Since the first discovery of antipsychotics in the 1950s, targeting dopaminergic drugs has manifested to well manage the positive symptoms of schizophrenia with limited efficacy for the negative and cognitive symptoms. In past decades, extensive efforts have been undertaken towards the development of innovative agents that can effectively stabilize the dopamine and serotonin systems or target to nondopaminergic pathways, leading to various promising drug candidates entering into clinical trials. Notably, the sigma-2, 5-HT2A, and α1A receptor antagonist roluperidone, as well as a fixed-dose combination of the M1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5-HT1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small-molecule entities and fixed-dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics.

Traditionally, Phase 1 clinical trials were largely conducted in healthy normal volunteers and focused on collection of safety, tolerability, and pharmacokinetic data. However, in the CNS therapeutic area, with more drugs failing in later phase development, Phase 1 trials have undergone an evolution that includes incorporation of novel approaches involving novel study designs, inclusion of biomarkers, and early inclusion of patients to improve the pharmacologic understanding of novel CNS-active compounds early in clinical development with the hope of improving success in later phase pivotal trials. In this chapter, the authors will discuss the changing landscape of Phase 1 clinical trials in CNS, including novel trial methodology, inclusion of pharmacodynamic biomarkers, and experimental medicine approaches to inform early decision-making in clinical development.

ASP4345, a novel dopamine D₁ receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.