Towards Novel Treatments for Schizophrenia: Molecular and Behavioural Signatures of the Psychotropic Agent SEP-363856

Abstract

Schizophrenia is a complex psychopathology whose treatment is still challenging. Given the limitations of existing antipsychotics, there is urgent need for novel drugs with fewer side effects. SEP-363856 (SEP-856) is a novel psychotropic agent currently under phase III clinical investigation for schizophrenia treatment. In this study, we investigated the ability of an acute oral SEP-856 administration to modulate the functional activity of specific brain regions at basal levels and under glutamatergic or dopaminergic-perturbed conditions in adult rats. We found that immediate-early genes (IEGs) expression was strongly upregulated in the prefrontal cortex and, to a less extent, in the ventral hippocampus, suggesting an activation of these regions. Furthermore, SEP-856 was effective in preventing the hyperactivity induced by an acute injection of phencyclidine (PCP), but not of d-amphetamine (AMPH). The compound effectively normalized the PCP-induced increase in IEGs expression in the PFC at all doses tested, whereas only the highest dose determined the major modulations on AMPH-induced changes. Lastly, SEP-856 acute administration corrected the cognitive deficits produced by subchronic PCP administration. Taken together, our data provide further insights on SEP-856, suggesting that modulation of the PFC may represent an important mechanism for the functional and behavioural activity of this novel compound.

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies

“…While TAAR1 partial and full agonists can differentially modulate baseline DA neuron firing, consistent antipsychotic-like effects of both partial and full agonists have been reported in several rodent models of schizophrenia (Table 2). TAAR1 agonists robustly block hyperactivity induced by cocaine, amphetamine, PCP and L-687,414 in rodents [74,86,106,111,112,122], likely through direct effects on DA neurotransmission and/or upstream modulation of glutamatergic activity. Thus, various TAAR1 agonist profiles are effective in paradigms based on hyperdopaminergic activity (i.e., cocaine, amphetamine) and NMDA receptor hypofunction (PCP, L-687,414), similar to antipsychotics.…”

Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia

“… 2 , 3 Nonclinical studies support agonism at TAAR1 and 5-HT1A receptors as contributing to the mechanism of action. 4 In vivo , ulotaront has demonstrated broad efficacy in nonclinical models of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, 4 , 5 prepulse inhibition (PPI) of the acoustic startle response, 4 and subchronic PCP-induced deficits in social interaction. 4 , 5 It also significantly reduced ketamine-induced increases in striatal dopamine synthesis capacity, 6 and it demonstrated inhibitory effects in ventral tegmental area (VTA) neurons in slice and in vivo electrophysiology studies, 4 likely mediated via action of TAAR1.…”

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia

“…Among the numerous compounds currently under investigation, the development of the selective GlyT1 inhibitor BI 425809 [97][98][99] and the TAAR1 agonist ulotaront (SEP-363856) [288][289][290][291] is the most advanced. The breakthrough therapy designation granted for both substances by the FDA enables regulatory monitoring of the approval process.…”

“…The results of the 26-week open-label extension study [ 289 ] revealed a continuous reduction in the PANSS total score and in the Clinical Global Impression-Severity score, with a relatively high completion rate and absence of extrapyramidal-related adverse effects. While neither publication specifically addresses the effects of SEP-363856 on CIAS, preclinical studies indicate a benefitial effect of the substance on cognitive deficits in a psychosis animal model [ 290 ]. Ulotaront was granted a breakthrough therapy designation by the FDA for the treatment of patients with schizophrenia in May 2019 [ 291 , 286 ].…”