Beyond dopamine: novel strategies for schizophrenia treatment

The takeaway

Emerging non-dopaminergic therapeutic strategies-targeting muscarinic M₁/M₄, TAAR1, GlyT‑1, and 5‑HT_2A receptors-show promise in addressing the cognitive and negative symptoms of schizophrenia inadequately treated by dopamine-based antipsychotics.

The science

All approved antipsychotics act on dopamine D₂ receptors, which effectively control psychosis but leave cognitive deficits and negative symptoms largely untreated. This review evaluates late-stage clinical candidates with non-dopaminergic mechanisms:
- KarXT (xanomeline + trospium) and emraclidine: muscarinic receptor modulators improving positive, negative, and cognitive domains with fewer peripheral side effects.
- Ulotaront (TAAR1 agonist/5-HT_1A partial agonist): the first-in-class antipsychotic without direct D₂ action, effective in acute psychosis with a favorable safety profile.
- Iclepertin (BI 425809): a GlyT-1 inhibitor that enhances NMDA signaling, improving cognition in phase 2 trials.
- Pimavanserin and roluperidone: selective 5-HT_2A antagonists showing benefits for negative symptoms and cognition, though phase 3 results remain mixed.
Together, these agents expand treatment paradigms toward circuit-specific interventions rather than broad dopamine blockade.

Why it matters

Addressing negative and cognitive symptoms-the major unmet needs in schizophrenia-could transform long-term outcomes. Success with these compounds would mark the first real mechanistic advance in antipsychotic therapy since the advent of dopamine blockers.

Original article

https://doi.org/10.1002/med22042