2023+意大利全国共识：难治性抑郁症的临床管理（英文版.pdf

Mainaetal.Annals of General Psychiatry (2023)22:48 https:/doi.org/10.1186/s12991-023-00478-7RESEARCHOpen Access The Author(s)2023.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the articles Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the articles Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http:/creat iveco mmons.org/licen ses/by/4.0/.The Creative Commons Public Domain Dedication waiver(http:/creat iveco mmons.org/publi cdoma in/zero/1.0/)applies to the data made available in this article,unless otherwise stated in a credit line to the data.Annals of General PsychiatryNationwide consensus ontheclinical management oftreatment-resistant depression inItaly:aDelphi panelGiuseppe Maina1,2,Marina Adami3,Giuseppe Ascione3,Emi Bondi4,Domenico De Berardis5,Dario Delmonte3,Silvia Maffezzoli3,Giovanni Martinotti6,Alessandra Nivoli7,Elena Ottavianelli8*,the Delphi Panel Collaboration Group and Andrea Fagiolini9 Abstract Background Treatment-resistant depression(TRD)is defined by the European Medicines Agency as a lack of clini-cally 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 esketa-mine 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 aug-mentation therapies and in the meantime about the need for long-term maintenance therapy.A high level of con-sensus 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.*Correspondence:Elena Ottavianellielena.ottavianellifullcro.orgFull list of author information is available at the end of the articlePage 2 of 11Mainaetal.Annals of General Psychiatry (2023)22:48 Keywords Treatment-resistant depression,Major depressive disorder,Antidepressants,Consensus statement,Customized treatment,EsketamineBackgroundThe primary goal of treating depression is to achieve complete resolution of symptoms,but approximately 30%of patients with major depressive disorder(MDD)do not respond adequately to treatment 1,2.Non-response to medication is common and can persist after multi-ple attempts with different medications 2.The suc-cess rate of treatment decreases with each subsequent trial,as shown in the Sequenced Treatment Alternatives to Relieve Depression(STAR-D)trial 1.Treatment-resistant depression(TRD)is defined by the European Medicines Agency(EMA)as a lack of clinically mean-ingful improvement after treatment with at least two different antidepressants 3.TRD is a complex condi-tion influenced by genetic,clinical and environmental factors,as well as comorbidities and psychosocial fac-tors 4.Patients with TRD experience a higher burden of illness compared to responders,including more severe symptoms,greater disability,and reduced quality of life 2,5.The economic burden of TRD is also significant,with higher direct and indirect costs compared to non-treatment-resistant depression 6.Current management of TRD is challenging due to the lack of evidence-based guidelines or a consensus strategy in Europe,leading to variation in treatment choices 7.Pharmacological options,that include selective serotonin reuptake inhibi-tors(SSRI),serotoninnorepinephrine reuptake inhibi-tors(SNRI),tricyclic antidepressants(TCA),monoamine oxidase inhibitors(MAOIs),and atypical antidepressants and non-pharmacological treatments(neurostimulation,psychotherapeutic interventions)could be used,alone or in combination,with different strategies,such as dose escalation,medication switching,combination therapy,and augmentation/additional therapy.The everyday Ital-ian clinical practice is not different from the European context;in Italy it can be documented,on the one hand the frequent use of SSRI,SNRI and augmentation strate-gies,and on the other hand the rare utilization of psycho-social approaches 5.However,in real-world practice,treatment response rates are low.A recent observational study on TRD in Europe confirmed that TRD patients have a poor chance of achieving remission at both 6 and 12months;more-over,the study found that patients who had achieved remission at 6months were then unable to maintain it for a long time 7.Despite low remission rate,TRD patients often remain on the same pharmacological treatment for extended periods of time 7,8.There is a need for additional therapeutic strategies for TRD that are rapid acting and have proven efficacy in this population 4,9,10.Ketamine and its S-enantiomer,esketamine,have shown promise in targeting the glutamate pathway and restoring synaptic connections in the brain to improve mood symptoms 11,12.Esketamine nasal spray,devel-oped and approved specifically for TRD,provides an additional treatment option with rapid onset of action and demonstrated efficacy compared with other well-established pharmacological strategy such as augmen-tation with quetiapine XR 13.Few adverse events are reported with esketamine(the most common are tran-sient dissociative symptoms,nausea,dizziness)14 and the safety concerns can be managed by administering esketamine under healthcare professional supervision in accordance with best practices 15.Cost-utility analysis suggests that esketamine may be a cost-effective option for the treatment of TRD 16.Future developments in pharmacological treatments of TRD are testing ketamine derivatives or other glutamatergic agents.In addition,GABAergic agents(e.g.,zuranolone),opioid receptor and voltage-gated ion channels modulators,orexin antago-nists,but also anti-inflammatory,as well as thyroid hor-mones are under investigation in TRD 15.Given the lack of clear guidelines and the availabil-ity of new medications,it is important to understand the consensus regarding the clinical characteristics and treatment pathways for patients with MDD and TRD in routine clinical practice,particularly regarding esketa-mine nasal spray.MethodsThe Delphi technique,developed in 1962 17,derives the name from the Delphic oracles skills of interpretation and foresight;it is a process used to achieve a consensus concerning real-world knowledge from experts about certain areas.Delphi is a well-established methodology used in the scientific field 18,19.The Delphi process traditionally begins with a small group of experts prepar-ing a questionnaire based upon an extensive review of the literature;this questionnaire