Exploratory Analysis of the Effects of Celecoxib on Cognitive Function in Vortioxetine-Treated Patients With Major Depressive Disorder in the PREDDICT Study: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Emma Sampson, BHlthSc(Honours); Natalie T. Mills, MBBS, PhD; Hikaru Hori, MD, PhD; Kathrin Schwarte, MTLA; Christa Hohoff, PhD; K. Oliver Schubert, MD, PhD; Scott R. Clark, MBBS, PhD; Célia Fourrier, PhD; Bernhard T. Baune, MD, PhD

J Clin Psychiatry 2023;84(6):23m14829

ABSTRACT

Objective: Major depressive disorder (MDD) remains difficult to treat, with many patients resistant to existing treatments or experiencing relapse. Cognitive dysfunction is associated with more severe clinical outcomes. Vortioxetine has shown efficacy in remediating depression-associated cognitive impairment. Anti-inflammatory augmentation of antidepressants is a new strategy in treating depression and has not previously been assessed for effects on cognition in depression.

Methods: Exploratory analyses were performed on secondary outcome cognitive data from the PREDDICT parallel-group, randomized, double-blind, placebo-controlled trial at the University of Adelaide (Australia). Participants (N = 119) with MDD (validated with Mini-International Neuropsychiatric Interview for DSM-IV) were treated with vortioxetine and celecoxib or vortioxetine and placebo for 6 weeks between December 2017 and April 2020. Measures included objective cognition composite scores (Choice Reaction Time, N-Back, Digit Symbol Substitution Test, Trail Making Task Part B), subjective cognition scores (Perceived Deficits Questionnaire), and global cognition composite scores (combined objective and subjective scores) derived from the THINC integrated tool (THINC-it). High-sensitivity C-reactive protein (hsCRP) measured at baseline and week 6 was tested for a predictive relationship with cognitive outcomes.

Results: Cognition composite scores demonstrated improvement by week 6 in both treatment groups. However, there was no significant interaction between change over time and treatment group. HsCRP did not have a significant relationship with any tested cognition measures.

Conclusions: Both treatment groups showed a reduction in depression-associated cognitive impairment. No superior clinical effect was reported for the add-on celecoxib group. HsCRP was modulated by neither vortioxetine nor add-on celecoxib.

Trial Registration: ANZCTR identifier: ACTRN12617000527369

J Clin Psychiatry 2023;84(6):23m14829

Author affiliations are listed at the end of this article.

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References (58)

