Resistant or not resistant depression: that is the question

Raffaella Zanardi 1,2, Francesco Attanasio 2, Valentina Fazio 2,Melania Maccario 2, Cristina Colombo 1,2

1 IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Mood Disorder Unit, Milan, Italy; 2 University Vita-Salute San Raffaele, Department of Clinical Neurosciences, Milan, Italy

DOI 10.36148/2284-0249-453


Depression is still a leading cause of worldwide disability, and its management remains a major public health challenge. According to the most used criteria, treatment-resistant depression (TRD) is defined as an inadequate response to different classes of antidepressants administered at adequate dose and duration. However, such an assumption is not globally shared in clinical practice, and the treatment strategies for TRD are still largely empirical.

In the present study, we have sought to extend and deepen the evidence on TRD, focusing on the difficulty of its correct identification and classification, causing misdiagnosis, ineffective treatment strategies, and lack of specific guidelines for the management of TRD.


Over 12 months, 200 consecutively admitted depressed inpatients at the Mood Disorders Unit of San Raffaele Hospital in Milan were recruited. On the day of admission, according to clinical and anamnestic backgrounds, patients were classified as resistant or non-resistant, based on the staging system by Thase and Rush and the definition of TRD by Souery and colleagues. Every patient was treated with adequate pharmacological approaches and underwent a two-months follow-up after discharge. Clinical and sociodemographic variables were collected during hospitalization and follow-up. 


At the admission 27% of the sample displayed anamnestic drug resistance characteristics, meeting the TRD definition criteria. The resistant group differed from the responder one for older age at the admission (p = 0.015), more severe episodes and less psychotic features (p < 0.001). Analyzing the drug-specific remission rates throughout the whole sample, we observed no remission difference between drug classes (SSRI 78.20% vs SNRI 63.16% vs TCA 69.23%, p = 0.215). We also found no difference in remission rates between groups when treated with SSRI (non-resistant 79.03% vs resistant 75.00%, p = 0.728) and SNRI (non-resistant 68.18% vs resistant 56.25%, p = 0.452). The groups globally reached symptomatic remission in 77.88 and 59.52% of cases respectively (p = 0.022).


Studying a depressed population in mood disorders center it was possible to observe that 60% of patients categorized as treatment-resistant revealed a response to pharmacotherapies, often reaching a complete symptomatic remission using first-line treatments. This result reveals how the diagnosis of resistance could be often inaccurate and the actual pharmacoresistance prevalence much lower than what is usually shown by literature data.

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