Treatment-resistant depression and intranasal esketamine: Spanish consensus on theoretical aspects

Fernando Mora^1,2*Jose Antoni Ramos-Quiroga^3,4,5,6Enrique Baca-Garcia^{10,11,12,13,7,8,9}José Manuel Crespo¹⁴Luis Gutiérrez-Rojas^15,16Aránzazu Madrazo¹⁷Lucia Pérez-Costillas^18,19,20,21Pilar A Saiz^{22,23,24,25,26}Vicente Tordera²⁷Eduard Vieta^{28,29,30,31,32}

• ¹Hospital Universitario Infanta Leonor, Madrid, Spain
• ²Department of Legal Medicine and Psychiatry, Complutense University, Madrid, Spain
• ³Department of Mental Health, Hospital Universitari Vall d'Hebron, Barcelona, Spain
• ⁴Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
• ⁵Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
• ⁶Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain
• ⁷Department of Psychiatry, Jimenez Diaz Foundation Hospital, Madrid, Spain
• ⁸Biomedical Research in Mental Health Networking, CIBERSAM, Madrid, Spain
• ⁹Department of Psychiatry, Madrid Autonomous University, Madrid, Spain
• ¹⁰Department of Psychiatry, Rey Juan Carlos University Hospital,, Mostoles, Spain
• ¹¹Department of Psychiatry, General Hospital of Villalba, Madrid, Spain
• ¹²Department of Psychiatry, Infanta Elena University Hospital, Valdemoro, Spain
• ¹³Department of Psychiatry, Nimes University Hospital, Nimes, Spain
• ¹⁴Complejo Hospitalario de A Coruña, A Coruña, Spain
• ¹⁵Department of Psychiatry and CTS-549 Research Group, Institute of Neurosciences, University of Granada, Granada, Spain
• ¹⁶Psychiatry Service, Hospital Universitario San Cecilio, Granada, Spain
• ¹⁷Hospital Universitario de Basurto, Bilbao, Spain
• ¹⁸Mental Health Clinical Unit, University Regional Hospital of Málaga, Malaga, Spain
• ¹⁹Biomedical Research Institute of Malaga (IBIMA), Malaga, Spain
• ²⁰Grupo de Investigación en Salud Mental (INTRAM) (PAIDI CTS456), Malaga, Spain
• ²¹Department of Public, Health and Psychiatry, Faculty of Medicine, University of Malaga, Malaga, Spain
• ²²Department of Psychiatry, University of Oviedo, Oviedo, Spain
• ²³Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Oviedo, Spain
• ²⁴Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
• ²⁵Instituto Universitario de Neurociencias del Principado de Asturias (INEUROPA), Oviedo, Spain
• ²⁶Servicio de Salud del Principado de Asturias (SESPA), Oviedo, Spain
• ²⁷Psychiatry Service, Hospital Lluis Alcanyis,, Xativa, Spain
• ²⁸Department of Medicine, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
• ²⁹Bipolar and Depressive Disorders Unit, Hospital Clínic de Barcelona, Barcelona, Spain
• ³⁰Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
• ³¹Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain
• ³²Instituto de Salud Carlos III, Madrid, Spain

Introduction: Depression is a highly prevalent disease that severely impacts the life of patients.Inadequate response to at least two antidepressants despite adequacy of treatment and adherence is known as treatment-resistant depression (TRD), which entails a higher social and economic burden than non-resistant major depression. The lack of consensus on the definition of TRD and other aspects complicates management of the disease. Intranasal esketamine has a novel mechanism of action that differs from that of traditional antidepressants by improving neuroplasticity and synaptogenesis.A scientific committee comprising ten psychiatrists, experts in TRD in Spain, reviewed the literature (grey literature and articles or scientific communications published between January 2014 and January 2024 in PubMed) and developed statements on theoretical and conceptual aspects of TRD. Statements were developed in a first meeting following a discussion group approach, refined in a second meeting following a nominal group technique, and consensus was finally drafted in a third meeting.Results: A series of statements and recommendations were developed. Definitions for TRD and clinical response were proposed. The impact of therapeutic inertia was highlighted, identifying its causes and consequences. The role of intranasal esketamine in the TRD therapeutic treatment landscape was reviewed, and a treatment algorithm was developed, including specifics on evaluation of response to avoid therapeutic inertia and ensure an adequate treatment.Conclusions: This is the first consensus developed in Spain regarding theoretical aspects of TRD and the role of intranasal esketamine in TRD therapeutic approach. A definition of TRD was proposed, together with a treatment algorithm.