“Increasing dopamine synthesis capacity in the dorsal striatum and tonic acetylcholine: implications for the new muscarinic agents in the treatment of schizophrenia”

The recent positive phase 3 trials of the selective muscarinic 1,4 receptor agonist xanomeline used in combination with trospium (KARXT, Cobenfy TM ) has rekindled interest in the possibility of therapies for schizophrenia that are not based on dopaminergic receptor antagonism. Targeting acetylcholine (Ach) signalling makes sense as it is involved in numerous behaviours associated with the disorder such as attention, learning, memory, motivation, anxiety, mood, appetite, and reward. Xanomeline was 1st shown to be effective in reducing psychotic symptoms in Alzheimer patients decades ago [ 1 ]. This new approach builds on a long legacy of post-mortem studies in patients with schizophrenia showing alterations in muscarinic receptors targeted by Cobenfy TM i.e. M1-4 receptors [ 2 ].