Pentoxifylline as a New Adjuvant in Adult Patients With Major Depressive Disorder: Randomized, Double Blind, Placebo Controlled Trial.
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Mahmoud Samy Abdallah

 
 
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  Tanta University
 
 
 
Faculty of Pharmacy 
 
Clinical Pharmacy Department  
                                 
 
Role of pentoxifylline as an adjuvant therapy in  
treatment of adult patients with major depressive disorder 
 
A proposal submitted for partial fulfillment of Doctor of Philisophy degree in Pharmacy 
(Clinical Pharmacy) 
 
By
 
 
Mahmoud Samy Abdallah Mohamed
 
 
M.Sc. in Pharmaceutical Science (Clinical Pharmacy), Tanta University, 2014
 
 
Under supervision of:
 
 
                       Dr.                                                                      Prof. Dr.                 
 
  Mai Abdel-Raouf Eissa
 
     Sahar Mohamed El-Haggar                               
 
 Assistant professor of Clinical Pharmacy,                             Professor of Neuropsychiatry,
 
Faculty of Medicine,
 
                       Faculty of Pharmacy,                                         
 
                    Tanta University.                                                             Tanta Univrsity.                    
                             
 
   Dr.                                                                         Dr.                             
 
     Khaled Sabry El-Attar                                         Tarek Mohammed Mostafa
 
Counsellor of Psychiatry                                                    Lecturer of Clinical pharmacy,       
 
Armed Commander of Military Psychiatry hospital                           Faculty of Pharmacy,  
 
                                                                                              Tanta University.
 
  
 
April, 2015 
 
 

 
 
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Introduction 
 
Major depressive disorder (MDD) is a common and sometimes fatal disorder that is a leading cause of disability 
worldwid (1). Available antidepressant medications, which largely target monoamine and serotonin pathways, are 
effective; however, more than 33% of depressed patients fail to achieve remission despite multiple treatment 
trials (2).  
 
Chronic inflammation has been implicated in the pathophysiology of MDD (3-5). It has been established that pro-
inflammatory cytokines such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-α (TNF-α) induce not only 
symptoms of sickness, but also true major depressive disorders in physically ill patients with no previous history 
of mental disorders (6, 7). Changes regarding the immune system and specifically the cytokine system in which 
TNF-α is a pro-inflammatory key signalling molecule have been shown to be involved in the development of 
psychiatric disorders (8-10). TNF-α might contribute to the pathogenesis of depression, it reduces the production of 
central serotonin (5-HT) neurotransmitter by stimulating the enzyme indoleamine 2,3-dioxygenase (IDO), which 
converts tryptophan, the precursor of 5-HT, into kynurenine. Overstimulation of IDO lead to depletion of 
tryptophan and, therefore, reduces synthesis of 5-HT in the brain (11, 12). In addition, a growing body of evidence 
also points to increased oxidative stress in MDD. Elevated plasma level of oxidative stress markers were found 
in patients with MDD (e.g., increased 8-hydroxydeoxyguanosine [8-OHdG] or F2-isoprostanes (13). 
 
Pentoxifylline (PTX), a methylxanthine-derivative and nonspecific phosphodiesterase inhibitor with combined 
anti-inflammatory and antifibrogenic properties (14), can lower the levels of circulating proinflammatory 
cytokines, such as TNF-α, IL-1β and IL-6, by means of a cyclic adenosine monophosphate (cAMP)-dependent 
mechanism (15). Furthermore, pentoxifylline has been proposed to have antioxidant properties (15). Moreover, 
pentoxifylline facilitates synthesis and release of serotonin and inhibits its uptake, suggesting that pentoxifylline 
enhances serotonergic presynaptic response in the CNS (16). In addition, it showed antidepressive-like effects in a 
rat model of acute myocardial infarction (17). 
 
 
 
 
 
 
 

 
 
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Aim of the study 
 
The aim of the current study is to evaluate the potential antidepressant effect of pentoxifylline in adult patients 
with MDD. We hypothesized that MDD patients taking pentoxifylline as adjuvant would present greater 
amelioration of their depressive symptoms than patients taking placebo. Furthermore, we will assess the 
relationship between HAM-D score and several peripheral biomarkers as well as their role in diagnosis and 
therapeutic targets of MDD. 
 
