Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058

Abstract

Serotonin type-3 receptor (5-HT 3 R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT 3 R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT 3 R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT 3 R, and support the potential utility of CVN058 in correcting the excitatory/ inhibitory imbalance in schizophrenia.

Candidate biomarkers in psychiatric disorders: state of the field

“…Schizophrenia is the psychiatric diagnosis with the most research on personalized biomarker approaches after depression 83 . Recent papers have provided a broad overview of biomarkers for this disorder 84,85 , including target biomarkers for drug development 2,86 and diagnostic biomarkers for pathophysiological interrogation 84 . This section will mainly focus on candidate neuroimaging biomarkers that have shown potential for eventual clinical applications by virtue of their ability to allow out‐of‐sample predictions at the individual‐subject level (i.e., beyond in‐sample statistical associations at the group level).…”

Working memory and sensory memory in subclinical high schizotypy: An avenue for understanding schizophrenia?

“…There is some debate regarding neurotransmitter systems' roles in the auditory MMN. Some evidence indicates a restored MMN with nicotinic agonists, implicating acetylcholinergic modulation (Baldeweg et al, 2006; but see Knott et al, 2014), whereas other studies implicate acetylcholinergic (Kantrowitz et al, 2018) or serotonergic influence (Sehatpour et al, 2022).…”

Connecting Neurobiological Features with Interregional Dysconnectivity in Social-Cognitive Impairments of Schizophrenia

“…For instance, the use of positive allosteric GABA receptor modulators recovers social deficits as well as other symptoms in animal models of the disorder [257,258]. Other compounds such as serotonin type-3 receptor blockers may be of interest because of their potential to ameliorate the excitation/inhibition imbalance though actions on interneurons and have already shown positive effects on the MMN response in SZ [259]. Molecules rescuing immune dysregulations and neuroinflammation may be considered as well.…”