Nina Dedic

Trace amine-associated receptor 1 (TAAR1) agonists are being investigated as potential new treatments for schizophrenia, a disorder characterized by striatal hyperdopaminergia and dysregulated cortical and hippocampal glutamatergic function. Current evidence suggests that TAAR1 agonists reduce elevated striatal dopamine synthesis capacity and release, likely through direct inhibition of presynaptic dopaminergic neurons and modulation of upstream glutamatergic signaling. However, their impact on postsynaptic striatal neuronal dynamics and associated behaviors remains largely unexplored. Here we investigated the effects of TAAR1 agonists, RO5166017 and clinical drug candidate ulotaront, on in vivo calcium dynamics of D1- and D2-receptor expressing medium spiny neurons (MSNs) in freely behaving mice, under normal and phencyclidine (PCP)-induced, psychosis-like conditions. Both ulotaront and RO5166017 mitigated PCP-induced alterations in locomotor behavior, MSN activity levels and spatiotemporal dynamics. Interestingly, the neural effects were dependent on both locomotor activity and the psychosis-like state. While ulotaront and RO5166017 differentially affected neuronal activity levels under normal conditions, they both produced a similar increase in the PCP state, specifically during movement, with comparable effects observed in D1 and D2 MSNs. Although the established antipsychotics haloperidol and clozapine produced similar behavioral effects, their impact on striatal MSNs was distinct and lacked prominent state dependence. These findings provide new insights into the distinct neurocircuit changes associated with the antipsychotic-like effects of TAAR1 agonists, distinguishing them from D2 receptor-targeting treatments.

Background: Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine‐associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non‐clinical studies have also shown weight‐lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes. Methods: Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open‐label, crossover, two‐sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7‐6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post‐dose, participants ingested a ^99m Tc‐sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half‐time (T _1/2 ) and percentage gastric retention at 1, 2 and 4 h. Results: Thirty‐one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T _1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post‐meal. Conclusion: Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.

Aberrant dopaminergic and glutamatergic function, particularly within the striatum and hippocampus, has repeatedly been associated with the pathophysiology of schizophrenia. Supported by preclinical and recent clinical data, trace amine-associated receptor 1 (TAAR1) agonism has emerged as a potential new treatment approach for schizophrenia. While current evidence implicates TAAR1-mediated regulation of dopaminergic tone as the primary circuit mechanism, little is known about the effects of TAAR1 agonists on the glutamatergic system and excitation-inhibition balance. Here we assessed the impact of ulotaront (SEP-363856), a TAAR1 agonist in Phase III clinical development for schizophrenia, on glutamate function in the mouse striatum and hippocampus. Ulotaront reduced spontaneous glutamatergic synaptic transmission and neuronal firing in striatal and hippocampal brain slices, respectively. Interestingly, ulotaront potentiated electrically-evoked excitatory synaptic transmission in both brain regions, suggesting the ability to modulate glutamatergic signaling in a state-dependent manner. Similar striatal effects were also observed with the TAAR1 agonist, RO5166017. Furthermore, we show that ulotaront regulates excitation-inhibition balance in the striatum by specifically modulating glutamatergic, but not GABAergic, spontaneous synaptic events. These findings expand the mechanistic circuit hypothesis of ulotaront and TAAR1 agonists, which may be uniquely positioned to normalize both the excessive dopaminergic tone and regulate abnormal glutamatergic function associated with schizophrenia.