizophrenia has led to much interest in repurposing minocycline
for the treatment of early psychosis. I will report the results of a large multicentre trial.