REVIEW OF: Mohammad TM et al, Pharmacopsychiatry 2024;57:205–214

STUDY TYPE: Randomized, double-blind, placebo-controlled trial

Major depressive disorder (MDD) treatment remains a challenge, with one-third of patients experiencing inadequate responses to standard antidepressants. Recent studies have implicated many pathophysiological pathways, including immune dysregulation and inflammation. Mohammad and colleagues explored pentoxifylline (PTX), a phosphodiesterase inhibitor with anti-inflammatory properties used to treat claudication, as an adjunct to citalopram for MDD.

This study enrolled 100 adults with moderate to severe MDD. Participants were randomly assigned to receive citalopram (20 mg/day) plus placebo, or citalopram plus PTX (400 mg twice daily), for 12 weeks. Depression severity was measured twice weekly using the Hamilton Depression Rating Scale (HAM-D-17), which has 53 total possible points. Serum levels of inflammatory markers (IL-6, TNF-α, CRP, IL-10, and IL-1β), serotonin, and brain-derived neurotropic factor (BDNF) were assessed at baseline and week 12.

Symptom improvement: The PTX group showed significantly greater reductions in HAM-D-17 scores at weeks 4–12 compared to the placebo group. The mean score reduction at week 12 was 14.3 points with PTX vs 10.2 with placebo (p = 0.008).

Remission and response rates: Remission (HAM-D-17 scores ≤ 7) occurred in 79% of the PTX group vs 40% in the placebo group (p = 0.01). Response rates (≥ 50% decrease in HAM-D-17 score) were 83% vs 49%, respectively (p = 0.006).

Biological changes: PTX led to greater reductions in ­pro-inflammatory markers and larger increases in serotonin and BDNF levels than placebo. These reductions in ­pro-inflammatory markers and increases in serotonin/BDNF levels were significantly correlated with HAM-D-17 scores in both groups before and after treatment.

Tolerability: Both groups experienced mild adverse events, with no severe side effects. Five patients from the placebo group dropped out due to medical psychiatric complications, as did three from the PTX group (two due to nausea, the most common reported side effect of PTX, and the third due to “worsening psychiatric status”).

CARLAT TAKE
PTX appeared to be effective and well tolerated as an adjunct to antidepressants in this small trial. Consider augmentation with PTX in patients with partial response to selective serotonin reuptake inhibitors, especially in those with comorbid peripheral vascular disease. PTX should be avoided in patients with recent cerebral/retinal hemorrhages or myocardial infarction, both of which are ­contraindications.