Beyond Dopamine: Emerging Non-Dopaminergic Treatments for ‎Schizophrenia-A Review of Muscarinic, TAAR۱, and Glutamatergic ‎Pathways

Schizophrenia remains a major psychiatric disorder in which conventional dopamine D۲ receptor-‎centered treatments provide substantial benefit for positive symptoms but often show limited ‎effects on persistent negative and cognitive symptoms and may produce clinically important ‎adverse effects. These limitations have stimulated the development of non-dopaminergic ‎therapeutic strategies. This critical narrative review examines three emerging approaches-‎muscarinic receptor modulation, trace amine-associated receptor ۱ (TAAR۱) agonism, and ‎glutamatergic modulation-with emphasis on their biological rationale, clinical efficacy, effects ‎across symptom domains, safety, and level of clinical validation. A structured literature search ‎was conducted using PubMed/MEDLINE and supplementary major publisher and journal ‎platforms, with particular attention to randomized controlled trials, systematic reviews, meta-‎analyses, and recent clinical evidence. Muscarinic modulation, particularly xanomeline–trospium, ‎currently has the strongest clinical evidence. Three acute randomized trials demonstrated ‎significant improvements in overall and positive symptoms, with a smaller but significant pooled ‎effect on negative symptoms, leading to FDA approval in ۲۰۲۴. TAAR۱ agonism remains ‎biologically promising, but the initial positive findings with ulotaront were not replicated in ‎major phase ۳ trials, limiting current confidence in its efficacy. Glutamatergic strategies have ‎strong neurobiological rationale but heterogeneous clinical outcomes, with several late-stage ‎programs failing to demonstrate consistent benefit. Overall, non-dopaminergic pharmacotherapy ‎represents an important expansion of schizophrenia treatment, but the three pathways differ ‎substantially in clinical maturity. Muscarinic modulation has achieved the greatest level of ‎validation, whereas TAAR۱ and glutamatergic approaches require further clinical replication, ‎improved patient selection, and more precise translational strategies.‎

کلیدواژه ها:

schizophrenia ، non-dopaminergic treatment ، muscarinic receptors ، TAAR۱ ، glutamatergic ‎signaling.