Emerging 5-HT receptor antagonists for the treatment of Schizophrenia

While antipsychotics have been generally successful in treating psychosis in schizophrenia, there is a major treatment gap for negative symptoms and cognitive deficits. Given that these aspects of the disease contribute to poor functional outcomes independently of positive symptoms, treatments would have profound implications for quality of life. The 5-HT_2A- receptor has been considered a potential target for interventions aimed at negative and cognitive symptoms and multiple antagonists and inverse agonists of this receptor have been tested.

Ritanserin and volinanserin, are historically important compounds in this area, while pimavanserin, roluperidone, and lumateperone are either newly approved, in late stages of development, or currently being tested for efficacy in schizophrenia-related features. The focus will be on their efficacy in the treatment of negative symptoms, with a limited secondary discussion of cognition.

In addition to their efficacy in treating negative symptoms and cognition, these compounds may also have a role in modulating antipsychotic-induced dopamine super-sensitivity and preventing relapse. They may also show efficacy in treating patients with milder symptoms such as patients with schizotypal personality disorder and attenuated psychosis syndrome. Their utility may also expand outside the spectrum of schizophrenia to encompass Parkinson's Disease psychosis, major depression, bipolar depression, and dementia-associated apathy.