(#70) A Comparative Pharmacodynamic Framework for Dopamine 2 Receptor Engagement Across Antipsychotics

Abstract: For decades, antipsychotic efficacy has been framed around a striatal dopamine D2 receptor occupancy range of approximately 65%-80%, with higher levels linked to increased extrapyramidal symptom (EPS) risk. Although this model has guided clinical dosing, it does not explain the variability in efficacy and tolerability observed with newer antipsychotics, indicating that D2 occupancy alone cannot account for clinical outcomes. This study proposes a comparative pharmacodynamic framework that integrates receptor occupancy, binding kinetics, and intrinsic activity to better characterize antipsychotic effects.


We conducted a comparative narrative synthesis of published pharmacodynamic data across first-, second-, and third-generation antipsychotics. Representative agents were selected to capture the spectrum of dopamine receptor engagement, spanning high-affinity antagonists, broad-spectrum atypicals, and dopamine system modulators.


Findings indicate that D2 occupancy alone is an incomplete predictor of antipsychotic efficacy and tolerability. Clinical outcomes are better understood through an integrated model incorporating binding affinity, receptor kinetics, intrinsic activity, and multimodal mechanisms. This framework supports a shift from fixed occupancy thresholds toward mechanism-informed, individualized prescribing strategies for psychotic disorders.



Short Description: This poster presents a comparative pharmacodynamic framework for understanding dopamine D2 receptor engagement across antipsychotics. Moving beyond the traditional 65%-80% occupancy model, it integrates receptor occupancy with binding kinetics and intrinsic activity to explain variability in clinical efficacy and tolerability. By categorizing antipsychotics into distinct engagement profiles, this framework offers a practical, mechanism-informed approach to prescribing and supports more individualized treatment strategies in psychotic disorders.

Name of Sponsoring Organization(s):N/A



Authors:

Liberty Olive Macias, DNP, APRN, PMHNP (she/her/hers) - psychnp1@protonmail.com - Loma Linda Psychiatric Medical Group

Danielle Viray (she/her/hers) - Research Assistant, daniellenviray@gmail.com, Loma Linda University

Paarth Kansal (he/him/his) - Medical Student, paarthkansal@gmail.com, California University of Science and Medicine

Shreya Kansal (she/her/hers) - Medical Student, shreyakansal@ymail.com, Touro University