Patients and methods 
 
Eighty adult outpatients who will meet the diagnostic and statistical manual of mental disorder IV (DSM-IV) 
criteria for major depression will be participated in the trial (18). Patients will be recruited from the armed 
psychiatry hospital, Egypt. Patients have a baseline Hamilton Rating Scale for Depression (Ham-D) score of at 
least 18 (19). Patients will be allocated in a random fashion: 40 patients will receive escitalopram 20 mg/day plus 
placebo (Control group) and 40 patients will receive escitalopram 20 mg/day plus pentoxifylline 800 mg/day 
(400mg bid) (morning and evening). Treatment duration will be 12 weeks. Adherence to the study medication 
will be assessed by collecting the empty blister packs of the consumed drugs from the patients every 4 weeks. 
Patients will be assessed by a psychiatrist at baseline, 4, 8, and 12 weeks after starting the medication. Any 
unexpected risks appeared during the course of the research will be cleared to participants and the ethical 
committee on time. An informed consent will be obtained from all participants in this research. 
 
Measurements: 
 
1. Full patient history, demographic data and clinical examination. 
2. Patients will be assessed by a psychiatrist at baseline, 4, 8, and 12 weeks after starting the medication. 
The principal measure of the outcome will be the 17-item Ham-D. Remission is defined as an endpoint 
Ham-D total score < or = 7. Treatment response is defined as at least 50% improvement during the study 
period in the Ham-D scale. The mean decrease in Ham-D score from baseline will be the main outcome 
measure of response of depression to treatment (Primary outcome).  
3. Questinnaire to evaluate the side effects of the study medications. 
4. Biological markers (Secondary outcome): Blood sample collection at baseline and after the treatment 
to evaluate the following: 
i) Serum level of Brain-derived Neurotrophic Factor (BDNF) 
ii) Serum Serotonin level 
iii) Serum levels of the following proinflammatory and anti-inflammatory markers: 
 Tumor necrosis factor-alpha (TNF-a) 

 
 
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 Interlukin-6 (IL-6) 
 Interlukin-10 (IL-10) 
iv) Serum levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative damage. 
 
 
Inclusion criteria: 
1- Eighty adult outpatients with the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-
IV) diagnosis of MDD based on a MINI Neuropsychiatric Interview (MINI) (American Psychiatric 
Association., 2000; Sheehan et al., 1998), without psychotic features and a total 17 item HAM-D 
score of at least 18 with item 1 (depressed mood) scored 2 or greater were eligible. 
2- Patients were requested to be free of all the psychotropic and anti-inflammatory medications for at 
least 4 weeks before participating in the study. 
 
Exclusion criteria: 
1. Patients with bipolar I or bipolar II disorder 
2. Patients with personality disorders 
3. Patients with eating disorders 
4. Patients with substance dependence or abuse 
5. Patients with concurrent active medical condition 
6. Patients with history of seizures 
7. Patients with history of receiving Electroconvulsive therapy (ECT) 
8. Patients with inflammatory disorders 
9. Patients with allergy or contraindications to the used medications 
10. Patients with finally pregnant or lactating females 
Statistical analysis:
 
All tests of treatment effect will be conducted by external statistician blind to group allocation, at a 
two-sided significance level of 0.05, and no adjustments were made for multiple comparisons. Type III 
sums of squares will be used to adjust for unbalanced data in the interactions of these models of 
variance. Importantly, general linear model for analysis of covariance (ANCOVA) model will be used 
for the primary analysis of change from baseline to endpoint in HAM-D total score. The primary 
analysis was performed using a mixed-effects model repeated measures (MMRM) ANCOVA. As a 
sensitivity analysis, will be carried out using the last observation carried forward (LOCF) approach in 
case of dropouts. Furthermore, a two-way repeated measures analysis of variance (ANOVA) for HAM-
D score (time–treatment interaction) will be used. The two groups as a between-subjects factor (group) 
and the four time interval measurements during treatment as the within-subjects factor (time) will be 

