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Tijdschrift voor Psychiatrie 63 (2021) 11, 804 - 809

Review article

An antipsychotic without dopamine receptor blockade?

S.K. Spoelstra, R. Bruggeman, H. Knegtering

Background Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated receptor 1 (TAAR1) agonist and a serotonin 5-HT1a agonist with potential antipsychotic properties.
Aim To describe the rationale for the development of SEP-363856, the pharmacology of TAAR1/5-HT1a agonists, and the clinical efficacy of SEP-363856.
Method A narrative review of the literature using PubMed, Embase and PsychINFO.
Results Six publications were identified, one of which was a phase 2 clinical trial with SEP-363856. This phase 2 study shows that SEP-363856 is an effective and well-tolerated antipsychotic; positive, but also negative symptoms decreased; motor side effects (akathisia) and prolactin increase did not occur, while metabolic side effects hardly occurred. Reported side-effects were somnolence and nausea. The antipsychotic activity of SEP-363856 appears to be (pre)clinical not based on D2 antagonism, but on TAAR1 and 5-HT1a agonism.
Conclusion TAAR1 and 5-HT1a agonists such as SEP-363856 may be a treatment option for psychosis. Hopefully they can be further developed into an antipsychotic with a favorable effectiveness and tolerability profile.