World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. WHO; 2017.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. American Psychiatric Publishing; 2013.
Cambridge OR, Knight MJ, Mills N, et al. The clinical relationship between cognitive impairment and psychosocial functioning in major depressive disorder: a systematic review. Psychiatry Res. 2018;269:157–171. PubMed CrossRef
McIntyre RS, Soczynska JZ, Woldeyohannes HO, et al. The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project. Compr Psychiatry. 2015;56:279–282. PubMed CrossRef
Weightman MJ, Knight MJ, Baune BT. A systematic review of the impact of social cognitive deficits on psychosocial functioning in major depressive disorder and opportunities for therapeutic intervention. Psychiatry Res. 2019;274:195–212. PubMed CrossRef
Knight MJ, Baune BT. Cognitive dysfunction in major depressive disorder. Curr Opin Psychiatry. 2018;31(1):26–31. PubMed CrossRef
Knight MJ, Baune BT. Executive function and spatial cognition mediate psychosocial dysfunction in major depressive disorder. Front Psychiatry. 2018;9:539. PubMed CrossRef
Knight MJ, Fourrier C, Lyrtzis E, et al. Cognitive deficits in the THINC-Integrated Tool (THINC-it) are associated with psychosocial dysfunction in patients with major depressive disorder. J Clin Psychiatry. 2018;80(1):18m12472. PubMed CrossRef
Knight MJ, Lyrtzis E, Baune BT. The association of cognitive deficits with mental and physical quality of life in major depressive disorder. Compr Psychiatry. 2020;97:152147. PubMed CrossRef
Pu S, Setoyama S, Noda T. Association between cognitive deficits and suicidal ideation in patients with major depressive disorder. Sci Rep. 2017;7(1):11637. PubMed CrossRef
Roca M, Vives M, López-Navarro E, et al. Cognitive impairments and depression: a critical review. Actas Esp Psiquiatr. 2015;43(5):187–193. PubMed
Prévot T, Sibille E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry. 2021;26(1):151–167. PubMed CrossRef
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917. PubMed CrossRef
Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21(12):1696–1709. PubMed CrossRef
Knight MJ, Mills NT, Baune BT. Contemporary methods of improving cognitive dysfunction in clinical depression. Expert Rev Neurother. 2019;19(5):431–443. PubMed CrossRef
Chiu WC, Su YP, Su KP, et al. Recurrence of depressive disorders after interferon-induced depression. Transl Psychiatry. 2017;7(2):e1026. PubMed CrossRef
Fourrier C, Singhal G, Baune BT. Neuroinflammation and cognition across psychiatric conditions. CNS Spectr. 2019;24(1):4–15. PubMed CrossRef
Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71(12):1381–1391. PubMed CrossRef
Abbasi SH, Hosseini F, Modabbernia A, et al. Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord. 2012;141(2–3):308–314. PubMed CrossRef
Akhondzadeh S, Jafari S, Raisi F, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety. 2009;26(7):607–611. PubMed CrossRef
Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11(7):680–684. PubMed CrossRef
Hashemian F, Majd M, Hosseini S, et al. A randomized, double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in the treatment of a drug-naive women with major depression. Klin Psikofarmakol Bul. 2011;21:S183–S184.
Rosenblat JD, Kakar R, McIntyre RS. The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials. Int J Neuropsychopharmacol. 2015;19(2):pyv082. PubMed CrossRef
Skvarc DR, Berk M, Byrne LK, et al. Post-operative cognitive dysfunction: an exploration of the inflammatory hypothesis and novel therapies. Neurosci Biobehav Rev. 2018;84:116–133. PubMed CrossRef
Fourrier C, Sampson E, Mills NT, et al. Anti-inflammatory treatment of depression: study protocol for a randomised controlled trial of vortioxetine augmented with celecoxib or placebo. Trials. 2018;19(1):447. PubMed CrossRef
Baune BT, Sampson E, Louise J, et al. No evidence for clinical efficacy of adjunctive celecoxib with vortioxetine in the treatment of depression: a 6-week double-blind placebo controlled randomized trial. Eur Neuropsychopharmacol. 2021;53:34–46. PubMed CrossRef
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22–33, quiz 34–57. PubMed
Mills NT, Sampson E, Fourrier C, et al. Clinical switching strategies of various antidepressants to vortioxetine in the PREDDICT trial. Int J Neuropsychopharmacol. 2020;24(4):314–321. PubMed
McIntyre RS, Best MW, Bowie CR, et al. The THINC-Integrated Tool (THINC-it) screening assessment for cognitive dysfunction: validation in patients with major depressive disorder. J Clin Psychiatry. 2017;78(7):873–881. PubMed CrossRef
