How to Improve Methodological Issues in Clinical Trials to Confirm that Pentoxifylline is Useful as an Add-on Therapy for Major Depressive Disorder

Dear editors,

The article authored by Mohammad et al. [1], published in Pharmacopsychiatry in July 2024, presents preliminary evidence on the impact of pentoxifylline (PTX) in alleviating depressive symptoms, improving patientsʼ quality of life, and assessing potential adverse effects. Investigating this novel therapeutic approach is essential for broadening the treatment options available to patients with major depressive disorder (MDD) and for advancing strategies to manage this complex condition. However, certain aspects of the study require careful consideration to strengthen the findings and facilitate more comprehensive discussions in future research.

Firstly, the paper mentions that patients were admitted to the hospital, but it does not specify whether they were inpatients or outpatients. Clarifying the treatment setting is crucial, as it provides context for evaluating the severity of the depression being treated.

Secondly, considering that patients in both the control group and the PTX group had numerous episodes of depression, 7.1 (±17.2) and 6.8 (±16), respectively, and that the current episode duration was 13.7 (±18.3) months in the control group and 12.4 (±20.3) months in the PTX group, there is strong evidence that these patients experienced recurrent episodes and likely had treatment-resistant depression (TRD). It raises the question of why they did not receive antidepressant treatments for weeks prior to enrollment.

Thirdly, psychotherapy significantly contributes to the improvement of patients with depression [2]. If patients were receiving psychotherapy, it could have influenced their outcomes, potentially altering the study results and introducing confounding bias in the comparison of the analyzed groups. Therefore, documenting whether patients underwent psychotherapy is crucial for a more rigorous and precise analysis. The paper does not specify how many patients in each group were receiving psychotherapy.

Fourthly, the authors highlight the importance of electroconvulsive therapy (ECT) as a treatment for depression. Although they considered the use of ECT in the past two months an exclusion criterion for participants, they did not address the patientsʼ prior use of this treatment. This omission could bias the data, as Jelovac [3] reports that 59% of patients who underwent ECT experienced remission within one year. Additionally, ECT can have lasting effects on cognitive functioning, a key parameter assessed by the HDRS, as noted by Nuninga [4].

Fifthly, Table 2 reports a 79% remission rate in the pentoxifylline (PTX) group and a 40% remission rate in the placebo group. At baseline, the mean Hamilton Depression Rating Scale (HDRS) scores were 27.6 (±9) for the PTX group and 26.1 (±1.9) for the control group. According to standard criteria, remission requires an HDRS score of seven or lower. However, Figure 2 indicates that no patient achieved remission status. Thus, the reported remission rates of 79% in the PTX group and 40% in the placebo group are inconsistent with the observed data.

Sixthly, the inclusion of serotonin serum levels in the biomarkers analysis is unclear. Currently, there is no evidence supporting the clinical relevance or correlation of this biomarker with improvements in depressive symptoms. Recent reviews have shown that larger decreases in 5-HT are not consistently associated with better treatment outcomes, and the results have been inconclusive [5] [6].

In conclusion, this paper expands therapeutic options for MDD by exploring pentoxifylline as an add-on treatment to antidepressants. Pentoxifylline, a low-cost and well-tolerated medication, may enhance the antidepressant effects of traditional therapies. However, these findings require validation through further clinical trials involving larger samples and diverse settings worldwide. Such studies are essential to replicate and generalize the results, thereby confirming the efficacy of pentoxifylline as an adjunctive treatment for MDD.

Publication History

Received: 10 August 2024
Received: 15 November 2024

Accepted: 23 November 2024

Article published online:
16 December 2024

• References

• 1 Merza Mohammad TA, Merza Mohammad TA, Salman DM. et al. Pentoxifylline as a Novel Add-on Therapy for Major Depressive Disorder in Adult Patients: A Randomized, Double-Blind, Placebo-Controlled Trial. Pharmacopsychiatry 2024; 57: 205-214
• 2 Cuijpers P, Karyotaki E, Weitz E. et al. The effects of psychotherapies for major depression in adults on remission, recovery and improvement: a meta-analysis. J Affect Disord 2014; 159: 118-126
• 3 Jelovac A, Kolshus E, McLoughlin DM. Relapse following bitemporal and high-dose right unilateral electroconvulsive therapy for major depression. Acta Psychiatr Scand 2021; 144: 218-229
• 4 Nuninga JO, Claessens TFI, Somers M. et al. Immediate and long-term effects of bilateral electroconvulsive therapy on cognitive functioning in patients with a depressive disorder. J Affect Disord 2018; 238: 659-665
• 5 Holck A, Movahed P, Westrin Å. et al. Peripheral serotonin levels as a predictor of antidepressant treatment response: A systematic review. Prog Neuropsychopharmacol Biol Psychiatry 2024; 133: 111031
• 6 Moncrieff J, Cooper RE, Stockmann T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 2023; 28: 3243-3256