Emerging Treatments in Schizophrenia

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.