Smith EE. Choice reaction time: an analysis of the major theoretical positions. Psychol Bull. 1968;69(2):77–110. PubMed CrossRef
Owen AM, McMillan KM, Laird AR, et al. N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp. 2005;25(1):46–59. PubMed CrossRef
Baune BT, Brignone M, Larsen KG. A network meta-analysis comparing effects of various antidepressant classes on the digit symbol substitution test (DSST) as a measure of cognitive dysfunction in patients with major depressive disorder. Int J Neuropsychopharmacol. 2018;21(2):97–107. PubMed CrossRef
Reitan RM. The relation of the trail making test to organic brain damage. J Consult Psychol. 1955;19(5):393–394. PubMed CrossRef
OECD JRC European Commission. Handbook on Constructing Composite Indicators: Methodology and User Guide. OECD Publishing; 2008.
Mazziotta M, Pareto A. Normalization methods for spatio-temporal analysis of environmental performance: revisiting the Min-Max method. Environmetrics. 2022;33(5):e2730. CrossRef
Rosenberg JM, Beymer PN, Anderson DJ, et al. tidyLPA: an R package to easily carry out latent profile analysis (LPA) using open-source or commercial software. J Open Source Softw. 2018;3(30):978. CrossRef
Dziak JJ, Dierker LC, Abar B. The interpretation of statistical power after the data have been gathered. Curr Psychol. 2020;39(3):870–877. PubMed CrossRef
Molenberghs G, Thijs H, Jansen I, et al. Analyzing incomplete longitudinal clinical trial data. Biostatistics. 2004;5(3):445–464. PubMed CrossRef
Bates D, Maechler M, Bolker B, et al. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67(1):1–48. CrossRef
Kuznetsova A, Brockhoff PB, Christensen RHB. {lmerTest} package: tests in linear mixed effects models. J Stat Softw. 2017;82(13):1–26. CrossRef
Australian Qualifications Framework Council. Australian Qualifications Framework Second Edition January 2013. Australian Qualifications Framework Council; 2013.
Iovieno N, Papakostas GI, Feeney A, et al. Vortioxetine versus placebo for major depressive disorder: a comprehensive analysis of the clinical trial dataset. J Clin Psychiatry. 2021;82(4):20r13682. PubMed CrossRef
Bang-Andersen B, Ruhland T, Jørgensen M, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011;54(9):3206–3221. PubMed CrossRef
Dale E, Zhang H, Leiser SC, et al. Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus. J Psychopharmacol. 2014;28(10):891–902. PubMed CrossRef
Dale E, Grunnet M, Pehrson AL, et al. The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT₃ receptor expressing interneurons: an in vitro study in rat hippocampus slices. Brain Res. 2018;1689:1–11. PubMed CrossRef
Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45(9):1085–1098. PubMed CrossRef
Campbell S, Marriott M, Nahmias C, et al. Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry. 2004;161(4):598–607. PubMed CrossRef
Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 2002;25(3):154–159. PubMed CrossRef
Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–487. PubMed CrossRef
Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–795. PubMed CrossRef
Talmon M, Rossi S, Pastore A, et al. Vortioxetine exerts anti-inflammatory and immunomodulatory effects on human monocytes/macrophages. Br J Pharmacol. 2018;175(1):113–124. PubMed CrossRef
Hayley S, Hakim AM, Albert PR. Depression, dementia and immune dysregulation. Brain. 2021;144(3):746–760. PubMed CrossRef
Capone ML, Tacconelli S, Di Francesco L, et al. Pharmacodynamic of cyclooxygenase inhibitors in humans. Prostaglandins Other Lipid Mediat. 2007;82(1-4):85–94. PubMed CrossRef
Benhamou M, Gossec L, Dougados M. Clinical relevance of C-reactive protein in ankylosing spondylitis and evaluation of the NSAIDs/coxibs’ treatment effect on C-reactive protein. Rheumatology (Oxford). 2010;49(3):536–541. PubMed CrossRef
Gong L, Thorn CF, Bertagnolli MM, et al. Celecoxib pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22(4):310–318. PubMed CrossRef
Maes M. Targeting cyclooxygenase-2 in depression is not a viable therapeutic approach and may even aggravate the pathophysiology underpinning depression. Metab Brain Dis. 2012;27(4):405–413. PubMed CrossRef
Chang HH, Lee IH, Gean PW, et al. Treatment response and cognitive impairment in major depression: association with C-reactive protein. Brain Behav Immun. 2012;26(1):90–95. PubMed CrossRef
Lane P. Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharm Stat. 2008;7(2):93–106. PubMed CrossRef