Reviewing Non-Dopaminergic Mechanisms for Positive and Negative Schizophrenia Symptom Management

Schizophrenia is a chronic and debilitating mental health condition that significantly impacts quality of life and can shorten patients' lifetime by decades. It is characterized by symptoms including hallucinations and delusions, apathy, and cognitive impairment, and people with schizophrenia also experience many somatic comorbidities, such as metabolic disturbances, infectious diseases, cardiovascular issues, and respiratory illnesses. For decades, treatment for schizophrenia has focused on antipsychotics (APs) that reduce excess dopamine signaling to the associative striatum, which also blocks dopamine signaling in the dorsal striatum, creating movement disorders. Second-generation APs have a lower propensity to cause drug-induced movement disorders than first-generation APs. Nonetheless, only 1 out of 3 patients respond to any of the available APs; moreover, negative and cognitive symptoms tend to persist, while side effects and long-term risks can contribute to poor outcomes. However, there are new understandings in how to reduce dopamine release both presynaptically and selectively in circuits governing psychotic symptoms. These mechanisms offer a different treatment approach for patients with schizophrenia.