Nationwide consensus on the clinical management of treatment-resistant depression in Italy: a Delphi panel
Authors: Maina Giuseppe , Adami Marina , Ascione Giuseppe , Bondi Emi , De Berardis Domenico , Delmonte Dario , Maffezzoli Silvia , Martinotti Giovanni , Nivoli Alessandra , Ottavianelli Elena ,   the Delphi Panel Collaboration Group, Acciavatti Tiziano , Albert Umberto , Andreoli Sara , Andriola Ileana , Romanini Fausto Antonielli , Bassetti Roberta , Bettini Francesca , Boi Graziella , Cacciani Paolo , Calò Paola , Carano Alessandro , Casolaro Ilaria , Chiappini Stefania , Clemente Paola , D’Ambrosio Virginia , d’Andrea Giacomo , Dario Tiziana , De Fazio Pasquale , de Filippis Renato , Di Carlo Francesco , Di Nicola Marco , Di Paolo Luca , Di Piazza Giampaolo , Di Salvo Gabriele , Fiori Monica , Gentile Alessandro , Lupi Matteo , Manchia Mirko , Marcatili Matteo , Marchiaro Livio , Martiadis Vassilis , Menculini Giulia , Migliarese Giovanni , Nappi Gaetano , Nucifora Domenica , Olivola Miriam , Palumbo Claudia , Paschetta Elena , Pasculli Ettore , Pessina Enrico , Pinna Federica , Pinto Marianna , Piu Davide , Posadinu Donato Gerolamo , Raffone Fabiola , Ricci Valerio , Ritacco Ilario , Rosso Gianluca , Simonini Elisa , Ventriglio Antonio , Fagiolini Andrea 
Published: November 2023

Abstract
Background
Treatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray.

Methods
A Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues’ responses. Stata 16.1 software was used for the analyses.

Results
Sixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement.

Conclusions
This Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients.