Experimental Serotonergic Agents for the Treatment of Schizophrenia

Abstract

Schizophrenia remains one of the most chronic and highly disabling mental disorder. To date, the pathomechanism of schizophrenia is not fully understood and current treatments are characterized by some limitations. First- and second-generation antipsychotics have shown clinical efficacy in treating positive symptoms, while are poorly effective on both negative symptoms and cognitive deficits. Moreover, they can involve many metabolic and neurological side effects, leading to low therapeutic compliance. Many evidence suggested that serotonin may play a complex role in the neurobiology of schizophrenia. Therefore, new drugs targeting 5-HT receptors (5-HTRs) have become an important area of research in schizophrenia in the hope that treatment efficacy may be improved without inducing side effects observed with currently available antipsychotics. Research using the main database sources was conducted to obtain an overview of preclinical and clinical pharmacological 5-HTR-targeted therapies in patients with schizophrenia. We identified 17 experimental serotonergic agents, under study for their potential use in schizophrenia treatment. Particularly, AVN-211, LuAF-35700 and Brilaroxazine are currently under clinical development. Moreover, some compounds showed some pro-cognitive and antipsychotic-like properties in animal models, while other agents showed contradictory effects in improving symptoms and were removed from the development program. Although some serotonergic drugs seem promising for improving the treatment of schizophrenia, further studies regarding the pathophysiological mechanisms of schizophrenia and novel compounds as well as high-quality trials are necessary in order to improve schizophrenia outcomes.

The Relation between the Plasma Concentrations of Long-Acting Atypical Antipsychotics and Clinical Effectiveness in Patients Affected by Schizophrenia or Schizoaffective Disorder: A Comprehensive Overview

“…Second, the lack of a convincing association between LAI SGA plasma concentrations and direct/indirect parameters of clinical effectiveness can not only be explained by a non-linear relationship [34], but also by the fact that D2 receptor dysfunction represents only one of the mechanisms underlying SCZ [5]. In this sense, other biological factors might be more directly related to LAI SGA plasma concentrations and be concomitantly reliable biomarkers of clinical amelioration (e.g., Brain-Derived Neurotrophic Factor-BDNF or sex steroids plasma concentrations) [48,49].…”

“…While such antipsychotics have a robust efficacy against the positive symptoms of SCZ, they are considered poorly effective in treating negative symptoms [4]. Second-generation antipsychotics (SGAs) were introduced to address these unmet clinical needs, resulting to be equally effective or better than FGAs, particularly for negative, depressive and cognitive symptoms [5,6], and relapse prevention [7,8]. For these reasons, clinical practice guidelines recommend SGAs as first-line compounds to treat patients with SCZ, also for the reduced risk of extrapyramidal side effects generally associated with FGAs.…”

Recent Advances in Psychopharmacology: From Bench to Bedside Novel Trends in Schizophrenia

“…This compound has established the safety and efficacy in Phase 2 double-blind, multicenter RCT, showing improvement in total PANSS score compared to placebo. The Brilaroxazine (RP5063) was compared in various doses, including 15 mg, 30 mg, and 50 mg, along with aripiprazole 15 mg as a placebo in patients with acute symptoms of SCZ [ 11 ]. This study showed significant improvement in PANSS score with all the doses mentioned above [ 11 ].…”

“…The Brilaroxazine (RP5063) was compared in various doses, including 15 mg, 30 mg, and 50 mg, along with aripiprazole 15 mg as a placebo in patients with acute symptoms of SCZ [ 11 ]. This study showed significant improvement in PANSS score with all the doses mentioned above [ 11 ]. The improvement in symptoms with 15 mg of RP5063 was shown in 34% of patients, while 30 mg and 50 mg showed improvement in symptoms in 34% vs. 46%, respectively [ 11 ].…”

The role of lumateperone in the treatment of schizophrenia

“…5,22,28,[45][46][47][48][49] It is also a dopamine D 1 receptor-dependent indirect modulator of glutamatergic α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid 52 and N-methyl-D -aspartate (NMDA) GluN 2B receptors. 5,19,24,53,54…”