For over half a century, antipsychotic efficacy for schizophrenia treatment has been tied to dopamine D2 receptor antagonism, with predictable trade-offs: limited impact on negative and cognitive symptoms, and substantial metabolic, endocrine, and motor adverse effects. In the past few years, schizophrenia drug development has re-accelerated, including the first US approval of a non-D2 antipsychotic mechanism (xanomeline–trospium), and several late-stage programmes aiming to treat symptom domains that matter most to long-term functioning. At the same time, several high-profile “dopamine-sparing” agents have failed in phase 2 and 3 trials, underscoring that mechanistic novelty alone is insufficient. Successful translation requires alignment among biological targets, trial design, and patient phenotypes. In this review, we examine emerging interventions and propose a pragmatic translational framework centered on domain-specific prescribing, earlier implementation of measurement-based care, and biomarker-informed stratification.
Fernandez-Egea et al. (2026) studied this question.