Rationale for Adjunctive Treatment Targeting Multiple Mechanisms in Schizophrenia

Importance: Schizophrenia is a complex syndrome with taxing symptoms and for which treatment challenges remain. Current dopamine D₂ receptor–blocking antipsychotics have well-known limitations, including ineffectively treating across all symptom domains and generating common side effects such as motor disturbances, weight gain, and metabolic dysfunction. New approaches are sorely needed to address the continued unmet treatment needs for individuals living with schizophrenia. Observations: Although current antipsychotic drugs indicated for the treatment of schizophrenia interact with various neurotransmitter receptors, they all commonly act as dopamine D₂ receptor antagonists or partial agonists. While antipsychotics primarily relieve positive symptoms, residual positive symptoms are still common, and management of negative symptoms and cognitive impairment remains an unmet need. Problematic side effects are common with current agents and can contribute to nonadherence. In addition to alterations in dopaminergic pathways, increasing evidence indicates that the pathophysiology of schizophrenia also includes dysfunction in other neurotransmitter systems including glutamate, acetylcholine, serotonin, and γ-aminobutyric acid. While the pathophysiology of schizophrenia is complex, treatments with novel pharmacologic actions that target these systems are of interest as adjunctive treatment for individuals with schizophrenia. Conclusion and Relevance: An unmet need exists for effective treatment of all the core symptoms of schizophrenia. Novel antipsychotics with a nondopaminergic mechanism of action may be useful candidates for antipsychotic adjunctive treatment in people with schizophrenia who are showing inadequate responses, treatment resistance, or low tolerance to dopamine D₂ receptor–blocking antipsychotics.