M208. Measures of Cognition and Social Functioning in Schizophrenia Patients Receiving Sep-363856

Abstract

Background SEP-363856 is a novel trace amine associated receptor-1 (TAAR1)/5-HT1A agonist with no dopamine-D2/5-HT2A antagonist activity. SEP-363856 showed significant antipsychotic efficacy in patients with schizophrenia, and a safety and tolerability profile similar to placebo and consistent with a non-D2 mechanism of action. Here, we examined measures of cognition and social functioning in schizophrenia patients receiving SEP-363856. Methods Patients aged 18–40 years with an acute exacerbation of schizophrenia were randomized, double-blind (DB), to 4-weeks of flexible-dose treatment with once daily SEP-363856 (N=120; 50 or 75 mg) or placebo (N=125). Patients (N=156) entering a subsequent 26-week open-label (OL) extension study were evaluated utilizing the Cogstate Brief Battery, administered at DB baseline and week 4, and OL baseline and weeks 12 and 26. Standardized z-scores were calculated for the Cogstate composite and subscale tasks (Detection task, Identification task, One Card Learning task, One Back task). The University of California San Diego Performance Based Skills Assessment (UPSA-B) scale was assessed at the same time-points, as were the following psychiatric scales: Positive and Negative Syndrome Scale (PANSS), the Brief Negative Symptom Scale (BNSS), the Montgomery–Åsberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale, severity scale (CGI-S), and the Pittsburgh Sleep Quality Index global score (PSQI-global). Pearson correlation analyses were performed between DB baseline to Week 26 change in Cogstate composite and subscale scores and Week 26 change in the psychiatric scale scores. Results Small improvements, from DB baseline to Week 26, were observed in standardized scores on the Cogstate composite (+0.29), Identification task (+0.19), Detection task (+0.28); One Card learning task (+0.33); and One Back task (+0.33). Improvement from OL baseline at Week 26 was also observed on the mean [SD] UPSA-B total score (+6.2 [11.6]). At DB baseline, there were no correlations between CogState composite score and individual test scores with any of the psychiatric scales. Week 26 improvement in the following Cogstate composite and subscale tasks were correlated with Week 26 improvement in the following psychiatric scale scores: Cogstate composite score (PANSS total, r=-0.26; BNSS total, r=-0.31; CGI-S, r=-0.30; MADRS total, r=-0.23; PSQI-global, r=-0.23); Identification task (PANSS total, r=-0.30; BNSS total, r=-0.30), Detection task (BNSS total, r=-0.30; CGI-S, r=-0.28; PSQI-global, r=-0.23); One Card learning task (MADRS total, r=-0.29); and One Back task (PANSS total, r=-0.26). Discussion During 6-months of open-label extension treatment with SEP-363856, improvement in overall functioning was observed on the UPSA-B scale; and small but consistent improvement in cognition was noted in the Cogstate composite and subscale task scores. Endpoint reduction in the severity of schizophrenia-related symptomatology (eg, on the PANSS, BNSS, MADRS, insomnia) were associated with modest correlations, in the range of 0.2 to 0.3, in cognitive performance as measured by the Cogstate composite and subscale task scores.

A New Treatment Paradigm

“…9). 23,24 The extension study also confirmed the effect of ulotaront on negative symptoms: significant improvements from baseline were noted using the PANSS negative subscale, Brief Negative Symptom Scale (BNSS) total score, and uncorrelated PANSS score matrix Negative Apathy/Avolition Factor and Negative-Deficit of Expression Factor scores 23 …”

“…There is reason to be optimistic that patients with schizophrenia may soon have a truly novel treatment option. Based on the clinical trial data for ulotaront, [22][23][24] it seems TAAR1 agonists have the potential to be both tolerable and effective, including for ameliorating negative and cognitive symptoms. Other emerging therapies include agents targeting muscarinic receptors, oral glycine transporter-1 inhibitors, and medications blocking serotonin 5-HT 2A receptors.…”

“…Examples of past disappointments are varied, including a glutamate receptor agonist, 18 an α-7 nicotinic receptor agonist, 19 a phosphodiesterase 10A inhibitor, 20 and a glycine reuptake inhibitor. 21 Given the strong performance of the TAAR1 agonist ulotaront in a recent phase 2 clinical trial, [22][23][24] as well as the existence of ralmitaront, another TAAR1 agonist being investigated in clinical trials, there is good reason to believe that these novel agents may hold greater promise than previous approaches. Here, we review the biologic, preclinical, and clinical data available for TAAR1 agonists, so that if and when they are approved for the treatment of schizophrenia, psychiatry specialists will be ready to use them to optimize patient outcomes.…”

“…However, available data suggest that they may represent a valuable alternative to traditional antipsychotics in treating schizophrenia because they seem to target negative and cognitive symptoms as well as positive symptoms. [22][23][24] Because negative and cognitive symptoms are such important predictors of patients' quality of life and ability to function, 43,46 agents that can help ameliorate these symptoms could help many individuals with schizophrenia achieve recovery. In addition, because ulotaront affects 5-HT 1A receptors, it may have beneficial effects on mood and anxiety.…”

“…Because TAAR1 agonists are only now being characterized, it remains to be seen how they might eventually be used in clinical practice. However, available data suggest that they may represent a valuable alternative to traditional antipsychotics in treating schizophrenia because they seem to target negative and cognitive symptoms as well as positive symptoms 22–24 . Because negative and cognitive symptoms are such important predictors of patients' quality of life and ability to function, 43,46 agents that can help ameliorate these symptoms could help many individuals with schizophrenia achieve recovery.…”