Current pharmacotherapy of dementia-related psychosis and agitation/aggression relies on the off-label administration of atypical antipsychotics, which have limited clinical efficacy and induce various adverse reactions.

Genetic studies have suggested several druggable targets that correspond with the etiology of dementia-related psychosis and agitation/aggression: serotonin 5-HT2A and 5-HT1A receptors, serotonin transporter, alpha-1 adrenoceptor, and dopamine D1 and D3 receptors.

Novel therapeutic approaches may benefit particularly from targeting the serotoninergic system with serotonin 5-HT2A and 5-HT1A ligands or serotonin transporter inhibitors, which are currently being investigated in phase III clinical trials.

Preclinical and clinical studies have suggested other relevant molecular targets that may result in therapeutically acceptable efficacy: cannabinoid receptors, metabotropic glutamate 2 receptors, muscarinic M1/M4 receptors, and glutamate N-methyl-D-aspartate receptors.

Blockade of M1, alpha-2 adrenergic, and histamine H1 receptors and the human ether-a-go-go-related gene channel should be avoided because elderly patients are particularly sensitive to adverse reactions induced by the drugs acting on these targets.