Glyceryl trinitrate in first-episode psychosis unmedicated with antipsychotics: A randomised controlled pilot study

Kate Merritt, Ana Catalan, Samuel Cowley, Arsime Demjaha, Matthew Taylor, Philip McGuire, Ruth Cooper, Paul Morrison, Kate Merritt, Ana Catalan, Samuel Cowley, Arsime Demjaha, Matthew Taylor, Philip McGuire, Ruth Cooper, Paul Morrison

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.

Keywords: Clinical trial; glyceryl trinitrate; psychosis; schizophrenia; sodium nitroprusside.

Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MT reports personal fees from Lundbeck, Sunovion, and Otsuka, outside the submitted work. KM, AC, SC, AD, PM, RC and PM declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
CONSORT flow diagram of participant recruitment.
Figure 2.
Figure 2.
(a) Individual patient PANSS positive scores plotted over time. The change in PANSS positive score over time did not differ between treatment groups. Graphs are split based on treatment arm; the left panel shows patients receiving placebo, the right panel shows patients receiving GTN. (b) Number of words viewed by each participant during the JTC task over time (mean of three trials on each day). Only one participant demonstrated jumping to conclusions by viewing three or fewer words at baseline. Group mean at each visit is shown in black, grey ribbon indicates between-subjects standard error.

