Tryciclic Antidepressants in Refractory GERD: Poorly Effective Drugs or Wrong Patients?

we read with great interest the paper by Limsrivilai et al carried out to assess the benefit of low dosage imipramine (25 mg daily) compared with placebo for 8 weeks in patients with esophageal hypersensitivity (EH) and functional heartburn (FH). The Authors enrolled NERD patients with no or partial response to once-daily PPIs and classified them as EH or FH by impedance-pH off-therapy. Imipramine was not more effective than placebo in achieving symptomatic relief (37,2% vs 37,5%, respectively) in the above combined subpopulations, thus reducing the role of tryciclic antidepressants in the management of refractory GERD patients. However, few limitations of this study need to be underlined. First of all, they enrolled patients with no or partial response to a single standard dose of PPI and we know that symptom resolution can be achieved in part of them by simply doubling the PPI dose, as suggested by current guidelines, and therefore they should not be considered as true refractory patients. Secondly, the Authors used the positive results to one of the two traditional indices of symptom association analysis, that is SI and SAP, to identify EH. Recent studies emphasized the limitations of this method and suggested to apply with caution these reflux monitoring features to distinguish patients with GERD from those without. Therefore, it has been suggested that a more reliable diagnosis could be obtained by considering only cases positive to both indices. Further, an alternative and more pathophysiological approach has been recently suggested, always with the use of impedance-pH monitoring, which includes the use of modern impedance variables, such as baseline impedance (BI) and post-reflux swallow-induced peristaltic wave (PSPW), which were found to be more accurate in distinguishing the various forms of GERD. This new diagnostic approach has been recently supported by data on the positive correlation between mucosal integrity abnormalities and histological reflux-related changes with BI levels. In conclusion, we believe that studies aiming to evaluate the effectiveness of novel therapeutic approaches in refractory GERD should be performed in better selected populations.