Abstract
Serotonin type-3 receptor (5-HT3R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT3R 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-HT3R 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-HT3R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia.
Highlights
Schizophrenia is a major public health problem that affects ~1% of the population worldwide, and is associated with both positive and negative symptoms and neurocognitive deficits [1,2,3,4,5]
Deficits in mismatch negativity (MMN) generation were first demonstrated in schizophrenia almost 30 years ago [83]
MMN was subsequently shown to be sensitive to effects of N-methyl-D-aspartate-type glutamate receptor (NMDAR) antagonists both during intracortical infusion in non-human primates and IV infusion in healthy human volunteers
Summary
Schizophrenia is a major public health problem that affects ~1% of the population worldwide, and is associated with both positive and negative symptoms and neurocognitive deficits [1,2,3,4,5]. Antipsychotics are the primary treatment for schizophrenia, but in addition to significant side effects [6, 7], marketed antipsychotics have limited efficacy for neurocognitive deficits [8], indicating the need for alternative approaches. A key challenge in the development of novel treatments for schizophrenia is the need for target engagement biomarkers, which facilitate dose selection and initial proof-of-mechanism assessment [9,10,11,12,13,14,15]. We evaluate the utility of auditory mismatch negativity (MMN) as a target engagement biomarker for development of serotonin type receptor (5-HT3R) antagonists in the treatment of persistent neurocognitive impairments in schizophrenia. The most widely studied GABAergic interneuron classes in schizophrenia are parvalbumin (PV) and somatostatin (SOM) interneurons, that target primarily axons and dendrites of pyramidal neurons, respectively
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