No abstract

Background: There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such as sodium nitroprusside (SNP). Recent studies of SNP in patients with psychosis have mixed results, and the drug has to be administered intravenously. Glyceryl trinitrate (GTN) is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally. Aims: We explored the safety and potential effects of GTN in unmedicated patients with a first episode of psychosis. Methods: This was a single-centre, randomised, double-blind, placebo-controlled trial from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients received 3 × sprays of GTN or placebo for three consecutive days, and were re-assessed on Days 1, 2, 3 and 7. The primary outcome was cognition (Jumping to Conclusions task), secondary outcomes were symptoms (Positive and Negative Syndrome Scale (PANSS)), verbal memory (Hopkins Verbal Learning task), and mood (Bond–Lader Visual Analogue Scales). Results: Nineteen patients were randomised, and 13 participants were included in the analyses. Compared with placebo, GTN was well tolerated, but was not associated with significant effects on cognition, symptoms, or mood. Bayesian statistics indicate that our results were 2× more likely under the null hypothesis than the alternative hypothesis, providing anecdotal evidence that GTN does not improve psychotic symptoms. Conclusions: We found no indication of an effect of GTN on symptoms of psychosis or cognition.

Background There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such as sodium nitroprusside (SNP). Recent early phase studies of SNP in patients with psychosis have had mixed results, and the drug has to be administered intravenously. GTN is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally. We explored the safety and effectiveness of GTN in unmedicated patients with a first episode of psychosis. Methods A single-centre, randomized, double-blind, placebo-controlled trial was conducted from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients with a first episode of psychosis were recruited from the South London and Maudsley NHS Trust, London, UK. Nineteen patients were randomised to receive 3 x sprays of GTN or placebo for 3 consecutive days, and re-assessed on Day 7. Thirteen participants were included in the final analyses. At each assessment point, symptom levels were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive performance was evaluated using the Jumping to Conclusions (JTC) and the Hopkins Verbal Learning (HVLT) tasks. Results Compared to placebo, GTN was well tolerated, but it was not associated with significant effects on either psychotic symptoms or cognition. Bayesian statistics indicated with moderate confidence that GTN does not have a therapeutic effect. Discussion This study indicates that nitric oxide donors are not therapeutically beneficial in psychosis. It also highlights the difficulties in recruiting unmedicated patients with psychosis. Future clinical trials would benefit from frameworks built into clinical services, to signpost patients not responding to medication and those discontinuing medication to clinical trials of alternatives.

BackgroundIt has been reported that more than a quarter of patients with polymyalgia rheumatica (PMR) have subclinical giant cell arteritis (GCA) [1]. Risk markers for subclinical GCA in PMR have not been clearly established and it is unclear if the pattern of vascular involvement on ultrasound differs from that seen in GCA.ObjectivesTo identify the characteristics of PMR patients that have subclinical GCA and to compare the ultrasound features of subclinical GCA in PMR to a GCA cohort.Methods58 newly diagnosed PMR patients who met a clinical diagnosis for PMR were examined with ultrasound of their temporal and axillary arteries at time of diagnosis. US of all 6 branches of the superficial temporal arteries and both axillary arteries was performed using a GE P9 device. Sonographic abnormalities considered indicative of vasculitis in the temporal arteries included the halo sign and non-compressible arteries with a thickened intima-media complex. In the axillary arteries, a halo sign, and an intima-media thickness of >1.0mm was considered positive. Clinical and laboratory characteristics were recorded. Halo scores were calculated for positive cases. Ultrasound findings were compared to a cohort of 57 GCA patients.ResultsOur cohort consisted of 58 patients with newly diagnosed PMR. The mean age was 68 years and 48% were male and 53% were female. ACR/EULAR classification criteria were met in 46/58 patients (primarily due to prior corticosteroid use in primary care resulting in normal ESR/CRP). 15 patients (25.8%) were identified as having subclinical GCA on ultrasound. Of these, 12 were male and 3 were female (p=0.0201). The mean ESR at baseline for those with isolated PMR was 35, compared to 53 for those with subclinical GCA (p=0.0419). The mean baseline ESR for our GCA cohort was 58. There was no significant difference in the baseline CRP levels, between those with subclinical GCA and isolated PMR (p=0.1150).The extent of involvement of the temporal and axillary arteries of the 58 patients in the subclinical GCA group was compared to a cohort of 57 GCA patients. The total halo count was the similar for both subclinical GCA and clinical GCA at 4.33 and 4.36. However, GCA patients had higher halo scores in both temporal and axillary vessels of 13.17 and 13.28 respectively, compared to those with subclinical GCA with scores of 5 and 9.6.Table 1.Isolated PMR (43)Subclinical GCA (15)GCA (57)Age (mean + range)67 (50-84)70 (53-84)74 (56-92)Female27324Male161233BMI28.327.927.8Mean ESR at baseline (mm/h)355358Mean CRP at baseline (mg/l)244066Mean Halo count04.334.36Mean temporal artery halo score0513.17Mean axillary artery halo score09.6013.28ConclusionPMR patients with subclinical GCA have a similar halo count to patients with clinical GCA suggesting a similar pattern of vascular involvement. However, those with clinical GCA have higher halo scores indicating more advanced vessel oedema which may be a key factor in causing headache symptoms. Male gender and a higher ESR at the time of PMR diagnosis appear to be risk markers for subclinical GCA though this requires analysis in larger cohorts of patients.Reference[1]Hemmig, A.K., et al.,Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.Semin Arthritis Rheum, 2022.55: p. 152017.Acknowledgements:NIL.Disclosure of InterestsSharon Cowley: None declared, Colm Kirby: None declared, Patricia Harkins Grant/research support from: Janssen, Ronan Mullan: None declared, Richard Conway: None declared, Grainne Murphy: None declared, David Kane: None declared.