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

Abstract

Background: There is evidence for an association between major depressive disorder (MDD) and both inflammatory and phosphodiesterase (PDE) pathways. This study aimed to evaluate the adjunct role of the PDE inhibitor pentoxifylline (PTX), a compound with anti-inflammatory properties, in the treatment of adult patients with MDD. Methods: This was a prospective, 12-week, double-blind study of parallel groups. Eighty adult outpatients who met the DSM-IV criteria for MDD participated in the trial. Patients were required to have a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 18. Patients were allocated randomly: 40 received escitalopram 20 mg/day plus placebo while the other 40 received escitalopram 20 mg/day plus PTX (400 mg b.i.d.). Patients were assessed by a psychiatrist at baseline, and 4, 8, and 12 weeks after the medication had been started. The serum levels of TNF-α, IL-6, IL-10, BDNF, 8-OHdG, and serotonin were measured at baseline and after therapy. Results: After 8 and 12 weeks, the PTX group showed a statistically significantly greater improvement in HAM-D score compared to the control group (least squares mean difference [LSMD] –3.29, p = 0.000 and LSMD –3.49, p = 0.000, respectively). Moreover, the PTX group showed a statistically significantly greater reduction in the serum levels of TNF-α, IL-6, IL-10, and 8-OHdG along with a statistically significant increase in the levels of BDNF and serotonin in comparison with the control group after the treatment. Conclusion: The findings of this study suggest that PTX could be a promising adjunct to antidepressants in the treatment of MDD patients.

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“… 12 , 31 , 33 Regarding the response and remission rates in the placebo group, which were 65% and 50%, they were also comparable to the previously reported response and remission rates for monotherapy in two published studies, which were 58%–76%, and 27%–64%, respectively. 12 , 34 , 35…”

“…It has been reported that using combined medications at the beginning of the treatment of MDD patients may provide additional therapeutic benefits as ~50% of the patients do not respond to the first‐line antidepressants. 2 , 3 Although study designs make direct comparison a difficult issue, the response rate of 90% in the CLS combination group is consistent to that of previous studies (89%–92%) including simvastatin, 31 metformin, 32 or pentoxifylline 12 as adjuvant therapies in MDD patients over 6 and 12 weeks. Furthermore, the remission rate of 80% in our study is also consistent with the 59%–85% remission rates in the above‐mentioned trials.…”

“…9,10 On the other hand, cumulative evidence has shown that an increased inflammatory response of the central nervous system (CNS) plays a critical role in MDD pathophysiology. 11,12 Proinflammatory cytokines such as interleukin-1beta (IL-1β), IL-6, and tumor necrosis factorα (TNFα) are elevated in patients with MDD and decreased after therapy. [11][12][13][14] Furthermore, these cytokines can disrupt the synthesis of 5-hydroxytryptamin (5-HT) 15 and glutamatergic transmission, which are profoundly implicated in the pathophysiology MDD.…”

“… 11 , 12 Pro‐inflammatory cytokines such as interleukin‐1beta (IL‐1β), IL‐6, and tumor necrosis factor‐α (TNF‐α) are elevated in patients with MDD and decreased after therapy. 11 , 12 , 13 , 14 Furthermore, these cytokines can disrupt the synthesis of 5‐hydroxytryptamin (5‐HT) 15 and glutamatergic transmission, which are profoundly implicated in the pathophysiology MDD. 16 FAM19A5 is a novel peptide‐like chemokine that is highly expressed in the brain and developed during neurogenesis.…”

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“…Furthermore, inflammatory cytokines may influence astrocytes, leading to a reduction in glutamate reuptake and increase in its release, together with a decrease in the synthesis of brain-derived neurotrophic factor (BDNF), which has an impact on neuronal integrity and neurogenesis [7]. Recent clinical studies have demonstrated that patients with MDD have elevated serum levels of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukins IL-1b and IL-6 [8,9]. The results of these studies showed an improvement in mood and enhanced antidepressant response as a result of the suppression of cytokine signaling in MDD patients [10].…”