The Role of Nitric Oxide in Cognition in Schizophrenia (NOC)

This study evaluates the role of the Nitric Oxide system in cognition in patients with schizophrenia. Participants will be randomised to 2 equal groups and receive either the Nitric Oxide donor molecule glyceryl trinitrate, or a placebo. Performance on several cognitive tasks will be assessed.

Nitric oxide [NO] is a gaseous neurotransmitter substance found in the brain. Nitric oxide is integrated with the glutamate system. Glutamate has received considerable attention as an important factor in the cognitive distortions and cognitive impairments that underlie schizophrenia. Deficits in glutamate in schizophrenia may impact upon cognition via the NO system, as glutamate receptors signal by way of NO. Here the investigators aim to extend knowledge of glutamate-NO systems by directly examining the role of NO in cognition in patients with psychosis. We aim to assess the role of the NO system in cognition, downstream of glutamate and before patients are started on any anti-psychotic medication which perturb brain neurochemistry. The primary outcome measure is change in a particular style of cognition referred to as 'jumping to conclusions' following the administration of a potent Nitric Oxide donor molecule [glyceryl trinitrate (GTN)], under placebo-controlled, double-blind conditions. This will shed light on the direct role of NO in cognition in psychosis, beyond the glutamate system.

The formulation composition of the placebo will be the same as the active spray minus the Glyceryl Trinitrate.

Inclusion Criteria: 18-40 years of age Patients undergoing an acute psychotic episode (defined as score > 4 on question P1 of the PANSS positive subscale) requiring full-time hospitalisation according to clinical referral by the relevant mental health service Demonstrates capacity and willing to give informed consent Female participants willing to have a pregnancy test before treatment Currently unmedicated with antipsychotic medication Exclusion Criteria: Major physical illness Prior history of intolerance to glyceryl trinitrate Homicidal or suicidal Pregnant or breast feeding

Merritt K, Catalan A, Cowley S, Demjaha A, Taylor M, McGuire P, Cooper R, Morrison P. Glyceryl trinitrate in first-episode psychosis unmedicated with antipsychotics: A randomised controlled pilot study. J Psychopharmacol. 2020 Aug;34(8):839-847. doi: 10.1177/0269881120922967. Epub 2020 May 21.