 
 
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considered. Moreover, repeated measures ANOVA will be used to test the time x group interaction on 
the changes in the biomarkers between baseline and week 12 in the two groups. Chi square test was 
used for the qualitative variables. The statistical analysis was performed with IBM©SPSS® Statistics V 
22. Pearson’s correlation will be calculated to assess the relationship among variables. 
References: 
 
1- Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic diseases, and decrements in health: 
results from the World Health Surveys. Lancet. 2007; 370(9590): 851-8. 
2- Miller AH, Maletic V, and Raison CL. Inflammation and its discontents: the role of cytokines in the 
pathophysiology of major depression. Biological Psychiatry. 2009; 65(9):732-41.  
3- Berk M, Kapczinski F, Andreazza AC, et al. Pathways underlying neuroprogression in bipolar 
disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neuroscience & 
Biobehavioral Reviews. 2011; 35(3): 804–17. 
4- Capuron L and Miller AH. Immune system to brain signaling: neuropsychopharmacological 
implications.Pharmacology & Therapeutics. 2011; 130(2):226-38.  
5- Himmerich H, Fulda S, Linseisen J, et al. Depression, comorbidities and the TNF-alpha system. 
European Psychiatry. 2008; 23(6):421-9.  
6- Krügel U, Fischer J, Radicke S, et al. Antidepressant effects of TNF-α blockade in an animal model of 
depression. Journal of Psychiatric Research. 2013; 47(5):611-6. 
7- Slavich GM and Irwin MR. From stress to inflammation and major depressive disorder: a social signal 
transduction theory of depression. Psychological bulletin. 2014; 140(3):774-815.  
8- Himmerich H, Berthold-Losleben M, and Pollmächer T. The relevance of the TNF-alpha system in 
psychiatric disorders. Fortschritte der Neurologie - Psychiatrie. 2009; 77(6):334-45.  
9- Himmerich H, Fulda S, Linseisen J, et al. Depression, comorbidities and the TNF-alpha system. 
European Psychiatry. 2008; 23(6):421-9.  
10- Schmidt FM, Kirkby KC, and Himmerich H. The TNF-alpha inhibitor etanercept as monotherapy in 
treatment-resistant depression - report of two cases. Psychiatria Danubina. 2014; 26(3):288-90. 

 
 
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11- Reichenberg A, Kraus T, Haack M, et al. Endotoxin-induced changes in food consumption in healthy 
volunteers are associated with TNF-alpha and IL-6 secretion. Psychoneuroendocrinology. 2002; 
27(8):945-56. 
12- 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. Journal of the American Medical Association psychiatry. 2014; 71(12):1381-91.  
13- Rawdin BJ, Mellon SH, Dhabhar FS, et al. Dysregulated relationship of inflammation and oxidative 
stress in major depression. Brain, behavior, and immunity. 2013; 31:143-52.  
14- Gutierrez-Reyes G, Lopez-Ortal P, Sixtos S, et al. Effect of pentoxifylline on levels of pro-
inflammatory cytokines during chronic hepatitis C. Scandinavian Journal of Immunology. 2006; 
63(6):461-7. 
15- Akhondzadeh S, Fallah J, Mohammadi MR, et al. Double-blind placebo-controlled trial of 
pentoxifylline added to risperidone: effects on aberrant behavior in children with autism. Progress in 
Neuro-psychopharmacology & Biological Psychiatry. 2010; 34(1):32-6.  
16- Gupta S. Immunological treatments for autism. Journal of Autism and Developmental Disorders. 2000; 
30:475–9. 
17- Bah TM, Kaloustian S, Rousseau G, and Godbout R. Pretreatment with pentoxifylline has 
antidepressant-like effects in a rat model of acute myocardial infarction. Behavioural Pharmacology. 
2011; 22(8):779-84. 
18- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text 
Revision. Washington, DC: American Psychiatric Association; 2000. 
19- Hamilton M. A rating scale for depression. Journal of Neurology, Neurosurgery & Psychiatry.1960; 
23:56-62.