is used as the instrument of the survey.Each Delphi participant is asked to review and rate the summarized statements so that areas of con-sensus and non-consensus can be identified.Each Delphi participant receives,in subsequent rounds,a question-naire that includes the statements and ratings(from the previous round)and are asked to re-evaluate their initial judgment.Page 3 of 11Mainaetal.Annals of General Psychiatry (2023)22:48 Expert board andconsensus panelIn September 2022,a board of 6 experts,based on their documented expertise in the TRD field,met to review the current landscape of the disease and identify key top-ics for clinical management.All members of the expert board disclosed potential conflicts of interest.At the end of the topic selection process,replies and redundancies were eliminated and 17 statements were generated for testing across a wider audience using the Delphi questionnaire.The statements can be grouped as follows:Clinical characteristics and diagnosis of patients with TRD(statements:1,2,3)Treatment journey and organizational implications(statements:4,5,6,13,16,17)Antidepressant treatment in routine clinical practice(statements 7,8,9,10,11,12,14,15).The panellists have been identified by the experts board according to the following criteria,decided during the first meeting and were asked for volunteer participation:specialized in psychiatry,with specific expertise in the field of depression(at least 100 patients/year)and direct or indirect experience with esketamine nasal spray;years of experience(at least 5 including specializa-tion);working in the Italian National Health Service(pub-lic service,outpatient/territorial setting,University in agreement with NHS);representative of the Italian territory.Questionnaire andstatistical analysesThe Delphi questionnaire was administered via a web-based system.The platform used for the data collection,called NPCdata_survey DE9 Version 1.0 is dedicated to the management of Delphi conferences.The system has been validated according to GAMP V guidelines and resides in a protected area on ARUBA servers.Data integrity security is guaranteed by ARUBA back-up sys-tems and Fullcros internal procedures.The access to the system was done through LogIn.Each user was assigned a unique code and link to the system.This method granted anonymity and absence of inter-ference among the panellists.The link to the web was sent by e-mail with a maximum of one reminder.The definitions for consensus and non-consensus were decided a priori.A Likert scale was used(1=no agree-ment to 7=maximum agreement)to evaluate the degree of agreement with each of the statements proposed in the questionnaire.In the first round,the user logged into the system and provided a score to all the statements(mandatory responses).After saving,the access is removed to pre-vent any change to the answers provided.At the end of the first round(October 27Novem-ber 15,2022),the median value and the 25th and 75th percentiles(75th p25th p,interquartile range)of each statement were calculated.In the second round(21 November19 December 2022),the system presented,for each statement,the answers provided by the user in the first round and the interquartile ranges calculated across the entire data-base(which represents the range in which 50%of the answers fell)as an index of their colleagues responses.Those who answered outside the interquartile range(IQR)in the second round were asked by the system to give a reason for their response.In the absence of this information the system does not save the session.At the end of the second round,the median value and the 25th and 75th percentiles of each statement and IQR were calculated again.The results of the first and second rounds and the motivations of those who had answered outside the interquartile range,were discussed by the expert board at the“verification meeting”(January 2023).After dis-cussing and commenting on the results of each of the 17 statements,the expert board members formulated the counter-motivations.Since all 17 statements reached agreement and consensus;it was decided not to proceed with the third round.The flow chart of the analysis is presented in Fig.1.The statements were ranked based on the 25th per-centile,75th percentile and the interquartile range(IQR)(Fig.2):Agreement and consensus with the statement:Affir-mations that have the 25th percentile 4 and IQR 2 but different from 4 to 4 belong to this group.Agreement and low consensus with the statement:Those statements that have the 25th percentile 4 and IQR 3 belong to this group.Indecision in the evaluation and consensus with the statement:Those statements that have the 25th per-centile 4 and IQR 44 or 25th percentile 4 and IQR 2 belong to this group.Indecision in the evaluation and low consensus with the statement:Those statements that have the 25th percentile 4 and IQR 3.Disagree and consensus with the statement:Those statements that have the 25th percentile 4,75th per-centile 4 and IQR 2 belong to this group.Page 4 of 11Mainaetal.Annals of General Psychiatry (2023)22:48 Disagree and low consensus with the statement:Those statements that have the 25th percentile 4,75th percentile 4 and IQR 3 belong to this group.Median and 25th percentile,75th percentile and IQR were reported for each statement and round(Additional file1).Stata 16.1 software was used for the analyses.ResultsParticipantsSixty panellists answered the questionnaire at the first round,and 58 at the second round.With regard to the geographic distribution,the panel was well representative of the Italian situation(33%North,20%Centre,47%South and Islands).Among the 60 participants 21 worked in universities,39 in public structures as Department of Mental Health,organized in day-care Mental Health Centers or Hospital Diagnosis and Treatment of Psychiatric Services.The overall result of the 17 statements is summarized in Table1 and displayed in graphical form(level of agree-ment/disagreement distribution by box plot and bar graph)in Fig.3.For 8 among the 17 statements of the Delphi more than 75%of panellists assigned a score of 4 or more reach-ing agreement(25th percentile 4).These statements also reached a high consensus(