References

    1. Bond A, Lader M. (1974) The use of analogue scales in rating subjective feelings. Br J Clin Psychol 47: 211–218.
    1. Brown HE, Freudenreich O, Fan X, et al. (2019) Efficacy and tolerability of adjunctive intravenous sodium nitroprusside treatment for outpatients with schizophrenia. JAMA Psychiatry 76: 691–699.
    1. Bujas-Bobanovic M, Bird DC, Robertson HA, et al. (2000) Blockade of phencyclidine-induced effects by a nitric oxide donor. Br J Pharmacol 130: 1005–1012.
    1. Catalan A, Simons CJ, Bustamante S, et al. (2015) Data gathering bias: Trait vulnerability to psychotic symptoms? PLoS One 10: e0132442.
    1. De Hert M, Detraux J, van Winkel R, et al. (2012) Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 8: 114–126.
    1. Dienes Z. (2014) Using Bayes to get the most out of non-significant results. Front Psychol 5: 781.
    1. Divakaran S, Loscalzo J. (2017) The role of nitroglycerin and other nitrogen oxides in cardiovascular therapeutics. J Am Coll Cardiol 70: 2393–2410.
    1. Dudley RE, John CH, Young AW, et al. (1997) Normal and abnormal reasoning in people with delusions. Br J Clin Psychol 36: 243–258.
    1. Egerton A. (2019) The potential of 1H-MRS in CNS drug development. Psychopharmacology (Berl). Epub ahead of print 5 September 2019. DOI: 10.1007/s00213-019-05344-7.
    1. Eldridge SM, Chan CL, Campbell MJ, et al. (2016) CONSORT 2010 statement: Extension to randomised pilot and feasibility trials. Pilot Feasibility Stud 2: 64.
    1. Faraone SV, Biederman J, Spencer TJ, et al. (2000) The drug-placebo response curve: A new method for assessing drug effects in clinical trials. J Clin Psychopharmacol 20: 673–679.
    1. Fleischhacker WW, Czobor P, Hummer M, et al. (2003) Placebo or active control trials of antipsychotic drugs? Arch Gen Psychiatry 60: 458–464.
    1. Garety P, Joyce E, Jolley S, et al. (2013) Neuropsychological functioning and jumping to conclusions in delusions. Schizophr Res 150: 570–574.
    1. Gill KM, Cook JM, Poe MM, et al. (2014) Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia. Schizophr Bull 40: 341–350.
    1. Hallak JE, Maia-de-Oliveira JP, Abrao J, et al. (2013. a) Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: A randomized, double-blind, placebo-controlled trial. JAMA Psychiatry 70: 668–676.
    1. Hallak JE, Maia-de-Oliveira JP, Abrao J, et al. (2013. b) Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: A randomized, double-blind, placebo-controlled trial. JAMA Psychiatry 70: 668–676.
    1. Hoyt KR, Tang L-H, Aizenman E, et al. (1992) Nitric oxide modulates NMDA-induced increases in intracellular Ca2+ in cultured rat forebrain neurons. Brain Res 592: 310–316.
    1. Ivanova A, Qaqish B, Schoenfeld DA. (2011) Optimality, sample size, and power calculations for the sequential parallel comparison design. Stat Med 30: 2793–2803.
    1. JASP Team (2019) JASP (Version 0.10.2). Available at:
    1. Javitt DC, Zukin SR. (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148: 1301–1308.
    1. Jeffreys H. (1998) Theory of Probability. Oxford: Clarendon Press.
    1. Kay SR, Fiszbein A, Opler LA. (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 13: 261–276.
    1. Lacro JP, Dunn LB, Dolder CR, et al. (2002) Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: A comprehensive review of recent literature. J Clin Psychiatry 63: 892–909.
    1. Lancaster GA, Dodd S, Williamson PR. (2004) Design and analysis of pilot studies: Recommendations for good practice. J Eval Clin Pract 10: 307–312.
    1. Leucht S, Arbter D, Engel RR, et al. (2009) How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14: 429–447.
    1. Leucht S, Hierl S, Kissling W, et al. (2012. a) Putting the efficacy of psychiatric and general medicine medication into perspective: Review of meta-analyses. Br J Psychiatry 200: 97–106.
    1. Leucht S, Tardy M, Komossa K, et al. (2012. b) Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: A systematic review and meta-analysis. Lancet 379: 2063–2071.
    1. Lieberman JA. (2007) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: Efficacy, safety and cost outcomes of CATIE and other trials. J Clin Psychiatry 68(2): e04.
    1. Maia-De-Oliveira JP, Baker GB, Dursun SM, et al. (2017, April 1) Letter to the editor: Sodium nitroprusside for schizophrenia: Could methodological variables account for the different results obtained? Psychol Med 47: 981–982.
    1. Manzoni O, Prezeau L, Desagher S, et al. (1992) Sodium nitroprusside blocks NMDA receptors via formation of ferrocyanide ions. Neuroreport 3: 77–80.
    1. McLean BF, Mattiske JK, Balzan RP. (2016) Association of the jumping to conclusions and evidence integration biases with delusions in psychosis: A detailed meta-analysis. Schizophr Bull 43: 344–354.
    1. Menon M, Mizrahi R, Kapur S. (2008) “Jumping to conclusions” and delusions in psychosis: Relationship and response to treatment. Schizophr Res 98: 225–231.
    1. Menon M, Pomarol-Clotet E, McKenna PJ, et al. (2006) Probabilistic reasoning in schizophrenia: A comparison of the performance of deluded and nondeluded schizophrenic patients and exploration of possible cognitive underpinnings. Cogn Neuropsychiatry 11: 521–536.
    1. Merritt K, Egerton A, Kempton MJ, et al. (2016) Nature of glutamate alterations in schizophrenia a meta-analysis of proton magnetic resonance spectroscopy studies. JAMA Psychiatry 73: 665–674.
    1. Morrison AP, Law H, Carter L, et al. (2018) Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: A randomised controlled pilot and feasibility study. Lancet Psychiatry 5: 411–423.
    1. Pitsikas N. (2015) The role of nitric oxide donors in schizophrenia: Basic studies and clinical applications. Eur J Pharmacol 766: 106–113.
    1. Quintana DS, Williams DR. (2018) Bayesian alternatives for common null-hypothesis significance tests in psychiatry: A non-technical guide using JASP. BMC Psychiatry 18: 178.
    1. R Core Team (2014) R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing.
    1. Ripke S, Neale BM, Corvin A, et al. (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511: 421–427.
    1. Rummel-Kluge C, Komossa K, Schwarz S, et al. (2010) Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis. Schizophr Res 123: 225–233.
    1. Samara MT, Nikolakopoulou A, Salanti G, et al. (2019) How many patients with schizophrenia do not respond to antipsychotic drugs in the short term? An analysis based on individual patient data from randomized controlled trials. Schizophr Bull 45: 639–646.
    1. Shapiro AM, Benedict RH, Schretlen D, et al. (1999) Construct and concurrent validity of the Hopkins Verbal Learning Test – Revised. Clin Neuropsychol 13: 348–358.
    1. Stone JM. (2011) Glutamatergic antipsychotic drugs: a new dawn in the treatment of schizophrenia? Ther Adv Psychopharmacol 1: 5–18.
    1. Stone JM, Morrison PD, Koychev I, et al. (2016) The effect of sodium nitroprusside on psychotic symptoms and spatial working memory in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. Psychol Med 46: 3443–3450.
    1. Wang X, Zhao J, Hu Y, et al. (2018) Sodium nitroprusside treatment for psychotic symptoms and cognitive deficits of schizophrenia: A randomized, double-blind, placebo-controlled trial. Psychiatry Res 269: 271–277.
    1. Wickham H. (2009) Ggplot2: Elegant Graphics for Data Analysis. Available at:

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj