Pharmacopsychiatry
DOI: 10.1055/a-2291-7204
Original Paper

Pentoxifylline as a Novel Add-on Therapy for Major Depressive Disorder in Adult Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

Talar A. Merza Mohammad
1   Department of Clinical Pharmacy, College of Pharmacy, Hawler Medical University, Kurdistan Region-Erbil, Iraq
,
Tavgah A. Merza Mohammad
2   University of Sulaimani, College of Nursing, Department of Community Health Nursing, Kurdistan Region-Erbil, Iraq
,
Dyar M. Salman
1   Department of Clinical Pharmacy, College of Pharmacy, Hawler Medical University, Kurdistan Region-Erbil, Iraq
3   Tishk International University, Faculty of Pharmacy, Kurdistan Region-Erbil, Iraq
,
Halmat M. Jaafar
1   Department of Clinical Pharmacy, College of Pharmacy, Hawler Medical University, Kurdistan Region-Erbil, Iraq
› Institutsangaben
Funding This study did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Abstract

Background Evidence indicates an association between immune dysregulation and major depressive disorder (MDD). Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to reduce pro-inflammatory activities. The aim of this study was to evaluate changes in depressive symptoms and pro-inflammatory markers after administration of PTX as an adjunctive agent to citalopram in patients with MDD.

Methods One hundred patients were randomly assigned to either citalopram (20 mg/day) plus placebo (twice daily) (n=50) or citalopram (20 mg/day) plus PTX (400 mg) (twice daily) (n=50). The Hamilton Depression Rating Scale-17 (HAM-D-17) scores at baseline, weeks 2, 4, 6, 8, 10, and 12 and serum levels of interleukin1-β (IL-1-β), tumor necrosis factor-α, C-reactive protein, IL-6, serotonin, IL-10, and brain-derived neurotrophic factor (BDNF) at baseline and week 12 were evaluated.

Results HAM-D-17 score in the PTX group significantly reduced in comparison to the control group after weeks 4, 6, 8,10, and 12 ((LSMD): − 2.193, p=0.021; − 2.597, p=0.036; − 2.916, p=0.019; − 4.336, p=0.005; and − 4.087, p=0.008, respectively). Patients who received PTX had a better response (83%) and remission rate (79%) compared to the placebo group (49% and 40%, p=0.006 and p=0.01, respectively). Moreover, the reduction in serum concentrations of pro-inflammatory factors and increase in serotonin and BDNF in the PTX group was significantly greater than in the placebo group (p<0.001).

Conclusion These findings support the safety and efficacy of PTX as an adjunctive antidepressant agent with anti-inflammatory effects in patients with MDD.



Publikationsverlauf

Eingereicht: 28. Januar 2024
Eingereicht: 10. März 2024

Angenommen: 11. März 2024

Artikel online veröffentlicht:
06. Mai 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Malhi GS, Mann JJ. Depression. Lancet 2018; 392: 2299-2312
  • 2 Cuijpers P, van Straten A, Warmerdam L. et al. Psychotherapy versus the combination of psychotherapy and pharmacotherapy in the treatment of depression: A meta-analysis. Depress Anxiety 2009; 26: 279-288
  • 3 Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008; 358: 55-68
  • 4 Judd LL, Akiskal HS, Zeller PJ. et al. Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch Gen Psychiatry 2000; 57: 375-380
  • 5 Wells KB, Stewart A, Hays RD. et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA 1989; 262: 914-919
  • 6 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: 1905-1917
  • 7 Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med 2007; 357: 1939-1945
  • 8 Park LT, Zarate CA. Depression in the primary care setting. N Engl J Med 2019; 380: 559-568
  • 9 Cipriani A, Furukawa TA, Salanti G. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet 2018; 391: 1357-1366
  • 10 Osimo EF, Pillinger T, Rodriguez IM. et al. Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behav Immun 2020; 87: 901-909
  • 11 Khandaker GM, Pearson RM, Zammit S. et al. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: A population-based longitudinal study. JAMA Psychiatry 2014; 71: 1121-1128
  • 12 Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: A systematic review and meta-analysis of longitudinal studies. J Affect Disord 2013; 150: 736-744
  • 13 Frank P, Jokela M, Batty GD. et al. Association between systemic inflammation and individual symptoms of depression: A pooled analysis of 15 population-based cohort studies. A J Psychiatry 2021; 178: 1107-1118
  • 14 Milaneschi Y, Kappelmann N, Ye Z. et al. Association of inflammation with depression and anxiety: Evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts. Mol Psychiatry 2021; 26: 7393-7402
  • 15 Miller AH, Maletic V, Raison CL. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732-741
  • 16 Papakostas GI, Shelton RC, Kinrys G. et al. Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: A pilot and replication study. Mol Psychiatry 2013; 18: 332-339
  • 17 Lanquillon S, Krieg JC, Bening-Abu-Shach U. et al. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 2000; 22: 370-379
  • 18 Dantzer R. Role of the kynurenine metabolism pathway in inflammation-induced depression: Preclinical approaches. Curr Top Behav Neurosci 2017; 31: 117-138
  • 19 Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 2006; 31: 2121-2131
  • 20 Zhu CB, Lindler KM, Owens AW. et al. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 2010; 35: 2510-2520
  • 21 Brymer KJ, Romay-Tallon R, Allen J. et al. Exploring the potential antidepressant mechanisms of TNFα antagonists. Front Neurosci 2019; 13: 98-98
  • 22 Widner B, Laich A, Sperner-Unterweger B. et al. Neopterin production, tryptophan degradation, and mental depression--what is the link?. Brain Behav Immun 2002; 16: 590-595
  • 23 Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: Translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37: 137-162
  • 24 Neurauter G, Schröcksnadel K, Scholl-Bürgi S. et al. Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab 2008; 9: 622-627
  • 25 Koo JW, Russo SJ, Ferguson D. et al. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA 2010; 107: 2669-2674
  • 26 Haroon E, Miller AH. Inflammation effects on brain glutamate in depression: Mechanistic considerations and treatment implications. Curr Top Behav Neurosci 2017; 31: 173-198
  • 27 Köhler CA, Freitas TH, Stubbs B. et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: Systematic review and meta-analysis. Mol Neurobiol 2018; 55: 4195-4206
  • 28 El-Haggar SM, Eissa MA, Mostafa TM. et al. The phosphodiesterase inhibitor pentoxifylline as a novel adjunct to antidepressants in major depressive disorder patients: A proof-of-concept, randomized, double-blind, placebo-controlled trial. Psychother Psychosom 2018; 87: 331-339
  • 29 Liu JJ, Wei YB, Strawbridge R. et al. Peripheral cytokine levels and response to antidepressant treatment in depression: A systematic review and meta-analysis. Mol Psychiatry 2020; 25: 339-350
  • 30 Uzzan S, Azab AN. Anti-TNF-α compounds as a treatment for depression. Molecules 2021; 26 (8) 2368
  • 31 Aviado DM, Porter JM. Pentoxifylline: A new drug for the treatment of intermittent claudication. Mechanism of action, pharmacokinetics, clinical efficacy and adverse effects. Pharmacotherapy 1984; 4: 297-307
  • 32 Gutierrez-Reyes G, Lopez-Ortal P, Sixtos S. et al. Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C. Scand J Immunol 2006; 63: 461-467
  • 33 Alzoubi KH, Khabour OF, Ahmed M. Pentoxifylline prevents post-traumatic stress disorder induced memory impairment. Brain Res Bull 2018; 139: 263-268
  • 34 Bowton DL, Stump DA, Prough DS. et al. Pentoxifylline increases cerebral blood flow in patients with cerebrovascular disease. Stroke 1989; 20: 1662-1666
  • 35 Crouch SP, Fletcher J. Effect of ingested pentoxifylline on neutrophil superoxide anion production. Infect Immun 1992; 60: 4504-4509
  • 36 Bah TM, Kaloustian S, Rousseau G. et al. Pretreatment with pentoxifylline has antidepressant-like effects in a rat model of acute myocardial infarction. Behav Pharmacol 2011; 22: 779-784
  • 37 Adderley SP, Sprague RS, Stephenson AH. et al. Regulation of cAMP by phosphodiesterases in erythrocytes. Pharmacol Rep 2010; 62: 475-482
  • 38 Fernandes JL, de Oliveira RTD, Mamoni RL. et al. Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease--a randomized placebo-controlled study. Atherosclerosis 2008; 196: 434-442
  • 39 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: 22-33
  • 40 Vahia VN. Diagnostic and statistical manual of mental disorders 5: A quick glance. Indian J Psychiatry 2013; 55: 220-223
  • 41 Abbasi SH, Amirhossein FM, Shahin MA. 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: 308-314
  • 42 Park C, Rosenblat JD, Lee Y. et al. The neural systems of emotion regulation and abnormalities in major depressive disorder. Behav Brain Res 2019; 367: 181-188
  • 43 Rosenblat JD, McIntyre RS, Alves GS. et al. Beyond monoamines-novel targets for treatment-resistant depression: A comprehensive review. Curr Neuropharmacol 2015; 13: 636-655
  • 44 Toma S, MacIntosh BJ, Swardfager W. et al. Cerebral blood flow in bipolar disorder: A systematic review. J Affect Disord 2018; 241: 505-513
  • 45 Bech P, Gram LF, Dein E. et al. Quantitative rating of depressive states. Acta Psychiatr Scand 1975; 51: 161-170
  • 46 Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clin Sci (Lond) 2006; 110: 175-191
  • 47 Kim YK, Lee HP, Won SD. et al. Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 78-85
  • 48 Becker S, Wojtowicz JM. A model of hippocampal neurogenesis in memory and mood disorders. Trends Cogn Sci 2007; 11: 70-76
  • 49 Siegel AN, Rodrigues N, Nasri F. et al. Novel therapeutic targets in mood disorders: Pentoxifylline (PTX) as a candidate treatment. Prog Neuropsychopharmacol Biol Psychiatry 2021; 104: 110032
  • 50 Patas K, Penninx BW, Bus BA. et al. Association between serum brain-derived neurotrophic factor and plasma interleukin-6 in major depressive disorder with melancholic features. Brain Behav Immun 2014; 36: 71-79
  • 51 Felger JC, Lotrich FE. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience 2013; 246: 199-229
  • 52 Ma K, Zhang H, Baloch Z. Pathogenetic and therapeutic applications of tumor necrosis factor-α (TNF-α) in major depressive disorder: A systematic review. Int J Mol Sci 2016; 17 (5) 733
  • 53 Black CN, Bot M, Scheffer PG. et al. Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 2015; 51: 164-175
  • 54 Czarny P, Wigner P, Galecki P. et al. The interplay between inflammation, oxidative stress, DNA damage, DNA repair and mitochondrial dysfunction in depression. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80: 309-321
  • 55 Ohgi Y, Futamura T, Kikuchi T. et al. Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. Pharmacol Biochem Behav 2013; 103: 853-859
  • 56 Baumeister D, Ciufolini S, Mondelli V. Effects of psychotropic drugs on inflammation: Consequence or mediator of therapeutic effects in psychiatric treatment?. Psychopharmacology (Berl) 2016; 233: 1575-1589
  • 57 Elgarf AS, Aboul-Fotouh S, Abd-Alkhalek HA. et al. Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: Reversibility by imipramine and pentoxifylline. Pharmacol Biochem Behav 2014; 126: 152-162
  • 58 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: 607-611
  • 59 Raison CL, Rutherford RE, Woolwine BJ. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. JAMA Psychiatry 2013; 70: 31-41
  • 60 Griffiths CEM, Fava M, Miller AH. et al. Impact of ixekizumab treatment on depressive symptoms and systemic inflammation in patients with moderate-to-severe psoriasis: An integrated analysis of three phase 3 clinical studies. Psychother Psychosom 2017; 86: 260-267
  • 61 Fleischhacker WW, Hinterhuber H, Bauer H. et al. A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. Neuropsychobiology 1992; 26: 59-64
  • 62 Liao W, Wang Z, Zhang X. et al. Cerebral blood flow changes in remitted early- and late-onset depression patients. Oncotarget 2017; 8: 76214-76222
  • 63 Neves KR, Nobre HV, Leal LK. et al. Pentoxifylline neuroprotective effects are possibly related to its anti-inflammatory and TNF-alpha inhibitory properties, in the 6-OHDA model of Parkinson's disease. Parkinsons Dis 2015; 2015: 108179
  • 64 Valvassori SS, Bavaresco DV, Feier G. et al. Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes. Psychiatry Res 2018; 264: 192-201
  • 65 Farajollahi-Moghadam M, Sanjari-Moghaddam H, Ghazizadeh Hasemi M. et al. Efficacy and safety of pentoxifylline combination therapy in major depressive disorder: A randomized, double-blind, placebo-controlled clinical trial. Int Clin Psychopharmacol 2021; 36: 140-146
  • 66 Yasrebi S-O, Momtazmanesh S, Moghaddam HS. et al. Pentoxifylline for treatment of major depression after percutaneous coronary intervention or coronary artery bypass grafting: A randomized, double-blind, placebo-controlled trial. J Psychosom Res 2021; 150: 110635
  • 67 Nassar A, Azab AN. Effects of dexamethasone and pentoxifylline on mania-like and depression-like behaviors in rats. Pharmaceuticals 2022; 15: 1063