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, multiple high-profile “dopamine-sparing” candidates have failed in phase 2–3, reminding us that mechanistic novelty is not enough; translation succeeds when targets, trial designs, and patient phenotypes align. We review emerging interventions and propose a pragmatic translational agenda: domain-specific prescribing, earlier measurement-based care, and biomarker-informed stratification.
Egea et al. (Mon,) studied this question.