Third-Generation Antipsychotics: The Quest for the Key to Neurotrophism

Antipsychotic drugs (APs) have profoundly changed the treatment landscape for psychiatric disorders, yet their impact on neuroplasticity and neurotrophism remains only partially understood. While second-generation antipsychotics (SGAs) are associated with a better side effect profile than their predecessors, the emergence of third-generation antipsychotics (TGAs)-such as brexpiprazole, cariprazine, lurasidone, iloperidone, lumateperone, pimavanserin, and roluperidone-has prompted renewed interest in their potential neuroprotective and pro-cognitive effects. This review attempts to carefully examine the evidence on the neurotrophic properties of TGAs and their role in modulating brain plasticity by analyzing studies published between 2010 and 2024. Although data remain limited and focused primarily on earlier SGAs, emerging findings suggest that some TGAs may exert positive effects on neuroplastic processes, including the modulation of brain-derived neurotrophic factors (BDNFs) and synaptic architecture. However, robust clinical data on their long-term effects and comparative efficacy are lacking; therefore, further research is necessary to validate their role in preventing neurodegenerative changes and improving cognitive outcomes in patients with psychiatric conditions.